Review

EFFECT OF INTERNAL LIMITING MEMBRANE

PEELING DURING VITRECTOMY FOR DIABETIC
MACULAR EDEMA
Systematic Review and Meta-analysis
TAKUYA NAKAJIMA, MD, MURILO F. ROGGIA, MD, YASUO NODA, MD, TAKASHI UETA, MD, PHD
Purpose: To evaluate the effect of internal limiting membrane (ILM) peeling during
vitrectomy for diabetic macular edema.
Methods: MEDLINE, EMBASE, and CENTRAL were systematically reviewed. Eligible
studies included randomized or nonrandomized studies that compared surgical outcomes
of vitrectomy with or without ILM peeling for diabetic macular edema. The primary and
secondary outcome measures were postoperative best-corrected visual acuity and central
macular thickness. Meta-analysis on mean differences between vitrectomy with and
without ILM peeling was performed using inverse variance method in random effects.
Results: Five studies (7 articles) with 741 patients were eligible for analysis. Superiority
(95% condence interval) in postoperative best-corrected visual acuity in ILM peeling
group compared with nonpeeling group was 0.04 (0.05 to 0.13) logMAR (equivalent to 2.0
ETDRS letters, P = 0.37), and superiority in best-corrected visual acuity change in ILM
peeling group was 0.04 (0.02 to 0.09) logMAR (equivalent to 2.0 ETDRS letters, P =
0.16). There was no signicant difference in postoperative central macular thickness and
central macular thickness reduction between the two groups.
Conclusion: The visual acuity outcomes using pars plana vitrectomy with ILM peeling
versus no ILM peeling were not signicantly different. A larger randomized prospective
study would be necessary to adequately address the effectiveness of ILM peeling on visual
acuity outcomes.
RETINA 35:17191725, 2015

strict metabolic and blood pressure control, which are

considered essential elements of the treatment,3,4 progression of central vision loss due to persistent DME is
often observed.
Since the denitive reports of the Early Treatment
Diabetic Retinopathy Study on photocoagulation treatment for DME in 1985, laser therapy has been the
standard treatment for clinically signicant macular
edema.5 Recently, randomized controlled trials on the
treatment of DME with anti-vascular endothelial
growth factor (VEGF) therapy have shown signicant
improvement in visual acuity.69 However, there are
several concerns for anti-VEGF therapy: 1) the
requirement of repetitive injections over time can be

entral visual loss caused by diabetic macular

edema (DME) is a prevalent manifestation of diabetic retinopathy.1 Affecting both patients with Type 1
and 2 of the disease, macular edema is associated with
a 10-year cumulative incidence of 20% and 25% for
Type 1 and Type 2 diabetes, respectively.2 Despite the
From the Department of Ophthalmology, Graduate School of
Medicine and Faculty of Medicine, The University of Tokyo, Tokyo,
Japan.
None of the authors have any nancial/conicting interests to
disclose.
Reprint requests: Takashi Ueta, MD, PhD, Department of
Ophthalmology, Graduate School of Medicine and Faculty of
Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku,
Tokyo 113-8655, Japan; e-mail: ueta-tky@umin.ac.jp

1719

1720 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

a burden for patients and ophthalmologists, 2) the

safety in systemically high-risk patients has not been
evaluated,10 and 3) long-term efcacy and safety
remain unclear.
The vitreous has been implicated as a contributing
factor for macular edema in some patients with
diabetes. Macular traction caused by a taut, thickened,
and rmly attached posterior hyaloid is associated with
increased vascular permeability and uid accumulation.11 The observation that spontaneous posterior vitreous detachment (PVD) was associated with an
improvement of the macular edema supported the role
of vitrectomy in the management of DME.11,12 Surgical removal of the posterior hyaloid using vitrectomy
has been associated with improved visual acuity in
patients with vitreomacular adhesion.1316 Recently,
the importance of internal limiting membrane (ILM)
peeling has been discussed in the context of surgical
management of DME. Several authors described a positive effect of including the ILM peeling during vitrectomy for DME. More favorable anatomical and visual
outcomes with ILM peeling have been postulated.17,18
However, some studies have reported that reduction of
macular edema did not lead to functional improvement
in vision.16,19,20 The objective of this meta-analysis
was to investigate the effect of ILM peeling adjunct
to vitrectomy compared with vitrectomy alone in surgical management of DME.
Methods
Systematic review and meta-analysis were performed according to instructions and recommendations by the Cochrane Handbook for Systematic
Reviews of Interventions. Inclusion of nonrandomized
studies in meta-analysis is specically discussed in
chapter 13 of the handbook. There was no funding
support for this systematic review.

2015  VOLUME 35  NUMBER 9

identied by Internet-based searches for other potentially eligible articles.

Selection Criteria
All captured publications by the Internet-based search
were rst screened by predened selection criteria.
Eligible studies included randomized or nonrandomized
studies comparing the visual outcomes of ILM peeling
with and without in the management of DMR. A period
of up to 12 months was considered a suitable duration of
follow-up for the evaluation of surgical outcomes, as
long as at least 70% of the patients stayed in the study.
Although some studies might follow-up with patients
for a longer period of time, there is an increasing chance
of additional confounders that might hinder the appropriate evaluation of surgical outcomes, which led to the
follow-up period being limited to a maximum of 12
months in this study. There was no limitation with the
language used in the reports.
Data Extraction
Two independent reviewers (T.N. and M.F.R.)
screened the Internet-based searches and obtained full
texts of all citations that were likely to meet the
selection criteria. Disagreements were resolved by
consensus after discussion with a third reviewer
(T.U.). We extracted data on the study design, number
of subjects, age, diagnosis, surgical procedures, PVD
before surgery, preoperative lens status, adjuvant treatments including laser, follow-up period, and outcome
measures comprising best-corrected visual acuity
(BCVA) by logMAR before and after surgery, and
central macular thickness (CMT) before and after
surgery. In this study, BCVA was the primary outcome
measure, whereas CMT was the secondary outcome.
We contacted study authors for missing outcomes.
Qualitative and Risk of Bias Assessment

Literature Search
We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases systematically with no language restrictions
from inception until May 2014. Two independent
reviewers (T.U. and T.N.) performed the internetbased searches. The key terms used for the systematic
search were macular edema [MeSH], internal
limiting membrane, inner limiting membrane,
diabetic retinopathy [MeSH], and vitrectomy
[MeSH]. For each key term, we searched using commands of /exp and adj6 to include as many relevant articles as possible. We collected reference lists
of original studies manually, and review articles were

Qualitative assessment was conducted for design

and quality of the studies as well as baseline characteristics. Especially, confounders that might increase the
risk of selection bias were carefully discussed.
In the meta-analysis, inclusion of nonrandomized
studies is an alternative strategy when the number of
randomized controlled studies (RCTs) is limited and
insufcient to synthesize a meaningful pooled effect
size. In the meta-analysis of nonrandomized studies, the
risk of bias needs to be carefully discussed, especially
when the outcome of intervention is the interest of
the meta-analysis. More attention should be paid to
selection bias, confounders, or heterogeneity in and
among studies, as described by the Cochrane Handbook

EFFECT OF INTERNAL LIMITING MEMBRANE PEELING  NAKAJIMA ET AL

for Systematic Reviews of Interventions (Chapter 13).

Exclusion of studies from the meta-analysis might occur
because of the signicant concern for the risk of bias,
which will be carefully described below.
Statistical Analysis
The meta-analysis was performed using the RevMan 5.2 software. The mean difference with a 95%
condence interval (CI) in a random effect model was
used to estimate the difference in the outcomes
between the vitrectomy group with ILM peeling
(ILM peeling group) and that without ILM peeling
(i.e., ILM nonpeeling group). Heterogeneity was
assessed by calculating the I2 statistics and by performing the chi-square test (assessing the P value). I2
is the proportion of the total variation observed
between the trials attributable to differences between
trials rather than to sampling error (i.e., chance), and
an I2 of .50% is considered as considerable heterogeneity. Validity and robustness of the meta-analysis
was tested by sensitivity analysis applying the leaveone-out method.
Results
Selection of Studies
The rst database query yielded 644 reports. Of
these, we screened their titles and abstracts for
potentially relevant articles and identied 15 reports
for which we obtained full articles. Among the 15
reports, two21,22 were excluded because they did not
directly compare pars plana vitrectomy with and without ILM peeling. Six reports were excluded because
they did not have sufcient visual acuity data for analysis.2328 Finally, 5 studies with 7 reports2935 were
selected for the meta-analysis (Figure 1).
Characteristics and Quality of the Included Studies
Table 1 shows the characteristics of the 5 studies
that compared visual and structural outcomes between

Fig. 1. Selection of included studies.

1721

patients who underwent pars plana vitrectomy with

and without ILM peeling. Among the ve studies,
one was an RCT, two were prospective comparative
studies, and the remaining two were retrospective
observational studies. In the RCT study, the randomization procedures had not been described.
According to the Cochrane Handbook for
Systematic Reviews of Interventions, RCTs with
insufcient randomization procedures are called
quasi-randomized studies, and can be dealt with
as a type of non-RCTs. Therefore, data in the study
were included in the meta-analysis together with
other non-RCT reports on the basis of its high
risk-of-bias nature. The mean age of the enrolled
patients, preoperative lens status, and preoperative
absence of PVD were balanced between the 2
groups in most studies (Table 1). In addition, the prevalence of proliferative diabetic retinopathy,2931,34,35
previous macular laser therapy,2931,35 the duration of
DM,31,33,35 and HbA1c29,31,35 were also balanced preoperatively between the compared groups.
Because many of the included studies were not
RCTs, there was a concern about the selection bias,
where patients with severer DME might have
undergone ILM peeling more frequently compared
with those with milder DME. However, in addition
to the balanced preoperative characteristics between
the 2 groups, the meta-analysis of the preoperative
visual acuity and CMT (Figure 2) indicated that
there was no signicant difference in the baseline
severity of DME. The RCT study was considered
afliated with a relatively high risk of bias because
the specic procedures of random sequence generation, allocation concealment, and masking had not
been described.

Effect of Internal Limiting Membrane Peeling on

Visual Acuity
Figure 3 shows the results of a meta-analysis comparing postoperative BCVA between the ILM peeling and nonpeeling groups. The mean postoperative
BCVA improved in patients who underwent vitrectomy regardless of ILM peeling in four of ve studies.2934 When evaluated by postoperative BCVA
itself, the meta-analysis showed that the superiority
in BCVA by additional ILM peeling was 0.04 (95%
CI: 0.05 to 0.13) by logMAR (equivalent to 2
ETDRS letters) and not statistically signicant
(P = 0.37). When evaluated by the change in BCVA
before and after surgery, the meta-analysis showed
that the further improvement in visual acuity by
additional ILM peeling was 0.04 (95% CI: 0.02

1722 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

2015  VOLUME 35  NUMBER 9

Table 1. Characteristics of the Studies Included for Meta-analysis

Study
Yamamoto et al

29

Design

PC

15
15
41
17
308
178
66
62
19
20

Bahadir et al30

PC

Kumagai et al31,32

RO

Kamura et al33 and Shiba et al34

RO

Hoerauf et al35

RCT

Age Phakia, n PVD (), n Surgical Procedure Follow-up (months)

59
62
58
60
60
60
61
66
64

13
12
NR

11
10
NR

446

NR

NR

29
28
19
20

17
19

PPV alone
PPV + ILM peeling
PPV alone
PPV + ILM peeling
PPV alone
PPV + ILM peeling
PPV alone
PPV + ILM peeling
PPV alone
PPV + ILM peeling

10
10
12
12
12
12
12
12
6
6

NR, not reported; PC, prospective comparative; PPV, pars plana vitrectomy; RO, retrospective observational.

to 0.09) by logMAR (equivalent to 2 ETDRS letters)

and not statistically signicant (P = 0.16).
Effect of Internal Limiting Membrane Peeling on
Central Macular Thickness
Figure 4 shows the results of the meta-analysis
comparing postoperative CMT between vitrectomy
with and without ILM peeling. When evaluated by
postoperative CMT itself, the meta-analysis showed
that the thinner CMT by additional ILM peeling was
31.6 (95% CI: 207.2 to 144.0) mm and not
statistically signicant (P = 0.72). When evaluated
by the change in CMT before and after surgery, the
meta-analysis showed that the further decrease in
CMT by additional ILM peeling was 87.7 (95%
CI: 24.9 to 200.3) mm and not statistically significant (P = 0.13).

Sensitivity Analysis
Applying the leave-one-out method did not change
the statistical signicance of the meta-analysis,
except for the following: when one retrospective
study33,34 was removed, the mean difference in
BCVA improvement before and after surgery became
statistically signicant in the favor of ILM peeling
(0.06 [95% CI: 0.010.11] by logMAR, equivalent
to 2 ETDRS letters, P = 0.03).
Discussion
The role of ILM peeling in the treatment of DME is
controversial, and sufcient data to clarify its role have
not yet been available. The results of the present metaanalysis showed no difference in visual acuity outcomes and reduction of macular edema by optical

Fig. 2. Comparison of baseline visual acuity (VA) and CMT between patients who underwent vitrectomy with ILM peeling (ILM peeling group) and
without ILM peeling (ILM nonpeeling group). Mean and SD values were presented by logMAR and micrometers for VA and CMT, respectively. Metaanalysis was performed for the mean difference between the two groups using inverse variance method in random effects.

EFFECT OF INTERNAL LIMITING MEMBRANE PEELING  NAKAJIMA ET AL

1723

Fig. 3. Comparison of postoperative visual acuity (VA) and its change after surgery between patients who underwent vitrectomy with ILM peeling
(ILM peeling group) and without ILM peeling (ILM nonpeeling group). Mean and SD values were presented by logMAR. Meta-analysis was performed
for the mean difference between the two groups using inverse variance method in random effects.

coherence tomography among patients undergoing

vitrectomy with or without ILM peeling.
Because four of ve studies included in the metaanalysis were not RCTs, we carefully evaluated how
each study addressed selection bias and confounders.
We judged that the selection bias or the inuence of
confounders were not severe because many of the
studies took measures to balance the confounders in
terms of the preoperative lens status, preoperative
PVD, prevalence of proliferative diabetic retinopathy,
previous macular laser therapy, duration of DM, and
HbA1c. Obviously, the RCT design enabling the
inclusion of a larger sample size and with strict
procedures is desirable; however, as a recent metaanalysis report has revealed, such high-quality evidence has not been available on the topic of interest.36
The role of vitrectomy in the treatment of DME has
not been fully addressed, although it has been
established as a therapeutic choice.1416,20 Different
mechanisms underlying the role of vitrectomy in
DME have been suggested. Both anteroposterior and
tangential vitreomacular traction were described as
being associated with macular edema.37 Nevertheless,
different authors have also described vitrectomy to be
benecial even when macular traction is absent.17,19
Vitrectomy causes an increase in the levels of oxygen
delivered to the inner retina, and higher perifoveal
capillary blood ow was observed in vitrectomized

eyes.38,39 In addition, the removal of the posterior

hyaloid reduces levels of histamine, VEGF, and free
radicals that might exist in the preretinal space.40
The ILM of patients with diabetes is characterized by
a higher expression of collagen, bronectin, and
laminin.41,42 The ILM of patients with diabetes is thicker
than that of nondiabetic eyes, contributing to alterations
in the uid dynamics between the vitreous and retina.43
Receptors for both VEGF and interleukin 6 were found
in the components of epiretinal membranes surgically
excised from patients with diabetes, possibly contributing to the development of the disease.44 Furthermore,
higher levels of VEGF in the vitreous of diabetic eyes
might decrease the expression of occludin and consequently enhance vascular permeability in patients with
DME.45 The rationale supporting the removal of ILM
during vitrectomy is a better elimination of tractional
forces at the vitreoretinal interface recognized to contribute to DME. Furthermore, the condensed vitreous
pocket in the premacular area is strongly attached to
the ILM, and thus, the induction of a PVD will only
allow the anterior surface of the pocket to be released.46
The association of ILM peeling would remove the posterior surface of the precortical vitreous pocket and
would resolve the macular edema more efciently.17,25
Internal limiting membrane is known to serve as
a scaffold for proliferating astrocytes. Thus, its
removal may inhibit the reproliferation of astrocytes

1724 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

2015  VOLUME 35  NUMBER 9

Fig. 4. Comparison of CMT and its change after surgery between patients who underwent vitrectomy with ILM peeling (ILM peeling group) and
without ILM peeling (ILM nonpeeling group). Mean and SD values were presented by micrometers. Meta-analysis was performed for the mean
difference between the two groups using inverse variance method in random effects.

on the retinal surface, avoiding the formation of the

epiretinal membrane.17 In this study, we analyzed
postoperative data up to 1 year; however, the merit
of ILM peeling may appear only later after vitrectomy.
Among the 5 studies included, only one retrospective
study evaluated the outcomes later than 1 year postoperatively, although the follow-up completion rate
declined signicantly.32
In conclusion, the visual acuity outcomes using pars
plana vitrectomy with ILM peeling versus no ILM
peeling were not signicantly different. A larger
randomized prospective study would be necessary to
adequately address the effectiveness of ILM peeling
on visual acuity outcomes.
Key words: diabetic macular edema, vitrectomy,
internal limiting membrane, meta-analysis.
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