Management of Submacular Hemorrhage Secondary to Neovascular Age-Related Macular Degeneration With Anti-Vascular Endothelial Growth Factor Monotherapy.
ABSTRACT PURPOSE: To report the visual and anatomic outcomes of anti-vascular endothelial growth factor (VEGF) monotherapy in the management of marked submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, consecutive case series. METHODS: Nineteen eyes of 18 patients with neovascular AMD and fovea involving submacular hemorrhage comprising greater than 50% of the lesion area were treated with anti-VEGF monotherapy. Main outcome measures included mean visual acuity change from baseline, mean central lesion thickness change from baseline, mean number of injections at 6 months, and adverse events. Snellen visual acuity was converted to approximate ETDRS letter score for the purpose of statistical analysis. RESULTS: The mean change in approximate ETDRS letter score from baseline was +12 letters at 3 months (P = .003), +18 letters at 6 months (P = .001), and +17 letters at 12 months follow-up (P = .02). Seven eyes received ranibizumab, 6 eyes received bevacizumab, and 6 eyes received both at various time points. The mean number of injections at 6 months was 4.7. The mean OCT central lesion thickness decreased from 755 μm to 349 μm at 6 months follow-up (P = .0008). CONCLUSIONS: Management with anti-VEGF monotherapy may yield visual and anatomic improvements in eyes with marked submacular hemorrhage secondary to neovascular AMD.
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ABSTRACT: To evaluate the outcome of pars plana vitrectomy, subretinal tissue plasminogen activator (t-PA) infusion and intraocular gas tamponade with and without post surgical anti-vascular endothelial growth factor (VEGF) injection for thick submacular hemorrhage due to exudative age-related macular degeneration (AMD) DESIGN: Retrospective, comparative, interventional case series. Setting: Two retina referral centers. Patient population: 101 eyes of 101 patients with neovascular AMD with thick submacular hemorrhage who underwent surgical displacement of the hemorrhage with or without post-operative anti-VEGF injections. Main outcome measures included degree of blood displacement, best and final postoperative visual acuity (VA), and adverse events. Snellen acuity was converted to logMAR for statistical analysis. All patients were followed for a minimum of 3 months (mean 15.3 months, range 3 to 70 months). In 83 (82%) of 101 eyes, the procedure resulted in complete hemorrhage displacement from the fovea. Mean pre-operative VA was 20/2255 (2.05 logMAR). The acuity significantly improved to 20/893 (1.65 logMAR) at month 1 (p<0.001) at month 1, 20/678 (1.53 logMAR) at month 3 (p<0.001), and 20/1150 (1.76 logMAR) at month 12 (p=0.002). Best post-operative visual acuity improved by at least one line in 83 (82%) of 101 eyes and 19.6% of eyes gained 3 lines or more at month 3. The visual acuity of the group of eyes that received post-operative anti-VEGF injection (n=39) showed greater visual acuity improvement 6 months postoperatively compared to the group of eyes that did not receive post-operative anti-VEGF. Postoperative complications included vitreous hemorrhage in 2 eyes, rhegmatogenous retinal detachment in 4 eyes, and recurrent thick subretinal hemorrhage in 6 eyes. Vitrectomy with subretinal t-PA injection and gas tamponade was found to be relatively effective for displacement of thick submacular hemorrhage with a significant improvement in visual acuity. There is a loss of acuity over time; the addition of post-operative anti-VEGF therapy may help maintain the visual acuity gains.American Journal of Ophthalmology 02/2014; · 4.02 Impact Factor
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ABSTRACT: To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy for patients diagnosed with exudative age-related macular degeneration (AMD) accompanied by submacular hemorrhage. Retrospective, observational case series. Ninety-one eyes of 91 patients who initially presented with submacular hemorrhage associated with exudative AMD from October 2009 to September 2012. Patients were followed up for at least 6 months after treatment. Best-corrected visual acuity (BCVA) was measured at diagnosis and at 1, 3, and 6 months after treatment. The duration of symptoms was estimated. The extent of hemorrhage was estimated using fundus photography, and central foveal thickness was measured using optical coherence tomography. Change in BCVA during 6 months after treatment was estimated. The correlation of BCVA at 6 months with duration of symptoms, extent of hemorrhage, and central foveal thickness was evaluated. The BCVA, duration of symptoms, extent of hemorrhage, and central foveal thickness. The mean duration of symptoms was 27.6±39.5 days. The mean extent of hemorrhage was 7.8±5.6 disc areas, and the mean central foveal thickness was 610.1±249.6 μm. All eyes were treated with 3.2±0.8 (range, 1-5) monthly intravitreal anti-VEGF injections during the 6-month follow-up period. The logarithm of the minimum angle of resolution BCVA at diagnosis and at 1, 3, and 6 months after the initial diagnosis was 1.38±0.53 (Snellen equivalent, 20/479), 1.27±0.57, 1.05±0.58, and 0.96±0.65 (Snellen equivalent, 20/182), respectively. The BCVA at 6 months significantly improved from baseline (P < 0.001). Poor BCVA at 6 months correlated with a longer duration of symptoms, greater extent of hemorrhage, and greater central foveal thickness (P = 0.008, P = 0.004, and P = 0.014, respectively). Anti-VEGF monotherapy was found to be a useful treatment option for exudative AMD accompanied by submacular hemorrhage. However, the limited efficacy in eyes with large hemorrhage may suggest the need for more aggressive treatment in these cases. The author(s) have no proprietary or commercial interest in any materials discussed in this article.Ophthalmology 12/2013; · 5.56 Impact Factor
Management of Submacular Hemorrhage Secondary to
Neovascular Age-Related Macular Degeneration With
Anti–Vascular Endothelial Growth Factor Monotherapy
GARY SHIENBAUM, CARLOS ALEXANDRE A. GARCIA FILHO, HARRY W. FLYNN, JR,
RENATA PORTELLA NUNES, WILLIAM E. SMIDDY, AND PHILIP J. ROSENFELD
? PURPOSE: To report the visual and anatomic outcomes
of anti–vascular endothelial growth factor (VEGF)
monotherapy in the management of marked submacular
macular degeneration (AMD).
? DESIGN: Retrospective,
? METHODS: Nineteeneyesof18patientswithneovascu-
lar AMD and fovea involving submacular hemorrhage
comprising greater than 50% of the lesion area were
treated with anti-VEGF monotherapy. Main outcome
measures included mean visual acuity change from base-
line, mean central lesion thickness change from baseline,
mean number of injections at 6 months, and adverse
ETDRS letter score for the purpose of statistical analysis.
? RESULTS: The mean change in approximate ETDRS
letter score from baseline was D12 letters at 3 months
(P [ .003), D18 letters at 6 months (P [ .001),
eyes received ranibizumab, 6 eyes received bevacizumab,
and 6 eyes received both at various time points.The mean
number of injections at 6 months was 4.7. The mean
OCT central lesion thickness decreased from 755 mm
to 349 mm at 6 months follow-up (P [ .0008).
? CONCLUSIONS: Management with anti-VEGF mono-
therapy may yield visual and anatomic improvements in
eyes with marked submacular hemorrhage secondary to
neovascular AMD.(Am J Ophthalmol 2013;155:
impairment. Potential mechanisms include iron toxicity,
shearing of photoreceptors by fibrin clots, and physical
separation of photoreceptors from the retinal pigment
epithelium.1–3A more obvious cause of severe visual loss
is subretinal fibrosis and disciform macular scar formation.
Historically, management options have included surgical
UBMACULAR HEMORRHAGE, A WELL-RECOGNIZED
complication of neovascular age-related macular
degeneration (AMD), may cause substantial visual
submacular clot evacuation or pneumatic displacement
with or without the use of tissue plasminogen activator
(tPA). These strategies have produced mixed visual
results with potentially high complication rates.4–15In
practice, many of these patients are probably simply
observed, usually with relatively poor visual results.
The Minimally Classic/Occult Trial of Anti-VEGF
Antibody Ranibizumab in the Treatment of Neovascular
AMD (MARINA) and Anti-VEGF Antibody for the
Treatment of Predominantly Classic Choroidal Neovascu-
larization in AMD (ANCHOR) study protocols excluded
patients with predominantly hemorrhagic neovascular
lesions.16,17However, the effectiveness of anti–vascular
endothelial growth factor (VEGF) therapy for neovascular
AMD has prompted its application in cases of submacular
hemorrhage secondary to choroidal neovascularization
(CNV).18To date, there are few clinical series validating
the efficacy of anti-VEGF therapy in treating these types
of lesions.19,20The present study therefore aims to
evaluate the visual and anatomic outcomes of anti-VEGF
monotherapy in the management of marked submacular
hemorrhage secondary to neovascular AMD.
INSTITUTIONAL REVIEW BOARD APPROVAL FROM THE
University of Miami Miller School of Medicine was
obtained to review patient data for this retrospective,
interventional, consecutive case series from 3 treating
physicians (H.W.F., W.E.S., P.J.R.) at Bascom Palmer
Eye Institute. Informed consent was not required for this
Medical records were reviewed for all patients presenting
between 2008 and 2011 with a diagnosis of neovascular
comprising greater than 50% of the lesion area for which
they were receiving anti-VEGF monotherapy. Eyes with
submacular hemorrhage secondary to causes other than
neovascular AMD, prior vitrectomy surgery, and less than
3 months follow-up were excluded. Of note, no eyes seen
matic displacement of submacular hemorrhage during the
time interval examined by this retrospective review. The
Accepted for publication Jan 8, 2013.
From the Department of Ophthalmology, Bascom Palmer Eye Institute,
University of Miami Miller School of Medicine, Miami, Florida.
? 2013 BY ELSEVIER INC. ALL RIGHTS RESERVED.
following data were collected: age, sex, date of submacular
hemorrhage diagnosis, baseline area of submacular hemor-
rhage, best-corrected Snellen visual acuity using the most
up-to-date distance correction at each visit, optical coher-
The Cirrus spectral-domain OCT (SDOCT) instrument
(Carl Zeiss Meditec Inc, Dublin, California, USA) was used
for all study evaluations. The central macula of each eye was
imaged using a 5-line raster scan pattern. This protocol
resulted in the acquisition of a data set organized as 4096
A-scans in each B-scan and as 5 horizontal B-scans in each
raster array. Central lesion thickness was manually measured
to be the distance from the internal limiting membrane to
Bruch membrane on SDOCT images centered on the fovea.
Snellen visual acuities were converted to approximate
Early Treatment Diabetic Retinopathy Study (ETDRS)
letter scores using a validated formula for the purpose of
statistical analysis.21Changes in visual acuity and OCT
central lesion thickness measurements from baseline were
assessed by a paired Student t test. A P value less than
.05 was considered statistically significant. Clinical
outcome measures included mean visual acuity change
from baseline, mean central lesion thickness change from
baseline, mean number of injections at 6 months, and
adverse events during treatment or follow-up.
NINETEEN EYES OF 18 PATIENTS MET THE INCLUSION AND
exclusion criteria. The mean age was 81 years. Seven
eyes received ranibizumab, 6 eyes received bevacizumab,
ination was 4-30 months. The mean number of injections
over the first 6 months was 4.7 (range 2-7, n ¼ 15). The
mean baseline area of submacular hemorrhage was
39.0 mm2(range 4.3-170.2 mm2, n ¼ 16).
Eighteen of 19 eyes (95%) were evaluated at the
3-month follow-up interval. Median Snellen visual acuity
improved from 20/400 (mean 20/300; range 20/40 to
hand motions) at baseline to 20/250þ1 (mean 20/160?2;
range 20/30 to count fingers [CF]) at 3 months following
presentation. Fifteen of 19 eyes (79%) were evaluated at
the 6-month follow-up interval. Median Snellen visual
acuity improved from 20/400 (mean 20/300þ2; range 20/
40 to CF) at baseline to 20/200 (mean 20/125þ1; range
20/20 to 20/800) at 6 months following presentation. Ten
of 19 eyes (53%) were evaluated at the 12-month follow-
up interval. Median Snellen visual acuity improved from
20/400?1 (mean 20/250?1; range 20/40 to CF) at baseline
to 20/125?2 (mean 20/125þ1; range 20/20 to 20/800) at
12 months following presentation. Table 1 lists the visual
acuity outcomes converted to approximate ETDRS letter
scores at 3, 6, and 12 months follow-up. The mean change
in approximate ETDRS letter score from baseline was þ12
letters at 3 months (P ¼ .003, n ¼ 18), þ18 letters at
6 months (P ¼ .001, n ¼ 15), and þ17 letters at 12 months
(P ¼ .02, n ¼ 10). Table 2 lists the distribution of visual
acuity gains in each cohort.
The hemorrhage was locatedin the subretinal space in4of
ment, endophthalmitis, cataract progression) or systemic
events were observed over the course of the study.
THIS STUDY HAS DEMONSTRATED AN IMPROVEMENT IN
visual acuity after nonsurgical, monotherapy treatment with
TABLE1.Managementof SubmacularHemorrhage SecondarytoNeovascular Age-Related MacularDegeneration withAnti-Vascular
Endothelial Growth Factor Monotherapy: Visual Acuity Change from Baseline at 3, 6, and 12 Months Follow-up
Follow-up PeriodEyes, No.
Mean Baseline Approximate
ETDRS Letter Score (SD)
Mean Follow-up Approximate
ETDRS Letter Score (SD)
Mean Approximate ETDRS
Letter Score Change (SD)P Value
ETDRS ¼ Early Treatment Diabetic Retinopathy Study; SD ¼ standard deviation; VA ¼ visual acuity.
TABLE 2. Management of Submacular Hemorrhage
Secondary to Neovascular Age-Related Macular
Degeneration with Anti-Vascular Endothelial Growth Factor
Monotherapy: Distribution of Visual Acuity Changesa
Month 3 (n ¼ 18)Month 6 (n ¼ 15)Month 12 (n ¼ 10)
> _3 lines gain
> _3 lines loss
aNumber (%) of patients.
AMERICAN JOURNAL OF OPHTHALMOLOGY
FIGURE 1. Submacular hemorrhage secondary to neovascular age-related macular degeneration. (Top left) Fundus photograph
demonstrates a submacular hemorrhage centered inferior to, but extending through, the fovea. Diffuse fine drusen were identified
in the posterior pole of both eyes. The visual acuity was 20/60. (Top right) Optical coherence tomography image demonstrates subre-
tinal hemorrhage. (Bottom left) Fifteen months and 10 intravitreal ranibizumab injections later, fundus photograph demonstrates an
area of scar inferior to the center of the macula. (Bottom right) Optical coherence tomography image through the center of the fovea
demonstrates resolution of the subretinal hemorrhage. The visual acuity was 20/30.
FIGURE 2. Submacular hemorrhage secondary to neovascular age-related macular degeneration. (Top left) Fundus photograph
strates a predominantly sub–retinal pigment epithelial (RPE) hemorrhage. (Bottom left) Seven months and a combination of 8 total
intravitreal ranibizumab and bevacizumab injections later, there is pigment epithelial atrophy and resorbing hemorrhage at the
temporal margin. (Bottom right) Optical coherence tomography image through the center of the fovea demonstrates resolution of
the sub-RPE hemorrhage with resultant atrophy and scar formation. The visual acuity was 20/200.
VOL. 155, NO. 6
ANTI-VEGF MONOTHERAPY FOR SUBMACULAR HEMORRHAGE
intravitreal anti-VEGF injections. Previous natural history
studies have shown that untreated patients with submacular
3 or more lines of vision at 3 years of follow-up.11,22
progression, vitreous hemorrhage, retinal detachment, and
proliferative vitreoretinopathy while offering limited visual
course.11,15Anti-VEGF monotherapy offers a less invasive
and safer alternative to submacular surgery or pneumatic
displacement in the treatment of marked submacular hemor-
rhage secondary to neovascular AMD.
Two other studies have suggested that anti-VEGF
monotherapy is beneficial for the treatment of significant
AMD.19,20A retrospective 21-case series of patients
managed with bevacizumab monotherapy reported stabili-
zation in mean visual acuity, decreased hemorrhage size,
and improved central foveal thickness on time-domain
OCT at 4 months follow-up.19More recently, a phase 1
therisk of cataract
the untreated clinical
prospective 1-year study reported a median gain of 1.5 lines
predominantly hemorrhagic CNV secondary to neovascu-
lar AMD in 7 patients.20These results, in addition to those
presented in the current study, support the assumption that
anti-VEGF therapy remains effective in targeting CNV in
the presence of significant submacular hemorrhage.
The limitations of the present study include its retro-
spective design, relatively small sample size, lack of
a control group, and the use of Snellen visual acuity rather
than protocol ETDRS visual acuity testing. It is possible
that eyes with more massive hemorrhages were observed
and not offered anti-VEGF therapy, but that data was not
collected as part of the present study.
In conclusion, favorable visual outcomes are possible
hemorrhage attributable to neovascular AMD. The
hypothesized mechanism is that by targeting the under-
lying neovascularization, the process of disciform scar
formation is biologically truncated.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
and the following were reported: Harry W. Flynn Jr: consultant, Alimera, Pfizer, Santen; Philip J. Rosenfeld: consultant, Oraya, Novartis, Chengdu
Kanghong Biotech, Acucela, ThromboGenics, Canon, Inc; research grants, Carl Zeiss Meditec, Alexion Pharmaceutical, Potentia, GlaxoSmithKline;
lecturer, Carl Zeiss Meditec, Allergan, Topcon. Publication of this article was supported in part by Research to Prevent Blindness, New York, New
York. Contributions of authors: design and conduct of the study (G.S., C.A.A.G.F., H.W.F., R.P.N., W.E.S., P.J.R.); collection (G.S., C.A.A.G.F.,
strates a submacular hemorrhage centered superior to, but extending through, the fovea. Examination of the fellow eye was notable for
strates subretinal hemorrhage. (Bottom left) Five months and 4 intravitreal bevacizumab injections later, the hemorrhage is resorbing
subretinal hemorrhage, resultant scar, and disrupted retinal pigment epithelial architecture. The visual acuity was 20/400.
AMERICAN JOURNAL OF OPHTHALMOLOGY
R.P.N.), management (G.S., C.A.A.G.F., R.P.N,), analysis (G.S., C.A.A.G.F., H.W.F., R.P.N., P.J.R.), and interpretation of the data (G.S., C.A.A.G.F.,
H.W.F., R.P.N., P.J.R.); and preparation (G.S., H.W.F., W.E.S., P.J.R.), review (G.S., H.W.F., W.E.S., P.J.R.), and approval of the manuscript (G.S.,
H.W.F., W.E.S., P.J.R.).
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