Original Article
Refractory Diabetic Macular Edema in Phakic Patients Looking for
Answer
Muhammad Irfan Karamat, Asad Aslam Khan, Nasir Chaudhary, Haroon
Tayyab
Pak J Ophthalmol 2018, Vol. 34, No. 1
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See end of
article for authors
affiliations …..……………………….. Correspondence
to: Irfan Karamat Department of Ophthalmology, KEMU, Mayo
hospital Lahore Email:
drirfankaramat@gmail.com |
Purpose:
To evaluate the efficacy of intra-vitreal triamcinolone acetate
(TA) in the treatment of macular edema secondary to diabetes mellitus, not
responding to intra-vitreal bevacizumab injection. Study
Design: Quasi experimental study. Place
and Duration of study: Study was conducted in Mayo hospital. Study
duration was six months from 1st January to 30th June
2017. Material
and Methods: Our study was prospective case series, which included 14
patients having diabetes and refractory diabetic macular edema, with history
of 3 – 8 injections of intra-vitreal bevacizumab. Patients included in the
study underwent phacoemulsification along with intra-vitreal injection of
triamcinolone acetate in a single sitting. Best corrected visual acuity
(BCVA) and central macular thickness (CMT) was documented pre-op and post-op
at 1, 4, 8 and 16 weeks. Results:
Mean age of study population was 44.5 ± 4.94 years. Out of 14
patients, 11 (78.6%) patients were males and 3 (21.4%) were females. Results
showed that 12 patients (85.7%) had improvement in BCVA, one patient (7.1%)
had no improvement in BCVA while one patient (7.1%) had decrease in visual
acuity from 0.2 Log MAR to 0.1 Log MAR. 12 (85.7%) patients showed decrease
in CMT, while 2 (14.2%) showed increase in CMT. Only 1 (7%) patient showed
increase in IOP which was outside normal limits. Conclusion:
Intra-vitreal triamcinolone, when given in an appropriate dose
is an effective treatment of refractory macular edema. Cataract extraction
can reduce steroid related complications; improve compliance and produce
better visual outcome. Key Words: Triamcinolone Acetate, Bevacizumab, Macular
edema, Best Corrected Visual Acuity, Central Macular Thickness. |
Diabetic eye disease, also known as diabetic
retinopathy is the leading cause of blindness. Prevalence of Diabetic
retinopathy among Pakistani population is 56.9%1. In spite the fact
that lasers, intra-vitreal injections and surgical interventions are frequently
done in these patients, a significant number still remain untreated. Clinically
significant macular edema (CSME) as defined by ETDRS was based on the
observation that retinal edema and exudates involving macula, especially fovea,
threatens vision2. The extent and severity of edema is the basis of
the international clinical macular edema disease severity scale which guides us
regarding prognosis and management.3 Both ocular and systemic
measures are taken in order to treat diabetic macular edema. American Diabetic
Association, United Kingdom prospective diabetes study (UKPDS), Diabetic
control and complications trial (DCCT), Action to control cardio-vascular risks
in diabetes (ACCORD) and other clinical trials strongly recommend hemoglobin
A1C of 7%, systolic blood pressure of 150 mmm Hg or less and a good control of
cholesterol in order to treat DME4-8. Focal/Grid laser,
intra-vitreal injection of Anti-VEGFs and vitrectomy are recommended treatment
options for DME. Data from ETDRS tells us that at 3 years, eyes with mild to
moderate non-proliferative diabetic retinopathy (NPDR) and DME at base line
treated with immediate focal/grid laser photocoagulation, shows 50% decrease in
rate of moderate visual loss, still leaving 50% patients at risk apart from
other laser induced complications like field defects, choroidal
neovascularization (CNV) and sub-retinal fibrosis. One of the four sub-groups
in Diabetic retinopathy clinical research network (DRCR.net; protocol I) evaluating
intra-vitreal injection of ranibizumab showed 9 letters of improvement of
snellen’s visual acuity at two years of follow-up, which includes 8 injections
given to the patient during this time period9. A large clinical
trial( DRCR.net, Protocol D) evaluating vitrectomy for DME showed improvement
in visual acuity in 38% of patients, decrease in visual acuity in 22% patients
whereas, 40% patients showed no improvement. Out of 87 patients, 1 had
endophthalmitis, 3 had retinal detachment, 5 had vitreous hemorrhage and 7 had
raised intra-ocular pressure (IOP)10.
All
these treatment modalities still leave a significant number of patients with
refractory macular edema. Results of DRCR.net do not support intra-vitreal
triamcinolone as first line therapy. However it shows promise as component of
combination therapy, particularly in settings of DME refractory to other
therapies and in settings of pseudophakia. A sub-group in clinical trial for
DME, treating pseudophakic eyes with intra-vitreal triamcinolone with prompt
laser showed comparable results to ranibizumab group and superior to laser
group.11 Major complications associated with intra-vitreal steroids
are cataract formation and raised intra-ocular pressure (IOP). In another
study, a short term quantitative analysis of hard exudates in diabetic macular
edema was done after giving intravitreal triamcinolone or dexamethasone implant
or bevacizumab. It was observed that intravitreal steroids significantly
reduced hard exudates on short term follow-up12.It was also observed
that dexamethasone implant was beneficial for patients of Diabetic Macular
Edema with a good safety profile.13 The aim of our study was to
evaluate efficacy of intra-vitreal triamcinolone acetate in the treatment of
macular edema secondary to diabetes mellitus, not responding to intra-vitreal
bevacizumab injection.
MATERIAL AND METHODS
After approval by the hospital ethical review committee,
informed written consent was taken from the patients prior to inclusion in the
study. Patients from either gender, aged between 40-65 years, diagnosed with
diabetic macular edema on the basis of visual acuity testing, fundus
examination and OCT findings were included in the study. The criteria also
included diabetes mellitus for 5-30 years, good glycemic control confirmed with
HBA1C level, controlled blood pressure and serum HDL and LDL levels within
normal range, and body mass index ranging from 20 – 35. Patients having
received intravitreal anti-VEGF without significant improvement were also included
in the study. Only phakic patients were included in the study. Patients with
known history of posterior or anterior uveitis, glaucoma, prostaglandins use,
or epiretinal membrane, taut posterior hyaloid or vitreomacular traction
confirmed on OCT were excluded. Patients who had developed macular ischemia on
FFA were also excluded. Subjects fulfilling the inclusion criteria underwent
ophthalmic examination including uncorrected and BCVA measurement and slit lamp
examination for IOP measurement using Goldmann applanation tonometry. After dilating pupils with one drop of 1%
Tropicamide, instilled three times, 10 minutes apart, fundus examination was
performed to confirm macular edema and to rule out other causes. CMT was
checked using SD OCT (Optovue RTVue Fourier Domain SD OCT system). Patients
then underwent phacoemulsification surgery with implantation of IOL. All
patients received intra-vitreal triamcinolone injection (1 mg/0.01 ml) at the
end of cataract surgery, in the same sitting. Patients were asked to sit upright
just after injection at-least for an hour in order to avoid macular staining.
For evaluation, patients having complicated surgery were excluded from the
study. BCVA, IOP and CMT were checked pre-operatively, 1 week, 4 week, 8 week
and 16 weeks post-operatively. All investigations/ examinations and surgeries
were undertaken by single researcher to eliminate observer bias. The
pre-designed proforma was completed endorsing subject’s demography, ocular
examination and investigation findings. Data was evaluated and analyzed using statistical
program for social sciences (SPSS) version 17. Mean and standard deviation was
reported for continuous variables (Age, duration of diabetes, number of
previous injections, BCVA, IOP, CMT) while frequency and percentage for
nominal/ordinal data (gender, history of laser). Shapiro Wilk’s test was used
to check normality of data. Post normality testing, paired t test was used to
compare change in BCVA, IOP and CMT from pre-operative value. A p value of ≤ 0.05 was considered
statistically significant.
RESULTS
A total of 14 eyes of 14 patients were analysed. Mean age of
the study population was 44.5 ± 4.94 years(Range 45 – 63 years). Out of 14
patients, 11 (78.6%) patients were males and 3 (21.4%) were females. Out of
study population, 7 (50%) had undergone previous laser photocoagulation and 7
(50%) did not undergo previous photocoagulation, and there was no statistically
significant difference between the two groups. Demographic and clinical data of
study population is given in Table 1. Mean pre-operative, 1 week, 4 weeks, 8
weeks and 16 weeks BCVA,
Table
1: Demography and Clinical
Data of Study Population (n = 14).
|
Variable |
Study Population(n
= 14) |
|
Age (Years) Mean ± SD |
54.5 ± 4.94 |
|
Gender
(Male/Female) |
11/3
(78.6%)/(21.4%) |
|
Laterality Right/Left |
8/6
(57.1%)/(42.9%) |
|
Previous IVA (No
of injections) Mean ± SD |
4.43 ± 1.65 |
|
Previous Laser History (Yes/No) |
7/7 (50%)/(50%) |
Table
2: Mean Values of BCVA,
IOP and CMT (n = 14).
|
Variable |
Findings(n = 14) |
p Value* |
|
Pre-Operative BCVA (logMAR) Mean ± SD |
0.15 ± 0.11 |
- |
|
Pre-Operative IOP (mmHg) Mean ± SD |
16.57 ± 2.24 |
- |
|
Pre-Operative CMT (µm) Mean ± SD |
403.86 ± 103.80 |
- |
|
Week 1 BCVA (logMAR) Mean ± SD |
0.26 ± 0.14 |
.001 |
|
Week 1 IOP (mm Hg) Mean ± SD |
17.36 ± 1.73 |
.127 |
|
Week 1 CMT(µm) Mean ± SD |
414.64 ± 97.34 |
.033 |
|
Week 4 BCVA (logMAR) Mean ± SD |
0.29 ± 0.15 |
.000 |
|
Week 4 IOP (mm Hg) Mean ± SD |
17.29 ± 2.55 |
.231 |
|
Week 4 CMT (µm) Mean ± SD |
391.64 ± 96.26 |
.075 |
|
Week 8 BCVA (logMAR) Mean ± SD |
0.31 ± 0.14 |
.000 |
|
Week 8 IOP (mm Hg) Mean ± SD |
17.29 ± 2.55 |
.286 |
|
Week 8 CMT (µm) Mean ± SD |
369.08 ± 95.81 |
.003 |
|
Week 16 BCVA (logMAR) Mean ± SD |
0.34 ± .16 |
.000 |
|
Week 16 IOP (mm Hg) Mean ± SD |
17.86 ± 1.79 |
.036 |
|
Week 16 CMT (µm) Mean ± SD |
335.71 ± 81.50 |
.001 |
*From Pre-operative
value using Paired t test
IOP and CMT are shown in Table 2. Out of study population,
one patient (7.1%) had decrease in visual acuity from 0.2 Log MAR to 0.1 Log
MAR. Out of study population, 12 (85.7%) patients showed decrease in CMT, while
2 (14.2%) showed increase in CMT. Both of these patients showed decrease in
BCVA as mentioned before. Out of 14 patients, 3 (21.4%) patients showed decrease
in IOP, 2 (14.2%) patients had no effect on their IOP, while 8 (57.1%) patients
showed increase in IOP but it was within normal range. Only 1 (7%) patient
showed increase in IOP which was outside normal limits. Difference in BCVA from
pre-operative value was significant at week 1, week 4, week 8 and week 16.
Difference in IOP from pre-operative value was significant at week 16 (p =
0.03), while it was not significant at week 1, week 4 and week 8. Difference in
CMT from pre-operative value was significant at week 1, week 8 and week 16
while it was not significant at week 4 (p = 0.07).
DISCUSSION
Intra-ocular use of steroids for different ocular
pathologies is common and effective but not recognized as first line therapy in
diabetic macular edema. Role of steroids in DME is evolving from injections to
implants as second line of treatment.
Multiple neurodegenerative and inflammatory pathways play
their role in the development of macular edema. A cascade of events leads to
chronic low grade inflammation of micro-vasculature leading to breakdown of
tight junctions of blood retinal barrier. This in turn leads to increase in
vascular permeability which results in macular edema.
Our study was based on the observation that corticosteroids
inhibits prostaglandins, interleukin 6, VEGF-α, leukotriene and block
other pathways14. They also decrease paracellular permeability and
increase tight junction integrity by restoring tight junction proteins at cell
border15.
A recent study was conducted by Schmit-Eilenberger,
analyzing the role of corticosteroids on refractory diabetic macular edema on
15 patients (n = 15) out of which 10 (66.6%) were pseudophakic16 All
patients included in the study had a history of treatment failure. Out of these
patients 73% patients showed improvement in visual acuity. Another case series
published by Elaraoud et al of 22 patients, who received Fluocinolone Acetate
implant over 8 months period. All patients in this study were pseudophakic and
all of them had history of intra-vitreal anti-VEGF. Six patients also had a
history of intra-vitreal triamcinolone as well. After 3 months, mean reduction
in central retinal thickness was 148 microns and average improvement in visual
acuity was 6.4 letters. In this study, 68% patients showed reduction in central
retinal thickness (CRT) whereas 4 (18.18%) showed no improvement in CMT. Two
major complications of steroids in ocular treatment are cataract formation and
rise of intraocular pressure.17 FAME trial showed that 62% patients
enrolled in the study were phakic. 82% of phakic patients developed cataract at
36 months period. After cataract surgery, overall visual benefit in these
patients was similar to pseudophakic patients in the study. This shows us that
use of steroids in pseudophakic patients is more productive18.
A randomized controlled trial conducted by DRCR.net showed
that two sub-groups getting steroids for treatment of DME showed increase in
IOP. DME was treated by giving 1mg and 4 mg in these sub groups and increase in
IOP was noted in 16% and 33% patients respectively. Even in FAME trial increase
in IOP was observed in almost 45% of the patients19,20.
What we believe from above discussion that if intra-vitreal
steroid is given in appropriate dose and circumstances, it can be more
effective and less damaging. As stated earlier, best eyes are pseudophakic eyes
and low sustained dose is most effective. We selected phakic patients with a
previous average history of 4.4 intra-vitreal Avastin injections for DME. What
we observed that almost all of them had nuclear sclerosis of grade 2 or more.
So for treatment purposes we did cataract surgery along with steroid as
combination therapy. Advantage was two folds, cataract surgery not just gave an
early improvement in visual function which helped us to build patient
confidence and regular follow up but also reduced the fear of development of
most common complication.
Steroid injection dose was 1 mg/0.05 ml. The incidence of
rise in IOP above the normal range with 1 mg was 16 % according to DRCR.net. Removal
of cataract also reduces IOP. Both these factors helped to keep IOP within
normal limits. In our study we observed that at 16 weeks, out of 14 patients 9
(64.2%) patients showed increase in IOP. 88.8% of these patients still had
their IOP within normal limit. Only one patient (7.1%) showed IOP more than 20
mmHg which was controlled through medication. This incidence of increase in IOP
outside normal limits (7.1%) is less than the incidence of rise of IOP in
DRCR.net (16%) and FAME study 45%.
Our study revealed that there was an average decrease of 69
microns in CMT at end of 4 months. 12 (85.7%) patients showed decrease in CMT
out of 14 which is even more than the international data we mentioned above
(69%). Average improvement in BCVA was 1.8 Log MAR. 12(85.7 %) patients showed
improvement in VA which made it significant. Our study was a prospective case
series without any control group. All surgeries were performed by single surgeon;
no patient was lost to follow-up. It was a pilot study with a small sample size
and short follow up period. Perhaps a large trial with a lengthy follow up is
needed.
CONCLUSION
Intra-vitreal triamcinolone, when given in an appropriate
dose is an effective treatment of refractory macular edema. Cataract extraction
can reduce steroid related complications, improve compliance and achieve better
visual outcome. Both these tools can be an effective combination therapy in
order to treat refractory macular edema.
Author’s Affiliation
Dr.
M. Irfan Karamat
MBBS,
FCPS, MRCS
Senior
Registrar
KEMU/Mayo
Hospital, Lahore
Prof.
Dr. Asad Aslam Khan
MBBS,
MS, FCPS, PhD
Professor
of Ophthalmology
KEMU/Mayo
Hospital, Lahore
Dr.
Nasir Chuadhry
MBBS,
FCPS
Fellowship
in VR
Assistant
Professor
KEMU/Mayo
Hospital, Lahore
Dr.
Haroon Tayyab
MBBS,
FCPS, FCPS (VR)
Assistant
Professor
KEMU/Mayo
Hospital, Lahore
Role
of Authors
Dr.
M. Irfan Karamat
Data
collection, analysis, compilation, writing of manuscript.
Prof.
Dr. Asad Aslam Khan
Critical
review.
Dr.
Nasir Chuadhry
Collection
of data, writing of article, compilation.
Dr.
Haroon Tayyab
Manuscript
writing.
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