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

TL;DR: In this paper, the efficacy of dexamethasone intravitreal (DEX) implant in treating refractory macular edema caused by retinal vein occlusion was investigated.

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

Summary

Introduction

• Vision loss from retinal vein occlusion (RVO) is frequently due to macular edema (ME).
• 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.
• Mean values for logMAR VA and CSFT, as well as standard deviations and range, were calculated at each follow-up visit.
• Subsequent injections were administered on an as needed basis for persistent macular edema on OCT affecting the foveal center.

Results:

• The study included 22 eyes of 22 patients with ME caused by venous occlusion (10 patients with BRVO and 12 with CRVO).
• Ultimately, BRVO patients maintained an improved 6-month and 1 year mean BCVA, while the CRVO patients experienced loss of mean BCVA (Table 3 and Figure 1).
• A statistically significant relationship was found between mean CSFT and number of DEX implants administered (p=3.28 x 10-9), but not for mean CSFT and number of days followed (p=0.40).
• The difference in logMAR VA was statistically significant (p=0.05), while the difference in CSFT was not significant (p=0.27).
• Regarding lens status, 6 of 12 initially phakic patients (50%) experienced cataract progression for which they underwent cataract surgery.

Conclusions

• This study evaluated outcomes of repeated DEX implant injections to treat refractory ME caused by RVO.
• Other studies have suggested that patients with chronic edema fare poorly.
• In the current study, the neuroretinal atrophy caused by chronic macular edema may be responsible for the worsening of vision in these patients despite reduction of macular edema.
• The authors analysis indicates that patients with duration of ME >12 months prior to treatment with DEX had statistically significant less improvement in logMAR after one treatment compared to those with <12 months duration, which may support these findings, as greater duration of ME would be more likely to cause chronic structural alterations in the retina despite reduction of edema.
• The authors results followed a similar pattern of significant improvement of mean BCVA and mean CSFT within the first 7 weeks, with diminished effects by 3 month follow-up and onward, despite repeated DEX implants.

Figures

Table 2. Summary of mean number of treatments given for macular edema prior 0.7 mg DEX implant.

Table 1. Baseline patient characteristics

Full text

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

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Running title: dex implant for retinal vein occlusion efficacy of dexamethasone intravitreal implant for refractory macular edema caused by retinal vein occlusion" ?

In this paper, the authors investigated the efficacy of dexamethasone intravitreal implant ( DEX ) in treating refractory macular edema caused by retinal venous occlusion ( RVO ). 

Q2. What are the common treatments for macular edema?

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). 

Q3. What is the pathogenesis of ME following RVO?

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). 

Q4. How many treatments did these patients receive prior to the initial DEX implant?

Prior to treatment with DEX implant, this group of eyes received an average of 7prior treatments (22 eyes received 2-19 treatments including macular laser, intravitreal7bevacizumab, ranibizumab, or triamcinolone acetonide). 

Q5. What is the effect of the dex implant on the phakic patients?

In the current study, the neuroretinal atrophy caused by chronic macular edemamay be responsible for the worsening of vision in these patients despite reduction of macular edema. 

Q6. Why did the patients with refractory ME have a washout period?

the washout period had a wide range of 38-402 days, which was likely due to poor follow up for selective patients that had failed to respond adequately to previous treatments. 

Q7. How many patients were discontinued from DEX?

5 of 22patients (22.7%) were discontinued from additional treatment with DEX implant, due to development of ocular hypertension (IOP >30). 

Q8. How long did Alshahrani et al have the effect of a single?

Alshahrani et al reported that a single DEX implant caused a statistically significant improvement in both VA and CSFT in patients with refractory ME, which peaked at one and three months, and then lost significance by 6 months. 

Q9. How long did the patient wait for the initial DEX implant?

The mean washout period, inwhich no treatment was given prior to initial DEX implant, was 133 ± 97 days (median117 days, range 38-402 days). 

Q10. What is the effect of DEX on the visual acuity of patients with ME?

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 

Q11. What is the effect of DEX on CSFT?

The results suggest that DEX implant is effective in reducing CSFT for a sustained period, but improvements in BCVA were transient. 

Q12. What is the definition of refractory ME?

Refractory ME was diagnosed if the patients experienced persistent ME of at least4 months duration despite at least 2 prior treatments, including any combination of macular laser photocoagulation, intravitreal triamcinolone acetonide, intravitreal bevacizumab, or intravitreal ranibizumab. 

Q13. What limitations of this study are there?

11Limitations of this study include its uncontrolled retrospective nature without astandardized refraction protocol, lack of standardized regimen prior to initiating DEX treatment, and limited sample size. 

Q14. What is the effect of repeated dex implants on the BCVA?

There was a high incidence of visually significant cataract (particularly posteriorsubcapsular cataracts) that developed in phakic patients receiving repeated DEX implants and this can partially account for the deteriorating BCVA. 

Q15. How was the grid pattern applied to the area with diffuse leakage?

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. 

Q16. What was the mean IOP prior to the first DEX implant?

With respect to intraocular pressure, mean IOP prior to the first DEX implant was16.7 ± 3.8, which increased to 21.2 ± 6 at the first follow-up visit (Table 3). 

Q17. What was the mean BCVA after the initial treatment?

BRVO patients maintained an improved 6-month and 1 year mean BCVA, while the CRVO patients experienced loss of mean BCVA (Table 3 and Figure 1).