Inflammatory cystoid macular edema Aniki Rothova Introduction

Inflammatory cystoid macular edema
Aniki Rothova
Purpose of review
The aim of this article is to update our current understanding
and management of inflammatory cystoid macular edema.
Recent findings
Cystoid macular edema is a common cause of visual loss in
uveitis, which occurs predominantly in older patients with
chronic uveitis forms and might be heralded by subclinical
changes on optic coherence tomography. Cystoid macular
edema is emerging as a major cause of visual loss in
HIV-infected patients with immune recovery uveitis.
Elevated levels of proinflammatory cytokines and vascular
endothelial growth factor were found in all types of cystoid
macular edema. Treatment with anti-inflammatory and
anti-vascular endothelial growth factor drugs is widely
applied for all forms of cystoid macular edema and usually
has a beneficial, but temporary effect. So far, there are no
clear guidelines for the treatment of subclinical cystoid
macular edema in uveitis. The effect of vitrectomy in
inflammatory cystoid macular edema is not yet clear and
might become more important in the future. Recent
advances in management include intravitreal drug delivery
systems of cystoid macular edema-modifying drugs.
Summary
This review summarizes current thoughts on inflammatory
cystoid macular edema focusing on the new, clinically
relevant findings. Upcoming data on aqueous constituents
in cystoid macular edema and imaging with the new
generation of optic coherence tomography offer the hope
that a better treatment strategy will soon be established.
Keywords
cystoid macular edema, uveitis
Curr Opin Ophthalmol 18:487–492.
ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Department of Ophthalmology, University Medical Center, Utrecht,
The Netherlands
Correspondence to Aniki Rothova, MD, PhD, Department of Ophthalmology,
University Medical Center Utrecht, E.03-136, Heidelberglaan 100,
3584 CX Utrecht, The Netherlands
Fax: +31 30 2505417; e-mail: a.rothova@umcutrecht.nl
Current Opinion in Ophthalmology 2007, 18:487–492
Abbreviations
CME
CMV
IOP
IRU
IVTA
OCT
RPE
VEGF
cystoid macular edema
cytomegalovirus
intraocular pressure
immune recovery uveitis
intravitreal triamcinolone acetonide
optic coherence tomography
retinal pigment epithelium
vascular endothelial growth factor
ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8738
Introduction
The huge negative impact of inflammatory cystoid macular edema (CME) on visual acuity has become evident in
recent years [1,2,3,4]. CME develops regularly in the
wake of diverse diseases affecting the inner or outer
blood–retina barrier and represents a complication with
a final pathway common to all these various disorders [3].
This review focuses on the recent literature about inflammatory CME, its treatment and currently gained insights
into its pathogenesis.
CME represents a major cause of visual loss in uveitis
[1,3]. In a large cross-sectional survey of 581 patients with
uveitis, 35% of all uveitis eyes had a visual acuity of 20/60 or
less, of which CME had caused 42% [1]. Clinically
significant CME developed in 30% of patients with uveitis.
The mean visual acuity for eyes with CME was significantly worse than for eyes without CME. Although CME
represented the most common cause of visual loss
in adults, the most frequent causes of visual loss in children
with uveitis were retinal scars and glaucoma [5,6]. In
contrast to adult patients, CME does not frequently
develop in children. The higher resistance of young tissues
to external damage could in part explain this phenomenon
[7].
The standard prognosticators of poor visual outcome in
uveitic eyes with CME are a prolonged duration of uveitis
and of CME itself, a large foveal avascular zone as well as
the presence of incomplete vitreous detachment [1,2,3].
Recently, the increased macular thickness on optic coherence tomography (OCT) was also linked to poor outcome
and in addition, the advanced age of patients was identified
as an independent factor for the early development and
poor outcome of CME in uveitis [2,8,9].
Pathogenesis
Several hypotheses have been proposed to explain how
the diverse diseases may lead to the formation of CME.
The initial factors might be entirely different and include
mechanical forces, various toxic effects on the retinal
cells, vessels and retinal pigment epithelium (RPE) as
well as a release or diffusion of inflammatory mediators in
the eye. Following these events, the leakage of fluids
across the retinal vessel wall and through RPE occurs and
leads to the accumulation of fluid in the macular area with
a characteristic distribution of fluid usually located in the
outer plexiform layer. The inflammatory mediators play
probably the essential initiating role in the development of
inflammatory CME, but the exact factors and events
487
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488 Ocular manifestations of systemic disease
responsible for further CME development and its
chronicity have not yet been identified. Recent progress
in aqueous analysis, in particular multiplexed bead immunoassays and proteomics analyses, have facilitated the
measurements of intraocular cytokines and chemokines
present in uveitis with and without CME [10,11]. So far,
these studies have repeatedly shown that elevated
intraocular levels of diverse proinflammatory cytokines
[12,13,14], specifically vascular endothelial growth factor
(VEGF) and IL-6, were correlated with the presence of
CME, not only in uveitis [15,16], but also in CME of noninflammatory origins where the intraocular levels of VEGF
and IL-6 correlated with the severity of CME [17,18]. In
uveitis, CME was not yet linked to a characteristic pattern
of intraocular cytokines [16]. It should be taken into
account, however, that all previous studies included only
a limited number of samples of uveitis from various origins.
Future studies containing large numbers of patients and
uniform etiologic groups are essential for the further
understanding of CME pathogenesis.
It is clear that the integrity of the retinal vessels and RPE is
essential for the intricate macular functions. The presence
of inflammation, however, does not explain the apparent
arbitrariness of uveitis patients developing CME.
Concurrent cardiovascular disease, hypertension, hyperlipidemia, albuminuria and smoking contributed to the
development of CME in diabetes mellitus and vascular
occlusions [19]. Not surprisingly, also in uveitis, microalbuminuria and advanced age in patients (independent of
the duration of the uveitis) were associated with the
presence of CME. Coexisting cardiovascular disease in
uveitis was associated with an early onset of CME [2,20].
These observations suggest that the presence of systemic
vascular disease in patients with inflammatory CME might
be a predisposing factor for the (early) development of
CME [21]. It might be possible that a vascular wall already
damaged by whatever means induces a higher vulnerability to further pathogenic stimuli such as a release
of inflammatory mediators in uveitis. Three months’
use of angiotensin-converting enzyme inhibitor (10 mg
lisinopril), however, had no effect on chronic CME
although the effect on hypertension and microalbuminuria
was noted [21]. Several drugs may induce CME, including
the topical applications of prostaglandin analogues, the
systemic use of nicotinic acid, zidovudine and rifabutin.
Clinical manifestations
The clinical features of CME are well known [3]. Recently,
contrast sensitivity, reading acuity and reading speed were
recognized as more impaired functions than distance visual
acuity [4,22]. These observations suggest that contrast
sensitivity and reading functions might become important
parameters when following patients with CME and
evaluating the treatment regimens. Yellow tinted filters
gave a slight improvement in contrast sensitivity and visual
acuity in uveitic CME [22].
According to anatomical types, intermediate and panuveitis had the highest frequency of CME (60 and 66%,
respectively); panuveitis was associated with a more severe
CME with poor visual outcome [1]. Specific uveitis entities linked to the frequent development of CME included
birdshot chorioretinopathy, sarcoidosis and acute retinal
necrosis. OCT exhibited a persistence of CME in uveitic
eyes long after the uveitis has been quiescent and clinical
signs of CME disappeared [23,24]. The concurrent optic
disc leakage, present also in phakic patients, is of unknown
origin and might be in part caused by vitreoretinal traction
[2,6,25].
The reliable prognostic factors distinguishing CME eyes
with a potential for improvement from the eyes with
definitively damaged visual acuity, are not yet known.
The beneficial effect of treatment was noted for patients
with pinhole and interferometric acuity exceeding the
initial Snellen acuity. Poor contrast sensitivity, impaired
color vision, chronicity of CME and advanced age of
patients were all associated with impaired visual outcomes as well as the macular ischemia and flat OCT
indicating thin and atrophic macula.
AIDS and cystoid macular edema
Cytomegalovirus (CMV) and other opportunistic ocular
infections have decreased in the era of highly active antiretroviral therapy (HAART). Patients with regressed
CMV retinitis, however, may still lose vision from
CME, epiretinal membranes and complications secondary
to immune recovery uveitis (IRU) [26,27,28]. Eyes with
IRU have a several times higher risk of CME and epiretinal
membrane than eyes affected by other types of uveitis.
The presence of IRU was associated with the intraocular
production of IL-12, whereas in eyes with active CMV
elevated levels of IL-6 were found [29,30]. The treatment
of CME in IRU is not different from CME in nonHIV infected, even intravitreal triamcinolone acetonide
(IVTA) was successfully used [31]. Intraocular infections
following IVTA, even a case of CMV retinitis, however,
were reported in immunocompetent patients [32].
Diagnostic tests
The OCT quickly replaced fluocinolone acetonide as a
main (and a less aggressive) diagnostic tool for CME.
Moreover, OCT characterized the morphologic changes
associated with macular edema, especially the vitreomacular relationship and subclinical serous macular detachment (SMD). SMD, the pathogenesis of which is not yet
known, occurred in about 50% of uveitic CME and did
not correlate with poor visual acuity [33]. Contradictory
findings were published on the association of macular
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Inflammatory cystoid macular edema Rothova 489
thickening and visual acuity [9], which is not surprising as
visual acuity depends on diverse factors including the
duration of macular edema, and photoreceptor impairment
as well as media opacities. The role of the tractional
component in uveitic CME has not yet been systematically studied [25]. New generations of OCT will undoubtedly further recognize the vitreomacular adherence
changes in uveitis.
Treatment of cystoid macular edema
There are no official guidelines for the treatment of uveitic
CME. The definition of clinically significant CME,
frequently used in diabetes mellitus, is essential for comparison studies, but was never an indication for treatment
in patients with uveitis. CME responsible for severe
decrease of visual acuity will usually be treated, but there
is no management consensus for various subclinical CME
forms, without significant or any decrease in visual acuity.
It is my opinion that, in uveitis, any CME should be
carefully followed and eventually treated until disappearance. Since the crucial mechanisms involved in the
development and persistence of uveitic CME have not
yet been established, the treatment possibilities are
limited to anti-inflammatory drugs, carbonic anhydrase
inhibitors and the release of traction and removal of
possible toxic mediators. In active inflammation, antiinflammatory treatment is imperative. Recent OCT study
[8] documented a more rapid decrease of CME with oral
administration than with periocular steroid injections, so
an initial treatment with oral steroids might be preferred
when the rapidity of recovery is essential. In recent years,
new administrations of corticosteroids became available
and anti-VEGF administration has been embarked on, but
so far, significant progress in the treatment of uveitic CME
has not been made. The potential role of topical forms of
carbonic anhydrase inhibitors on CME in uveitis has not
yet been investigated.
IVTA used in variable dosages had a short-term effect on
CME and improved vision transiently but, despite
repeated injections, most patients had no sustained
improvement of acuity compared with baseline [34–36].
The side-effect profile of IVTA is significant with corticosteroid-induced intraocular pressure rises. The rate of
posterior subcapsular cataract formation is higher than
previously reported, and there is a small but potential risk
of endophthalmitis [37]. The rise in intraocular pressure is
more common in relatively young patients with uveitis
than in elderly patients with other reasons for CME,
and increases with multiple injections [38]. Intravitreal
application of 4 mg triamcinolone in diabetic patients
with already abnormal electroretinographic findings
showed no additional evidence of a retinotoxic effect
[39]. In contrast, benzyl alcohol at concentrations slightly
higher than what is present in commercial triamcinolone
preparations caused histological changes to retinal
elements of the outer retina in rabbits [40]. Therefore
the removal of preservatives from commercial preparations
of triamcinolone has been recommended before the IVTA
application [40,41]. Macular thickness and edema were
reduced as early as 1 h after IVTA and this early effect was
hypothetically attributed to immediate intraocular
pressure (IOP) rise [42,43]. Although the immediate
IOP rise may last only for a few minutes, it still may
cause damage to fragile retinal structures. Although the
guidelines do not recommend routine paracentesis before
intraocular injections, the discussion on this topic is still
ongoing [44].
Intraocular sustained drug release via implantable devices
or injectable microparticles has been investigated for treating uveitis and CME [45,46]. An intraocular sustained
release implant containing fluocinolone acetonide has
been developed and assessed in a prospective randomized
study [47] (278 patients with recurrent noninfectious
posterior uveitis) using a 0.59 mg or 2.1 mg fluocinolone
acetonide implant. The fluocinolone acetonide implants
significantly reduced uveitis recurrences, improved visual
acuity, and decreased the need for adjunctive therapy. The
most common side effects included increased IOP and
cataract progression. Of 110 patients with CME, 25% of
implanted eyes had a 3-line or greater increase in visual
acuity at 34 weeks. The subsequent complications and
infections have already been reported [48].
The dexamethasone drug delivery system (DDS) is
composed of a biodegradable copolymer of lactic acid
and glycolic acid. As dexamethasone is released, the polymer slowly degrades into carbon dioxide and water. Since
the implant dissolves completely, sequential implants can
be placed into the eye over time without the need for
surgical removal. A single intraocular application of 700 mg
of dexamethasone had a good effect on visual acuity at
the 3-month follow-up in patients with CME of various
origins including nine patients with uveitis [49]. The
development of intraocular DDS using a biodegradable
implant with CME-modifying drugs might become a
preferred treatment for uveitic CME in the future.
Surgical treatments for inflammatory cystoid macular
edema
The advantageous effect of pars plana vitrectomy (PPV) on
CME has been regularly reported in the noncontrolled
studies; large randomized trials have so far not been
performed [50,51]. A randomized pilot study [52] (23 eyes)
established that PPV had a beneficial effect on visual
function and angiographic findings compared to a slighter
effect of systemic treatment with steroids and immunosuppressants. Internal limiting membrane peeling did not
affect the vision outcomes in patients with diabetic CME,
but was not yet assessed in uveitis [53,54]. Further, a novel
surgical technique consisting of cystoid macular edema
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
490 Ocular manifestations of systemic disease
puncture was attempted in eight patients with longstanding diabetic or vascular CME refractory to standard
treatments. Although an anatomical improvement was
noted for all, functional improvement was not observed
[55].
Anti-vascular endothelial growth factor, interferons,
anti-tumor necrosis factor-a and somatostatin
analogues
VEGF is a major regulator of angiogenesis and vascular
permeability and is strongly implicated in the development
of CME of various origins. The anti-VEGF drugs inhibit
the breakdown of the blood–retinal barrier and intravitreal
applications of bevacizumab were associated with shortterm improvement in visual acuity and decreased retinal
thickness in CME of various causes, including uveitis.
Unfortunately, the beneficial effect was of short duration
[56,57]. The histological and electroretinography studies
showed no retinal toxicity after intravitreal administration
of bevacizumab in rabbits, but some inflammatory cells
were found in the vitreous after the 5 mg intraocular dose
[58]. Although several cases of uveitis occurring after
bevacizumab injections were reported, no inflammatory
response was detected clinically and by the laser flare meter
following the 61 injections in patients with neovascular
age-related macular degeneration [59,60]. Ranibizumab
also showed a beneficial effect in diabetic CME, but
in several cases mild to moderate ocular inflammation
developed following the injections [61]. Ranibizumab
was associated with subsequent development of uveitis
from 0.7 to 1.3% [62,63]. Treatment trial [64] with a high
dose of vitamin E, which blocks the effector mechanisms of
VEGF that lead to vascular permeability, did not find any
apparent benefit to either visual acuity or retinal thickening. Interferons are implicated in inducing as well as in
treating autoimmunity and reduced intraocular inflammation, especially in Behcet’s disease [65,66]. German
studies have shown promising results of IFNa in eight
patients with CME and inactive uveitis. Side effects of the
IFNa treatment are frequent and include flu-like symptoms, fatigue, hepatotoxicity and psychological disturbances [67]. In addition, a beneficial effect of IFNb on
uveitic CME was noted in a retrospective study [68] of
13 patients with multiple sclerosis-associated intermediate
uveitis. In contrast, 12 patients undergoing treatment with
IFNa for diverse systemic diseases including hepatitis C
developed ischemic microangiopathy of the retina and
optic nerve several weeks after the start of interferon
therapy [69]. Therefore monitoring of interferon therapy
by an ophthalmologist, especially of patients with systemic
vascular risk factors, was recommended. Anti-tumor necrosis factor (TNF)-a biological agents are considered a major
advance in the treatment of noninfectious inflammations
and their effect on inflammatory CME is to be expected
[70,71]. The place of anti-TNF in the treatment of CME
has not yet been identified. Somatostatin analogues such as
octreotide may be effective in the treatment of CME by
blocking the local and systemic production of growth
hormone, insulin-like growth factor and VEGF, which
were all associated with angiogenesis and endothelial cell
proliferation. Somatostatin is a small neuropeptide that is
produced in the central nervous system, where it acts as a
neurotransmitter and is also a potent inhibitor of hormone
release. In the eye, it is probably being produced by retinal
cells [72]. Octreotide resulted in marked improvement
or complete resolution of CME in seven of nine uveitic
eyes [73].
Conclusion
The precise indications and treatment strategies for
inflammatory CME have not yet been identified. At
present, intraocular sustained drug release via implantable
devices or injectable microparticles are being investigated
for treating of uveitic CME. With upcoming data on CME
pathogenesis using new generation of OCT images and
studies of intraocular fluids and tissues it is hoped that a
more optimal treatment strategy will soon be established.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 518).
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37 Jonas JB. Intravitreal triamcinolone acetonide: a change in a paradigm.
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42 Benz MS, Albini TA, Holz ER, et al. Short-term course of intraocular pressure
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46 Hsu J. Drug delivery methods for posterior segment disease. Curr Opin
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47 Jaffe GJ, Martin D, Callanan D, et al., Fluocinolone Acetonide Uveitis Study
Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior
uveitis: thirty-four-week results of a multicenter randomized clinical study.
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This is the most recent publication of a prospective multicenter study demonstrating the efficacy of the fluocinolone acetonide implant in patients with noninfectious
uveitis. At 34 weeks follow-up, uveitis recurrences were significantly reduced,
visual acuity improved, and adjunctive therapy decreased.
48 Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalovirus retinitis
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143:334–335.
49 Kuppermann BD, Blumenkranz MS, Haller JA, et al., Dexamethasone DDS
phase II study group. Randomized controlled study of an intravitreous
dexamethasone drug delivery system in patients with persistent macular
edema. Arch Ophthalmol 2007; 125:309–317.
This large prospective cohort study evaluated dexamethasone intravitreous drug
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