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Journal ArticleDOI

Efficacy of dexamethasone intravitreal implant for refractory macular edema caused by retinal vein occlusion.

01 Dec 2016-Retinal Cases & Brief Reports (Retin Cases Brief Rep)-Vol. 12, Iss: 4, pp 294-299

Abstract: Purpose:To investigate efficacy of dexamethasone intravitreal (DEX) implant in treating refractory macular edema caused by retinal vein occlusion.Methods:Retrospective chart review.Results:Twenty-two eyes with refractory macular edema caused by retinal vein occlusion were treated with a mean of 2.2
Topics: Dexamethasone Intravitreal Implant (75%), Macular edema (61%), Retinal Vein (58%), Dexamethasone (52%), Visual acuity (52%)

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Running title: DEX implant for retinal vein occlusion
Efficacy of Dexamethasone Intravitreal Implant For Refractory Macular Edema
Caused by Retinal Vein Occlusion
Rehan M. Hussain, M.D.,
1
Thomas A. Ciulla, M.D., M.B.A
1,2
, Lauren M. Ciulla
2
,
Bethany Sink
2
, Alon Harris, Ph.D.
1
1
Department of Ophthalmology, Indiana University School of Medicine, 1160 W.
Michigan St, Indianapolis, IN 46202
2
Retina Service, Midwest Eye Institute, 200 W. 103
rd
St, Indianapolis, IN 46290
Corresponding Author:
Thomas A. Ciulla, M.D., M.B.A.
Volunteer Clinical Professor of Ophthalmology
Indiana University School of Medicine
Retina Service, Midwest Eye Institute
200 W. 103
rd
Street
Indianapolis, IN 46290
Thomasciulla@gmail.com
Phone: 317-817-1822
Fax: 317-817-1898
TC received contracted research funding from Acucela, Alcon, Ophthotec,
Thrombogenics, and Xoma within the past year. He currently has an employment
relationship with Ophthotech. AH would like to disclose that he receives remuneration
from CIPLA, Stemnion, Biolight, Nano Retina, AdOM, Science Based Health, Isarna
Therapeutics, and ONO Pharmaceuticals for serving as a consultant. AH also holds an
ownership interest AdOM, Oxymap and Nano Retina. All relationships listed above are
pursuant to IU's policy on outside activities. None of the other authors have any financial
disclosures. There are no conflicts of interest to report.
No funding was received for this work.
___________________________________________________________________
This is the author's manuscript of the article published in final edited form as:
Hussain, R., Ciulla, T., Ciulla, L., Sink, B., & Harris, A. (2018). Efficacy of Dexamethasone Intravitreal Implant for
Refractory Macular Edema Caused by Retinal Vein Occlusion. Retinal Cases & Brief Reports, 12(4), 294–299.
https://doi.org/10.1097/ICB.0000000000000496

2
Key Words: BRVO, CRVO, corticosteroids, dexamethasone, macular edema, optical
coherence tomography, Ozurdex
Summary Statement: Dexamethasone intravitreal implant effectively reduced
recalcitrant macular edema caused by retinal vein occlusion. Visual acuity initially
improved with treatment. However at one year follow-up, it worsened compared to
baseline in both phakic and pseudophakic eyes. 50% of phakic eyes underwent cataract
surgery and 23% of eyes developed ocular hypertension.
Abstract
Purpose: To investigate efficacy of dexamethasone intravitreal implant (DEX) in treating
refractory macular edema (ME) caused by retinal venous occlusion (RVO).
Methods: Retrospective chart review.
Results: 22 eyes with refractory ME caused by RVO were treated with a mean of 2.2
DEX over 12 months. Patient had previously received a mean of 7 treatments (laser,
bevacizumab, and/or triamcinolone) for ME present for at least 4 months duration (mean
20.8 months 20.8 ± 17.6, range 4-72 months) prior to starting DEX. Mean baseline visual
acuity (VA) was 20/91 and mean central subfield thickness (CSFT) was 506 μm. DEX
improved mean BCVA to 20/75 and 20/66 at 7 week and 6 month follow-up, although it
worsened to 20/132 at 12 months. Mean CSFT improved to 292, 352, and 356 μm at 7
week, 6 month, and 12 month follow-up respectively. There was a statistically significant
association between number of DEX treatments and CSFT (p=3.28 x 10
-9
). There was a
statistically significant association between number of days followed and BCVA
(p=0.006). 6 of 12 (50%) phakic patients developed visually significant cataract requiring

3
surgery. 5 of 22 (23%) patients developed ocular hypertension (intraocular pressure >30),
and consequently did not undergo further treatment with DEX.
Conclusions: DEX resulted in sustained anatomic reduction of RVO-associated
refractory ME, although this did not translate into long term BCVA improvement in
either phakic or pseudophakic patients, possibly related to chronic structural alterations in
the retina despite reduction of edema.

4
Introduction
Vision loss from retinal vein occlusion (RVO) is frequently due to macular edema
(ME).
1
The pathogenesis of ME following RVO is related to a variety of factors,
including hydrostatic effects from increased venous pressure, inflammatory cytokines,
dysregulation of endothelial tight junctions, and increased amount of vascular
permeability factors, including vascular endothelial growth factor (VEGF).
2-4
Macular
laser photocoagulation, intravitreal anti-VEGF agents, and intravitreal corticosteroids are
commonly utilized treatments for macular edema caused by central retinal vein occlusion
(CRVO) or branch retinal vein occlusion (BRVO). However, there are certain patients
who develop refractory ME despite multiple treatments with the aforementioned
modalities.
The dexamethasone (0.7 mg) intravitreal implant (DEX implant; OZURDEX,
Allergan, Inc., Irvine, CA) was approved in 2009 to treat macular edema caused by
retinal vein occlusion. It is contained in a solid bioerodable polymer for sustained-release,
and can exert clinical effects for three to six months. The OZURDEX GENEVA study
showed that both the 0.35g and 0.7 mg DEX implant groups were both superior to sham
in preventing visual acuity loss, and improving the rapidity and incidence of visual acuity
recovery in treatment-naïve eyes with ME secondary to CRVO or BRVO.
5
The authors of
this present study performed retrospective review of 0.7 mg DEX implant used to treat
RVO-associated macular edema that had been refractory to multiple prior treatments.
Methods

5
This retrospective, uncontrolled chart review studied patients diagnosed with
refractory ME due to RVO, who were treated with their first DEX implant from March
2010 through July 2015. This project was reviewed by Indiana University’s IRB and
considered exempt. Fluorescein angiography was performed on each patient on initial
presentation to the clinic. Only patients diagnosed with CRVO or BRVO were included.
Refractory ME was diagnosed if the patients experienced persistent ME of at least
4 months duration despite at least 2 prior treatments, including any combination of
macular laser photocoagulation, intravitreal triamcinolone acetonide, intravitreal
bevacizumab, or intravitreal ranibizumab. In those patients who had undergone macular
laser treatment, a grid pattern had been applied to areas with diffuse leakage, between
500 and 3000 microns from the fovea; 532 nm laser was set to spot size of 50 microns at
0.05 to 0.1 sec.
Exclusion criteria included other causes of macular edema, such as diabetic
retinopathy or neovascular age-related macular degeneration. Patients were excluded if
the baseline best corrected visual acuity (BCVA) was better than 20/40, the central
subfield thickness (CSFT) on spectral domain optical coherence tomography (OCT) was
less than 300 microns, or if the foveal avascular zone (FAZ) was enlarged to greater than
1000 microns. A minimum of 6 months of follow-up was required to be eligible for the
study.
Patient charts were reviewed for eligibility, and data were extracted regarding the
patient’s age, gender, previous interventions, and CSFT. The BCVA, CSFT, intraocular
pressure (IOP), lens status, treatment dates from the initial visit and follow-up visits were
recorded. Snellen visual acuity was converted to logarithm of minimal angle of

Citations
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01 Jan 2021
TL;DR: Slurry TA appears to be an easily reproducible, safe, and cost-effective alternative to long-term intraocular steroid delivery, with significant improvement of CME and visual acuity.
Abstract: Purpose:This work reports the duration, safety, and viability of intravitreal slurry triamcinolone acetonide (TA; 1.0 mL of 40-mg/mL TA centrifuge concentrated into a 0.1-mL pellet) to treat cystoi...

Journal ArticleDOI
Young Hwan Bae1, Seong Mi Kim2, Jin-Young Kim2, So Hyun Bae1  +2 moreInstitutions (2)
Abstract: Purpose. To evaluate whether treatment with intravitreal corticosteroid and anti-vascular endothelial growth factor (VEGF) injections alternately can improve treatment outcomes of macular edema (ME) caused by retinal vein occlusion (RVO). Methods. This dual-center retrospective study included 112 eyes with treatment-naive ME secondary to RVO that were alternately treated with intravitreal corticosteroid and anti-VEGF injections (33 eyes, alternate group) or treated only with intravitreal anti-VEGF injections (79 eyes, anti-VEGF group) on a pro re nata basis. Results. During the 12-month follow-up period, the alternate group achieved a visual acuity gain of 0.39 logMAR, while the anti-VEGF group achieved a gain of 0.21 logMAR ( ). The alternate group demonstrated a reduction in the central macular thickness of 229.9-μm, while the anti-VEGF group achieved a reduction of 220.1 μm ( ). The alternate group required an average of 5.2 injections, while the anti-VEGF received 4.2 injections ( ). In a propensity score-matched cohort to compensate for the differences in the injection numbers between the two groups, the alternate group achieved a better visual acuity gain than the anti-VEGF group at month 12 (0.39 logMAR vs. 0.17 logMAR, ). Conclusions. In ME secondary to RVO, treatment with intravitreal corticosteroid and anti-VEGF injections alternately resulted in a more favorable visual outcome compared with intravitreal anti-VEGF monotherapy.

References
More filters

Journal ArticleDOI
Abstract: Objective To evaluate the safety and efficacy of dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc., Irvine, CA) compared with sham in eyes with vision loss due to macular edema (ME) associated with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Design Two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials (each of which included patients with BRVO and patients with CRVO). Participants A total of 1267 patients with vision loss due to ME associated with BRVO or CRVO. Intervention A single treatment with DEX implant 0.7 mg (n = 427), DEX implant 0.35 mg (n = 414), or sham (n = 426). Main Outcome Measures The primary outcome measure for the pooled data from the 2 studies was time to achieve a ≥15-letter improvement in best-corrected visual acuity (BCVA). Secondary end points included BCVA, central retinal thickness, and safety. Results After a single administration, the time to achieve a ≥15-letter improvement in BCVA was significantly less in both DEX implant groups compared with sham ( P P P ≤0.036). Improvement in mean BCVA was greater in both DEX implant groups compared with sham at all follow-up visits ( P ≤0.006). Improvements in BCVA with DEX implant were seen in patients with BRVO and patients with CRVO, although the patterns of response differed. The percentage of DEX implant-treated eyes with intraocular pressure (IOP) of ≥25 mmHg peaked at 16% at day 60 (both doses) and was not different from sham by day 180. There was no significant between-group difference in the occurrence of cataract or cataract surgery. Conclusions Dexamethasone intravitreal implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with ME secondary to BRVO or CRVO and may be a useful therapeutic option for eyes with these conditions. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

873 citations


Journal ArticleDOI
David A. Antonetti1, Alistair J. Barber, Sonny Khin2, Erich Lieth2  +2 moreInstitutions (2)
01 Dec 1998-Diabetes
TL;DR: These data show that diabetes selectively reduces retinal occludin protein expression and increases BRB permeability, and suggest that the elevated VEGF in the vitreous of patients with diabetic retinopathy increases vascular permeability by downregulating occlUDin content.
Abstract: Blood-retinal barrier (BRB) breakdown is a hallmark of diabetic retinopathy, but the molecular changes that cause this pathology are unclear. Occludin is a transmembrane component of interendothelial tight junctions that may regulate permeability at the BRB. In this study, we examined the effects of vascular endothelial growth factor (VEGF) and diabetes on vascular occludin content and barrier function. Sprague-Dawley rats were made diabetic by intravenous streptozotocin injection, and age-matched animals served as controls. After 3 months, BRB permeability was quantified by intravenous injection of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA), Mr 66 kDa, and 10-kDa rhodamine-dextran (R-D), followed by digital image analysis of retinal sections. Retinal fluorescence intensity for FITC-BSA increased 62% (P < or = 0.05), but R-D fluorescence did not change significantly. Occludin localization at interendothelial junctions was confirmed by immunofluorescence, and relative protein content was determined by immunoblotting of retinal homogenates. Retinal occludin content decreased approximately 35% (P < or = 0.03) in the diabetic versus the control animals, whereas the glucose transporter GLUT1 content was unchanged in rat retinas. Additionally, treatment of bovine retinal endothelial cells in culture with 0.12 nmol/l or 12 nmol/l VEGF for 6 h reduced occludin content 46 and 54%, respectively. These data show that diabetes selectively reduces retinal occludin protein expression and increases BRB permeability. Our findings suggest that the elevated VEGF in the vitreous of patients with diabetic retinopathy increases vascular permeability by downregulating occludin content. Decreased tight junction protein expression may be an important means by which diabetes causes increased vascular permeability and contributes to macular edema.

572 citations


Journal ArticleDOI
TL;DR: Intraocular injections of ranibizumab provide an effective treatment for macular edema after central retinal vein occlusion, with low rates of ocular and nonocular safety events.
Abstract: Purpose Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO). Design Prospective, randomized, sham injection-controlled, double-masked, multicenter trial. Participants A total of 397 patients with macular edema after BRVO. Methods Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met. Main Outcome Measures The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed. Results Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5–18.4) and 18.3 (15.8–20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6–14.6) in the sham/0.5 mg group ( P Conclusions At month 12, treatment with ranibizumab as needed during months 6–11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

560 citations


Journal ArticleDOI
Rehák J1, Matus Rehak2Institutions (2)
TL;DR: Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors.
Abstract: In branch retinal vein occlusion (BRVO), abnormal arteriovenous crossing with vein compression, degenerative changes of the vessel wall and abnormal hematological factors constitute the primary mechanism of vessel occlusion. In general, BRVO has a good prognosis: 50–60% of eyes are reported to have a final visual acuity (VA) of 20/40 or better even without treatment. One important prognostic factor for final VA appears to be the initial VA. Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors. Vitrectomy with or without arteriovenous sheathotomy combined with removal of the internal limiting membrane may improve vision in eyes with macular edema which are unresponsive to or ineligible for laser treatment.

339 citations


Journal ArticleDOI
TL;DR: Data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.
Abstract: Macular edema is a major cause of vision loss in patients with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). It is not clear how much of the edema is due to hydrodynamic changes from the obstruction and how much is due to chemical mediators. Patients with macular edema due to CRVO ( n = 20) or BRVO ( n = 20) were randomized to receive three monthly injections of 0.3 or 0.5 mg of ranibizumab. At the primary endpoint, month 3, the median improvement in letters read at 4 m was 17 in the 0.3-mg group and 14 in the 0.5-mg group for CRVO, and 10 and 18, respectively for the BRVO group. Optical coherence tomography (OCT) showed that compared to injections of 0.3 mg, injections of 0.5 mg of ranibizumab tended to cause more rapid reductions of central retinal thickening that lasted longer between injections, but in 3 months, excess central retinal thickening which is a quantitative assessment of the macular edema, was reduced by ∼90% in all four treatment groups. There was no correlation between the amount of improvement and duration of disease or patient age at baseline, but there was some correlation between the aqueous vascular endothelial growth factor (VEGF) level at baseline and amount of improvement. These data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.

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