Drugs
DOI 10.1007/s40265-013-0055-x
REVIEW ARTICLE
Drug-Induced Macular Edema
Olga E. Makri • Ilias Georgalas •
Constantine D. Georgakopoulos
Ó Springer International Publishing Switzerland 2013
Abstract Macular edema constitutes a serious pathologic
entity of ophthalmology resulting in vision loss with a
remarkable impact on the quality of life of patients. It is the
final common pathway of various systemic diseases and
underlying intraocular conditions, with diabetes mellitus
being the most frequent cause. Other causes include venous
occlusive disease, intraocular surgery, and inflammatory
conditions of the posterior segment of the eye. Macular
edema is a recognized side effect of various systemic and
local medications and requires special consideration among
ophthalmologists and other clinicians. Recently, antidia-
betic thiazolidinediones have been implicated in the
development of macular edema, and a review of the Eng-
lish literature revealed that other systemically administered
drugs like fingolimod, recently approved for relapsing
forms of multiple sclerosis, the anticancer agents tamoxifen
and the taxanes, as well as niacin and interferons have been
reported to cause macular edema. Ophthalmologic phar-
maceutical agents, like prostaglandin analogs, epinephrine,
timolol, and ophthalmic preparation preservatives have
also been reported to cause macular edema as an adverse
event. The purpose of this article is to provide a short,
balanced overview of the available evidence in this regard.
The available data and the possible pathophysiologic
mechanisms leading to the development of macular edema
are discussed. Possible therapeutic strategies for drug-
induced macular edema are also proposed.
O. E. Makri
C. D. Georgakopoulos (&)
Department of Ophthalmology, Medical School, University of
Patras, Rio, 26504 Patras, Greece
e-mail: cgeorg@upatras.gr
I. Georgalas
1st Department of Ophthalmology, University of Athens Medical
School, Athens, Greece
1 Introduction
Macular edema (ME) constitutes a serious ophthalmic
condition, impairing patients’ vision and quality of life. It
refers to accumulation of fluid in the outer plexiform layer
and the inner nuclear layer as well as a swelling of Müller
cells of the retina at the macula, which is the part of the
retina responsible for sharp vision due to its high density of
cone photoreceptors. If fluid accumulation is in form of
honeycomb-like spaces, ME is characterized as cystoid ME
(CME). Pathophysiologically, fluid accumulation may be
initially intracellular or extracellular. In the former (cyto-
toxic edema), there is alteration of the cellular ionic
exchanges of excess of Na? intracellularly. In the latter
(vasogenic edema) there is a predominantly extracellular
accumulation of fluid associated directly with disturbance
of the blood–retinal barrier (BRB). In cytotoxic edema,
there is primarily a redistribution of fluid from its normal
extracellular location to the intracellular space, resulting in
cell damage and release of vasoactive substances that may
finally induce vasogenic edema through alteration of the
BRB [1]. Fluorescein angiography (FA) may be required to
establish the diagnosis of ME (Fig. 1a). Optical coherence
tomography (OCT), however, has become the first-line
diagnostic imaging modality for the accurate diagnosis of
ME and for monitoring its response to possible therapy
(Fig. 1b).
ME is not a specific disease, but rather a clinical feature
occurring in a variety of conditions. Ocular conditions
associated with CLO include ocular surgery, inherited
dystrophies, ocular tumors, retinal vascular disease, vitre-
oretinal adhesions and traction, inflammatory conditions,
and medications. Several systemically and locally admin-
istered drugs have been implicated in the development of
ME. A review of the English literature was performed to

Fig.1 Cystoid macular edema (CME) diagnostic modalities. a Fluo-
rescence angiography reveals a typical, petalloid-like pattern of
hyperfluorescence in the macula during the late phase, due to dye
leakage from the perifoveal capillaries and its accumulation within
microcystic spaces in the outer plexiform layer. b Optical coherence
tomography, which has become the ancillary test of choice for the
diagnosis of CME, provides high-resolution cross-sectional imaging
of the macula, showing cyst-like hyporeflective spaces within the
outer layers of retina, macular thickening, and loss of the foveal
depression
obtain insight into the issue. The MEDLINE database was
used as a search engine to identify the drugs that have been
implicated in inducing ME. The following keywords were
employed: ‘‘macular edema’’ and ‘‘reduced vision’’ com-
bined with ‘‘drug-induced,’’ ‘‘chemically induced,’’
‘‘adverse effect,’’ ‘‘adverse event,’’ ‘‘associated with drug,’’
‘‘as cause of drug,’’ and ‘‘as side effect.’’ Occasionally,
reference citations from selected review articles were also
used. Additional screening was done by searching indi-
vidual drug names. Only articles published in the English
language were included.
The review revealed that the antidiabetic agents, the
thiazolidinediones; fingolimod, a recently approved drug
for the relapsing forms of multiple sclerosis (MS); the
anticancer agents, tamoxifen and the taxanes; and inter-
ferons and niacin are the main systemic drugs reported to
cause ME. Furthermore, ophthalmologic pharmaceutical
agents, like prostaglandin analogs, epinephrine, timolol,
and ophthalmic preparation preservatives, have also been
reported to cause ME.
The purpose of this article is to review the available data
and to provide a short, balanced overview of the available
evidence regarding the frequency and severity of ME
O. E. Makri et al.
induced from each drug category. When available, the
possible pathophysiologic mechanisms leading to the
development of ME are discussed. Possible therapeutic
strategies for drug-induced ME are also proposed.
2 Systemically Administered Agents
2.1 Thiazolidinediones
Thiazolidinediones (TZDs) are oral antidiabetic agents and
act as insulin sensitizers, increasing sensitivity of muscle,
fat, and liver to insulin [2]. They are a second-line treat-
ment used when the glycemic goal with the maximal tol-
erated dose of metformin is not achieved or sustained, and
can be used as monotherapy or combined with oral antid-
iabetics or insulin [3]. TZDs include rosiglitazone and
pioglitazone, with pioglitazone becoming one of the major
antidiabetic drugs prescribed.
TZDs are reported to cause or exacerbate ventricular
failure, pulmonary edema, fluid retention, and peripheral
edema, especially in patients with left ventricular dys-
function or chronic renal insufficiency [4–7]. More pre-
cisely, peripheral edema is described in 4.8 % of patients
using pioglitazone alone, 6–7.2 % if combined with other
oral agents, and up to 15 % of patients using pioglitazone
with insulin [7]. Postulated mechanisms of TZD-induced
peripheral edema include increased renal sodium absorp-
tion and plasma volume, sympathetic activation, intestinal
ion transport alterations, and increased production of vas-
cular endothelial growth factor (VEGF), resulting in
increased vascular permeability [5, 8, 9].
Recently, TZDs were related to development and
worsening of ME in diabetic patients. Literature review has
revealed inconclusive findings and an increasing contro-
versy regarding TZD-induced ME.
The potential association of TZDs with ME was initially
highlighted by Colucciello [10], who published a single case
report where up-titration of the administered rosiglitazone
resulted in bilateral ME and peripheral edema. After rosig-
litazone dosage was decreased, ME resolved (Table 1).
Ryan et al. [11], in a noncontrolled, nonrandomized,
retrospective chart review of 30 diabetic patients on TZD
treatment stated that TZD appears to cause ME and dete-
riorate peripheral edema. They estimated the incidence of
worsening of ME due to TZD use to 1.5–2.6 %. Resolution
of ME with improved vision once off TZDs, without laser
treatment, implicated a direct cause-and-effect relationship.
The authors associated the pathogenesis of ME with TZD-
induced fluid retention and hypothesized that fluid accu-
mulation in the retina might be caused by up-regulation of
VEGF [12], leading to both increase in plasma volume and
vascular permeability.
Drugs and Macular Edema
Table 1 Published isolated case reports of the occurrence of macular edema in association with thiazolidinedione use
Reference Drug Duration of treatment until onset of
ME
Colucciello [10] Rosiglitazone 3 years; dosage had increased from
2 to 8 mg/day 1 month before
Oshitari et al. [13] Pioglitazone 2 weeks
Kendall et al. [14] Rosiglitazone More than 1 year
Liazos et al. [15] Rosiglitazone 8 months at 4 mg/day
Asensio-Sánchez Rosiglitazone 1 month at 4 mg/day
et al. [16]
ME Macular edema, OS left eye, OU both eyes
Ryan et al. [11] recognized that their study had several
weaknesses due to its retrospective nature. Furthermore,
visual acuity (VA) and macula were not examined before
TZD administration, and could not be determined whether
ME was associated with TZD treatment or the natural
course of diabetic maculopathy [13].
Consequently, the manufacturer of the rosiglitazone,
GlaxoSmithKline, announced ME being reported in an
undisclosed number of postmarketing cases worldwide
[14]. Isolated case reports also described TZD-induced ME
(Table 1) [13–16].
Conversely, a retrospective analysis of 76 patients
concluded that rosiglitazone was not linked to ME [17].
Moreover, in a 2.8-year follow-up study of proliferative
diabetic retinopathy, rosiglitazone was not associated with
an increased incidence of ME in patients without ME or
with mild ME at baseline [18]. This study though, was
significantly limited by its very small sample size [19].
Association of TZDs with an increased 1-year incidence
of ME was confirmed in a large, 170,000-strong, prospec-
tive cohort study [20]. Even after adjustment for con-
founding factors of age, glycemic control, and insulin use,
modest association between TZDs and ME was revealed.
The authors, though, could not account for duration of
diabetes or TZD use, and other confounders [19].
Eventually, in a cross-sectional analysis of 9,690 par-
ticipants (ACCORD Eye Substudy) [21], no association
was found between TZD and ME, while the previous
reports were ascribed to possible idiosyncratic mecha-
nisms. Authors reserve for a definitive answer from the
4-year follow-up data which will enable prospectively
examination of the incidence of ME during continuation or
initiation of TZD.
Commenting on the ACCORD Eye Substudy, Colucci-
ello and Ryan [22] argued that it had selection bias that
Peripheral Eye Outcome
edema involved
Yes OU Reversed 3 weeks after dosage was
decreased to 2 mg/day
Yes OU ME persisted 2 weeks after pioglitazone
discontinuation
Significant reduction of ME after
administration of 25 mg spironolactone
Yes Not Resolved upon drug discontinuation
specified
Yes OS Complete resolution 3 months after
rosiglitazone cessation
Yes OU ME persisted despite drug discontinuation
influenced its final outcome, because the exclusion of
previous laser photocoagulation treatment for diabetic
retinopathy or ME excluded those patients who most pos-
sibly would have developed ME on TZD exposure. Fur-
thermore, by excluding patients with marginal renal and
cardiac function, the high-risk population for peripheral
edema and potentially ME was automatically excluded.
They also remarked that because OCT analysis was not
used, subtle ME could possibly be missed.
Based on the hypothesis that TZDs induce subclinical
increase in retinal thickness, Tarbett et al. [23] used OCT to
screen for ME in a cross-sectional study. They compared
retinal thickness in TZD-treated and non-TZD-treated
diabetic patients and showed that there was no difference in
retinal thickness between the TZD and the non-TZD group.
A disproportionality analysis of the reports of the 4-year
period on US Food and Drug Administration (FDA)
Adverse Event Reporting System Database concluded that
the frequency of reporting of ME was significantly higher
for TZDs compared to other antidiabetics [24]. Separate
analysis of the two TZDs showed that only rosiglitazone
was associated with ME. Motola et al. [24] emphasized that
because TZDs represent a second-line treatment, TZD-
treated subjects may be affected by a more advanced or
severe stage of diabetes, and be at increased risk of ME.
The most recent published data, a retrospective cohort
study of 103,368 diabetic patients, evaluated the short-term
and long-term risks of developing ME among TZD users
and nonusers [25]. Conclusively, TZDs were associated
with increased risk of ME at 1-year and 10-year follow-up
evaluations, even after adjustment for various confounding
factors known to influence diabetic retinopathy, like age,
systolic blood pressure, levels of hemoglobin A1c, etc. The
association was apparent with both TZDs. The authors
declared as strengths of their analysis the very large sample
 O. E. Makri et al.

size and the long duration of follow-up, and, as an
important limitation, the lack of information about duration
of diabetes and TZD treatment in each patient.
Commenting on the above study, Singh and Segal [19]
stated that because TZDs are typically used as second-line
agents, the reported differences between TZD users versus
nonusers may reflect the underlying diabetes severity rather
than a TZD effect. The direction that this biases the results
is unknown.
To summarize, a definite conclusion regarding associa-
tion of TZD treatment and ME cannot be drawn with
certainty. Large, adequately powered, prospective studies
and more detailed meta-analysis of randomized controlled
trials are required to evaluate the exact causal association
between TZDs and ME and to establish the risk–benefit
profile of TZDs in patients with, or at risk of, diabetic ME
[24]. Despite the uncertainty regarding the association of
TZDs with ME, patients taking TZDs who report any kind
of visual symptom should be promptly referred to an
ophthalmologist, as noted in the current drug labels [6, 7].
2.2 Fingolimod
Fingolimod was initially tested as an immunomodulator
after renal transplantation. An unexpected finding of the
1-year multicenter, randomized, phase III study in renal
transplant patients was that fingolimod was associated with
the occurrence of ME (2.2 and 1.3 % at a dose 5.0 and
2.5 mg, respectively) [26]. One case report described CME
3 months after administration of 5 mg/day fingolimod in a
renal transplant recipient (Table 2) [27]. CME caused
reduction of VA, was confirmed with FA and OCT, and
resolved after fingolimod discontinuation.
Recently, fingolimod became the first oral medication
approved by FDA, at a dose of 0.5 mg/day, for relapsing
forms of multiple sclerosis (MS). In two phase III clinical
studies (TRANSFORMS [28] and FREEDOMS [29]), ME
was a prominent reported adverse event. More precisely, in
TRANSFORMS [28], 1 % of the subjects in the 1.25-mg
fingolimod group and 0.5 % in the 0.5-mg group developed
ME during the study period, while in FREEDOMS [29],
1.6 % of the subjects receiving 1.25 mg fingolimod
developed ME, whereas none of the patients on the lower
dose of 0.5 mg fingolimod had this side effect.
Fingolimod-associated ME appears to be dose depen-
dent (observed in only two patients taking the FDA-
approved 0.5-mg dose), in the majority of cases occurred
within 3–4 months of initiation of treatment, may be
asymptomatic and typically resolves upon fingolimod
cessation [30].
The pathogenesis of fingolimod-associated ME is
unspecified. Fingolimod is a structural analog to sphingo-
sine-1-phosphate (S1P), a naturally occurring signaling
lysophospholipid, with an important role in immune and
vascular biology. Fingolimod-P, fingolimod’s active
metabolite, induces internalization and degradation of the
S1P1 receptor, which plays a role in regulating vascular
permeability, providing a possible explanation of fingoli-
mod-associated ME [30–32]. Tauseef et al. [33] showed
that knockdown of S1P1 receptor in cultured pulmonary
endothelial cells enhanced the increase in vascular per-
meability. The disturbance of vascular endothelial integrity
may induce breakdown of the inner BRB and result in ME.
Two cases of fingolimod-associated ME in MS patients
have since been published (Table 2) [34, 35]. In the first
case, ME was bilateral and resulted in profound reduction
in VA [34]. In both cases, fingolimod was discontinued and
additional therapy with topical corticosteroid with or
without nonsteroidal anti-inflammatory medication
(NSAID) was administered. In one eye, ME persisted
despite therapy [34]. Ontaneda et al. [36] describing the
early experience with fingolimod, stated that among 317
patients, ME occurred in 3.
According to FDA recommendations, patients should
undergo a baseline ophthalmic examination prior to initi-
ation of fingolimod therapy, and a second examination
3–4 months later, or whenever the patient notices vision
changes during fingolimod treatment [37]. Jain et al. [30]
recommend further evaluation at 6 months and then
annually. Given the limited clinical experience with

Table 2 Case reports of fingolimod-induced macular edema

Reference Duration and dosage of Eye Outcome
treatment until CME onset involved

Saab et al. [27] 3 months at 5 mg/day OD Complete resolution of CME 2 months after fingolimod discontinuation
Liu and 5 days at 0.5 mg/day OU CME decreased 3 months after fingolimod discontinuation; topical 1 %
Cuthbertson prednisolone and ketorolac was administered OU for 2 months afterward with
[34] complete resolution of CME OS and persistence of minimal CME OD
Turaka and 3 months at 0.5 mg/day OS Complete resolution of CME after fingolimod cessation and topical prednisolone
Bryan [35] administration
CME Cystoid macular edema, VA visual acuity, OD right eye, OS left eye, OU both eyes
Drugs and Macular Edema

fingolimod, long-term follow-up of patients treated with
the drug is required to better determine the incidence and
management of fingolimod-associated ME.
2.3 Taxanes
Taxanes (docetaxel and paclitaxel) are widely used che-
motherapy agents. They act as mitotic inhibitors, prevent-
ing normal reorganization of the microtubule network
within cells [38].
Isolated case reports have raised concern, providing
compelling association between taxanes and CME occur-
rence. Review of the literature yielded two cases of doce-
taxel-induced CME [39, 40] and ten due to paclitaxel in
both the polyethylated castor oil-based and protein-bound
forms (Table 3) [41–49]. Taxane-induced CME tends to be
bilateral, symptomatic, and characteristically angiographi-
cally silent, because FA fails to show any significant cap-
illary leakage. OCT demonstrates fluid accumulation into
multiple well-defined cyst-like spaces prominently in the
outer and inner plexiform layers [42, 46].
Therapeutically, discontinuation of the causative factor
is the common decision, with favorable outcome. In some
cases, this was accompanied with administration of topical
steroids and NSAIDs [41, 46] or oral acetazolamide [40,
46]. For those cases where withdrawal of the causative
factor is not recommended, Meyer et al. [45] suggested the
consideration of oral acetazolamide.
The pathophysiological mechanism of taxane-induced
CME is not clearly understood. Joshi and Garretson [41]
suggested a toxic effect of paclitaxel on Müller cells, which
are responsible for maintaining osmotic gradients within
the neurosensory retina, resulting in intracellular fluid
accumulation. Another theory suggests the partial com-
promise of the BRB with leakage of small molecules and
proteins, but not of the larger fluorescein molecules [40,
42]. Recently, Kuznetcova et al. [47] based on spectral-
domain OCT findings, suggested retinal pigment epithe-
lium dysfunction due to taxane effects on microtubule
functions. VEGF is probably not involved in the pathoge-
netic mechanism, because paclitaxel-induced CME has
been described in patients while administered systemic

Table 3 Case reports of paclitaxel-induced macular edema

Reference Number Drug Duration and dosage of Outcome
of cases administered treatment

Joshi and 1 Paclitaxel 175 mg/m2 for 10 months Resolution of CME 6 weeks after drug cessation
Garretson [41]
Smith et al. [42] 1 Albumin- 2.5 years at 400 mg every Complete resolution 15 weeks after drug discontinuation
bound paclitaxel 3 weeks
Murphy et al. 2 NAB paclitaxel First patient: 6 weeks First patient: rapid recovery of visual function 3 weeks after
[43] (dosage not specified) paclitaxel discontinuation combined with topical
administration of steroids and NSAIDs
Second patient: 11 months Second patient: marked decrease of CME 3 months after drug
(dosage not specified) cessation
Baskin and Garg 1 NAB paclitaxel 6 months (dosage not Resolution of CME 4 months after drug discontinuation
[44] specified)
Meyer et al. [45] 1 Paclitaxel 12 cycles of 200 mg/m2 Complete regression of CME 8 weeks after treatment with oral
acetazolamide (500 mg/day) while still on treatment with
paclitaxel
Georgakopoulos 1 Paclitaxel 2 weeks after the 5th, and Ten weeks after the last administration of paclitaxel and under
et al. [46] as per plan the last, cycle treatment with topical ketorolac and oral acetazolamide
of 175 mg/m2 (375 mg/day), CME regressed
Kuznetcova 1 Paclitaxel 3 months (cumulative CME refractory to oral acetazolamide (250 mg/day), topical
et al. [47] dose 2,741.12 mg/m2) indomethacin, and prednisolone
Resolution 1 month after paclitaxel discontinuation
Ham et al. [48] 1 Paclitaxel 6 cycles of 175 mg/m2 per CME refractory to paclitaxel discontinuation and intravitreal
cycle injections of bevacizumab and triamcinolone
Spontaneous resolution of CME 1 year later
Rahman et al. 1 NAB paclitaxel 3 months (dosage not CME persisted after intravitreal injections of bevacizumab,
[49] specified) while still under treatment with NAB paclitaxel for the
following 4 months
CME Cystoid macular edema, NAB nanoparticle albumin bound, NSAID nonsteroidal anti-inflammatory drug

bevacizumab [44, 46, 49], whereas in some cases CME
persisted after intravitreal administration of bevacizumab
[48, 49].
Taxane-induced CME seems to be a rare but potential
entity. Consequently, clinicians and ophthalmologists
should be alert to that possibility and ophthalmologic
evaluation could be considered at baseline and at regular
intervals during taxane therapy.
2.4 Tamoxifen
Tamoxifen is an oral nonsteroidal antiestrogen primarily
approved as prophylaxis in women regarded as being at
high risk for developing breast cancer [50] and therapy
against estrogen receptor-positive breast cancer. Besides
systemic side effects like menopausal symptoms, throm-
boembolic effects, etc., several reports discuss tamoxifen-
induced retinopathy and ME in patients administered
mainly high cumulative doses. Regarding tamoxifen-
induced ME, information is derived primarily from isolated
case reports, reflecting the relative rareness of the
condition.
Tamoxifen-induced ME was first described by Kaiser-
Kupfer and Lippman [51] who reported a profound VA
reduction in three patients treated with high-dose tamoxifen.
VA decrease was attributed to tamoxifen-induced ME, evi-
dent clinically and on FA, accompanied by superficial white
refractile deposits in the inner layers of retina, and forming
clusters in the macular and paramacular area. ME persisted
despite tamoxifen cessation. Subsequently, other reports [52,
53] supported the aforementioned association, while low-
dose tamoxifen-induced ME was also described [54].
Gorin et al. [55] conducted a single-masked, cross-sec-
tional study that comprised patients treated with low-dose
tamoxifen. ME was reported in 7 out of 205 cases. In
another study, among 129 women treated with low-dose
tamoxifen, no case of ME reported [56]. In a prospective
study of 63 patients on long-term, low-dose tamoxifen
treatment, ocular toxicity was noted in 4 patients [57]. All 4
patients had decreased VA and characteristic retinopathy
consisted of bilateral ME and yellow-white dots in the
paramacular and fovea areas.
OCT findings in two cases of tamoxifen maculopathy
demonstrated a foveal cystoid space, occupying most of the
foveolar thickness combined with focal disruption of the
photoreceptor line, with no evidence of ME [58]. These
features are not consistent with previously described
tamoxifen-induced ME but indicate some degree of atro-
phy of the retinal tissue in the foveola and disruption of the
photoreceptor line.
Subsequently, Bourla et al. [59] described a case where,
while FA revealed late leakage consistent with mild CME,
OCT failed to detect CME or macular thickening. In two
O. E. Makri et al.
patients with ME, confirmed by FA, OCT revealed exten-
sive parafoveal retinal thickening with cystoid spaces
located in the deep retina, while tamoxifen crystals were
visualized in the superficial retinal layers [60]. The authors
concluded that angiographic evidence of ME may not
unanimously correlate with the presence of ME on OCT
[59].
High-resolution Fourier-domain OCT (Fd-OCT) con-
firmed the findings described by Gualino et al. [58]. In a
woman under tamoxifen treatment, with vision loss and a
normal appearing fundus, Fd-OCT demonstrated scattered
microcystoid changes in the fovea extending from the inner
nuclear layer to the photoreceptor outer segment layer with
focal loss of photoreceptors [61]. Development of foveal
microcystoid spaces might predispose to the subsequent
development of macular holes [62, 63].
Pathogenesis of tamoxifen toxicity is unknown.
Tamoxifen has been demonstrated in vitro to act as an
antagonist of glutamate transporters in retinal pigment
epithelium cells [64]. Accordingly, Gualino et al. [58]
suggested that tamoxifen-induced glutamate increase in the
outer retina could result in axonal degeneration and Müller
cell impairment [65], and, consequently, atrophy and for-
mation of the intraretinal foveolar cyst, as depicted in OCT.
After tamoxifen withdrawal, ME may persist [51–53],
whereas in some reports ME resolved [54, 57]. Interest-
ingly, off-label administration of anti-VEGF agents was
reported to have favorable outcomes [60, 66]. In one case,
ME responded to intravitreous administration of sodium
pegaptanib [60]. The most recent publication reports a case
of severe persistent bilateral tamoxifen-induced CME
treated successfully with intravitreous bevacizumab
administration [66].
In summary, rather limited information is available
regarding the frequency of tamoxifen-induced ME. Patients
treated with tamoxifen could have a thorough baseline and
regular follow-up ophthalmic evaluation, especially with
OCT, long before visual disturbance is noticed [67].
2.5 Niacin
Niacin (nicotinic acid) is an organic compound that acts as
a cholesterol-lowering agent when administered orally in
high doses. Gass [68] first described a maculopathy that
developed in a minority of patients taking high doses of
niacin. Maculopathy was suggestive of CME, but, charac-
teristically, no leakage was noted during FA. Since then,
only a few cases have been reported [69–75].
In a retrospective survey of patients taking medication
for hyperlipidemia, those taking niacin were more likely
(p \ 005) to report CME [71]. The incidence of niacin
maculopathy has been estimated to be 0.67 % of patients
administered niacin [70].
Drugs and Macular Edema
Niacin-induced CME seems to be bilateral and occurs
primarily in patients receiving 3 g/day of niacin or more,
although it has been described in patients taking as little as
1.5 g [71]. Although in all cases CME was confirmed
biomicroscopically, FA failed to show any leakage. Spirn
et al. [73] described OCT findings of niacin maculopathy as
cystoid spaces in the outer plexiform and inner nuclear
layers. CME reverses after niacin discontinuation with
restoration of vision and anatomy [73].
The pathophysiology of niacin-induced CME is unclear.
Jampol [69] proposed a prostaglandin-induced toxic effect
on Müller cells and intracellular accumulation of fluid
secondary to intracellular metabolism deregulation. Based
on OCT features, Spirn et al. [73] questioned that theory,
because Müller cell engorgement should be confined to two
discrete areas. Instead, they suggested a niacin-induced
disruption of the BRB, resulting in a very slow and
selective leakage of small molecules but not of molecules
the size of fluorescein, explaining the lack of leakage
during FA.
2.6 Interferons
Interferons (IFN) (alpha, beta, and gamma) are naturally
occurring cytokines that modulate the activity of the
immune system. Interferon-alpha is approved as treatment
of hairy cell leukemia, melanoma, Kaposi’s sarcoma,
chronic myeloid leukemia, and chronic hepatitis C, while
IFN-beta is used for treatment of MS. Furthermore, IFN-
alpha seems to be an effective therapy for chronic refrac-
tory uveitic CME [76].
The most frequent ocular complication of IFN therapy is
IFN retinopathy, typically characterized by retinal hemor-
rhages and cotton wool spots [77]. IFN-induced ME is a
very rare reported complication given that review of the
literature has revealed only six cases [78–82]. Two cases
were associated with treatment with IFN-beta [79, 80], one
case with IFN-alpha [80], and three cases with pegylated
IFN-alpha administered in combination with ribavirin [78,
81, 82]. All the patients suffered from chronic hepatitis C
except for one [80] who suffered from chronic myeloid
leukemia. Two of the patients had a history of diabetes
mellitus with nonproliferative diabetic retinopathy [80, 82].
In the above cases, IFN was administered for 6–48 weeks
and in all patients reduction of VA was documented. ME
was associated with IFN retinopathy, except for one case
[81]. Cessation of IFN therapy resulted in restoration of
vision and resolution of ME in four cases [78–80], while in
the remaining two cases VA remained poor whereas ME
resolved [81, 82].
The possible pathogenesis of IFN-induced ME is
unknown, although several theories have been proposed.
In three out of six cases, hypoalbuminemia and
thrombocytopenia were observed concurrently with ME,
and resolution of ME was associated with normalization of
blood parameters [79, 80]. Hypoalbuminemia might play a
role in the induction of ME, because it decreases plasma
osmotic pressure, and therefore the osmotic pressure dif-
ference between plasma and interstitial fluid. Conse-
quently, the suppression of water influx from the interstitial
space to the capillary may decrease water reabsorption,
resulting in ME [79]. Furthermore, thrombocytopenia may
lead to dysfunction of some platelet-derived factors and
increase endothelial permeability [80]. Finally, it has been
shown that IFN interferes with retinal microcirculation
[83]. In this respect, patients with abnormal microcircula-
tion diseases, such as diabetes mellitus, may be at high risk
of suffering IFN-associated ocular complications [82, 83].
To summarize, ophthalmologists and physicians should
be familiar with IFN-induced ME. High suspicion of this
condition is required for patients who report a decrease of
vision during and after IFN therapy. Baseline and follow-
up examination could be proposed, especially for high-risk
patients like diabetics.
2.7 Other Agents
Review of the literature has revealed isolated case reports
where several drugs have been recognized as the causative
factor of ME. More precisely, the antiretroviral drug
zidovudine has been recognized as a cause of bilateral
CME in a HIV patient [84]. In that case, CME recurred
after zidovudine reinstitution. The use of the bactericidal
antibiotic drug rifabutin in two different cases of Myco-
bacterium avium complex pulmonary disease resulted in
CME [85, 86]. In these cases, CME was accompanied by
anterior uveitis with hypopyon and vitritis. Acitretin, a
retinoid used to treat severe skin disorders like psoriasis,
was recognized by Lois and White [87] as the causative
factor for bilateral CME associated with retinal pigment
epithelium abnormalities. Barak et al. [88] described a
single case of bilateral CME due to the pyrimidine syn-
thesis inhibitor leflunomide administered in a patient with
rheumatoid arthritis. CME resolved 3 months after leflun-
omide discontinuation. Furthermore, the tyrosine-kinase
inhibitor imatinib, administered for the treatment of
chronic myeloid leukaemia, was documented as the trig-
gering factor for ME in three different cases [89–91].
Magrath et al. [92] described a patient with meningeal
coccidioidomycosis treated with oral fluconazole for three
consecutive years. Bilateral CME, confirmed with FA and
OCT, occurred with complete resolution 2 months after
fluconazole withdrawal. Bussone et al. [93] described two
patients with refractory Wegener’s granulomatosis, where
unilateral CME was diagnosed with OCT 1–2 months after
initiation of treatment with rituximab. The final outcome
 O. E. Makri et al.

was favorable after treatment with corticosteroids in both
cases. Finally, the diuretic hydrochlorothiazide has also
been implicated as the cause of angiographically silent
bilateral CME [94]. Table 4 summarizes the drugs impli-
cated and the clinical course of ME in each case.
3 Ophthalmologic Agents
3.1 Prostaglandin Analogs
Latanoprost was the first prostaglandin analog (PGA)
approved by the FDA as an antiglaucoma agent. It lowers
intraocular pressure mainly by increasing the uveoscleral
outflow [95, 96]. Since its release, it has become the most
popular antiglaucoma medication. The adverse effects of
latanoprost have been relatively mild, consisting of topical
irritation, conjunctival hyperemia, and changes in iris
pigmentation, while CME is an assumed side effect. In
phase III studies and in the compassionate use studies of
latanoprost, CME incidence was 0.7 and 0.05 %, respec-
tively [97].
Since the introduction of latanoprost, several indepen-
dent case reports describing latanoprost-induced CME have
engendered considerable interest and controversy [97–
117]. In these case reports, the temporal association
between latanoprost administration and CME occurrence,
and resolution of CME after latanoprost discontinuation
raised suspicion. Furthermore, recurrence of CME after
rechallenging with latanoprost in some cases [101, 104,
114, 117] reinforced the causal relationship, suggesting a
causative association between latanoprost and CME.
However, in the majority of these reports, several risk
factors coexisted that could have potentially altered the
BRB and resulted in CME; these include open or absent
posterior capsule, complicated surgical history with vitre-
ous loss, history of CME and anterior uveitis, retinal
inflammatory disease, retinal vascular disease, diabetic
retinopathy, etc. [97, 107, 118]. Consequently, a direct
cause-and-effect relationship is difficult to establish
between latanoprost and CME.
Angiographically documented clinical CME was also
reported in patients with absent or open posterior lens
capsule treated with the use of each of the three newly
available PGAs (unoprostone, travoprost, bimatoprost)
[119]. Review of the English literature revealed four iso-
lated cases of travoprost-induced CME [119–122], three
cases of CME associated with bimatoprost administration

Table 4 Systemic medications associated with CME

Reference Cause Ocular manifestation Outcome

Lalonde et al. [84] HIV infection treated with zidovudine Bilateral CME Improvement 1 month after zidovudine
1,200 mg/day for 4 days discontinuation and topical CS
Vaudaux and Rifabutin 300 mg/day for 9 months for Unilateral Rifabutin discontinuation. Complete resolution 5
Guex-Crosier MAC pulmonary disease CME ? hypopyon, weeks after treatment with sub-Tenon’s
[85] AU, vitritis CS ? topical diclofenac ? oral acetazolamide
Smith et al. [86] Rifabutin 900 mg/week for 8 months for Bilateral Resolution 1 month after stopping rifabutin
MAC pulmonary disease CME ? vitritis with
hypopyon OS
Lois and White Acitretin 30 mg/day for 1 year for psoriasis Bilateral CME Resolution 3 days after acitretin
[87] discontinuation ? oral acetazolamide
Barak et al. [88] Leflunomide for 2 weeks for rheumatoid Bilateral CME Resolution 3 months after leflunomide
arthritis discontinuation
Kusumi et al. [89] CML treated with imatinib 600 mg/day for Unilateral ME Resolution 14 days after imatinib
3 months discontinuation
Masood et al. [90] CML treated with imatinib 600 mg/day for Unilateral CME Almost complete resolution 6 weeks after
2 months imatinib cessation
Georgalas et al. CML treated with imatinib 600 mg/day for Bilateral CME Improvement after imatinib cessation
[91] 1 month
Magrath et al. [92] Fluconazole for Meningeal Bilateral CME Complete resolution of CME 2 month after drug
coccidioidomycosis cessation
Bussone et al. [93] 2 patients with refractory WG treated with Unilateral CME Recession of CME after CS administration
rituximab
Iakono et al. [94] Hypertension treated with Bilateral CME Spontaneous recovery with the discontinuation
hydrochlorothiazide 25 mg/day for of the drug
6 months
CME Cystoid macular edema, CS corticosteroids, MAC Mycobacterium avium-complex, AU anterior uveitis, RPE retinal pigment epithelium,
CML chronic myeloid leukaemia, ME macular edema, WG Wegener’s granulomatosis
Drugs and Macular Edema
[119, 121, 123], while unoprostone has been implicated as
the causative factor in only one case of CME [119].
It should, however, be noted that the number of such
published reports is very low when compared to the
number of eyes treated with PGAs globally [107]. Thus, no
epidemiologic conclusions can be drawn regarding the
frequency of PGA-induced CME. In a retrospective review
of 136 eyes receiving latanoprost, Warwar et al. [124]
reported 1.2 % incidence of CME.
The possibility of latanoprost-induced changes in the
BRB was addressed prospectively in a randomized clinical
trial by Hoyng et al. [125] who administered latanoprost
(0.006 %) twice daily for a month to uncomplicated
pseudophakic patients; at the end of the trial, FA showed
no CME. In addition, six aphakic cynomolgous monkeys
given seven times the usual daily dose for 6 months failed
to develop CME [125]. In a 6-month prospective study
using OCT, in 68 eyes with a normally functioning blood–
ocular barrier treated with latanoprost, no change in retinal
thickness was noted [126].
Miyake et al. [127] in a short-term, prospective study
demonstrated that latanoprost therapy indirectly acceler-
ated blood–aqueous barrier (BAB) disruption, as was
shown by a laser flare cell meter, and significantly
increased the incidence of angiographic CME formation in
the early postoperative period after uneventful phacoe-
mulsification cataract surgery. Of 37 eyes receiving
latanoprost and fluorometholone in the postoperative per-
iod, 81 % developed angiographic CME, while NSAID eye
drops prevented latanoprost-associated CME.
In a retrospective study of 225 postcataract eyes on
latanoprost therapy, 100 of which had open or absent
posterior lens capsule, clinical CME was documented only
in 3 eyes (1.4 %) with history of ruptured posterior capsule
requiring vitrectomy during cataract surgery [128]. Wand
et al. [129] studied the effect of latanoprost on 40 aphakic
or pseudophakic eyes, with 29 having one or more addi-
tional risk factors for developing CME. Clinically signifi-
cant CME occurred in 2 eyes (5 %) after a mean follow-up
of 5.7 months, suggesting latanoprost as an additional risk
factor.
In a 3-year unmasked prospective study on 145 latano-
prost-administered eyes, 1 case of CME was reported in a
pseudophakic patient with an intact posterior lens capsule
[130].
Finally, in a randomized, prospective, 6-month clinical
trial on pseudophakic and aphakic glaucomatous patients,
27 % of latanoprost-treated eyes, 6 % of bimatoprost-
treated eyes, and 6 % travoprost-treated eyes developed
angiographic CME [131].
In a literature review on the side effects of prostaglandin
analogs [132], most of the article dealt with latanoprost,
probably because it was the first PGA released, and the
most popular antiglaucoma agent used. However, we may
assume that similar observations could apply to all cur-
rently available PGAs.
These studies confirm the rare incidence of PGA-
induced CME even in high-risk eyes, and cannot establish
any causal relationship. The best way to ascertain any
causal relation between PGA and CME, is a prospective,
randomized study comparing the PGA to a placebo in high-
risk eyes. Such a study may not be feasible because of the
large number of patients required to evaluate this rare
potential side effect [97, 133].
The pathogenesis of PGA-induced CME is unknown.
Pharmacokinetic considerations indicate that the expected
latanoprost concentration in the posterior segment of the
eye is too low to have a pharmacologic effect, while
latanoprost is not known to exhibit vasoactive or inflam-
matory properties [97]. Latanoprost itself is probably not
the major factor related to CME formation, but its instil-
lation may affect the wound healing process of lens epi-
thelial cells shortly after surgery, resulting in biosynthesis
of endogenous prostaglandins and other mediators that
eventually lead to disruption of the blood–ocular barriers
and to angiographic CME [127]. However, there must be
other factors involved because even the most high-risk eyes
administered PGAs do not develop CME [133].
The lack of an established causal relationship between
PGA and CME results in an absence of official guidelines
concerning discontinuation or no use of PGAs periopera-
tively. Interestingly, in a survey of cataract surgeons in the
United Kingdom, 40.3 % of the responders reported stop-
ping PGAs in patients having uneventful cataract surgery,
with about half discontinuing PGAs in all patients, and the
remainder stopping PGAs only in patients with risk factors
for CME [112]. Among Greek cataract surgeons, 80 %
discontinue PGAs perioperatively, of whom 65 % do so
routinely when undertaking phacoemulsification regardless
of the occurrence of intraoperative complications or the
existence of risk factors for postoperative CME [134].
In summary, the association between PGAs and CME
continues to be a subject of debate. Until a definite causal
relationship is proved or disproved, caution is recommended
when they are administered in pseudophakic patients, espe-
cially in those with additional risk factors for CME.
3.2 Epinephrine
Epinephrine is used as an antiglaucoma agent or pupil
dilator. Kolker and Becker [135] first reported glaucoma-
tous aphakic patients who were administered topical epi-
nephrine and developed the so-called epinephrine
maculopathy, characterized by FA findings identical to
Irvine-Gass syndrome. Reports of reversible CME due to
epinephrine [136–139] and epinephrine-like drugs [140] in

aphakic eyes where published afterward. Thomas et al.
[139] noted 28 % incidence of angiographic CME in 120
aphakic glaucoma eyes on epinephrine. It seems that epi-
nephrine induces the synthesis of endogenous prostaglan-
dins, which in the aphakic eyes readily reach the macula,
resulting in breakdown of the BRB and CME, a patho-
physiologic sequence similar to that of Irvine–Gass syn-
drome [133, 141]. In addition, topical indomethacin
inhibits the disruption of the BAB after epinephrine
administration, suggesting that epinephrine induces pro-
duction of endogenous proinflammatory mediators like
prostaglandins [142].
Interestingly, a recent prospective study showed that
intracameral injection of 0.2 ml of epinephrine (1:5,000
solution) did not increase the risk of ME in eyes with no risk
factors after uneventful phacoemulsification [143]. These
results highlight the protective role of the intact posterior
lens capsule in eyes administered with epinephrine.
3.3 Beta-Blockers and Preservatives
One isolated case report describes angiographically proven
CME after betaxolol therapy that resolved after discontin-
uation and recurred after a monocular therapeutic trial
[144], while no case of CME secondary to timolol has been
published. Miyake et al. [145] proved that both timolol and
its preservative, benzalkonium chloride, can cause disrup-
tion of the BAB in early postoperative pseudophakia and
increased incidence of angiographic CME and suggest
concurrent administration of NSAIDs to prevent these
adverse reactions without interfering with the desirable
effect of timolol on intraocular pressure.
This was the first suggestion that benzalkonium chloride
might affect the blood–aqueous barrier, and result in CME
in early postoperative pseudophakic eyes [145]. Consider-
ing that almost all antiglaucoma drugs contain preserva-
tives, similar complications produced by other
antiglaucoma eyedrops could be attributed to their preser-
vatives and not to the active substance of the drug itself. A
year later, Miyake et al. [146] proposed the term ‘‘pseud-
ophakic preservative maculopathy’’ for CME caused by
antiglaucoma eyedrops, indicating that it is the added
preservative rather than the principal agent that is the major
factor in the onset of postoperative CME. They proposed
the following pathogenetic mechanism for the development
of pseudophakic preservative maculopathy. Benzalkonium
chloride comes in contact with lens epithelial cells in the
wound-healing process and triggers the synthesis of pros-
taglandins. Consequently, damage is done to the BAB and
the BRB deteriorates, enhancing the development of CME.
These reactions are inhibited by simultaneous administra-
tion of NSAID eye drops. The authors concluded that
because preservatives are added not only to antiglaucoma
O. E. Makri et al.
drugs but to almost any topically administered ophthalmic
drug, it is also possible that other agents may induce
postoperative CME due to their preservatives [146].
4 Conclusion
Macular edema is a well-established cause of painless
impairment of central vision. Subtle ME, however, could
remain undiagnosed in young patients, because accommo-
dation could compensate for any mild disturbance of central
vision. Consequently, drug-induced ME might remain
undiagnosed in some cases. Interestingly, the introduction of
high-resolution spectral-domain OCT and its use in everyday
practice might help overcome several diagnostic dilemmas
like the aforementioned and offers a diagnostic tool for
recognition of even subtle ME as an adverse event of several
other medications in the future. Drug-induced ME, although
rare and not always established, is a possible side effect of
some drugs. It is important for ophthalmologists and other
clinicians to be aware of the potential risks of any therapy
they recommend and to choose an adequate treatment plan
with the best benefit–risk ratio for their patients [133].
Acknowledgments No funding was received to assist in the prep-
aration of this review. The authors declare no conflicts of interest.
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