Albert J.

Augustin
Editor

Intravitreal Steroids

123
Intravitreal Steroids
Albert J. Augustin
Editor

Intravitreal Steroids
Editor
Albert J. Augustin
Stdt. Klinikum Karlsruhe, Augenklinik
Karlsruhe, Germany

ISBN 978-3-319-14486-3 ISBN 978-3-319-14487-0 (eBook)

DOI 10.1007/978-3-319-14487-0
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Springer International Publishing Switzerland 2015

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Preface

Corticosteroids are well known for their antiangiogenic, antiedematous, and

anti-inflammatory properties. Consequently, the drugs have been widely used
in the treatment of many retinal diseases since the early 1950s. Later,
intravitreal steroids emerged as an essential tool, allowing for optimal drug
efficacy when given locally. The topical or local route offers the great
advantage that there is no significant systemic side effect.
Randomized studies have properly shown that steroids are very effective
in the treatment of posterior segment diseases such as retinal vascular
occlusion, diabetic macular edema, and uveitis. This is true for both, disease
activity and visual outcome. Today because of the anti-inflammatory,
antiangiogenic, and antipermeability properties, steroids are an attractive
therapeutic option for vascular and inflammatory retinal diseases.
Recent advances in ocular drug delivery methods led to the development
of intraocular implants, which help to provide prolonged treatment with a
continuous drug release. An increasing number of ophthalmologists use
intravitreal steroids for the treatment of various posterior segment disorders,
not only when traditional therapeutic methods have failed, but more and more
as a first-line therapy.
Through careful selection of cutting edge authors and timely subjects, to
the fine details of quality editing and illustrations, we have created a most
useful book. In this book the reader is treated to an exceptional update on
current topics concerning the pathophysiology and clinical value of intravit-
real steroids.
The depth and breadth of the information presented is intended to bring
the reader the newest diagnostic and therapeutic approaches in our rapidly
advancing field.

Karlsruhe, Germany Albert J. Augustin, MD

v
Contents

1 Pathophysiology of Macular Edema: Results

from Basic Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Ana Bastos-Carvalho and Jayakrishna Ambati
2 Pathophysiology of Macular Edema in Diabetes,
Retinal Vein Occlusion, and Uveitis:
A Disease-Related Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Edoardo Midena and Silvia Bini
3 Devices for the Delivery of Steroids to the Eye . . . . . . . . . . . . . . 25
Raja Narayanan and Baruch D. Kuppermann
4 Imaging Before, During,
and After Steroid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Antonio Caimi and Giovanni Staurenghi
5 Treatment of DME with Steroids . . . . . . . . . . . . . . . . . . . . . . . . . 55
Couturier Aude and Pascale Massin
6 Intravitreal Steroids for the Treatment of Macular
Edema in Retinal Vein Occlusions . . . . . . . . . . . . . . . . . . . . . . . . 69
Eran Zunz and Anat Loewenstein
7 Treatment of Uveitis with Intraocular Steroids . . . . . . . . . . . . . 81
Lazha Talat, Filis Ismetova, Susan Lightman,
and Oren Tomkins-Netzer
8 Steroids in a Combination Strategy . . . . . . . . . . . . . . . . . . . . . . . 91
Paolo Lanzetta, Daniele Veritti, and Valentina Sarao
9 Intravitreal Steroids as a Surgical Adjunct . . . . . . . . . . . . . . . . . 105
Stanislao Rizzo, Tomaso Caporossi, and Francesco Barca

vii
 Pathophysiology of Macular
Edema: Results from Basic 1
Research

Ana Bastos-Carvalho and Jayakrishna Ambati

Contents 1.1 Introduction

1.1 Introduction 1
Macular edema (ME) is the final common path-
1.2 Anatomy of the Macula 1
way of numerous retinal diseases, and ocular dis-
1.3 Definition of Macular Edema 2 orders associated with this condition are, when
1.4 The Blood-Retinal Barrier 2 considered together, a major cause of blindness
1.4.1 Inner BRB 3 in the Western world [1]. In a physiological set-
1.4.2 Outer BRB 7 ting, the blood-retinal barrier (BRB), which is
1.5 Physical Mechanisms Determining largely formed by the retinal pigment epithelium
Fluid Absorption/Retention in the and the retinal capillary endothelial cells, blocks
Retina 9
the passage of fluid and potentially harmful
1.6 Concluding Remarks 10 blood-borne molecules into the retina. When this
References 10 barrier is broken, water and proteins can enter the
retinal extra- and intracellular space, with fluid
accumulation leading to edema. Frequently, BRB
leakage occurs at the macula, causing ME and
vision loss.

1.2 Anatomy of the Macula

Anatomically, the macula (area centralis) is

defined as the central retinal region containing
more than one layer of ganglion cells and pre-
A. Bastos-Carvalho, MD (*)
senting xanthophyll pigment, which is located
Department of Ophthalmology and Visual Sciences,
University of Kentucky, 1095 VA Drive HSRB 252, mainly in the layer of the fibers of Henle and in
Lexington, KY, 40536, USA the inner nuclear layer [2]. At its center lies the
e-mail: aba253@uky.edy fovea, a 1.5 mm depression that is devoid of gan-
J. Ambati, MD glion cells and thinnest at its central area, the
Department of Ophthalmology and Visual Sciences, umbo. The macula has several anatomical fea-
University of Kentucky, 740 S. Limestone Street,
tures that diverge from the remaining retina;
Lexington, KY, 40536, USA
e-mail: jamba2@email.uky.edu, these include a high cell density with almost no
jayakrishna.ambati@uky.edu extracellular space [3], the loose arrangement of

A.J. Augustin (ed.), Intravitreal Steroids, 1

DOI 10.1007/978-3-319-14487-0_1, Springer International Publishing Switzerland 2015
2 A. Bastos-Carvalho and J. Ambati

thick fibers in Henles layer, and the avascularity Table 1.1 Conditions associated with macular edema
of its central zone, which is a watershed zone Etiology of macular edema
between the choroidal and retinal circulations Vascular diseases of the posterior segment
primarily supplied by the choriocapillaris. These Diabetic retinopathy (DR)
unique anatomical characteristics of the macula, Neovascular age-related macular degeneration (AMD)
combined with its high metabolic demand, make Retinal venous occlusion (RVO)
it a preferential site for fluid accumulation and Retinopathy of prematurity (ROP)
edema [4]. Radiation retinopathy
Hypertensive retinopathy
Macular telangiectasias type 2 (MacTel2)
Retinal arterial macroaneurysm
1.3 Denition of Macular Edema
IRVAN syndrome
Choroidal neovascularization of other causes
Macular edema is broadly defined as the retinal Inflammatory diseases
accumulation of fluid in the macula. Histologically, Postsurgical (intraocular surgery; laser procedures)
fluid accumulation may occur in the intercellular Uveitis
space or may be intracellular, causing cellular Drug induced
swelling, which most commonly occurs with Systemic drugs
Mller cells [5]. Clinically, ME can be classified Thiazolidinediones (glitazones)
as diffuse, with generalized leakage throughout Taxanes (docetaxel, paclitaxel)
the posterior pole, or focal, if discrete areas of Tamoxifen
retinal thickening are present (usually caused by Niacin (nicotinic acid)
leakage from microaneurysms or dilated capillar- Interferon-, interferon-, and interferon-
ies). This classification is mostly used in diabetic Topical drugs
ME where recognition of these forms has impor- Prostaglandin analogs
tant prognostic value [6]. In cystoid ME, clear Epinephrine
fluid-filled cystoid spaces are present in the retina, Inherited dystrophies
Autosomal dominant cystoid macular edema
most commonly in the outer plexiform and inner
(ADCMO)
nuclear layers, and they are visible by ophthal- Retinitis pigmentosa
moscopy, OCT, and/or fluorescein angiography, Tumors
which shows a typical petaloid pattern of fluores- Choroidal melanoma
cein leakage surrounding the fovea [7]. Retinal or choroidal hemangioma
Microcystic macular edema (MME) is a subtype Retinal detachment
of cystoid ME with microcysts in the inner Tractional disorders
nuclear layer. MME has often been associated Epiretinal membrane
with multiple sclerosis (with or without optic Vitreoretinal traction syndrome
neuritis) but can be found in numerous ocular Diseases of the optic nerve head
conditions [8]. ME can also be classified as acute Optic pit
or chronic, depending on the time elapsed since Optic coloboma
the diagnosis. Other clinically relevant parame- Optic neuropathy
ters in evaluating ME are the geographic extent
of the edema (i.e., the area that shows increased
retinal thickness), degree of foveal involvement, 1.4 The Blood-Retinal Barrier
signs of leakage in fluorescein angiography, asso-
ciation with retinal ischemia, and presence of The outer retina receives oxygen and nutrients
vitreous traction [9]. from the blood in the choriocapillaris, whereas
A myriad of ocular conditions can be associ- the retinal vessels, branches of the central retinal
ated with ME, summarized in Table 1.1 and dis- artery, supply the inner retinal layers. Similar to
cussed in further detail in Chap. 2. the blood-brain barrier (BBB) elsewhere in the
1 Pathophysiology of Macular Edema: Results from Basic Research
Fig. 1.1 Schematic
diagram of cell types that
form the inner
BRB. Retinal vascular
endothelial cells present
tight junctions that regulate
the permeability of the
paracellular pathway.
Pericytes closely envelop
the capillaries, and
astrocytes and Mller cells
extend their processes to
surround the retinal
microvasculature
Pericyte
Basement membrane
central nervous system (CNS), the eye possesses a
pair of mechanisms together named the blood-
ocular barrier that allow separation between
blood components and nervous tissues. This bar-
rier has two components: the blood-aqueous bar-
rier (BAB) and the blood-retinal barrier (BRB).
At the level of the BAB, plasma proteins are pre-
vented from crossing into the aqueous and vitre-
ous humor by the endothelium of the iris and
ciliary muscle capillaries, as well as by the non-
pigmented ciliary epithelium [10]. The BRB is the
major player maintaining the posterior segment
tissues, principally the retina and subretinal space,
in a state of relative deturgescence. It can be sub-
divided into an inner BRB (the retinal capillaries)
and an outer BRB (at the level of the retinal pig-
ment epithelium). In this chapter, we will focus on
the BRB component of the ocular barrier, as it is
the main factor influencing the movement of flu-
ids to and from the retina and subretinal space
and, hence, the absence or formation of ME.
As with any blood-tissue barrier, there are five
components at interplay in the BRB, namely, tight
junctions (TJs) between the cells of the monolayer
that comprises the barrier, facilitated diffusion
(through channels in the plasma membrane),
active transport (through ATP-consuming pumps),
3
Mller
cell
Astrocyte
Tight
junctions Endothelial cell
Retinal capillary
transcytosis (vesicular transport), and solute modi-
fication (degradation or modification of solutes
before these molecules pass the barrier) [11].
Below, we elaborate on each of these components
and their role in the inner and outer BRB.
1.4.1 Inner BRB
The inner component of the BRB is formed by
the retinal capillaries, which are distributed in
two plexuses: the inner vascular plexus, at the
ganglion cell and nerve fiber layers, and the outer
vascular plexus, between the inner nuclear and
outer plexiform layers [12]. Retinal capillaries
are composed of a single layer of endothelial
cells (ECs), a basement membrane, and peri-
cytes. These cells, together with the surrounding
glial cells, form the retinal neurovascular unit,
which is responsible for the meticulous regula-
tion of retinal blood flow and BRB integrity [13]
(Fig. 1.1). Retinal ECs are phenotypically dis-
tinct from other capillary ECs and similar only to
those found in the BBB. This continuous endo-
thelium is devoid of fenestrations and surrounded
by a thick basement membrane; it expresses
TJs surrounding every component cell and is
4 A. Bastos-Carvalho and J. Ambati
maintained and regulated by a high pericyte-to-
EC ratio. Below, we elaborate further on each of
these features.
A healthy BRB allows the passage of lipid-
soluble substances [14, 15] but is impermeable to
fluorescein [16]. The BRB maintains a tightly
regulated separation between the blood compo-
nents and the retina, and selective transport of
glucose, amino acids, small ions, and retinal
metabolites, as well as leukocytes, can take place
through two pathways: the paracellular pathway,
formed by inter-endothelial junctions, and the
transcellular route, mediated by vesicles, carri-
ers, transmembrane channels, and receptors [17].
When one or more of these mechanisms is dis-
turbed, fluid may accumulate in the retinal inter-
stitium, resulting in edema.
1.4.1.1 EC Paracellular Pathway
Endothelial cells in the retina are tightly joined
through specialized structures: tight junctions,
adherens junctions, and gap junctions, which
together form the junctional complex. The passage
of fluid and molecules through these intercellular
spaces constitutes the paracellular pathway. Aside
from the major function of regulating capillary
permeability, ECs junctions also play important
roles in modulation of angiogenesis and apoptosis,
contact inhibition of proliferation, and response to
blood flow and leukocyte diapedesis [18]. While
both tight and adherens junctions are constituted
by transmembrane proteins arranged in a zipper-
like structure along the cell border [18], the basic
organization of adherens junctions is determined
by VE-cadherin [19], whereas claudins and occlu-
din form TJs [20]. These transmembrane proteins
interact with cytoskeletal proteins inside the cell,
to which they are anchored. This allows tight and
adherens junctions to open and close and facili-
tates intracellular signaling.
Tight junctions (TJs) are present in high num-
bers in retinal ECs and are composed of mem-
brane proteins, adaptor/cytoskeletal proteins, and
effector proteins. TJ membrane proteins that have
been identified in retinal ECs include occludin
[20], claudin-1, claudin-2, claudin-5, and junc-
tional adhesion molecule-A (JAM-A), whereas
intracellular adaptor proteins that couple the
former to the actin cytoskeleton include ZO-1
and cingulin [21, 22]. Modulation of TJ protein
expression and phosphorylation are two of the
major regulators of paracellular permeability and
have been demonstrated in several animal models
of retinal vessel hyperpermeability. In diabetic
rats, occludin expression in retinal ECs is
decreased [21, 23], and insulin treatment reverses
this phenotype [24]; and in high glucose condi-
tions, human retinal ECs decrease their expres-
sion of occludin, JAM-A, and claudin-5 [25].
Additionally, occludin levels are also reduced
[23, 26] in models of vascular retinopathy
induced by VEGF a cytokine that is present in
increased quantities in the vitreous of diabetic
patients and is known to be a vascular permeabil-
ity factor. Exposing retinal ECs to the corticoste-
roid hydrocortisone a drug class used in the
treatment of ME of various etiologies also
increased expression of occludin and decreased
transport of water and solutes across the EC
monolayer [27]. Similarly, in a porcine model of
branch retinal vein occlusion (BRVO), treatment
with triamcinolone acetonide another cortico-
steroid used for management of ME caused a
decrease in VEGF expression and an increase in
occludin levels in the retina [28]. These results
suggest that the mechanism of action of cortico-
steroids in ME may be a reduction in available
VEGF and a subsequent increase in occludin
expression and localization at the TJs.
Adherens junctions (AJs) are composed of
VE-cadherin membrane proteins and several
intracellular partners, including b-catenin, p120-
catenin, and plakoglobin [19]. AJs have been
shown to modulate TJs through VE-cadherin-
dependent overexpression of claudin-5 [29], which
offers a possible explanation for the close associa-
tion and intermingling of these two types of junc-
tional complexes at the cell membrane.
Gap junctions are cell membrane hemi-
channels found in retinal ECs [30] and formed by
the assembly of six connexins, whose functions
include maintenance of the BRB and intercellular
(endothelial-endothelial or pericyte-endothelial)
communication [31].
Also worthy of note is the role of fenofi-
brate a peroxisome proliferator-activated
1 Pathophysiology of Macular Edema: Results from Basic Research
receptor- (PPAR-) agonist widely prescribed
as a cholesterol-reducing agent in BRB per-
meability, since this agent has been linked to a
decreased risk of ME in diabetic patients [32].
Consistent with this clinical evidence, oral feno-
fibrate supplementation ameliorates retinal vas-
cular leakage in rat and mouse models of type
1 diabetes [33]. Further studies are warranted
to determine the pathway by which this drug is
modulating permeability in the inner BRB of dia-
betic patients.
1.4.1.2 EC Transcellular Pathway
This pathway involves the transport of molecules
through the endothelial cells and may occur by
passive diffusion or mediated via receptors, carri-
ers, or vesicles (caveolae), the last being
employed for the transport of macromolecules.
Receptors and Carriers
Transport of nutrients and metabolites across the
BRB is done primarily via carriers, and these can
mediate facilitated transport, primary active efflux,
or secondary active influx and efflux [34]. Influx
transporters allow passage of hydrophilic sub-
stances, like D-glucose, amino acids, vitamins,
and nucleosides into the retina, and do so at the
high rates necessary to sustain this tissues high
metabolic demand. One such transporter is
GLUT1/SLC2A1, which transports D-glucose,
the main energy source of the retina, and dehydro-
ascorbic acid (reviewed in [35]). Regulation in the
expression of GLUT1 has been shown to occur in
the retinal vasculature of diabetic rats by some
groups [36, 37], but other reports suggest that the
expression of this transporter is not changed in
retinal vessels of diabetic retinopathy in the same
rat model [23] or in humans with diabetic retinop-
athy (DR) [38]. Interestingly, ECs of neovessels in
proliferative DR do not express GLUT1 [38],
which is consistent with the notion that this trans-
porter is characteristic of barrier tissues [39].
Other influx transporters in the retina include
the L-lactic acid transporter MCT1 [40]; CRT,
which transports creatine [41, 42]; and the
amino acid transporters LAT1, system Xc, and
CAT1, which are responsible for the transport of
large amino acids, L-cystine and L-arginine,
5
respectively [4345]. While the previously
referred transporters allow passage of nutrients
into the retina, elimination of metabolites is
achieved primarily via active efflux transport
systems, mostly mediated by ATP-binding cas-
sette (ABC) transporters and solute carrier
(SLC) transporters (reviewed in [46]).
Vesicle Transport
The transport of macromolecules, like albumin,
through the inner BRB, is tightly regulated so as to
maintain a low oncotic pressure in the retinal tis-
sue. This type of molecules can be shuttled in a
process called transcytosis, defined as the trans-
port of molecules across a cell via plasmalemmal
vesicles, or caveolae [17]. Macromolecules are
taken up by invagination of one of the sides of the
cell membrane. Thereafter, fission of the invagi-
nated membrane portion forms the caveola, which
then fuses with the opposite cell membrane and
releases the vesicular contents. Macromolecules
can be carried in the fluid phase of caveolae or
bound to receptors present at the membrane of
these vesicles. Albumin, insulin, lipoproteins, and
VEGF receptors, among others, have been identi-
fied in caveolae (reviewed in [47]). Numerous
studies indicate that vesicle-mediated transcytosis
may be partially responsible for the BRB hyper-
permeability seen in condition associated with
ME. Indeed, VEGF has been shown to induce
transcytosis [48] and to modulate the abundance
and location of vesicles in retinal endothelial cells,
thereby modulating vascular permeability [49].
Consistently, there is an overexpression of plasma-
lemmal vesicle-associated protein 1 (PLVAP), a
caveola-associated protein, at the sites of leakage
in DR patients and in primate VEGF-induced reti-
nopathy [50]. Further, in a mouse model of
autoimmune-induced uveitis, vesicular transport
plays a fundamental role in protein exudation to
the retina, whereas EC TJs are relatively conserved
[51]. The implications of transcytosis dysregula-
tion in diabetic retinopathy, not only for molecular
transport (as discussed above) but also for leuko-
cyte diapedesis, are thoroughly reviewed by
Klaassen and colleagues [17].
Recently, downregulation of the protein
Msfd2a in ECs has been implicated in increased
6 A. Bastos-Carvalho and J. Ambati
vascular permeability in the BBB, which is asso-
ciated with increased transcytosis and no evident
changes in EC TJs [52]. Future studies focusing
on regulation of this protein in the retina may
indicate whether this factor also has a role in
increased BRB permeability and ME.
1.4.1.3 Other Cell Types
Pericytes and glial cells can modulate the perme-
ability of the inner BRB by transmitting regula-
tory signals to endothelial cells [53].
Pericytes are a part of the neurovascular reti-
nal unit and contribute to the regulation of EC
function and blood flow in the nervous system
[54], thereby playing an important role in the
inner BRB. Pericytes are separated from ECs by
a basement membrane (BM) but can communi-
cate through holes, or gap junctions, in this lam-
ina. Retinal capillaries present the highest known
EC-to-pericyte ratio (1:1) and have a pericyte
coverage of 8595 % [55, 56], which supports the
notion that high EC-to-pericyte ratios are pres-
ent in tight inter-endothelial junctions and blood
barriers [57]. Indeed, pericytes have been shown
to decrease permeability to tracers and increase
trans-endothelial electric cell resistance (TEER; a
measure of EC permeability) in an in vitro model
of inner BRB [58]. Moreover, pericytes regulate
the expression of Mfsd2a a major BBB regu-
latory protein in ECs [52], which may facili-
tate BRB integrity. Importantly, the formation of
EC TJs during retinal embryonic development
is closely related to pericyte recruitment, both
spatially and temporally [59]. Pericyte loss is a
hallmark of early diabetic retinopathy [60], and
some evidence suggests that this loss may induce
BRB leakage in diabetes. Cocultures of ECs with
pericytes and glial cells show a higher TEER
and less permeability of tracers than ECs cul-
tured alone [58]. Pericytes seem to influence both
paracellular and transcellular pathways. Indeed,
animal and in vitro models of pericyte deficiency
associated with increased permeability in the
BBB show both TJ morphological changes and
an increase in cytoplasmic vesicles and uptake
of biotin by endocytosis [61]. Additionally, mice
with endothelium-specific ablation of PDGF-B,
which induces loss of capillary pericytes, develop
several features characteristic of diabetic retinop-
athy [62]. Another important signaling pathway
between pericytes and ECs is the angiopoietin1
(Ang1; ligand)/Tie2 (receptor) system. Pericytes
express Ang1, which binds to Tie2 in ECs [63],
and this signaling promotes vessel formation and
maturation [64]. Ang1 signaling can also induce
expression of occludin [65] and decrease vascular
leakage in ischemia [66]. Therefore, disruptions
of this signaling pathway may lead to increased
vessel leakiness. Indeed, Ang1 can block VEGF-
induced vessel leakage by VEGF, by prevent-
ing Src activation and consequent VE-cadherin
phosphorylation and redistribution [67]. Ang1/
mice also display defects in embryonic vascular
arrangement, including a loss of association with
periendothelial cells (such as cells that differenti-
ate into pericytes) and with the matrix [68]. In
contrast, Ang2 induces increased permeability
by binding to Tie2 and preventing Ang1 interac-
tion with this receptor. Ang2 is increased in the
vitreous of diabetic patients [69] and diabetic
mice, where it induces pericyte loss by apopto-
sis [70]. Further, intravitreous administration of
this molecule promotes vessel leakage in rats,
and treatment of human retinal ECs with Ang2
reduces expression of VE-cadherin and increases
monolayer permeability [71]. The data above
suggests that a balance in the Ang1/Ang2/Tie2
pathway maintains vascular stability and perme-
ability at physiological levels, and an imbalance
in this system can increase vessel leakage by loss
of EC-associated pericytes and disruption of tight
junctions.
Retinal glial cells that participate in the neu-
rovascular unit include astrocytes, Mller cells,
and microglia. Astrocytes and Mller cells are
macroglial cells that form a sheath around the
retinal capillaries and are separated from ECs
by the BL. As with pericytes, astrocytes and
Mller cells also enhance retinal ECs barrier
function (as measured by TEER, inulin flow,
and permeability to tracers [58, 72, 73]), and the
recruitment of these glial cells is related to an
increase in expression of ZO-1, a TJ protein, in
developing retinal vessels [59]. Mller cell con-
tributions to the BRB have been linked to their
secretion of glial cell line-derived neurotrophic
1 Pathophysiology of Macular Edema: Results from Basic Research
Fig. 1.2 Outer BRB
constituents. Tight junctions
between the retinal pigment
epithelial (RPE) cells modulate
the flow of fluid and molecules
from the subretinal space into
the choroidal circulation. Other
mechanisms regulating the
passage of substances through
the RPE barrier include
vesicle-mediated transcytosis
and transport via receptors or
carriers (not depicted)
factor (GDNF) [74] and pigment epithelium-
derived factor (PEDF) [75, 76]. Additionally,
Mller cells clear fluid from the retinal intersti-
tium by transporting water to the bloodstream
through their perivascular processes via con-
stitutive integral membrane aquaporin (AQ)
channels. This fluid flux is coupled with potas-
sium currents mediated by Kir channels [77].
Dysfunction or dysregulation of these chan-
nels may lead to fluid accumulation and retinal
edema [78]. Consistently, Mller cell down-
regulation of Kir4.1 and AQ4 was reported in
animal models of retinopathies that frequently
associate with ME, including diabetes [79],
ocular inflammation [80, 81], and retinal venous
occlusion [82]. Recently, intracellular edema
of Mller cells has been described in ME, and
it may be linked to the dysregulation of AQ4,
which causes osmotic swelling of the cells [83],
as well as to other factors such as the extrava-
sation of albumin from leaky vessels (reviewed
in [5]). Intriguingly, contrary to this physiologi-
cal function of fluid absorption and transport,
under hypoxic conditions Mller cells can pro-
mote vascular permeability via stabilization
of hypoxia-inducible factor 1- (HIF1-) and
production of angiopoietin-like 4 [84], which
suggests that retinal glial cells exert opposing
roles in healthy and diseased states.
1.4.2 Outer BRB
The outer BRB is formed by the retinal pigment
epithelium (RPE) cells, namely, by its
7
Retina
RPE Cell
Tight
junctions
Transcytosis
Choroid
intercellular TJs and pump functions. The RPE
is a monolayer of cuboidal pigmented cells,
located between the photoreceptors (PRs) in the
neural retina and the fenestrated vessels in the
choriocapillaris. The outer retina is supplied by
the choriocapillaris, which means nutrients
from the bloodstream have to pass the RPE bar-
rier to reach the PRs. Additionally, the end prod-
ucts resulting from the high metabolism of the
outer retina, as well as water and ions, are trans-
ported from the subretinal space to the blood-
stream by the RPE.
As with the inner BRB, the outer barrier has
both paracellular and transcellular transport com-
ponents, regulated by the RPE TJs and vesicles,
respectively (Fig. 1.2). A possible functional and
regulatory link between RPE transcellular and
paracellular pathways has been suggested [85].
In this work, Rajasekaran et al. report that
inhibiting ion channel transport, a transcellular
function, results in the increase of TJ permeabil-
ity. Importantly, as with the inner BRB, the outer
BRB can be disrupted in diseases associated with
ME, as demonstrated in subsets of patients with
DR and subretinal leakage [86, 87] and in animal
models of DR and retinopathy of prematurity
[88, 89].
1.4.2.1 RPE Paracellular Pathway
Similar to the ECs paracellular pathway, the
RPE junctional complex is constituted by tight
junctions, adherens junctions, and gap junctions.
The junctional complex lies on the apical
(PR-facing) side of RPE cells, separating this
aspect from the basolateral side. The apical
8 A. Bastos-Carvalho and J. Ambati
membrane of the pigmented cells has long
microvilli that interdigitate with the overlying
PRs, the space between the RPE and the PRs
being filled by interphotoreceptor matrix. This
close contact may be a factor that allows the neu-
ral retina to regulate the function of the RPE by
modulating the expression and localization of TJ
proteins [90].
As in other epithelial cells, proteins that form
TJs in the RPE can be grouped in three catego-
ries membrane, adaptor, and effector proteins
and include the families of claudins and cadherins,
occludin, JAMs, ZO-1, and many others (for an
excellent review on RPE tight junctions, see
[11]). In the RPE, the most studied of these pro-
teins are claudins and occludin. Both are constit-
uents of TJ strands that regulate their permeability
and selectivity.
Claudins
Twenty-four different claudins have been identi-
fied so far, and they have different patterns and
levels of expression depending on the cell, tissue,
and species [91]. Claudins are responsible for
paracellular selectivity to small ions, and their
properties vary between each member of the fam-
ily and their polymerization profile [92]. In the
human RPE, claudin-3 and claudin-19 have been
identified, while the presence and role of claudin-
16 is still a matter of controversy [11, 93, 94]. In
the RPE, TJ integrity and claudin expression are
regulated by miRNA 204/211 [93].
Occludin
Like claudins, occludin is a transmembrane pro-
tein present in RPE TJs. Although not essential
[95], occludin contributes to TJs stabilization and
barrier function, and its depletion has been
described in a mouse model of diabetes with a
leaky outer BRB [89]. Interestingly, unlike clau-
dins, occludin exhibits a dynamic behavior and
contributes to the constant remodeling of TJs [96],
which may allow regulation of these structures.
Numerous stress stimuli that have been linked
to the pathogenesis of diabetic retinopathy and
age-related macular degeneration like high glu-
cose concentrations [97, 98], oxidative stress
[99], endoplasmic reticulum (ER) stress [100],
IL-1 [101], TNF- [102], or hepatocyte growth
factor [103] regulate several RPE TJ compo-
nents, including claudins and occludin. The
effect(s) of VEGF (a growth factor produced by
RPE cells and known to be upregulated in DR) on
the regulation of TJs remains controversial.
While Peng et al. have shown that this cytokine
has minimal effects on RPE TJs [104],
Ghassemifar and colleagues report an increase in
ZO-1 expression and in TEER in RPE cell lines
supplemented with VEGF [105], and Ablonczy
and Crosson describe a breakdown of the outer
barrier induced by apically administered VEGF
in vitro [106]. In a similar line, DAmores group
showed that soluble VEGF reduces RPE barrier
properties in RPE-EC cocultures and that these
properties can be partially recovered by neutral-
izing VEGF [107]. As for placental growth factor
1 (PlGF-1), another member of the VEGF super-
family, its in vitro supplementation decreases
RPE TEER, and in vivo administration causes
sub- and intraretinal edema [108]. From the data
reviewed above, there may be a role of cytokines
that are overexpressed in hypoxic conditions in
increasing TJ permeability and inducing subreti-
nal accumulation of water. Fenofibrate, also dis-
cussed above in Sect. 1.4.1.1, may also decrease
the risk of diabetic ME by reestablishing the
outer BRB properties of RPE cells. Although fur-
ther studies are warranted, Villarroel et al. report
that treatment with fenofibric acid reverts the dis-
ruption of the RPE monolayer and the increase in
permeability induced by high glucose and IL-1
[109], while Trudeau and colleagues report that
the same agent reduces the expression of mole-
cules associated with blood-tissue barrier break-
down, namely, fibronectin and collagen type IV
[110]. Fenofibric acid also dampens ER stress,
reactive oxygen species (ROS) generation, and
apoptotic signals and increases insulin-like
growth factor I receptor (IGF-IR)-mediated sur-
vival signals in ARPE-19 cells under hyperglyce-
mia/hypoxia conditions. These works suggest
that aside from reestablishing inner BRB integ-
rity, fenofibrates may also contribute for the ame-
lioration of ME by modulating permeability at
the level of the RPE.
1 Pathophysiology of Macular Edema: Results from Basic Research
1.4.2.2 RPE Transcellular Pathway
The transcellular pathway, also present in endo-
thelial cells, involves the diverse set of transport
systems described in Sect. 1.4.1.2. Below, we
elaborate on the most relevant aspects of this
pathway in RPE cells.
Facilitated Transport
The GLUT family of proteins is responsible for
the transcellular facilitated transport of glucose
in the RPE. Namely, GLUT1 is expressed in the
RPE [39, 111], and its expression in these cells
does not vary in patients with diabetic retinopa-
thy (DR) [38] or in animal models of diabetes
[36]. Minor gene expression of GLUT3 and
GLUT5 has also been identified in the RPE [112],
but further studies on these isoforms are lacking.
Aquaporins (AQ), another family of transport-
ers, function as constitutive water channels (also
mentioned in Sect. 1.4.1.3). Several members of
the AQ family are expressed in the RPE [113,
114] and contribute to the transepithelial trans-
port of water, thereby preventing subretinal accu-
mulation of fluid [113, 115]. Experimental
conditions that mimic diseases or states associ-
ated with ME (such as diabetes, retinal vein
occlusion, high glucose concentrations, and
VEGF supplementation) induce a complex regu-
lation of AQ that may be responsible for the accu-
mulation of sub- or intraretinal fluid [114, 116].
Active Transport
RPE cells have numerous, varied functions, many
of which depend on ion channels (e.g., transport
and metabolism of vitamin A, regeneration of
PRs outer segments, phagocytosis, communica-
tion with neighboring cells, etc.). However, in the
context of outer BRB function and ME, we will
only discuss the role of ion channels and pumps
in the context of transcellular transport and regu-
lation of water in the subretinal space. Channel-
mediated ion transport plays a fundamental role
in the movement of water across the RPE and,
hence, in preventing its subretinal accumulation.
K+ and Cl channels have an important role in
supporting the absorption of water in the retina-
to-choroid direction and do so by controlling
the concentration of these ions in the subretinal
9
space [117]. Channels located at the apical mem-
brane, namely, the Na+/K+ ATPase and the Na+/
K+-2Cl cotransporter, transport the said cations
into the RPE cells, which in turn facilitate Cl-
transport through the cell [118, 119]. Transport
of this anion from the apical to the basolateral
membrane induces fluid transport in the same
direction, contributing to the absorption of sub-
retinal water into the choriocapillary system.
Interestingly, a decrease in Na+/K+ ATPase activ-
ity in RPE cells of diabetic rabbits [120, 121] and
in primary RPE cultures [122] has been reported,
which may be one mechanism by which retinal/
subretinal accumulation of fluid occurs.
Rehak and colleagues also describe downreg-
ulation of Kir4.1, an apical K+ channel involved
in subretinal water transport, and of aquaporin-1
and aquaporin-4 in RPE cells of an animal model
of central retinal vein occlusion [123]. Treatment
with triamcinolone reversed the downregulation
of Kir4.1, indicating a possible additional mecha-
nism by which steroids decrease retinal edema in
venous occlusions.
Transcytosis
There is evidence that apical-to-basal transport of
macromolecules via vesicles occurs in RPE cells
[104]. Interestingly, deletion of caveolin-1, an
integral component of caveolae, disturbs the
retina-RPE interface by impairing the fluid/ion
homeostasis in the subretinal space [124].
Furthermore, transcytosis has been shown to con-
tribute to the trans-RPE transport of macrophages
and microglia in DR [125]. Therefore, disruption
of this barrier mechanism may be an additional
factor contributing to the pathogenesis of ME.
1.5 Physical Mechanisms
Determining Fluid
Absorption/Retention
in the Retina
Aside from the BRB, which markedly limits the
passage of fluid and macromolecules to the retina
and subretinal space, physical forces and anatom-
ical features of this tissue determine that it
remains in a state of deturgescence in
10
physiological conditions. The physical forces
that drive fluid into or out of the retina obey
Starlings law in general terms, i.e., the fluid
movement due to filtration across the wall of a
capillary is dependent on the balance between the
hydrostatic pressure gradient and the osmotic
pressure gradient across the capillary [126].
Therefore, the absorption or retention of fluid in
the retina is, in part, a product of the balance
between hydrostatic pressure in the capillaries
and retinal interstitium and osmotic pressure in
these two compartments. As a result, in physio-
logical conditions where the protein content of
the retinal extracellular space is very low, fluids
will tend to be absorbed into the high osmotic
pressure compartment, the capillary lumen.
However, when a breakdown of the BRB occurs
and protein exudation occurs, this balance may
be inverted, leading to fluid accumulation in the
retina. Aside from the four classic Starling fac-
tors and the low permeability of the BRB, tissue
compliance is also a limiting factor to fluid pas-
sage into the interstitium. The retina has closely
interwoven cellular processes and minimal extra-
cellular space [7], which may influence fluid
flow. Indeed, flow conductivity of the retina is
low [127] and may, to some extent, decrease the
outflow of fluid from capillaries and also from
the vitreous into the retina. Indeed, the intraocu-
lar pressure constantly pushes water from the vit-
reous into the retina and toward the choriocapillaris
[128], where the oncotic pressure is high and the
EC fenestrations allow entry of fluid. Despite this
continuous force, which is not opposed by the
vitreoretinal interface or the internal limiting
membrane (as these do not constitute barriers to
the passage of fluid or small molecules [16]), the
retinal interstitium is dry in healthy condition.
This may be due to the retinas low fluid conduc-
tivity that limits water entry from the vitreous.
Fluid from the vitreous, as well as water pro-
duced by the retinas high metabolism, is directed
toward the subretinal space and reaches the RPE,
where it can be absorbed [129].
Finally, the retina is devoid of lymphatics,
therefore lacking a common route of intersticial
fluid removal in organs outside the central ner-
vous system.
A. Bastos-Carvalho and J. Ambati
1.6 Concluding Remarks
Both inner and outer components of the BRB play
a crucial role on the pathophysiology of macular
edema. Many efforts have been done to understand
the mechanisms that regulate the permeability of
this barrier, both in a healthy state and in disease
conditions. Although currently used models have
thus far provided important data on ME patho-
physiology, none of these closely mimics ME as it
happens in humans. Therefore, improved models
that better simulate human ME are warranted for a
faster development of treatments for this patho-
logic state. Additionally, it is important to consider
that ME is a common end stage for many different
ocular conditions, whose pathophysiology is very
distinct. Hence, differences in the mechanisms
governing ME in each disease may exist. Individual
studies focusing on specific etiologies of ME may
provide better insight into the molecular underpin-
nings and possible treatment avenues for each of
condition.
Acknowledgments We thank Flvia Carvalho for design-
ing the illustrations and S. Lee Ware for the constructive
suggestions on the text.
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 Pathophysiology of Macular
Edema in Diabetes, Retinal Vein 2
Occlusion, and Uveitis: A Disease-
Related Approach

Edoardo Midena and Silvia Bini

Contents
2.1 Introduction
2.1 Introduction 17
2.2 Macular Edema in Diabetes 18 Diabetic retinopathy (DR), retinal vascular dis-
2.2.1 Diabetes and Diabetic Retinopathy 18 orders (central and branch retinal vein occlu-
2.2.2 Mechanisms in DR Leading to DME 18
2.2.3 Morphological Findings in DR and DME 19 sions), and uveitis are the three major causes
2.2.4 Mediators in DME 20 of permanent visual acuity loss secondary to
2.3 Macular Edema in Retinal Vein
macular edema in the working population.
Occlusion 21 Macular edema (ME) is a common complica-
2.3.1 Definition of RVO 21 tion shared by these conditions leading to vision
2.3.2 Pathogenesis in RVO 21 loss. Nowadays, several treatment options are
2.4 Macular Edema in Uveitis 22 available for ME secondary to these clinical
2.4.1 Inflammatory Markers 22 situations. Notwithstanding ME represents a
2.4.2 Treatment Options 22 big therapeutic challenge for ophthalmologists,
References 23 due to its unpredictable therapeutic results. The
pathophysiological mechanisms leading to ME
are still poorly understood due to the complex
and multifactorial origin (Fig. 2.1).
Recent studies aim to clarify the mecha-
nisms and the molecules mainly involved in
the pathogenesis of fluid accumulation in the
outer and inner retina. Many cytokines, chemo-
kines, growth factors, and other molecules have
been investigated in human vitreous and aque-
ous humor samples. The correct understand-
E. Midena, MD, PhD (*) S. Bini, MD ing of pathways and interactions among these
Department of Ophthalmology, University of Padua, molecules in the pathogenesis of ME may lead
Via Giustiniani, n. 2, Padova 35128, Italy
e-mail: EDOARDO.MIDENA@UNIPD.IT; to the possibility of a more tailored therapeutic
silviabini85@hotmail.it approach.

A.J. Augustin (ed.), Intravitreal Steroids, 17

DOI 10.1007/978-3-319-14487-0_2, Springer International Publishing Switzerland 2015
18
Fig. 2.1 Tiny hyperreflective spots are evident both in
inner and outer retina (subsequently counted between the
two vertical red lines) in an eye with nonproliferative
2.2 Macular Edema in Diabetes
2.2.1 Diabetes and Diabetic
Retinopathy
DR is a common complication of both type 1
and type 2 diabetes mellitus (DM). It is a chronic
progressive, potentially sight-threatening dis-
order affecting the whole retinal components
associated with prolonged hyperglycemia and
other concomitant risk factors. The International
Diabetes Federation (IDF) in 2006 published
data showing that diabetes was affecting 246
million people worldwide. Nowadays, IDF
estimates 382 million people worldwide liv-
ing with diabetes. Recent data predict that by
2030, the diabetic population will raise to 552
million [2]. Diabetic macular edema (DME)
may occur at any stage of DR and represents
the leading cause of legal blindness among dia-
betics. Approximately 14 % of all diabetics are
affected by DME [3]. Systemic risk factors pro-
moting the development of DME include arterial
hypertension, hyperlipidemia, and poor blood
glucose control. The control of these risk factors
decreases the development of ME and lowers the
E. Midena and S. Bini
diabetic retinopathy and macular edema. Hyperreflective
spots are considered as aggregates of activated microglial
cells (for more details, please see reference number [1])
progression of DR [4, 5]. Aiello et al. recently
demonstrated that early effects of metabolic con-
trol continue to accrue over time because of the
presence of metabolic memory. For this rea-
son, it is important to reach the best glycemic
control in diabetic patients as early as possible
after the development or occurrence of diabetes
mellitus [6].
2.2.2 Mechanisms in DR Leading
to DME
For decades DR has been mainly considered
simply a microvascular disorder, caused by
endothelial cell damage, pericyte loss, and sec-
ondary breakdown of the inner blood-retinal bar-
rier (BRB), leading to DME formation. Other
factors such as hypoxia, altered blood flow, reti-
nal ischemia, and inflammation are also associ-
ated with the progression of DR and DME [7, 8].
However, an increasing body of evidence sug-
gests that neurodegeneration and retinal glial
cell activation occur even before the earliest
clinical manifestation of diabetic retinal micro-
vasculopathy [9].
2 Pathophysiology of Macular Edema in Diabetes, Retinal Vein Occlusion, and Uveitis
Fig. 2.2 Hyperreflective spots (white brilliant dots) in macular edema due to radiation maculopathy. This disorder is
now recognized as being mainly inflammatory in nature
2.2.3 Morphological Findings
in DR and DME
Morphological examination of DR and DME
classically includes biomicroscopy and fundus
photography, optical coherence tomography
(OCT), and fluorescein angiography. In particu-
lar, spectral domain OCT (SD-OCT) is largely
contributing to the understanding of DR patho-
physiology. In fact it allows to analyze indi-
vidual retinal layer changes secondary to DM,
both for thickness and for reflectivity aspects.
Recently, Vujosevic et al. confirmed the impor-
tance of studying retinal layers by means of
SD-OCT not only in nonproliferative DR but
also in the preclinical stages. These changes
are visible mainly in the inner retina, with the
massive involvement of Mller cells [10]. These
data have been recently reconfirmed and asso-
ciated with Mller cell biomarkers (Midena
et al. IOVS, 2014, ARVO e-abs # 4429). The
same authors recently demonstrated the pres-
ence of intraretinal hyperreflective spots (HRS)
in diabetic patients with and without detectable
retinopathy [1]. The HRS are initially present
in the same retinal location (inner retina) where
microglia is usually resident. Moreover, with
the progression of retinopathy, HRS migrate to
19
the outer retina. Thus, the HRS may represent
a sign of microglial activation [1] (see Fig. 2.1).
This hypothesis has been recently confirmed
in macular edema secondary to eye irradiation
(Midena et al. IOVS, 2014, ARVO e-abs# 5952),
a clinical entity considered mainly inflammatory
in nature (Fig. 2.2). Murakami et al. recently
reviewed SD-OCT aspects and measurement of
the retinal thickness in DME [11]. These authors
highlighted that central retinal thickness is mod-
estly correlated with visual impairment, whereas
it dramatically changes (reduces) after treat-
ments compared to visual acuity. This observa-
tion suggests that central retinal thickness may
be important in determining final visual acuity,
but other probably more relevant parameters
contribute to visual deterioration (i.e., external
limiting membrane integrity, which represents a
sign of Mller cells morpho-functional integ-
rity). Murakami et al. also reported the presence
of intraretinal hyperreflective spots (or foci) in
the outer retinal layers, sometimes associated
with serous retinal detachments. The location of
these spots once again suggests that the patho-
genesis of retinal fluid accumulation may be also
investigated at different levels of the retina, even
at the interface between outer retina and retinal
pigment epithelium [11].
20
2.2.4 Mediators in DME
Another factor to be considered as a key factor in
the onset and progression of DR is the oxidative
stress caused by DM. In fact, oxidative stress is
responsible for the increased generation of reac-
tive oxygen species and the decreased activity of
antioxidant enzymes [12]. Many authors have
contributed to the understanding of the metabolic
pathways that lead to progression of DR and
DME, by means of aqueous humor and vitreous
analysis. This kind of approach is extremely rel-
evant to clarify any molecule involved in the
pathogenesis of DME and may suggest a targeted
therapy.
2.2.4.1 Vascular Endothelial Growth
Factor (VEGF)
Aiello et al. demonstrated that the vascular endo-
thelial growth factor (VEGF) is increased in
human ocular fluids and plays a crucial role in
ischemic retinal diseases, such as DR and retinal
vein occlusions [13]. The VEGF family includes
different isoforms: VEGF-A has been shown to
be upregulated in hypoxic tissues. In DR, the loss
of retinal capillaries is believed to lead to hypoxia,
which is the main stimulus for increased retinal
expression of VEGF-A, mediated through
hypoxia-inducible factors. VEGF-A has an
angiogenic role that is responsible for the pro-
gression of DR to the proliferative stage. Apart
from its angiogenic role, VEGF-A increases vas-
cular permeability [14]. Thus, the role of
VEGF-A may be central to DME pathogenesis.
Moreover, several studies have demonstrated the
efficacy of anti-VEGF treatment of DME, thus
supporting the role of VEGF. However, more
recently, Funk et al. demonstrated that while anti-
VEGF treatment decreases aqueous VEGF to
sub-physiologic levels, this effect does not induce
a complete resolution of DME. This study, con-
firmed by many others, also demonstrated the
important correlation between high intraocular
cytokine levels and the presence of DME. These
data suggest that VEGF alone cannot be the
unique driving factor for the development of
DME [15].
E. Midena and S. Bini
2.2.4.2 The Inammatory Cascade
The other relevant mediator of DME formation
is the inflammatory cascade. This may be easily
hypothesized considering its well-known role in
vasopermeability and also looking at the efficacy
of intravitreal steroid treatment [16, 17]. The
inflammatory cascade includes a vast number of
cytokines and chemokines, which secondarily
also activate VEGF. The full and detailed inter-
actions are still poorly understood. The media-
tors showing the most relevant correlation with
the presence of DME and the highest accordance
among the different studies seem to be interleu-
kin 6 (IL-6), IL-8, and monocyte chemoattractant
protein-1 (MCP-1) [1821]. IL-6 is a cytokine,
acting widely throughout the inflammatory cas-
cade, and is known to induce acute-phase reac-
tions and increase vascular permeability. Higher
levels of IL-6 have been demonstrated in aqueous
humor of diabetic patients compared to nondia-
betics [18]. A more recent study also demon-
strated a correlation between elevated aqueous
IL-6 level and severity of DME, measured by
increased thickness at OCT [22]. MCP-1 is a
chemotactic chemokine that induces monocyte
and macrophage infiltration into tissue. The
recruitment of monocyte and macrophage to ves-
sel walls has been shown to promote vascular
permeability, increasing DME. Sohn et al. dem-
onstrated that aqueous MCP-1 levels were signif-
icantly elevated in patients with DME compared
to controls and elevated MCP-1 was significantly
reduced following treatment with intravitreal
steroid, associated also to a reduction of central
macular thickness at OCT [20]. IL-8 is a pro-
inflammatory and angiogenic cytokine produced
by endothelial and glial cells in ischemic retina
[23]. Aqueous levels of IL-8 have been shown to
increase with progression of DR [22] and are also
significantly elevated in ocular fluids of diabetic
patients with DME [15]. Furthermore, Sohn et al.
observed that IL-8 levels were unaffected follow-
ing intravitreal anti-VEGF or steroid treatment
in patients with DME [20]. Noticeably, IL-8 has
been found positively correlated with severity
of DME but not ME secondary to branch retinal
vein occlusion [19]. If these data are confirmed,
2 Pathophysiology of Macular Edema in Diabetes, Retinal Vein Occlusion, and Uveitis
it may suggest that IL-8 has a specific role in
the genesis of diabetic macular edema and may
represent a new specific target for therapy [24].
Different studies point out that there are several
mechanisms and complex pathways leading to
the breakdown of the BRB and the subsequent
development of DME. As suggested by Owen and
Hartnett, we can talk about a pathway overlap
and crosstalk, and the final common pathway
of DME still needs to be clarified [24]. More
studies are required for a better understanding of
all molecular events. Understanding the upstream
factors in the pathogenesis of DME will lead to
a more targeted therapy, conceived not only as
a unique therapy, but also as a combination of
treatments, with the goal of providing the most
effective and safest way to treat DME.
2.3 Macular Edema in Retinal
Vein Occlusion
2.3.1 Denition of RVO
Retinal vein occlusion (RVO) is the second most
common retinal vascular disorder after diabetic
retinopathy [25, 26]. It is caused by vascular
obstruction leading to the formation of intrareti-
nal hemorrhages, fluid exudation, and develop-
ment of a variable degree of retinal ischemia.
RVO is classified as central RVO (CRVO),
hemiretinal vein occlusions, and branch RVO
(BRVO) [27].
ME often occurs in the course of these vascu-
lar disorders and is the main cause of visual
impairment. Although ME is the main reason for
visual impairment, retinal ischemia may lead to
neovascularization as a late complication and
may result in vitreous hemorrhage and neovascu-
lar glaucoma.
2.3.2 Pathogenesis in RVO
The pathogenesis of ME in RVO is complex, as
reported for DME. When venous occlusion
occurs, vascular damage is accompanied by cel-
21
lular and inflammatory reactions, leading to vas-
cular dysfunction. Vascular dysfunction is
responsible for the breakdown of the BRB. As in
DME, in RVO the release of angiogenic and
inflammatory mediators has a crucial role in the
alteration of BRB.
2.3.2.1 Inhibition of VEGF
As previously reported, Aiello et al. demon-
strated pathologically high levels of VEGF in
intraocular fluid of patients with retinal neovas-
cularization secondary not only to DR but also to
RVO. In fact, hypoxia causes increased expres-
sion of VEGF, leading to increase in vascular
permeability. Moreover several studies have
demonstrated the efficacy of intravitreal injec-
tions of anti-VEGF agents, thus confirming the
pathogenetic role of VEGF. Clinical trials like the
BRAVO and the CRUISE study demonstrated
that in patients with RVO, the blockage of VEGF
with ranibizumab reduces macular edema and
improves vision [28, 29]. The role of inflamma-
tion in RVO is also considered. Some reports
showed that intraocular and periocular steroid
administration reduces ME in patients with RVO
[3032]. Moreover, the Geneva Study Group
demonstrated the efficacy and safety of dexa-
methasone intravitreal implant in reducing the
risk of vision loss due to ME in BRVO and
CRVO, compared to sham treatment [33].
2.3.2.2 Inhibition of Other
Inammatory Molecules
Many studies have evaluated the profiles of vari-
ous cytokines in intraocular fluid and the relation-
ship between their levels and ME in RVO.
A recent work by Sohn et al. analyzed several
cytokine levels and other factors like VEGF in
aqueous humor of patients with BRVO who under-
went two different intravitreal treatments: steroid
and anti-VEGF. They found aqueous levels of
IL-6, IL-8, IL-17, and VEGF significantly higher
in the BRVO group than in the control group
before the administration of any treatment. These
data agree with previous results [3437]. In the
steroid treatment group, the levels of inflammatory
molecules and VEGF were significantly reduced.
22
In the anti-VEGF treatment group, only VEGF
was significantly reduced (the reduction was more
relevant than in steroid-treated eyes). These results
clarify that intravitreal steroid treatment is able to
reduce plural inflammatory cytokines and VEGF
levels in aqueous humor in BRVO patients, while
anti-VEGF seems to have a selective influence on
VEGF levels but not on other cytokines [16].
These data once again suggest that the inflam-
matory cascade may have a crucial role in ME
pathogenesis, also in RVO. Moreover, patients
developing venous occlusion have atheroscle-
rotic lesions associated with chronic inflamma-
tion, preceding the acute event of vascular
occlusion. Thus, we may speculate that the
inflammatory cascade and the consequent cyto-
kine elevation in ocular fluids might precede or
be independent from VEGF expression observed
after ischemia. However, more studies are needed
to clarify the correct interactions among all the
involved mediators.
2.4 Macular Edema in Uveitis
Uveitis recognizes infectious and noninfectious
causes. As in DR and RVO, cystoid macular
edema (CME) is a major cause of reduced visual
acuity in patients affected by uveitis. The patho-
genesis is strictly connected with the prolonged
ocular inflammation and the consequent disrup-
tion of BRB. CME in uveitis may persist even
when intraocular inflammation is stabilized.
2.4.1 Inammatory Markers
Several studies have demonstrated an increased
release of molecules, such as interleukins, tumor
necrosis factors, and interferon- (IFN-), lead-
ing to a chronic inflammatory status [38].
Therefore, the therapy of CME in uveitis has
always been represented by steroid treatment:
either by intravitreal administration or by sub-
Tenon injection, as they both provide a signifi-
cant concentration of steroid reaching the
posterior segment of the eye [39]. Van Kooij et al.
analyzed the aqueous humor of patients with
E. Midena and S. Bini
infectious and noninfectious uveitis and demon-
strated an increased level of IL-6, IL-8, soluble
intercellular adhesion molecule, soluble vascular
cell adhesion molecule, and interferon-inducible
protein-10 compared to non-uveitic patients.
Higher levels of these and other factors were
found in patients with active uveitis compared to
quiescent uveitis. No differences in the inflam-
matory molecule levels were found between uve-
itic patients with and without CME [40]. More
recent studies have confirmed the increased lev-
els of these molecules during inflammatory uve-
itic processes, but the correct interactions and the
entire inflammatory cascade are not yet com-
pletely understood.
2.4.2 Treatment Options
A few studies have compared the efficacy of ste-
roid intravitreal treatment and anti-VEGF treat-
ment in controlling CME in uveitis. The results
show that anti-VEGF may be a supplementary
therapy for persistent CME, but steroid therapy
remains the best treatment option in reducing
CME at OCT and in improving visual acuity. In
particular VEGF has been demonstrated to play
an important role in CME genesis in Behet dis-
ease, more than in any other uveitis entity [41,
42]. This may be explained because Behet
disease is mainly an occlusive vasculitis associ-
ated with retinal capillary non-perfusion and pos-
sible secondary neovascularization [43].
Moreover, in Behet disease, IL-8 has been
demonstrated to increase as the inflammation
reactivates, thus suggesting that IL-8 may repre-
sent a marker of the inflammation activity in this
uveitic process [44, 45].
Conventional immunosuppressive agents like
intraocular methotrexate may represent a thera-
peutic option in patients untreatable with steroid.
Another new option may be offered by anti-tumor
necrosis factor (TNF)- agents, but randomized
clinical trials still show questionable results [46].
Many of these mediators are active not only in
uveitis but also in many conditions leading to
ME, such as DM and RVO. These observations
may suggest that a common pathway is involved
2 Pathophysiology of Macular Edema in Diabetes, Retinal Vein Occlusion, and Uveitis
in the genesis of retinal fluid accumulation in dif-
ferent clinical situations. More collaborative
studies are requested to correctly compare macu-
lar edema in these different clinical entities.
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 Devices for the Delivery
of Steroids to the Eye 3
Raja Narayanan and Baruch D. Kuppermann

Contents
3.1 Introduction
3.1 Introduction 25
3.2 Dexamethasone Drug Delivery System 26 Over the last two decades, there has been an
3.2.1 Dexamethasone 26 extensive increase in the usage of steroids to treat
3.3 Fluocinolone Acetonide Implant 27 macular edema due to diabetic retinopathy,
3.3.1 Fluocinolone 27 venous occlusive disease, ocular inflammation,
3.3.2 New-Generation Fluocinolone Device 27
and also in cases of CNV [14]. Dexamethasone
3.4 Summary and Key Points 28 is used clinically to reduce intraocular inflamma-
References 28 tion and macular edema, but its intraocular half-
life is on the order of hours so its duration of
action in free form is much less than that of
triamcinolone acetonide. However, a dexametha-
sone implant (OZURDEX, Allergan) is currently
approved by the FDA to treat patients with macu-
lar edema due to retinal vein occlusion as well as
for noninfectious posterior uveitis and for dia-
betic macular edema (DME). Fluocinolone ace-
tonide is another steroid in a FDA-approved drug
delivery system (Retisert, Bausch & Lomb) used
for the treatment of noninfectious posterior uve-
itis. Fluocinolone acetonide is also in an inject-
able drug delivery system (Iluvien, Alimera)
approved for the treatment of chronic DME in
several countries in Europe and pending approval
in the United States. Macular edema occurs due
R. Narayanan, MD to changes in retinal capillaries resulting in a
Department of Retina, L.V. Prasad Eye Institute, breakdown of the tight junctions that form the
L.V. Prasad Marg, Hyderabad, Telangana 50034, India blood-retinal barrier and subsequent increased
e-mail: narayanan@lvpei.org
retinal vascular permeability [5]. Chronic, low-
B.D. Kuppermann, MD, PhD (*) grade inflammation of the retinal microvascula-
Department of Ophthalmology,
ture appears to be a significant contributor to this
Gavin Herbert Eye Institute-UC Irvine,
850 Health Sciences Road, Irvine, CA 92697, USA process. The goals of therapy for macular edema
e-mail: bdkupper@uci.edu should be to reduce inflammation and restore

A.J. Augustin (ed.), Intravitreal Steroids, 25

DOI 10.1007/978-3-319-14487-0_3, Springer International Publishing Switzerland 2015
26
Table 3.1 Relative anti-inflammatory strength of various
corticosteroids
Steroid Relative potency
Hydrocortisone 1.0
Prednisolone 4.0
Methylprednisolone 5 Key features of the drug delivery system are
Triamcinolone 5 the sustained-release formulation of the
Fluocinolone 25
Dexamethasone 26
Betamethasone 33
Data from: Zimmerman et al. [10]
blood-retinal barrier patency. Corticosteroids act
upon most of the multiple processes in the patho-
physiology of macular edema. For example, cor-
ticosteroids are capable of inhibiting
prostaglandin and leukotriene synthesis as well
as interfering with ICAM-1, IL-6, VEGF-, and
SDF-1 pathways [6, 7]. Corticosteroids also have
been shown to decrease paracellular permeability
and increase tight junction integrity both by
directly restoring tight junctional proteins to their
proper location at the cell border and by increas-
ing the gene expression of those proteins [8, 9].
Table 3.1 shows the relative anti-inflammatory
potency of different corticosteroids.
The use of corticosteroids is indicated in the
following ocular diseases: cystoid macular
edema, diabetic macular edema, retinal vein
occlusion, and uveitis.
3.2 Dexamethasone Drug
Delivery System
3.2.1 Dexamethasone
The molecular weight for dexamethasone is
392.47 Da. The empirical formula is C22H29FO5.
The plasma half-life of parenterally adminis-
tered dexamethasone is 34 h. The intravitreal
dose of free dexamethasone is typically 1 mg in
0.1 cc. The DEX implant (OZURDEX; Allergan,
Inc., Irvine, CA) is a novel approach approved by
the US Food and Drug Administration (FDA) for
the intravitreal treatment of macular edema after
branch or central retinal vein occlusion and for
R. Narayanan and B.D. Kuppermann
the treatment of noninfectious uveitis affecting
the posterior segment of the eye [11] and has just
been granted approval by the FDA for the treat-
ment of DME in aphakic patients and patients
planning to undergo cataract surgery.
poly(lactic acid-coglycolic acid) (PLGA) matrix
material, which dissolves completely in vivo.
Due to the lipophilic nature and the relatively
low molecular weight of dexamethasone,
elimination is largely driven by diffusion through
the retina. There are two phases of drug release
after the implant administration. The first phase
provides high concentrations of dexamethasone
followed by a second phase in which a low con-
centration of dexamethasone is released, extend-
ing the therapeutic period to 6 months.
Dexamethasone concentrations in the retina and
vitreous humor reach a plateau within days of
administration and are maintained at high levels
for 2 months before declining over subsequent
months. The vitreoretinal pharmacokinetic pro-
files are similar between non-vitrectomized and
vitrectomized eyes.
The OZURDEX GENEVA study consisted of
two identical trials, each including patients with
BRVO and CRVO, randomized to receive either
sham or one of two strengths of dexamethasone
implant (0.35 or 0.7 mg) at baseline [12]. The pri-
mary endpoint for the study, combining the two
identical trials (each containing patients with
BRVO and CRVO), was amended to time to
achieve at least 15-letter improvement in BCVA.
This time was significantly faster in both of the
implant-treated groups. In the subgroup analysis
of individuals with CRVO, differences in BCVA
existed at days 30, 60, and 90 (29 % vs. 9 % for
three-line gain at 60 days), but by day 180, the
treatment group had returned to baseline and the
sham group had slightly worsened. Patients
receiving either the 350 g or the 700 g dose of
OZURDEX had a statistically significant
increase in vision based on a three-line or better
improvement in visual acuity compared to a sham
treatment. In addition, both doses of OZURDEX
were well tolerated in the studies. Less than 7 %
3 Devices for the Delivery of Steroids to the Eye
of patients receiving 700 or 350 g of
OZURDEX experienced an elevation of intra-
ocular pressure (IOP) greater than 35 mmHg at
any time during the 6-month study, and at
6 months, less than 1 % of patients had an IOP
above 25 mmHg.
3.3 Fluocinolone Acetonide
Implant
3.3.1 Fluocinolone
Fluocinolone acetonide has an empirical formula
of C24 H30 F2 O6 and a molecular weight of
452.49 Da. The fluocinolone acetonide intravit-
real implant (Retisert) contains 0.59 mg of the
medication. The rate of drug releasing initially is
0.6 ug/day, decreasing over the first month to a
steady rate between 0.3 and 0.4 ug/day over
approximately 30 months [13]. The concentra-
tion of fluocinolone acetonide was found to be
relatively constant from the first time point, 2 h,
through 1 year. In 2005, the FDA approved a
fluocinolone acetonide-containing intraocular
implant (Retisert, Bausch & Lomb, Rochester,
NY) for the treatment of chronic noninfectious
uveitis, affecting the posterior segment of the
eye. The fluocinolone implant reduced the recur-
rence rate from 62 % preimplantation to 4 %,
10 %, and 20 % at the 1-, 2-, and 3-year time
points postimplantation in the study eyes [14].
Comparatively, there was a significant increase in
the recurrence rate in the fellow non-implanted
eyes from 30 % preimplantation to 44 %, 52 %,
and 59 % at the 1-, 2-, and 3-year postimplanta-
tion study time points. The percentage of eyes
that required systemic medications, periocular
injections, and topical corticosteroids decreased
from 44 %, 69 %, and 37 %, respectively, preim-
plantation to 7 %, 4 %, and 18 % 1-year postim-
plantation. At 3 years postimplantation, 78 % of
implanted eyes required ocular antihypertensive
drops, and 40 % underwent glaucoma filtering
surgery compared to 36 % of fellow eyes requir-
ing antihypertensive drops and 2 % of fellow
eyes requiring filtering surgery. By year 3 post-
27
implantation, 93 % of implanted eyes required
cataract surgery compared to 20 % of non-
implanted eyes.
Pearson and colleagues also studied the effi-
cacy and safety results of the Retisert fluocino-
lone acetonide intravitreal implants in 196 eyes
with persistent or recurrent DME over 4 years
[15]. Patients were randomized 2:1 to receive
0.59-mg fluocinolone acetonide implant or stan-
dard of care (SOC additional laser or observa-
tion). The primary efficacy outcome was
15-letter improvement in VA at 6 months which
was achieved by 16.8 % of FA implanted eyes as
compared to 1.4 % in the SOC group which was
statistically highly significant, but this difference
was not maintained, and at the end of 3 years,
there was no statistically significant difference
between the two groups.
Intraocular pressure (IOP) 30 mmHg was
recorded in 61.4 % of implanted eyes (SOC,
5.8 %) at any time and 33.8 % required surgery
for ocular hypertension by 4 years. Of implanted
phakic eyes, 91 % (SOC, 20 %) had cataract
extraction by 4 years.
3.3.2 New-Generation Fluocinolone
Device
A much smaller, non-bioerodible, extended-
release fluocinolone acetonide injectable device
(Iluvien previously known as Medidur, Alimera,
Alpharetta, GA), which is injected via a 25-gauge
injector in a clinic setting, has been investigated
for the treatment of DME. The Fluocinolone
Acetonide for Macular Edema (FAME) studies
were two phase III RCTs that collectively ran-
domized 956 patients with persistent DME fol-
lowing photocoagulation to receive a 0.2-g/day
implant, a 0.5-g/day implant, or a sham injec-
tion [16]. In both treatment groups, approxi-
mately 28 % of patients gained vision by 15
letters or more, as opposed to approximately
16 % of sham-treated patients. The benefit was
even greater in patients with chronic DME (dura-
tion 3 years or more), with 34.0 % of patients
with chronic DME treated with the 0.2-g/day
28
implant gaining three or more lines of vision,
compared to 13.4 % of patients with chronic
DME in the sham-treated group.
Subsequent cataract surgery was reported in
80.0 % of patients receiving a 0.2-g/day implant,
87.2 % of patients receiving a 0.5-g/day implant,
and 27.3 % of patients receiving the sham injec-
tion. Increased IOP requiring incisional glau-
coma surgery was reported in 4.8 % of patients
receiving a 0.2-g/day implant, 8.1 % of patients
receiving a 0.5-g/day implant, and only 0.5 % of
patients receiving a sham injection.
The US FDA initially announced that it would
not approve the Iluvien device for DME. However,
the device has received approval in several
European nations and is being reconsidered for
approval by the US FDA.
Triamcinolone acetonide is designated chemi-
cally as 9-fluoro-11b,16a,17,21-tetrahydroxypregna-
1,4-diene-3,20-dione cyclic 16,17-acetal with
acetone. The empirical formula is C24H31FO6 and
the molecular weight is 434.50 Da.
3.3.2.1 The STRIDE Study
The prospective, randomized, double-masked
STRIDE (Sustained Triamcinolone Release for
Inhibition of Diabetic Macular Edema) trial is
assessing the safety and tolerability of the I-vation
TA (SurModics, Irvine, Calif.) in 30 patients. The
I-vation intravitreal implant is a titanium helical
coil coated with TA (925 g) and the nonbiode-
gradable polymers poly(methyl methacrylate)
and ethylene-vinyl acetate. The narrow wire
diameter of the implant allows for minimally
invasive placement through a 25-g to 30-g needle-
stick. The unique helical shape of the device
maximizes the surface area available for the
drug-eluting portion of the implant and enables
secure, sutureless anchoring of the device against
the surface of the sclera.
In the study, patients are randomized to either
a slow release (1 g/day) or fast release (3 g/
day), each containing 925 g of triamcinolone.
They also were stratified by baseline visual acu-
ity and by presence or absence of prior laser
treatment.
R. Narayanan and B.D. Kuppermann
From screening to 6 months, the proportion of
patients with visual acuity of at least 70 ETDRS
letters (in the study eye) increased from 14 to
46 % in the slow group and from 18 to 41 % in
the fast group. A gain of more than 15 letters
occurred in 8 % of patients in the slow group and
18 % in the fast group. Both implant formula-
tions were associated with improvements in mac-
ular thickness.
3.4 Summary and Key Points
In summary, corticosteroids are the one class of
agents that act upon most of the multiple pro-
cesses in the pathophysiology of macular edema.
However, despite their significant benefits, the
primary ocular adverse effects associated with the
use of steroids IOP rise and cataract are impor-
tant issues which may limit their use in certain
situations. The need for repeated injections may
be offset by the use of long-term sustained-release
implants. The Iluvien implant is not FDA
approved in the United States but is approved for
use in Europe and is being reconsidered for
approval by the US FDA. The other extended-
release devices (OZURDEX and Retisert) are
FDA approved for indications other than DME,
and the OZURDEX implant is currently undergo-
ing review by the FDA for the treatment of DME.
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14. Callanan DG, Jaffe GJ, Martin DF, Pearson PA,
Comstock TL. Treatment of posterior uveitis with a
fluocinolone acetonide implant: three-year clinical trial
results. Arch Ophthalmol. 2008;126(9):1191201.
15. Pearson PA, Cornstock TL, Ip M, et al. Fluocinolone
acetonide intravitreal implant for diabetic macular
edema: a 3-year multicenter, randomized, controlled
trial. Ophthalmology. 2011;118(8):15807.
16. Campochiaro PA, Brown DM, Pearson A, et al. Long-
term benefit of sustained-delivery fluocinolone ace-
tonide vitreous inserts for diabetic macular edema.
Ophthalmology. 2011;118(4):62635.e2.
 Imaging Before, During,
and After Steroid Therapy 4
Antonio Caimi and Giovanni Staurenghi

Contents 4.5.5 Red-Free Imaging 44

4.5.6 Fundus Autofluorescence Imaging 44
4.1 Introduction 31 4.5.7 Optical Coherence Tomography 45
4.2 History of Fundus Ocular Imaging 32 4.6 Postsurgical Macular Edema 45
4.3 Macular Edema in Retinal Vein 4.6.1 Color Fundus Photography 45
Occlusions 32 4.6.2 Fluorescein Angiography 45
4.3.1 Color Fundus Photography 32 4.6.3 Infrared Imaging 45
4.3.2 Fluorescein Angiography (FA) 32 4.6.4 Red-Free Imaging 45
4.3.3 Infrared Imaging (IR) 33 4.6.5 Fundus Autofluorescence Imaging 45
4.3.4 Red-Free Imaging (RF) 37 4.6.6 Optical Coherence Tomography 47
4.3.5 Fundus Autofluorescence Imaging (FAF) 37 4.7 Macular Edema and Retinal
4.3.6 Optical Coherence Tomography (OCT) 37 Macroaneurysm 48
4.4 Diabetic Macular Edema 37 4.7.1 Color Fundus Photography 48
4.4.1 Color Fundus Photography 37 4.7.2 Fluorescein Angiography 48
4.4.2 Fluorescein Angiography 37 4.7.3 Infrared Imaging 48
4.4.3 Infrared Imaging 38 4.7.4 Red-Free Imaging 48
4.4.4 Red-Free Imaging 38 4.7.5 Fundus Autofluorescence Imaging 48
4.4.5 Fundus Autofluorescence Imaging 38 4.7.6 Optical Coherence Tomography 51
4.4.6 Optical Coherence Tomography 38 References 51
4.5 Uveitic Macular Edema 41
4.5.1 Color Fundus Photography 41
4.5.2 Fluorescein Angiography 41
4.5.3 Indocyanine Green Angiography 41 4.1 Introduction
4.5.4 Infrared Imaging 44
Macular edema complicates numerous retinal
and choroidal diseases. It could lead to perma-
nent and severe visual loss. Therefore, differen-
tial diagnosis is crucial in the management of this
A. Caimi, MD disabling condition. The following section offers
Eye Clinic, Department of Clinical Science, Luigi
Sacco, Luigi Sacco Hospital, University of Milan,
an exhaustive overview on imaging macular
Via G.B. Grassi 74, Milan 20157, Italy edema in different ocular diseases and their treat-
e-mail: antonio.caimi81@gmail.com ment with intravitreal steroids.1
G. Staurenghi, MD (*)
Eye Clinic, Department of Clinical Science, Luigi
1
Sacco, Luigi Sacco Hospital, University of Milan, Every macular edema subtype is illustrated by imaging a
via Muratori, 29, Milan 20135, Italy single numbered patient before and after treatment with
e-mail: giovanni.staurenghi@unimi.it intravitreal steroids.

A.J. Augustin (ed.), Intravitreal Steroids, 31

DOI 10.1007/978-3-319-14487-0_4, Springer International Publishing Switzerland 2015
32
4.2 History of Fundus Ocular
Imaging
Fundus ocular imaging was born in 1851 with the
invention of the direct ophthalmoscope by
Hermann von Helmholtz [1]; only in 1886,
Jackman and Webster published the first attempt
of in vivo human retinal photography [2].
A great progress in ocular imaging was reached
in 1961 when two medical students, Novotny and
Alvis, first described retinal fluorescein angiogra-
phy (FA) [3]. This new technique allowed a better
understanding of vascular diseases of the retina.
Furthermore in 1970, using the filters for FA,
the hyper-fluorescence coming from the fluoro-
phores of lipofuscin granules in the retinal
pigment epithelium was noted [4]. This brilliant
observation opened the door to the modern fun-
dus autofluorescence (FAF) imaging, a precious
tool in the study of retinal diseases.
Pomerantzeff opened the era of wide-field
retinal imaging in 1975 when he reported the use
of contact lens-based device that allowed visu-
alization up to 148 of the retina with pupillary
dilation [5].
In the early 1980s, Webb and associates devel-
oped a new retinal imaging technique: the scan-
ning laser ophthalmoscope (SLO) [6].
Another great step forward in ocular imaging
came in the 1990s [7], when optical coherence
tomography was developed thanks to the efforts
of Fujimoto and Puliafito. This is a fast, noninva-
sive, radiation-free technique that provides in vivo
cross-sectional visualization of the human retina.
The attempt to integrate SLO and OCT technol-
ogies was started in the late 1990s by Podoleanu
and colleagues [8]. This idea laid the foundation
of modern multimodal imaging concept.
Today, multimodal imaging combined with
spectral domain OCT and wide-field imaging [9]
could allow a better understanding and manage-
ment of retinal and choroidal disorders.
4.3 Macular Edema in Retinal
Vein Occlusions
Macular edema is one of the leading causes of
visual loss in patients affected by retinal vein
occlusion [10].
A. Caimi and G. Staurenghi
The venous thrombosis elevates intravascular
pressure distal to the occlusion site inducing
vasodilation and venous stasis. This results in
transudation of fluid into the extracellular space.
In addition, upregulation of proinflammatory
cytokines and breakdown of blood-retinal barrier
could facilitate intraretinal exudation [1113].
4.3.1 Color Fundus Photography
(Fig. 4.1a, b)
Fundus examination shows variable amount of
intraretinal blot and/or flame-shaped hemor-
rhages, engorged retinal veins, and cotton wool
spots.
The distribution of these findings depends on
the site of the occlusion: typically one sector in
branch retinal vein occlusion (BRVO), hemiret-
ina in hemiretinal vein occlusion (HRVO), and
all the fundus in central retinal vein occlusion
(CRVO).
Notably, the severity of intraretinal hemor-
rhages and cotton wool spots seems to correlate to
extension of retinal capillary non-perfusion [14].
Additionally in BRVO, the arteriovenous
crossing site of the occlusion and in CRVO optic
nerve head swelling and hyperemia are often
visible.
Cystoid macular edema appears as cystic
spaces associated with loss of physiologic foveal
reflex.
4.3.2 Fluorescein Angiography (FA)
(Fig. 4.1cf)
Dynamic fluorescein angiography shows a vari-
able amount of retinal vein filling delay down
line the site of occlusion. Hypo-fluorescent
areas that correspond to retinal capillary non-
perfusion, hemorrhages, and intraretinal exu-
dates could characterize early phases. In mid
to late phases the petaloid pattern of CME is
visible as pooling in the intraretinal cystoid
spaces.
Sometimes in CRVO hot disk and vascular
peripheral leakage from the veins are present;
opto-ciliary shunt vessels could develop on the
top of the optic nerve head in long-standing
4 Imaging Before, During, and After Steroid Therapy
CRVO. Unlike neo-vessels, they typically do not
leak on FA.
In the chronic phase of the disease, areas of cap-
illary non-perfusion could be associated with micro-
vascular abnormalities such as microaneurysms and
collateral vessels. These areas could increase over
time leading to retinal, optic nerve, and/or anterior
segment neovascularization; then neovascular glau-
coma and hemovitreous could occur.
a b
Fig. 4.1 (a) (Patient 1) Central retinal vein occlusion
(color fundus photography): intraretinal blot (orange
arrow) and flame-shaped (red arrow) hemorrhages,
engorged retinal veins (blue arrow), cotton wool spots
(yellow arrow), and optic nerve head swelling (purple
arrow). (b) (Patient 2) Branch retinal vein occlusion
(color fundus photography): arteriovenous crossing site
(red arrow), hard exudates (yellow arrow), intraretinal
vascular abnormalities (orange arrow), and hyaline reti-
nal vein wall (blue arrow). (c) (Patient 1) Early FA: hot
disk (purple arrow), masking effect of cotton wool spots
(yellow arrow) and flame-shaped hemorrhages (red
arrow), and engorged retinal veins (blue arrow). (d)
(Patient 1) Late FA: extensive area of capillary non-per-
fusion (green arrow), masking effect of flame-shaped
hemorrhages (red arrow), diffuse breakdown of blood-
retinal barrier (brown arrow), and leakage from retinal
veins (sky blue arrow). (e, f) (Patient 2) 4.1e early FA and
4.1f late FA: arteriovenous crossing site (red arrow),
masking effect of hard exudates (yellow arrow), intrareti-
nal vascular abnormalities (orange arrow), area of capil-
lary non-perfusion (blue arrow), and pooling of cystoid
macular edema (green arrow). (g) (Patient 1) IR: cotton
wool spots (yellow arrow) and intraretinal fluid (brown
arrow). (h) (Patient 2) IR: hard exudates (orange arrow)
33
4.3.3 Infrared Imaging (IR)
(Fig. 4.1g, h)
Intraretinal fluid and hemorrhages appear as
hypo-reflective areas spreading on the site of
the occlusion, while cotton wool spots and
hard exudates are hyper-reflective ill-defined
lesions that follow the course of retinal nerve
fibers.
and intraretinal vascular abnormalities (purple arrow). (i)
(Patient 1) RF: cotton wool spots (yellow arrow), flame-
shaped hemorrhages (red arrow), and cystoid macular
edema (green arrow). (j) (Patient 2) RF: hard exudates
(orange arrow). (k) (Patient 1) FAF: cotton wool spots
(yellow arrow) and blot hemorrhages (red arrow). (l)
(Patient 2) FAF: hard exudates (orange arrow) and cys-
toid macular edema (green arrow). (m) (Patient 1)
Macular edema in central retinal vein occlusion, baseline
OCT: cotton wool spots (yellow arrow), intraretinal cysts
(green arrow), and subfoveal serous neuro-retinal detach-
ment (brown arrow). (n) (Patient 2) Macular edema in
branch retinal vein occlusion, baseline OCT: hard exu-
dates (orange arrow), cystoid macular edema (green
arrow), and incomplete posterior vitreous detachment
(blue arrow). (o) (Patient 1) Macular edema in central
retinal vein occlusion, OCT follow-up during 6 months
after treatment with dexamethasone intravitreal implant:
resolution of cotton wool spots, serous retinal detach-
ment, and macular edema. (p) (Patient 2) Macular edema
in branch retinal vein occlusion, OCT follow-up during
6 months after treatment with dexamethasone intravitreal
implant: normalization of foveal contour, residual macu-
lar hard exudates, and defects in inner segment/outer
segment junction
34 A. Caimi and G. Staurenghi

c d

e f

g h

Fig. 4.1 (continued)

4 Imaging Before, During, and After Steroid Therapy 35

i j

k l

Fig. 4.1 (continued)

36 A. Caimi and G. Staurenghi

Fig. 4.1 (continued)

4 Imaging Before, During, and After Steroid Therapy
4.3.4 Red-Free Imaging (RF)
(Fig. 4.1i, j)
It shows hemorrhages as dark areas along the
thrombotic vessel often in a flame-shaped distri-
bution. As in IR imaging, cotton wool spots and
hard exudates are hyper-reflective.
4.3.5 Fundus Autouorescence
Imaging (FAF) (Fig. 4.1k, l)
Hemorrhages and cotton wool spots appear as
hypo-autofluorescent areas due to the mask-
ing effect on the physiologic autofluorescence
coming from RPE. Cystoid spaces of macular
edema are visible as hyper-autofluorescent
oval-shaped areas due to the shifting of mac-
ular pigment from the fovea by intraretinal
fluid.
4.3.6 Optical Coherence
Tomography (OCT)
(Fig. 4.1mp)
It shows intra- and subretinal accumulation of
fluid as cystoid spaces located in all retina layers
and sometimes a serous neurosensory retinal
detachment. In BRVO and HRVO, edema is lim-
ited to the portion of the macula affected, while
in CRVO, it is typically diffuse. When the CME
becomes chronic, OCT could reveal various
amounts of retinal pigment epithelium atrophic
changes, subfoveal fibrosis, intraretinal exuda-
tion, and epiretinal membrane.
4.4 Diabetic Macular Edema
Diabetic macular edema (DME) is the most com-
mon cause of visual loss in patient affected by
diabetes mellitus [15].
Its incidence increases with older onset of dia-
betes and with higher grade of retinopathy sever-
ity [16].
37
4.4.1 Color Fundus Photography
(Fig. 4.2a)
According to the Early Treatment Diabetic
Retinopathy Study (ETDRS) [17], diabetic mac-
ular edema (DME) is defined as retinal thicken-
ing or presence of hard exudates within 1 disk
diameter of the center of the macula. In order to
state a severity scale, the study defined clinically
significant macular edema (CSME) when one of
the following conditions occurs: retinal thicken-
ing within 500 of the center of the macula, hard
exudates within 500 of the center of the mac-
ula with adjacent retinal thickening, and retinal
thickening at least 1 disk area in size, any part of
which is within 1 disk diameter of the center of
the macula.
The Global Diabetic Retinopathy Project
Group [18] defined DME as retinal thickening or
lipid exudates in the macula basing on slit-lamp
biomicroscopy and/or stereo fundus photogra-
phy. It was classified as mild, moderate, or severe
depending on distance of the thickening or exu-
dates from the fovea.
Different studies used the terms focal and dif-
fuse to differentiate two subtypes of DME basing
on the area of retinal thickening [19, 20].
Despite these efforts, the two subtypes have
not yet been defined univocally in the literature
[21].
4.4.2 Fluorescein Angiography
(Fig. 4.2b, d)
Fluorescein angiography (FA) is essential in the
study of patients with DME. It allows detecting
fluid leakage. Notably leakage itself is not syn-
onymous with retinal thickening or edema [22].
FA is also useful in evaluating foveal avascu-
lar zone (FAZ) enlargement and ischemic macu-
lopathy that could lead to permanent and severe
visual loss.
According to ETDRS [23], clinically signifi-
cant macular edema is classified into focal or dif-
fuse, depending on the leakage pattern.
38
Eyes with 67 % of leakage associated with
microaneurysms were classified as focal, those
with 3366 % of leakage from the same source as
intermediate, and those with <33 % as diffuse.
Early FA phase shows hyper-fluorescent
lesions such microaneurysms, intraretinal micro-
vascular anomalies (IRMAS), neo-vessels, and
hypo-fluorescent lesions such hard exudates, cot-
ton wool spots, and hemorrhages.
Foveal avascular zone and non-perfused areas
are easily detectable by means of dynamic
angiography.
Diabetic macular edema becomes evident in
mid to late phase as pooling of the cystoid intra-
retinal spaces with a honeycomb appearance
(cysts in the inner nuclear layer on OCT) or pet-
aloid disposition (cysts in the outer plexiform
layer on OCT) [24, 25].
4.4.3 Infrared Imaging (Fig. 4.2e)
Intraretinal fluid and hemorrhages appear hypo-
reflective, while microaneurysms and hard exu-
dates appear hyper-reflective.
4.4.4 Red-Free Imaging (Fig. 4.2f)
Hard exudates, microaneurysms, and hemorrhages
appear hypo-reflective. CME sometimes is visual-
ized as hyper-reflective round perifoveal areas.
Fig. 4.2 (a) (Patient 3) Clinically significant, center-
involved diabetic macular edema (color fundus photogra-
phy): intraretinal blot hemorrhages (yellow arrow) and
hard exudates (orange arrows). (b) Clinically significant,
center-involved, diffuse diabetic macular edema (early
FA): foveal avascular zone enlargement (red arrow),
microaneurysms (purple arrow), and blot hemorrhages
(brown arrow). (c) Clinically significant, center-involved,
diffuse diabetic macular edema (late FA): extensive
blood-retinal barrier rupture (yellow arrows) and late
pooling of cystoid macular edema (green arrow). (d):
Severe, nonproliferative diabetic retinopathy with incom-
plete pan-retinal photocoagulation (PRP) and diffuse
clinically significant macular edema (mid to late FA com-
posite). The right eye of the patient was already treated
A. Caimi and G. Staurenghi
4.4.5 Fundus Autouorescence
Imaging (Fig. 4.2g)
Intraretinal cysts of DME could be detected as
hyper-autofluorescent oval-shaped lesions sur-
rounding the fovea. This appearance is probably
due to the displacement of xanthophyll pigment
by the intraretinal fluid cavities [26].
Microaneurysms, IRMAS, neo-vessels, pre- or
intraretinal hemorrhages, and hard exudates can
be visualized as hypo-autofluorescent structures.
4.4.6 Optical Coherence
Tomography (Fig. 4.2h, i)
OCT is a noninvasive helpful tool in diagnosis
and follow-up of patients affected by DME.
Pathologic accumulation of extracellular fluid
may result in alterations of the normal retinal
architecture: small amount of fluid could lead to
global increase in retinal thickening, bigger one,
to characteristic cystoid spaces [27].
As in histologic studies sponge-like retinal
thickening mainly occurs in the OPL of the mac-
ula; cystoid spaces are primarily present in the
inner nuclear layer (INL) and outer plexiform
layer (OPL) [2830].
Numerous OCT patterns of DME have been
described [3133].
Kim and colleagues [34] proposed a compre-
hensive OCT classification of DME.
with PRP due to high-risk proliferative diabetic retinopa-
thy. (e) Clinically significant, center-involved, diffuse dia-
betic macular edema (IR): hard exudates (yellow arrows)
and microaneurysms (red arrows). (f) RF: hard exudates
(yellow arrows). (g) FAF: displacement of macular pig-
ment by intraretinal cysts (green arrow). (h) Clinically
significant, center-involved, diffuse diabetic macular
edema baseline OCT: intraretinal cystic spaces (green
arrows) and hard exudates (yellow arrow) with back-
shadowing effect (purple arrow). (i) Diffuse diabetic
macular edema, OCT follow-up during 6 months after
treatment with dexamethasone intravitreal implant: pro-
gressive restoration of foveal contour and diminishing of
hard exudates
4 Imaging Before, During, and After Steroid Therapy 39

b c

d
40 A. Caimi and G. Staurenghi

e f g

Fig. 4.2 (continued)

4 Imaging Before, During, and After Steroid Therapy
According to this, five patterns can be found:
1. Diffuse retinal thickening characterized by
increase in retinal thickness with reduced
intraretinal reflectivity, particularly in the
outer retinal layers
2. Cystoid macular edema characterized by
hypo-reflective cavities separated by highly
reflective septa
3. Posterior hyaloid traction characterized by a
highly reflective band over the retina
surface
4. Serous retinal detachment characterized by a
hypo-reflective dome-shaped space between
the retinal pigment epithelium and
neuro-retina
5. Posterior hyaloidal traction and tractional
retinal detachment resulting from a combina-
tion of pattern 3 and 4
Microaneurysms and dot hemorrhages appear
as spots in the inner retina and hard exudates as
round lesions in the outer retinal layers; all these
lesions including cotton wool spots show hyper-
reflective appearance on B-scan OCT with
back-shadowing.
The integrity of the inner segment/outer seg-
ment junction [3541] and the external limiting
membrane [4042] seems to be clinically rele-
vant in the interpretation of DME on OCT.
4.5 Uveitic Macular Edema
Cystoid macular edema represents the most fre-
quent cause of vision loss in patients affected by
uveitis [43]. In fact, it can be found in about 30 %
of patients [44]. It could complicate infectious,
autoimmune, toxic, and idiopathic uveitis [11].
4.5.1 Color Fundus Photography
(Fig. 4.3a)
Depending on the main site of inflammatory pro-
cess, fundus examination could reveal many dif-
ferent lesions: white dots, yellow creamy spots,
chorioretinal scars, intraretinal infiltrates, hard
and/or cotton wool exudates, flame-shaped and
dot/blot hemorrhages, retinal whitening, vitreitis,
41
snow balls, snow banking, perivascular segmen-
tal or continuous sheathing, optic nerve head
edema, and cystoid macular edema.
4.5.2 Fluorescein Angiography
(Fig. 4.3b, c)
Fluorescein angiography (FA) is essential in doc-
umenting the fundus alteration induced by under-
lying inflammatory process and its activity level.
Typical signs of posterior uveitis are late pool-
ing of dye in cystoid macular edema, late staining
and leakage from optic nerve (hot disk) and vas-
culitic vessels, and diffuse leakage due to the rup-
ture of blood-retinal barrier.
The FA is useful in detecting active inflamma-
tory foci (early hypo-fluorescence and late hyper-
fluorescence), choroidal neovascularization
(early hyper-fluorescence and late staining and
leakage), and progressive retinal scarring (early
hypo-fluorescence and late leakage from the bor-
ders of active lesions).
Furthermore, it is helpful in distinguishing
occlusive from nonocclusive vacuities; the first
one is characterized by areas of retinal ischemia
sometimes surrounded by capillary abnormalities
with late leakage of dye. This process could
involve the posterior pole leading to permanent
and severe visual loss.
4.5.3 Indocyanine Green
Angiography (Fig. 4.3d)
Due to its peculiar physical properties, indocyanine
green angiography (ICGA) is a precious tool in dis-
tinguishing inflammatory choriocapillaropathies
(such as white dots syndromes) and stromal choroi-
ditis; [45] the first one is characterized by hypo-
fluorescent areas of choriocapillary non-perfusion,
the second one by diffuse choroidal hyper-fluores-
cence in mid to late phase due to inflammatory vas-
culopathy of the bigger choroidal vessels.
In addition, ICGA findings seem to correlate
to visual field testing in patients affected by cho-
riocapillaropathies, allowing a more accurate
follow-up and therapeutic management [46].
42
b c
Fig. 4.3 (a) (Patient 4) Idiopathic segmental periphlebi-
tis (color fundus photography): segmental perivenular
sheathing (purple arrows) and foveal irregular appearance
(green arrow) due to macular edema. (b) Early FA: peri-
foveal capillary leakage (red arrow). (c) Late FA: hot disk
(yellow arrow), segmental perivenular sheathing (purple
arrows), leakage from vasculitic vessels (brown arrow),
diffuse breakdown of blood-retinal barrier (blue arrow),
and pooling of cystoid macular edema (green arrow). (d)
Mid-phase ICGA: foveal dishomogeneity (sky blue
arrow) due to macular edema, no choroidal or retinal pig-
ment epithelium permeability abnormalities. (e) IR:
foveal irregularity (green arrow) due to macular edema.
A. Caimi and G. Staurenghi
(f) RF: foveal irregularity (green arrow) due to macular
edema and segmental perivenular sheathing (purple
arrow). (g) FAF: foveal cysts (green arrow) due to macu-
lar edema. (h) Macular edema in idiopathic segmental
periphlebitis, baseline OCT: cystoid macular edema
(green arrow), subfoveal retinal pigment epithelium irreg-
ularity (yellow arrow), and incomplete posterior vitreous
detachment (blue arrow). (i) Macular edema in idiopathic
segmental periphlebitis, OCT follow-up during 6 months
after treatment with dexamethasone intravitreal implant:
progressive normalization of foveal contour, residual reti-
nal pigment epithelium irregularity, and incomplete poste-
rior vitreous detachment
4 Imaging Before, During, and After Steroid Therapy 43

e f g

Fig. 4.3 (continued)

44
Fig. 4.3 (continued)
The late phase of ICGA imaging could distin-
guish between full-thickness choroidal infiltrates
(late hypo-fluorescence) and partial thickness
(late iso-fluorescence).
Finally, ICGA is a reliable instrument in fol-
lowing up Vogt-Koyanagi-Harada disease and ser-
piginous choroiditis; these diseases, in fact, could
present occult choroidal lesions and progression
without clinical or FA counterparts [47, 48].
4.5.4 Infrared Imaging (Fig. 4.3e)
Infrared imaging shows a macula with irregular
appearance in case of macular edema. Intraretinal
fluid and hemorrhages are hypo-reflective, while
hard exudates are usually hyper-reflective.
A. Caimi and G. Staurenghi
4.5.5 Red-Free Imaging (Fig. 4.3f)
In red-free cotton wool spots, perivascular
sheathing and hard exudates appear hyper-
reflective; intra- or preretinal hemorrhages are
hypo-reflective. Secondary epiretinal membranes
are easily detected by the presence of typical
inner retinal folds of the surface. When the media
are clear, CME is usually detected as hyper-
reflective oval-shaped areas around the fovea.
4.5.6 Fundus Autouorescence
Imaging (Fig. 4.3g)
Uveitic CME in FAF appears as hyper-
autofluorescent round areas with a typical radial
4 Imaging Before, During, and After Steroid Therapy
distribution respect to the fovea; this aspect
seems to be related to displacement of macular
pigment by intraretinal cystoid spaces [49].
Increase FAF signal is documented also around
active choroidal neovascularization that might
complicate the course of posterior uveitis [50].
Finally, FAF imaging could show in one shot
the early atrophic alterations of the retinal pig-
ment epithelium non-detectable with color fun-
dus photography and the overall RPE damage.
This is helpful in evaluating the timing and the
aggressiveness of treatment required in these
patients.
4.5.7 Optical Coherence
Tomography (Fig. 4.3h, i)
OCT is useful in detecting uveitic macular
edema, epiretinal membranes, and vitreoretinal
interface abnormalities such as vitreo-macular
traction syndrome that could complicate the
course of the disease.
According to Markomichelakis and col-
leagues [51], three different patterns of fluid
accumulation could be found on OCT:
Diffuse macular edema (spongy appearance of
the thickened retina)
Cystoid macular edema (well-defined intra-
retinal cystoid spaces)
Serous retinal detachment (separation of the
neurosensory retina from the retinal pigment
epithelium)
In addition, chronic CME could be associated
to foveal atrophy and subretinal fibrosis.
4.6 Postsurgical Macular Edema
Macular edema (ME) could occur after any intra-
ocular surgery. It still represents one of the major
complications after both cataract surgery and
pars plana vitrectomy.
Although the pathophysiology of this condition
is not completely understood, inflammation seems
to play a crucial role in its development [11, 52].
45
Patient affected by clinically significant
ME complain a decrease in visual acuity gen-
erally during 412 weeks after surgery with a
peak of onset at 46 weeks postoperatively
[53].
4.6.1 Color Fundus Photography
(Fig. 4.4a)
On biomicroscopic examination loss of foveal
depression occurs, with intraretinal cystoid
spaces and often optic nerve head swelling.
Sometimes the alteration of fundus reflex and the
wrinkling of retinal surface associated to epireti-
nal membrane are present.
4.6.2 Fluorescein Angiography
(Fig. 4.4b, c)
Early phase of FA shows leakage from the perifo-
veal capillaries with late pooling of cysts: typical
petaloid like appearance in the foveal region is
frequently surrounded by a honeycomb pooling
pattern at posterior pole.
4.6.3 Infrared Imaging (Fig. 4.4d)
IR is characterized by nonhomogeneous aspect
of the foveal region.
4.6.4 Red-Free Imaging (Fig. 4.4e)
RF imaging could reveal hyper-reflective round
lesions corresponding to intraretinal cysts.
4.6.5 Fundus Autouorescence
Imaging (Fig. 4.4f)
FAF signal is increased with the typical hyper-
autofluorescent round-shaped cysts due to the
shifting of pigment from the macula.
46
b c
d e
Fig. 4.4 (a) (Patient 5) Postsurgical macular edema after
25 gauge pars plana vitrectomy with peeling of epiretinal
membrane and inner limiting membrane (color fundus
photography): foveal irregular appearance (green arrow)
due to macular edema. (b) Early FA: blood-retinal barrier
rupture (sky blue arrows). (c) Late FA: blood-retinal bar-
rier rupture (sky blue arrows), late pooling of intraretinal
cysts (yellow arrow), and hot disk (orange arrow). (d) IR:
nonhomogeneous foveal appearance (green arrow). (e)
RF: nonhomogeneous foveal appearance (green arrow)
A. Caimi and G. Staurenghi
f
and dissociated optical nerve fiber layer (brown arrows).
(f) FAF: displacement of macular pigment by intraretinal
cysts (green arrow). (g) Postsurgical macular edema base-
line OCT: wide intraretinal cystic spaces (green arrow)
and subfoveal inner segment/outer segment junction
defects (orange arrow). (h) Postsurgical macular edema,
OCT follow-up during 6 months after treatment with
dexamethasone intravitreal implant: progressive reduction
of macular edema; at 6 months some small intraretinal
cysts still persist
4 Imaging Before, During, and After Steroid Therapy
Fig. 4.4 (continued)
4.6.6 Optical Coherence
Tomography
OCT shows retinal thickening with cystic spaces
especially located in the outer nuclear layer of the
fovea and eventual subfoveal neuro-retinal detach-
ment [54]. In case of chronic CME, sometimes,
47
cystoid spaces coalesce in foveal macrocysts that
could evolve into a lamellar macular hole; addi-
tionally irregularity of the inner segment/outer
segment junction (IS/OS), atrophic changes in
subfoveal RPE, and the development of an epireti-
nal membrane or vitreo-macular traction could
occur.
48
4.7 Macular Edema and Retinal
Macroaneurysm
By definition, retinal macroaneurysm is an acquired
dilatation of the large arterioles of the retina [55].
Clinically, they can be classified as quiescent,
exudative, or hemorrhagic [56]. Both exudative
and hemorrhagic could present with macular
edema due to the increase in vascular permeabil-
ity of the lesion.
4.7.1 Color Fundus Photography
It shows saccular and fusiform dilatation of the
retinal artery with a preferential location on the
temporal side usually within the first three orders
of bifurcation.
The lesion could be associated with intra- or sub-
retinal exudation; pre-, intra-, or subretinal blood;
cystoid macular edema; perilesional retinal thicken-
ing; and serous retinal detachment; venous and arte-
rial occlusions have also been reported [57].
4.7.2 Fluorescein Angiography
(Fig. 4.5b, c)
In the early phase of FA, there is a rapid filling of
the lesion. Blood and hard exudates have masking
Fig. 4.5 (a) (Patient 6) Retinal macroaneurysm (color
fundus photography): arterial saccular dilatation (red
arrow), perilesional hard exudates (blue arrow), and
foveal and perifoveal hard exudates (yellow arrow). (b, c)
4.5b early FA and 4.5c late FA: filling and early leakage
(red arrow), late diffuse leakage (blue arrow) of arterial
macroaneurysm, and pooling of cystoid macular edema
(green arrow). (d) IR: foveal (blue arrow) and perifoveal
hard exudates (yellow arrow) and arterial saccular dilata-
tion (brown arrow). (e) RF: foveal irregularity (sky blue
arrow) due to macula edema, perifoveal hard exudates
(yellow arrow), and hyper-reflectant arterial saccular dila-
tation (brown arrow). (f) FAF: foveal cysts (green arrow)
due to macula edema and hypo-autofluorescence arterial
saccular dilatation (brown arrow). (i) Macular edema in
A. Caimi and G. Staurenghi
effect on the background fluorescence. Sometimes,
distal to the dilatation, arterial occlusion with the
corresponding area of capillary non-perfusion is
visible.
In the late phase, leakage from the lesion and
pooling of intraretinal cystic spaces are visible.
4.7.3 Infrared Imaging (Fig. 4.5d)
Infrared imaging is useful in detecting the lesion
especially when a dense hemorrhage occurs [58].
In fact, the longer wavelength of IR allows a bet-
ter visualization through media opacity.
4.7.4 Red-Free Imaging (Fig. 4.5e)
Hard exudates, cotton wool spots, and the mac-
roaneurysm itself are hyper-reflective. In the
chronic phase of the disease, sometimes retinal
wrinkling induced by concurrent epiretinal mem-
brane is evident.
4.7.5 Fundus Autouorescence
Imaging (Fig. 4.5f)
The macroaneurysm appears as dark hypo-
autofluorescent area along the vascular arcade.
retinal macroaneurysm, OCT follow-up during 6 months
after treatment with dexamethasone intravitreal implant:
progressive decrease in retinal thickness and hard exu-
dates; at 6 months subfoveal deposition of hard exudates
still persists. (g) (Patient 6) Retinal macroaneurysm
(OCT): hyper-reflective vascular wall (brown arrow),
medium- to high-reflectivity intravascular blood (red
arrow), hard exudates (sky blue arrow), perilesional reti-
nal thickening (orange arrow), and back-shadowing (yel-
low arrow). (h) Macular edema in retinal macroaneurysm
baseline OCT: perifoveal (purple arrow) and subfoveal
(orange arrow) hard exudates, intraretinal cystic spaces
(green arrow), and subfoveal neuro-retinal detachment
(blue arrow)
4 Imaging Before, During, and After Steroid Therapy 49

b c

d e f
50 A. Caimi and G. Staurenghi

Fig. 4.5 (continued)

4 Imaging Before, During, and After Steroid Therapy
Old pre, intra, or sub retinal bleeding usually
present an hyper-autofluorescent appearance due
to degradation of hemoglobin.
4.7.6 Optical Coherence
Tomography (Fig. 4.5gi)
OCT usually shows an oval lesion located in the
inner retina with hyper-reflective wall corre-
sponding to the dilatation and hypo-reflective
content; it elevates the internal limiting mem-
brane and retinal ganglion cell layer [58].
The lesion is often surrounded by retinal
thickening, hard exudates (as hyper-reflective
dots in the outer retina with back-shadowing),
and blood (as hyper-reflective area with
back-shadowing).
Macular edema and subfoveal serous retinal
detachment could be visualized.
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 Treatment of DME with Steroids
Couturier Aude and Pascale Massin
Contents
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1 Epidemiology. . . . . . . . . . . . . . . . . . . . . . . .
5.1.2 Systemic Factors . . . . . . . . . . . . . . . . . . . . .
5.1.3 Laser Photocoagulation . . . . . . . . . . . . . . . .
5.1.4 Intravitreal Therapy . . . . . . . . . . . . . . . . . . .
5.2 Pathophysiology of DME. . . . . . . . . . . . . .
5.3 Efficacity of Intravitreal Steroids
in DME . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.1 Triamcinolone . . . . . . . . . . . . . . . . . . . . . . .
5.3.2 Dexamethasone . . . . . . . . . . . . . . . . . . . . . .
5.3.3 Fluocinolone Acetonide . . . . . . . . . . . . . . . .
5.4 Comparison of Intravitreal Steroids
for the Treatment of DME. . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. Aude, MD (*) P. Massin, MD, PhD (*)
Department of Ophthalmology, Lariboisiere,
2 rue Ambroise Pare, 75003 Paris, France
e-mail: audecout@lrb.aphp.fr; pascale.massin@lrb.aphp.fr;
pascale.massin1@gmail.com
A.J. Augustin (ed.), Intravitreal Steroids,
DOI 10.1007/978-3-319-14487-0_5, Springer International Publishing Switzerland 2015
5
5.1 Introduction
55
55 5.1.1 Epidemiology
56
56 Diabetic macular edema (DME) is the main
56
cause of mild to moderate vision loss in patients
56 with diabetes. It is a major public health prob-
lem as the prevalence of diabetes is increasing.
57 In western countries, the expected prevalence
58
of diabetic retinopathy is close to 35 % in the
59
61 diabetic population, while DME may be present
in 710 % of patients [44]. After 2 years, over
63 half of patients with DME will lose two or more
lines of visual acuity (VA) [18]. Worldwide, it
65
has been estimated that 21 million people have
65 DME [44].
Two clinical subtypes of DME have been
described. Focal DME is defined by localized
retinal thickening, often surrounded by exu-
date rings, resulting from leakage from micro-
aneurysms, and/or intraretinal microvascular
abnormalities. The prognosis of focal DME is
generally good, as it responds well to focal laser
photocoagulation of leaking microaneurysms
[16]. Diffuse DME is characterized by general-
ized thickening of the central macula caused by
widespread leakage from dilated capillaries in
this area. The effect of laser treatment on diffuse
DME is limited. Finally, ischemic maculopathy
is secondary to extended occlusion of macu-
lar capillaries. Frequently, there is combined
pathology of focal and diffuse edema as well
as ischemia. However, there is no international
55
56
consensus on the definition of focal and diffuse
macular edema, and this classification tends to
be abandoned [7].
5.1.2 Systemic Factors
Risk factors for DME include duration of dia-
betes, poor glycemic control, hypertension, pro-
teinuria, and hypercholesterolemia. Treatment
of DME therefore begins with controlling these
factors. It is now widely accepted that control
of systemic factors, which may worsen DME,
is essential. The United Kingdom Prospective
Diabetes Study (UKPDS) trial showed that an
11 % reduction in hemoglobin A1c, from 7.9 to
7.0 %, in type 2 diabetics reduced the risk of
microvascular complications of diabetes, includ-
ing the need for photocoagulation, by 25 % [39].
Similarly, tight blood pressure control reduced
the risk of microvascular complications by 37 %
[40].
5.1.3 Laser Photocoagulation
Treatments for DME are evolving rapidly, and
while it was once treated solely with laser ther-
apy, today there are numerous alternative thera-
pies that have demonstrated promise. Over the
past 30 years, the first-line therapy has been laser
photocoagulation. Direct photocoagulation of
leaking microaneurysms combined with grid
laser photocoagulation reduces the risk of moder-
ate vision loss by 50 % in patients with DME, as
reported in the large 3-year Early Treatment
Diabetic Retinopathy Study (ETDRS) clinical
trial, but it often produces little or no improve-
ment in VA [15]. This result has been reinforced
in more recent trials by the Diabetic Retinopathy
Clinical Research Network [12]. DRCR.net study
showed that among eyes with DME treated at
4-month intervals with laser as needed, 32 %
gained at least ten letters in BCVA from baseline
to year 2, but 49 % had less than a ten-letter
change in BCVA, and 19 % lost at least ten letters
C. Aude and P. Massin
in BCVA. Approximately half of the eyes treated
with laser alone continued to have thickened reti-
nas at year 2.
Grid laser photocoagulation has been shown
to be effective to treat DME, but with a slow
effect and retinal scars [15], and new medical
therapeutic approaches have been developed
including intravitreous injections of corticoste-
roids or anti-vascular endothelial growth factors
(anti-VEGF) agents. In addition, in these eyes
with DME, more than 15 % of patients go on los-
ing vision despite previous laser photocoagula-
tion [22].
5.1.4 Intravitreal Therapy
Intravitreal anti-VEGF agents have revolution-
ized the treatment of DME by demonstrating
visual improvement in multiple randomized clin-
ical trials [34]. However, about 23 % of patients
are nonresponders to anti-VEGF therapy [6], and
their use may be compromised because of the dif-
ficulties for a monthly follow-up.
Intravitreal steroids are used in the treatment
of DME for their anti-inflammatory, angiostatic,
and antipermeability effects. While steroids
are broad-spectrum anti-inflammatory medica-
tions, the anti-VEGF agents specifically target
a molecule implicated in the pathogenesis of
DME. The use of corticosteroid injections for
treatment of DME has been widely evaluated,
due to their ability to inhibit pro-inflammatory
cells, pro-angiogenic cytokines such as IL6,
and VEGF expression [33]. These studies have
shown efficacy of steroids in controlling DME
and potentially in improving vision [23, 24]
(Fig. 5.1).
5.2 Pathophysiology of DME
DME is defined by retinal thickening involving
or threatening the center of the macula, consecu-
tive to the intraretinal accumulation of fluid in the
macular area. Although the pathogenesis of DME
5 Treatment of DME with Steroids
Fig. 5.1 Left eye of a 52-year-old woman with type 2 diabetes. OCT analyses show a diffuse macular edema with an
epiretinal membrane and a mild foveal serous detachment. The foveal thickness was measured at 606 m
is still not fully understood, it is mainly caused by
the breakdown of the inner bloodretinal barrier,
but capillary non-perfusion and possibly direct
neuronal damage are also major actors. The
pathophysiology of DME is complex and multi-
factorial, and inflammation has an important role
in the pathogenesis of DME. Chronic hypergly-
cemia results in the formation of advanced glyca-
tion end products [38], oxidative stress [43], and
the activation of protein kinase C. These changes
lead to the recruitment and adhesion of leuko-
cytes to the retinal vascular endothelium (leu-
kostasis) [32] and the expression of inflammatory
factors such as intercellular adhesion molecule-1,
vascular endothelial growth factor (VEGF),
tumor necrosis factor-, and interleukin-6 [19].
The upregulation of these factors causes endo-
thelial damage, hypoxia [27], alterations in
endothelial tight junction proteins, and increased
vessel permeability. As a result, the integrity of
the bloodretinal barrier becomes permeable to
fluid, leading to vascular leakage, accumulation
of fluid in the extravascular space of the retina,
and thickening of the macula [3]. Another aspect
of chronic inflammation is related to microglial
cells, which are chronically activated during
57
diabetes [37]. Because activated microglia
release pro-inflammatory cytokines and chemo-
kines, such as VEGF and tumor necrosis factor,
it is likely that they further exacerbate retinal
vascular permeability in diabetes.
Corticosteroids may be useful in the treatment
of DME because they block leukostasis; inhibit the
expression of prostaglandins, pro-inflammatory
cytokines, and VEGF [41]; and enhance the bar-
rier function of vascular tight junctions [17].
5.3 Efcacy of Intravitreal
Steroids in DME
Treatment for DME includes treatment of the sys-
temic disease by maintaining tight blood sugar
and blood pressure control, weight loss, and the
lowering of circulating triglycerides and choles-
terol. However, once there is progression to DME,
therapy is indicated to slow the rate of vision loss
and to attempt to improve the long-term progno-
sis. The addition of intravitreal corticosteroid
therapy to laser photocoagulation may help to
reduce further the risk of clinically significant
vision loss [45].
58
5.3.1 Triamcinolone
Triamcinolone has been shown to reduce VEGF
production, decrease prostaglandin production,
and stabilize the bloodretinal barrier [42]. This
action of decreasing vascular permeability has
led investigators to try triamcinolone in the treat-
ment of diffuse DME [29].
A few small, randomized trials have reported
improvement in VA in eyes with recalcitrant dif-
fuse DME treated with intravitreal triamcinolone
(IVTA) [1, 23, 26, 28, 30]. Yet, as a result of drug
absorption, these effects are not sustained and
there is a rather risk of recurrences of DME [26].
In a study of 69 eyes randomized to receive
either 4-mg IVTA injections or placebo, Gillies
et al. reported an improvement of five or more
letters in 56 % of eyes treated with IVTA com-
pared with 26 % eyes in the sham group
(P = 0.006), after 2 years [23]. OCT analysis
demonstrated a significant decrease in central
macular thickness in eyes treated with IVTA
compared to controls. IOP-lowering medication
was necessary in 44 % of treated eyes, and IOP
elevation required surgery in two eyes. Cataract
surgery was performed in 54 % of treated eyes.
When compared with laser therapy however,
the results have been inconclusive. The Diabetic
Retinopathy Clinical Research Network (DRCR.
net) conducted a trial in 840 eyes to evaluate
IVTA compared with focal/grid photocoagula-
tion [12]. Eyes were randomized to receive either
Mean visual acuity (letter score)
Fig. 5.2 Mean visual acuity
at each visit according to
treatment group
C. Aude and P. Massin
focal/grid photocoagulation (N = 330), 1-mg
IVTA (N = 256), or 4-mg IVTA (N = 254), with
the option to retreat for persistent edema every
4 months. After 4 months, the 4-mg IVTA group
had better VA than both the laser group (P < 0.001)
and the 1-mg IVTA group (P < 0.001). However,
the benefit diminished thereafter, and at 1 year
there was no significant difference between the
three groups. At the primary end point of 2 years,
the laser group had a small but significant
improvement in best-corrected VA compared to
the IVTA groups (P = 0.02 comparing 1-mg
IVTA and P = 0.002 comparing 4-mg IVTA) [12].
Change in VA from baseline to 3 years was + five
letters in the laser group and 0 in each IVTA
group [13]. It has been suggested that the acute
anti-inflammatory action of the steroid is effec-
tive in the short term, but due to the gradual
decline in concentration, it is not beneficial as a
long-term therapy. Similarly to other studies, the
eyes treated with 4-mg IVTA had significantly
higher rates of increased intraocular pressure
(IOP) (33 %) and need antiglaucoma medication
(30 %) compared with the laser treatment group
in the DRCR.net study (DRCR.net [12, 13]). The
cumulative probability of cataract surgery by
3 years was 31, 46, and 83 % in the laser and
1-mg IVTA and 4-mg IVTA groups, respectively
[13]. When compared to laser therapy, these
results indicate the absence of long-term benefit
of IVTA and an increased risk of side effects
(Fig. 5.2).
66
64
62
60
58
56 Laser
54 1 mg IVTA
4 mg IVTA
52
Baseline 4 months 12 months 24 months 36 months
5 Treatment of DME with Steroids
More recently, the DRCR.net study group con-
ducted a comparative clinical trial in 854 eyes to
evaluate four different treatments, including intra-
vitreal 0.5-mg ranibizumab combined with
prompt or deferred laser photocoagulation or
4-mg triamcinolone combined with focal/grid
laser, compared with sham injections combined
with focal/grid laser for center-involved DME
[14]. The study found that intravitreal ranibi-
zumab with prompt or deferred laser was more
effective through at least 1 year than triamcino-
lone combined with laser photocoagulation or
laser alone for the treatment of DME involving
the central macula, although uncommonly associ-
ated with endophthalmitis. In pseudophakic eyes,
intravitreal triamcinolone plus prompt laser was
as effective as ranibizumab combined with prompt
or deferred laser photocoagulation and was more
effective than laser alone, but the triamcinolone
plus prompt laser arm had an increased risk of
intraocular pressure elevation [14].
So, several studies have shown the efficacy of
IVTA to temporarily reduce DME and increase
visual acuity [1, 26, 29]. The mean reduction in
macular thickening reaches 85 % 3 months after
injection with a mean two-line improvement of
visual acuity [1, 23, 29]. However, recurrence of
DME occurs between 3 and 6 months after
injection. Due to the high rate of complications
and the absence of evidence of its superiority
over laser photocoagulation, IVTA is generally
reserved for patients refractory to focal/grid
laser therapy and anti-VEGF agents [46].
Despite the adverse events associated with ste-
roids, a recent Cochrane review supported the
use of intravitreal steroids in the treatment of
DME refractory to laser therapy [25]. IVTA has
the advantage over laser therapy that it can be
repeated several times, as long as IOP rise is
controlled.
5.3.2 Dexamethasone
The dexamethasone 700 g posterior segment
drug delivery system (Ozurdex) is a bioerodible
implant delivered intravitreally using a 22-gauge
injector. It has been approved by the US Food and
59
Drug Administration (FDA) for the treatment of
macular edema due to retinal vein occlusion and
noninfectious posterior segment uveitis.
Two phase II trials studied the effects of the
DEX-DDS (Ozurdex; Allergan Inc, Irvine,
California) compared with observation, in eyes
with DME treated with laser [8, 21].
In a phase II study [21], 315 eyes with persis-
tent macular edema, including 171 DME, were
randomized to receive either 350-g DEX-DDS,
700-g DEX-DDS, or observation. After 90 days,
an improvement of ten letters or more was
observed in significantly more DME eyes treated
with 700-g DEX-DDS (33.3 %) and 350-g
DEX-DDS (21.1 %) than with observation
(12.3 %; P = 0.007 vs. 700-g DEX-DDS) [20].
At day 180, a BCVA improvement of ten letters
or more was seen in 30 % of eyes in the 700-g
DEX-DDS group, 19 % in the 350-g DEX-DDS
group, and 23 % in the observation group (P 0.4
for treated vs. observed eyes). There were also
significantly greater improvements in retinal
thickness and fluorescein leakage in treated eyes
than observed eyes [20]. In both treatment
groups, 15 % of eyes had an increase in IOP
greater than 10 mmHg from baseline at any time
during follow-up, though the authors pointed out
that these elevations generally only occurred
once during follow-up, and only 2 % of patients
had sustained IOP elevations at 90 days. No
patients required IOP-lowering surgery (Fig. 5.3).
More recently, Callanan et al. randomized 253
eyes with DME either to treatment with DEX-
DDS at baseline plus laser at month 1 or sham
implant at baseline plus laser at month 1 [8].
They could receive up to three additional laser
treatments and one additional DEX implant as
needed. The percentage of patients who gained
ten letters or more at month 12 did not differ
between treatment groups (27.8 % in the combi-
nation treatment group and 23.6 % in the laser
alone group), but the percentage of patients was
significantly greater in the combination group at
month 1 (P < 0.001) and month 9 (P = 0.007). In
patients with angiographically verified diffuse
DME, the mean improvement in BCVA was sig-
nificantly greater with DEX-DDS plus laser
treatment than with laser treatment alone (up to
60
Fig. 5.3 Percentage of patients who
achieved 10 letters or more or 15
letters or more of improvement in
best-corrected visual acuity. P values
represent the comparison between the
700-g group and the observation
group. DDS indicates drug delivery
%age patients
system
7.9 vs. 2.3 letters) at all time points through
month 9 (P 0.013). At month 4, patients with
verified diffuse edema who were given DEX-
DDS before laser treatment were approximately
twice as likely to gain at least ten letters in BCVA
compared with patients who were given the sham
injection (23.2 % vs. 11.9 %; P = 0.035). Decrease
in the area of diffuse vascular leakage measured
angiographically was significantly larger with
DEX-DDS plus laser treatment through month
12 (P 0.041). Increased IOP was more common
with combination treatment (16.8 % of eyes). No
surgery for elevated IOP was required. Cataract
events were more common in phakic study eyes
in the DEX-DDS plus laser group (22.2 %) than
in the laser-alone group (9.5 %; P = 0.017). These
results suggest that a retreatment interval shorter
than 6 months may be needed to provide a better
sustained benefit.
DEX-DDS has also demonstrated efficacy for
the treatment of DME in vitrectomized eyes [4].
Fifty-five vitrectomized eyes with diffuse DME
were retrospectively studied. After 8 weeks,
30.4 % of eyes had an improvement in VA of ten
letters or more. During the follow-up, 16 %
developed IOP elevation.
The results of the phase III study evaluating
the efficacy and safety of dexamethasone intra-
vitreal implant in patients with diabetic macular
C. Aude and P. Massin
P = 0.01 P = 0.4
35
30
25
20
15
10
0
Day 90 Day 180
Observation group 700 g group2
350 g group
edema were recently published [5]. This study
consists of two randomized, multicenter, sham-
controlled, 3-year, phase III clinical trials con-
ducted in 22 countries. Because the trials were
identical in study design, the results were pooled
for analysis. A total of 1,048 patients were ran-
domized in a 1:1:1 ratio to study treatment with
DEX implant 0.7 mg, DEX implant 0.35 mg, or
sham procedure and followed for 3 years.
Retreatment was not allowed more often than
every 6 months. The predefined primary efficacy
end point for the US Food and Drug
Administration was achievement of 15-letter
improvement in BCVA from baseline at
study end.
The percentage of patients with a 15-letter
improvement from baseline at the year 3 was
greater with DEX implant 0.7 mg (22 %) and
DEX implant 0.35 mg (18.4 %) than with sham
(12 %, P 0.018). The mean (standard devia-
tion) average change in BCVA from baseline
during the study was 3.5 (8.4) letters with DEX
implant 0.7 mg, 3.6 (8.1) letters with DEX
implant 0.35 mg, and 2.0 (8.0) letters with sham.
Mean change in BCVA from baseline at each
study visit was significantly greater in both DEX
implant groups compared with sham at most
time points during the first 15 months. However,
the improvement in BCVA provided by DEX
5 Treatment of DME with Steroids
implants relative to sham was reduced after
month 15, due to the development of cataract. In
pseudophakic eyes, mean improvement in BCVA
provided by DEX implant relative to sham was
consistent across time in the 3-year study, and
there was no reduction in treatment benefit
observed in year 2. Mean number of treatments
received over 3 years was 4.1, 4.4, and 3.3 with
DEX implant 0.7 mg, DEX implant 0.35 mg, and
sham, respectively. Mean average reduction in
central retinal thickness from baseline was sig-
nificantly greater with DEX implant 0.7 and
0.35 mg than sham. Rates of cataract-related
adverse events in phakic eyes were 67.9, 64.1,
and 20.4 % in the DEX implant 0.7 mg, DEX
implant 0.35 mg, and sham groups, respectively.
Approximately one third of patients in each
DEX implant group had a clinically significant
increase in IOP requiring treatment during the
study, and only one patient (0.3 %) in each DEX
implant treatment group underwent glaucoma
incisional surgery for steroid-induced increases
in IOP. Increase in IOP of 10 mmHg from
baseline was observed in 27.7, 24.8, and 3.7 %
of eyes in the DEX implant 0.7 mg, DEX implant
0.35 mg, and sham groups, respectively. In con-
clusion, the DEX implant demonstrated efficacy
in the treatment of DME, meeting the primary
efficacy end points for improvement of
BCVA. The safety profile was favorable, being
consistent with previous reports.
In all studies, DEX-DDS treatment was well
tolerated and had an acceptable safety profile.
Similar to IVTA, DEX-DDS has the advantage of
repeatability, as long as the IOP and cataract
effects are mitigated. The advantages of DEX-
DDS over intravitreal triamcinolone include a
possible longer duration of action, the absence of
postinjection visual clouding or floater-like
symptoms, and a lower rate of IOP increase. In
all cases, the elevations in IOP were managed
with IOP-lowering medication or observation,
and no patient discontinued the studies because
of IOP or had an IOP of 25 mmHg or more at
month 12.
These studies have demonstrated the efficacy
of DEX implant for DME. Further studies are
warranted to address the optimal retreatment
61
interval for DEX-DDS in the treatment of
DME. A study directly comparing DEX-DDS
and ranibizumab in the treatment of DME is
underway. Recently, the European Medicines
Agency adopted a positive opinion on the use of
DEX-DDS in DME patients, who are pseudopha-
kic or considered insufficiently responsive to or
unsuitable for non-corticosteroid therapy.
5.3.3 Fluocinolone Acetonide
Two fluocinolone acetonide (FAc) intravitreal
devices have been studied for the treatment of
DME: a FAc implant (Retisert; Bausch and
Lomb Inc, Rochester, NY, USA) and a FAc insert
(ILUVIEN; Alimera Sciences, Inc, Alpharetta,
GA, USA). The results of the studies examining
the use of FAc in the treatment of DME have
been reviewed by Messenger et al. [31].
5.3.3.1 FAc Implant
Retisert contains 0.59-mg FAc and has an initial
release of approximately 0.6 g/day in the vitre-
ous. It is surgically implanted into the posterior
segment of the eye through a pars plana incision.
The FAc implant received initial FDA approval
for the treatment of chronic, posterior uveitis;
however, more recently investigators have exam-
ined its utility in the treatment of DME [35, 36].
In 2006 and 2011, Pearson et al. published the
results of two trials with 197 and 196 eyes with
refractory DME randomized in a 2:1 ratio, to
receive either 0.59-mg FAc implant or the stan-
dard of care (SOC) (focal/grid laser photocoagu-
lation or observation at the investigators
discretion). Inclusion criteria were a history of
persistent or recurrent DME with retinal thicken-
ing involving fixation of 1 disk area in size and
an ETDRS VA of 20 letters (20/400) to 68 let-
ters (20/50).
In the 2011 study, a 15-letter improvement
in VA was achieved in 16.8 % of implanted eyes
at 6 months (P = 0.0012), 16.4 % at 1 year
(P = 0.1191; SOC group, 8.1 %), 31.8 % at
2 years (P = 0.0016), and 31.1 % at 3 years
(P = 0.1566; SOC group, 20.0 %). Moreover, the
number of eyes with resolution of macular retinal
62
thickening was higher in the implanted eyes than
in the SOC group at 6 months (P < 0.0001), 1 year
(P < 0.0001; 72 % vs. 22 %), 2 years (P = 0.016),
and 3 years (P = 0.861); and a lower rate of
decline in diabetic retinopathy severity score
occurred in the implanted group (P = 0.0207 at
3 years).
However, this FAc implant has side effects,
including a high rate of steroid-induced ocular
comorbidities. Compared with the SOC, patients
treated with the FAc implant had significantly
higher rates of cataract extraction (91 % of
implanted phakic eyes compared with 20 % in
the SOC group). An IOP above 30 mmHg was
recorded in 61.4 % of implanted eyes (vs. 5.8 %
in the SOC group) at any time, and 33.8 %
required surgery to control elevated IOP by
4 years [35]. While potentially effective for
refractory DME, this implant has a substantial
risk of glaucoma and cataract progression.
5.3.3.2 FAc Insert
ILUVIEN is a non-bioerodible insert implanted
in the eye via injection through the pars plana
using a 25-gauge needle. ILUVIEN contains
0.19 mg of FAc. It is indicated in Europe for the
treatment of vision impairment associated with
chronic diabetic macular edema considered
insufficiently responsive to available therapies.
There are two clinical trials that studied the
effects of the FAc insert on DME [911]. The
Fluocinolone Acetonide for Macular Edema
(FAME) studies were two large prospective, ran-
domized, controlled studies that followed 956
eyes randomized to receive 0.2-g/day (low-
dose) or 0.50-g/day (high-dose) inserts or
sham. Subjects with persistent DME despite at
least one macular laser treatment and BCVA 19
and 68 letters on ETDRS chart were included.
Based on retreatment criteria, additional study
drug or sham injections could be given after
1 year.
A BCVA letter score 15 letters was achieved
at month 24 in 28.7 and 28.6 % in the low- and
high-dose FAc insert groups respectively com-
pared with 16.2 % in the sham group (P = 0.002
for each) and after 3 years in 28.7 % (low dose)
C. Aude and P. Massin
and 27.8 % (high dose) of the FAc insert groups
compared with 18.9 % in the sham group
(P = 0.018).
Interestingly, preplanned subgroup analysis
demonstrated a doubling of benefit compared
with sham injections in patients who reported
duration of DME 3 years at baseline. In a sub-
analysis of patients with DME for 3 years prior
to enrollment, patients in both the low-dose
(P < 0.001) and high-dose groups (P = 0.002)
were more likely to achieve a 15-letter gain
compared with patients in the sham group. Foveal
thickness was significantly reduced in both low-
dose and high-dose groups compared with the
sham group until month 30.
The percentage of patients that needed two
FAc insert injections at month 36 were 18.7 and
24.2 in the low- and high-dose insert groups,
respectively; and 5.3 and 7.0 % respectively
needed 3 study treatments at month 36.
Adverse effects were common in both low-
dose and high-dose insert groups. The most com-
mon adverse event was cataract, and almost all
phakic patients in the FAc insert groups devel-
oped cataract (81.7 and 88.7 % in the low- and
high-dose insert groups respectively compared
with 50.7 % in the sham group), but their visual
benefit after cataract surgery was similar to that
in pseudophakic patients. The incidence of
increased IOP (37.1 and 45.5 %, in the low-dose
and high-dose insert groups, respectively), need
for IOP-lowering medication (38.4 and 47.3 %,
respectively), incisional glaucoma surgery (4.8
and 8.1 %, respectively), and trabeculoplasty (1.3
and 2.5 %, respectively) was higher in the FAc
insert groups compared with the sham group.
The primary outcome, which was percentage
of patients with improvement of 15 letters from
baseline at months 24 and 36, was met in both
FAME trials. These results show that low-dose
FAc insert provides substantial benefit to patients
with refractory DME for 3 years. The maximum
benefit occurs at month 30, with 75 % of patients
requiring only one insert to obtain this benefit
(Fig. 5.4).
Messenger et al. reviewed and compared the
results of the studies of FAc devices in the treat-
5 Treatment of DME with Steroids
Eyes with 15 letter gain in BCVA (%) 40
35
30
25
20
15
10
5 DME. In Europe, FAc insert (ILUVIEN;
0
3 6 12
Months follow-up
FAc implant
0.2 g/day FAc
insert
Fig. 5.4 Vision outcomes through month 36 in patients
with diabetic macular edema treated with Fluocinolone
Acetonide (FAc): Percentage of eyes achieving 15 letter
gain in best-corrected visual acuity during follow-up
between FAc devices [31]
ment of DME [31]. Comparing the studies of
FAc devices head-to-head is complicated
because of differences in their inclusion/exclu-
sion criteria, retreatment protocols, and follow-
up time; both FAc devices appear to have similar
efficacy to treat DME. In both studies, 15 % or
more of eyes achieved a 15-letter increase in
BCVA. By 18 months, 20 % eyes treated with
the FAc implant or either doses of the FAc insert
maintained a 15-letter increase in BCVA. By
3 years, 30 % of eyes treated with a FAc device
achieved a 15-letter increase in BCVA
(Fig. 5.5).
The rate of cataract progression was similar
with the two FAc devices, with more than 80 %
of phakic eyes requiring cataract surgery after
4 years of treatment. However, the risk of
increased IOP and glaucoma progression was
significantly higher in the FA implant trial com-
pared with the FAc insert. An increased IOP
occurred in 69.7 % of FAc-implanted eyes com-
63
pared with only 45.5 % of high-dose FAc-inserted
eyes and 37.1 % of low-dose FAc-inserted eyes;
finally, 33.8 % of FAc-implanted eyes required
incisional surgery to control increased IOP com-
pared with only 4.8 and 8 % of low- and high-
dose FAc-inserted eyes, respectively [31].
Although the improvement in BCVA may be
similar, the significantly lower rate of ocular
hypertension in patients treated with FAc inserts
makes it the preferred FAc device to treat
Alimera Sciences, Inc, Alpharetta, GA, USA)
18 24 30 36 recently obtained authorities approval for the
treatment of chronic refractory DME in patients
with absence of response to other approved
0.5 g/day FAc therapies.
insert
5.4 Comparison of Intravitreal
Steroids for the Treatment
of DME
Comparing results from trials studying different
molecules is problematic because of the differ-
ences in follow-up time, patient populations, and
study design. However, large variations in rates
may elucidate important differences in the effi-
cacy and rates of adverse events between fluo-
cinolone, dexamethasone, and triamcinolone,
and Messenger et al. reviewed and compared the
results of the main steroid studies for DME [31]
(Table 5.1).
When comparing effects on VA, triamcinolone
appears less effective than both fluocinolone and
dexamethasone devices, with fewer patients achiev-
ing a BCVA improvement of 15 letters. The per-
centage of eyes achieving 15-letter improvement
with this DEX-DDS is comparable with that seen in
the FAc device studies and is greater than that seen
in the triamcinolone studies at similar follow-up
times [13, 21, 20, 35, 10]. Overall, these data show
greater efficacy of the FAc and dexamethasone
devices compared with triamcinolone injections
that is unlikely attributable simply to variations in
follow-up time or study design. IVTA may only
have a temporary effect on macular thickening and
VA, without long-term benefit.
64
Fig. 5.5 Right eye of a 39-year old woman with diffuse
DME treated with FAc insert. (a) OCT showing diffuse cys-
toid DME, VA was 26 letters on ETDRS chart and IOP was
measured at 14 mmHg. (b) One week after FAc insert injec-
The rate of serious adverse events was higher
in the FAc studies than in the triamcinolone and
dexamethasone studies [10, 12, 20, 21, 35].
The need for cataract surgery may be higher
in the FAc-treated eyes, with more than 85 % of
eyes requiring cataract surgery at 3 years com-
pared with 37 % of triamcinolone-injected eyes
at 2 years. Cataract progression occurred in
22 % of phakic eyes in the DEX-DDS group at
C. Aude and P. Massin
tion, OCT showing a decrease of DME and improvement in
foveal thickening, VA was 59 letters and IOP 21 mmHg. (c,
d) Improvement maintened at 1 and 3 months after FAc
insqert injection, VA was 61 letters and IOP 16 mmHg
month 12 [8]. The follow-up period of the phase
II dexamethasone study is short and still not
long enough to compare cataract progression
rates [20]. However, in the phase III trial evalu-
ating DEX implant for DME, 5259 % of DEX
implanted eyes required cataract surgery at
3 years. Rates of IOP increase were higher in the
FAc-implanted study and lower in the dexa-
methasone implant study. However, each study
5 Treatment of DME with Steroids 65

Table 5.1 Treatment of DME with steroids. Visual acuity, macular thickness, and adverse events among different
steroids for diabetic macular edema
Triamcinolone Dexamethasone FAc implant FAc insert
DRCR.net (2-year Healler et al. Pearson et al. Campochiaro et al.
follow-up) (6-month follow-up) (3-year follow-up) (3-year follow-up)
1 mg 4 mg 350 g 700 g 0.59 mg 0.2 g 0.5 g
(n = 256) (n = 254) (n = 103) (n = 105) (n = 127) (n = 375) (n = 393)
15 letter improvement in VA 15 % 16 % 15 % 18 % 31 % 33 % 32 %
15 letter loss in VA 21 % 21 % NR NR 17 % NR NR
Mean change in foveal 86 77 43 132 110 171 161
thickness (m)
Cataract surgery 23 % 51 % NR NR 91 % 80 % 87 %
Increased IOP 10 mmHg 16 % 33 % 15 % 15 % NR NR NR
from baseline
Need of IOP-lowering meds 12 % 30 % NR NR NR 38 % 47 %
Glaucoma surgery 0% 1% 0% 0% 33 % 6% 11 %
FAc fluocinolone acetonide, IOP intraocular pressure, NR not reported

reported different criteria of increased IOP,
making direct comparisons difficult. Of patients
with increased IOP, it appears that more patients
treated with FAc device needed glaucoma sur-
gery than did patients treated with triamcinolone
and dexamethasone.
Lastly, there was no difference in
endophthalmitis incidence, with this occurring in
less than 1 % of eyes treated with steroids.
Conclusions
Many randomized clinical studies have shown
the clinical efficacy of steroid injections to
treat DME, but their use is limited by their
adverse events, including cataract progression
and intraocular pressure (IOP) increase.
The Diabetic Retinopathy Clinical Research
Network study demonstrated the superiority
of focal/grid photocoagulation, over a 3-year
period, on intravitreal triamcinolone injections
[12, 13]. However, in pseudophakic patients,
the recent DRCR.net results showed a simi-
lar effect of triamcinolone plus laser com-
pared to ranibizumab associated plus prompt
or deferred laser [14]. Still, IOP increase has
been observed in 40 % of cases and remains a
current problem in clinical practice.
Phase 2 clinical studies suggested that
dexamethasone implant may be useful for
treatment of DME and was well tolerated with
significant improvements in BCVA and retinal
thickness at 1 year [20, 21]. The phase III trial
evaluating DEX-DDS for DME confirmed its
efficacy and safety.
Visual improvement obtained with fluo-
cinolone acetonide vitreous insert implants
was counterbalanced by a high level of ocular
hypertony and the need to perform IOP-
lowering procedure in a high percentage of
cases at 3 years, limiting the use of this device
to ancient, refractory DME [10, 35].
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Ophthalmology. 2002;109(5):9207.
 Intravitreal Steroids
for the Treatment of Macular 6
Edema in Retinal Vein Occlusions

Eran Zunz and Anat Loewenstein

Contents 6.1 Introduction

6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 69
Retinal vein occlusion is considered a multifac-
6.2 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
6.2.1 Intravitreal Triamcinolone
torial disease with a complex pathogenesis that
for Macular Edema in Central often reflects locally systemic vascular and hemo-
Retinal Vein Occlusion . . . . . . . . . . . . . . . . 70 dynamic disorders [11]. Nowadays, it is generally
6.2.2 Intravitreal Triamcinolone agreed that the RVO management should target
for Macular Edema in Branch
Retinal Vein Occlusion . . . . . . . . . . . . . . . . 70
the angiogenic factors as well as the inflamma-
6.2.3 Dexamethasone Implant Treatment tory compounds of this etiologic complex. The
of Macular Edema in RVO. . . . . . . . . . . . . . 71 inflammatory reactions put in motion by retinal
6.2.4 Fluocinolone Acetonide ischemia and subsequent macular edema in RVO
Intravitreal Implant . . . . . . . . . . . . . . . . . . . 74
6.2.5 Combined Treatments . . . . . . . . . . . . . . . . . 74
are closely associated to the angiogenic mani-
6.2.6 Systematic Reviews Comparing festation of the pathology and include various
Different Treatment Modalities interrelated processes such as vasodilatation, leu-
for RVO . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 kostasis, diapedesis, increased vascular perme-
6.3 Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . 75 ability, and inflammatory proteins secretion [2].
6.3.1 Intravitreal Triamcinolone . . . . . . . . . . . . . . 76 Macrophages, neutrophils, and microglia partici-
6.3.2 Dexamethasone Intravitreal Implant . . . . . . 76
pate in the concert of inflammatory responses,
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 in which several inflammatory mediators such
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 as prostaglandins, IL-1, TNF-alpha, VEGF, and
ICAM-1, among others, are involved [20]. These
factors promote hyperpermeability of blood ves-
sel wall, contributing to the breakdown of blood
retinal barrier, and subsequently leading to macu-
lar edema. In patients with CRVO, it was found
that ICAM-1 and VEGF levels in the vitreous
in vivo correlated with the severity of macu-
E. Zunz, MD A. Loewenstein, MD (*) lar edema [16]. The rationale of using steroids
Department of Ophthalmology, that are well known for their potent anti-inflam-
Sackler Faculty of Medicine, matory action in RVO is based on their ability,
Tel Aviv Medical Center, Tel Aviv University,
among others, to block IL-1 mRNA synthesis and
6 Weizmann St, Tel Aviv 64239, Israel
e-mail: eranzunz@gmail.com; ICAM-1-mediated leukocyte adhesion to vessel
anatl@tlvmc.gov.il walls and to inhibit VEGF expression [6, 16].

A.J. Augustin (ed.), Intravitreal Steroids, 69

DOI 10.1007/978-3-319-14487-0_6, Springer International Publishing Switzerland 2015
70
Steroids delivered into the vitreous have the
advantage of directly targeting the edematous
macula and leaking retinal blood vessels, with a
stronger and more efficient action against the dis-
ease processes and without inducing systemic
side effects. There are various drug formulations,
delivery methods, and treatment doses protocols.
In the present overview, we will evaluate the effi-
cacy and safety of the most commonly used intra-
vitreal steroids in current practice.
6.2 Efcacy
6.2.1 Intravitreal Triamcinolone
for Macular Edema in Central
Retinal Vein Occlusion
The first multicenter RCT that investigated the
efficacy and safety of intravitreal steroids was the
Standard Care vs. Corticosteroid for Retinal Vein
Occlusion (SCORE) Study. It included 271
patients with macular edema and perfused
CRVO. It evaluated two doses of intravitreal tri-
amcinolone (preservative-free), 1 and 4 mg, com-
pared to observation [10]. Eyes were treated with
intravitreal triamcinolone (IVTA) every 4 months
for up to a year. The study stated three criteria for
withholding retreatment during this year, which
included significant clinical improvement (VA
improved to 20/25 or better or OCT with
CMT = 225 m), significant side effect (such as
IOP elevation that required treatment), or nonsig-
nificant response to two consecutive injections
after 8 months (i.e., less than 20 % reduction in
retinal thickness compared to baseline and less
than five letters improvement in VA score). The
SCORE allowed salvage IVTA for some patients
with CRVO, who had significant visual loss at
two consecutive visits that was considered sec-
ondary to macular edema and not to other causes
such as cataract [10].
The SCORE study demonstrated a gain of VA
letter score of 15 or more in 26.5 % of eyes
treated with 1 mg IVTA, 25.6 % of eyes treated
with 4 mg IVTA, and 6.8 % of eyes under obser-
vation alone at 1 year. At 12 months, the mean
E. Zunz and A. Loewenstein
change in VA was a loss of 1.2 letters in the treat-
ment groups as opposed to 12.1 letters loss in the
observation group. The likelihood of VA gain
was five times greater in the IVTA groups than
the observation group. The mean number of
injections after 12 months was 2 in the 4 mg
group and 2.2 in the 1 mg group.
Although the subsequent 2-year extension of
the SCORE study lacked definitive data, the
authors noted that the visual acuity results after
2 years were similar to those at 12 months. As
cataract had some effect on 2 years visual acuity
results, cataract surgery was encouraged when-
ever it was clinically indicated by the investiga-
tors. The authors stated that these findings
support the continuation of IVTA for 2 years
when indicated.
The SCORE study demonstrated the efficacy
and safety of 1 mg preservative-free intravitreal
triamcinolone (Trivaris: Allergan) in the treat-
ment of CRVO. This preservative-free formula-
tion is not available in Europe, and there is no
extensive and clear evidence that the off-label
formulation of intravitreal triamcinolone aceton-
ide, which is non-preservative free presents simi-
lar efficacy and safety profile [2].
6.2.2 Intravitreal Triamcinolone
for Macular Edema in Branch
Retinal Vein Occlusion
In a parallel RCT on patients with BRVO, the
1 and 4 mg IVTA treatment arms were com-
pared to the standard treatment of BRVO with
grid laser for macular edema (as opposed to no
treatment in the CRVO patients). The results
showed that 28.9 % of the grid laser eyes
improved by 15 letters in VA, which was not
significantly different from the 1 and 4 mg
IVTA treatment groups in which the VA of
25.6 and 27.2 % of the eyes gained 15 letters
or more, respectively. The investigators con-
cluded that triamcinolone was not superior to
standard care (grid laser) in treating macular
edema secondary to BRVO. The mean change
in VA at 12 months was 4.2 in laser eyes, 5.7 in
6 Intravitreal Steroids for the Treatment of Macular Edema in Retinal Vein Occlusions
1 mg IVTA, and 4.0 in 4 mg IVTA. Three
additional reasons led to the abandonment
of IVTA as treatment for macular edema in
BRVO. Firstly, the 3-year results indicated that
the laser group achieved in average a better VA
than the IVTA groups (12.9 letters gain in laser
group, 4.4 letters gain in 1 mg IVTA group, and
8 letters gain in 4 mg IVTA group). Secondly,
pseudophakic eyes also failed to demonstrate
better improvement with steroids rather than
laser, and thirdly, adverse events such as cata-
ract formation and elevated IOP were more
frequent in the IVTA groups than in the laser
group, with the highest frequency in the 4 mg
treatment group [21].
6.2.3 Dexamethasone Implant
Treatment of Macular
Edema in RVO
Dexamethasone is a potent corticosteroid capa-
ble of reducing or suppressing the mediators
promoting macular edema. It is highly soluble
with a short half-life. To ensure a prolonged
intraocular action, a biodegradable implant was
developed (Ozurdex: Allergan). The implant
contains 0.7 mg dexamethasone in a polyglyco-
late-acetate coating. After being injected intra-
vitreally, it slowly releases dexamethasone into
the vitreous for up to 6 months with maximal
effect 60 days after injection [2]. The implanted
device is able to deliver a long-standing steroid,
and thus it has the potential to reduce the fre-
quency of injections with alternative or comple-
mentary treatments.
The GENEVA trial evaluated one to
two intravitreal dexamethasone biodegradable
implant injections in the treatment of macular
edema in CRVO and BRVO for 12 months. The
study was conducted as a randomized controlled
multicenter study in the first 180 days and then
as an open label in the following 180 days
extension.
Patients were randomized at baseline to either
0.7 or 0.35 mg dexamethasone implant or sham
injection, and they were followed up for 180 days.
71
After this period patients were eligible to a sec-
ond dexamethasone implant of 0.7 mg if BCVA
was lower than 20/20 or central macular thick-
ness higher than 250 m [9].
Improvement of 15 letters or more in visual
acuity was documented in the 0.7 mg dexametha-
sone group in 30 % of patients 60 days after the
first injection and in 32 % of patients 60 days
after the second injection. These figures dropped
to 16 and 24 % 180 days after the first and second
injection, respectively. The peak of visual acuity
gain of a mean of ten letters occurred 60 days
after the implant injections. Improvement of ten
letters or more was recorded in 55 % of eyes
treated with two dexamethasone implant injec-
tions and in up to 46 % of eyes treated with only
one dexamethasone injection at day 180 (delayed-
treatment group).
6.2.3.1 Effects of Treatment
in Different Study Groups
According to the subgroup analysis of the
GENEVA trial, patients with CRVO who had
received the injection at baseline returned to the
mean baseline visual acuity after 180 days but
gained an average of two letters (compared to
baseline) at conclusion of the study after 1 year,
i.e., 180 days after the second 0.7 mg Ozurdex
implant injection.
Patients treated for CRVO, who were initially
randomized to sham and then received their first
dexamethasone implant at day 180, did not catch
up with the early treatment group visual acu-
ity results. Not only that they did not achieve a
mean of 2 and 1 letters change in BCVA (as
compared with baseline) at day 180 and day
360, respectively, but they showed only a mean
of Four letters improvement peak (instead of
eight letters peak) 60 days after injection. This
reflects a mean improvement in VA of two letters
after 180 days as compared with no treatment
and of three letters as compared with delayed
single dexamethasone intravitreal implant in the
GENEVA trials.
Another important finding of this study was
that eyes with macular edema that were treated
within the first 3 months since the onset of
72
Fig. 6.1 (a) A 55-year-old man. Severe persistent CME
d/t CRVO in only eye after multiple bevacizumab injec-
tions and no satisfactory result. BCVA 6/15.
CMT = 656 m. (b) Nearly complete resolution of CME
macular edema had a higher probability to
improve as compared with eyes with longer-
standing macular edema [8]. Upon the evidence
gathered in the GENEVA trial, Ozurdex received
the approval for use in macular edema in CRVO,
indication for which it could be the first-line
treatment choice [2] (Fig. 6.1).
In patients with BRVO, treated eyes demon-
strated a mean peak of over ten letters gain at day
60 after first dexamethasone implant injection,
compared with five letters gain with no treat-
ment. At day 60 after injection, 29.6 % of BRVO
eyes treated with dexamethasone 0.7 mg gained
15 letters or more as compared with 12.5 % of the
sham group eyes [2]. By day 180, 41.2 % of
0.7 mg dexamethasone-treated eyes improved
by ten letters or more versus 33 % in the
E. Zunz and A. Loewenstein
6 weeks s/p Ozurdex injection. BCVA improved to 6/8.5.
IOP = 20, CMT = 286 m. (c) Complete resolution of mac-
ular edema at 11 weeks post Ozurdex injection. BCVA
6/8.5 IOP = 17, CMT = 280 m
no-treatment group. This difference was
statistically significant [2, 9]. Along all the time
points of the study, BRVO eyes treated with
dexamethasone 0.7 mg demonstrated a higher
mean visual gain than the sham BRVO group, the
difference being statistically significant. In
the open-label phase of the study, 60 days
after the second dexamethasone implant injec-
tion, visual acuity gain peaked to a mean of ten
letters as compared with eight letters gain in the
delayed-treatment group. After 1 year, the mean
gain was six letters, in both groups, the BRVO
eyes injected twice and eyes with a single injec-
tion at day 180 [8]. Similar to the findings in
CRVO eyes, in the open-label phase of the study,
the eyes with BRVO that had received delayed
treatment had a lower visual acuity gain than
6 Intravitreal Steroids for the Treatment of Macular Edema in Retinal Vein Occlusions
Fig. 6.2 (a) A 58-year-old woman with superotemporal
BVO. A macula at presentation with severe CME. BCVA
6/60. After single bevacizumab injection, the patient
developed subarachnoid hemorrhage, and anti-VEGF
agents were contraindicated. (b) 33 days s/p intravitreal
those in the initial-treatment groups [8]. Further
analysis found that delaying treatment for eyes
with BRVO and macular edema reduces the
chance to achieve 15 letters gain in vision with
73
dexamethasone implant (Ozurdex) OCT demonstrates
complete resolution of CME. BCVA improved to 6/30. (c)
10 weeks after Ozurdex injection, no macular edema, cen-
tral retinal thickness reduced to 267 m, and BCVA
improved to 6/12
dexamethasone intravitreal implant. Such proba-
bility was reduced by 54 %, 32 %, and 12 % if the
treatment was delayed by 6, 3, and 1 month,
respectively [2] (Fig. 6.2).
74
6.2.3.2 Effects of Treatment on Retinal
Thickness as Measured on OCT
Studies
In both CRVO and BRVO, 90 days after the sec-
ond implant injection, the mean retinal thickness
change was a reduction of 263 m, while a
decrease of 267 m was noted in patients who
had received their first dexamethasone implant at
day 180 (delayed-treatment group) [8].
More clinical data on extended use and results
of dexamethasone implants in retinal vein occlu-
sion have been added quite recently. A retrospec-
tive case series of 51 eyes with RVO and ME
examined the effectiveness of repeated dexa-
methasone intravitreal implant injections in 51
eyes. After 12 months of follow-up, 30 % of eyes
gained 15 or more letters. At 12 months BRVO
treated eyes had ETDRS letter gain of 5.7 and
CRVO eyes gained a mean of 11.5 letters com-
pared to baseline visual acuity versus 5 and 2 let-
ters gain, respectively, in the GENEVA trial. It
was found that, with repeated injections, the
dexamethasone implants effect had a shorter
duration. In this series, the mean number of dexa-
methasone implant injections after 12 months
was 1.9, but 23 % of the eyes required three or
more injections. The minimal interval between
repeated injections was 3 months. Retreatment
was performed if after an initial response to the
first injection, the patient experienced a visual
loss of at least five letters, with macular edema
relapse on OCT. This study concluded that, espe-
cially in eyes with CRVO, dexamethasone
implants can be injected on as-needed protocol,
but its outcomes remained similar to those
reported by the SCORE trial [12]. A latest post
hoc analysis of the GENEVA trial revealed that
visual gain in response to dexamethasone implant
injection occurred as early as 7 days postinjec-
tion, when 27.2 % of treated eyes presented with
a ten or more letters gain [13].
6.2.3.3 Anti-VEGF Versus
Dexamethasone Intravitreal
Implants Efcacy in RVO
A recent small randomized clinical trial com-
pared anti-VEGF (bevacizumab) as needed with a
single dexamethasone implant in 60 nonischemic
CRVO eyes. Thirty eyes were randomized to each
E. Zunz and A. Loewenstein
treatment arm and followed for 6 months. The
results demonstrated no statistically significant
difference in visual outcomes between groups.
The bevacizumab eyes had a significantly thinner
central retina at the end of month 1, but this effect
was not evident in any of the following months of
the study. As expected, the eyes with dexametha-
sone implant had a statistically significant higher
IOP between months 3 and 6 [5]. Considering the
scarce comparative clinical data, and despite its
small sample size and the non multicenter RCT
design, this study may have a significant impact
on future head-to-head, larger studies comparing
anti-VEGF agents with the dexamethasone intra-
vitreal implant. A large, ongoing multicenter RCT
(the COMO study (http://clinicaltrials.gov/show/
NCT01427751) was designed to compare the
efficacy of ranibizumab versus intravitreal dexa-
methasone implant in eyes with early BRVO of
less than 90 days. It is expected to complete the
data collection for the primary outcome measure
(the change from baseline in best corrected visual
acuity) only by the end of 2014. Clinical evidence
based on well-designed head-to-head RCTs of
different intravitreal substances is needed.
6.2.4 Fluocinolone Acetonide
Intravitreal Implant
The Iluvien intravitreal implant was designed to
release fluocinolone acetonide over a period of
36 months. In 2009, Alimera Inc. initiated the
FAVOR study to examine the efficacy and safety
of Iluvien for RVO. After the results were
reported, this treatment modality for RVO was
abandoned.
6.2.5 Combined Treatments
6.2.5.1 Combined Laser Grid
and Dexamethasone
Intravitreal Implants
A small prospective randomized study examined
the efficacy of dexamethasone implant versus
dexamethasone implant plus laser grid
68 weeks after injection. Each treatment arm
included 25 eyes, all of which were eligible for
6 Intravitreal Steroids for the Treatment of Macular Edema in Retinal Vein Occlusions
repeated dexamethasone intravitreal implant
injection when macular edema relapsed or when
there was a decrease in visual acuity. Although
at 6 months both groups improved the vision, the
combination group achieved a mean of 0.18
LogMAR, while the injections-only group 0.25
LogMAR. Interestingly, in the combination
treatment arm, only 12 % of patients were
retreated for macular edema relapse at 4 months
as opposed to 48 % of patients in the injections-
only group. At 6 months, macular edema per-
sisted in 12 % of the eyes in the injections-only
treatment arm and in none in the combined treat-
ment arm. This study demonstrated that the
combination of slow-release dexamethasone
implant with laser grid could achieve better
visual results and can secure longer intervals
between injections [18].
6.2.5.2 Combined Treatment
of Intravitreal Triamcinolone
and Ranibizumab
A new small but prospective study compared the
treatment results in 57 eyes with CRVO that were
assigned to either initial combined ranibizumab and
triamcinolone (30) or ranibizumab alone (27).
Improvement was seen in both treatment groups dur-
ing the study. The only statistically significant differ-
ence between the groups was the mean number of
injections, namely, 3.42 in the combination group as
compared with 4.23 in the initial ranibizumab alone.
Differences in central subfield thickness or visual
acuity between groups were not significant [3].
6.2.6 Systematic Reviews
Comparing Different
Treatment Modalities for RVO
Systematic reviews attempted to compare differ-
ent treatments available for RVO. To note that,
although systematic analyses have advantages
when comparing clinical outcomes, not all RCTs
are comparable in terms of patients selection cri-
teria and the measured outcomes. For this reason,
the systematic reviews emphasize in their conclu-
sions the need for large RCT for RVO comparing
different treatments head to head similar to the
CATT study for AMD [14].
75
One such recent review [4] assessed eight
RCTs that evaluated the following available treat-
ments for CRVO: triamcinolone, dexamethasone,
bevacizumab, pegaptanib, ranibizumab, and
aflibercept. This systematic review concluded
that bevacizumab, triamcinolone, aflibercept, and
ranibizumab demonstrated a significant higher
proportion of eyes gaining 15 or more letters
compared with sham. The results for pegaptanib
and dexamethasone were mixed, because of
safety issues, with significant cataract formation
and IOP elevation under intravitreal steroids as
opposed to no significantly higher adverse event
rate under anti-VEGF therapies [4].
A recently published systematic review by
Glanville et al. [7] examined the effects of ranibi-
zumab or dexamethasone for both BRVO and
CRVO. This study found that dexamethasone
provided a significant improvement in visual
acuity in BRVO eyes but not in CRVO eyes. As
mentioned earlier, a head-to-head comparison
between these treatments was not possible due to
different patients baseline characteristics and
study design [7].
Another systematic review by Pielen et al.
[19] summarized data from 11 RCTs of different
treatment modalities for BRVO and CRVO. This
review found that in CRVO a visual improvement
of at least 13.9 letters was achieved with a mean
of 8.8 injections of different anti-VEGF agents
(either aflibercept, bevacizumab, or ranibi-
zumab), and a stabilization of vision (1.2 letters
compared to baseline) was achieved with a mean
of 2.2 injections of triamcinolone (either 4 mg or
1 mg). In BRVO, the ranibizumab-treated eyes
achieved 18.4 letters (in average 8.3 injections).
In both BRVO and CRVO, the Ozurdex-treated
eyes achieved a transient visual improvement
with a mean of 1.9 injections, but the comparison
is limited as the RCTs of dexamethasone did not
include the PRN treatment [19].
6.3 Safety Issues
In addition to side effects such as pain, subcon-
junctival hemorrhage, floaters, transient IOP
increase, or, rarely, endophthalmitis that are com-
monly related to the procedure itself regardless of
76
the therapeutic agent, there are some adverse
effects or complications attributed to intravitreal
steroids [17].
6.3.1 Intravitreal Triamcinolone
6.3.1.1 Elevated IOP
During the 12 months of CRVO SCORE Study,
IOP-lowering drops were prescribed for 35 % of
4 mg IVTA patients, 20 % of 1 mg IVTA, and 8 %
of the patients in the observation group. Two
patients who received 1 mg IVTA required tube
shunt operation during the first year, and two of
the patients receiving 4 mg IVTA underwent this
procedure during the second year. All of the oper-
ated patients suffered from neovascular glaucoma
and not from steroid-induced glaucoma [10].
In the BRVO SCORE Study, higher frequency
of IOP increase was noted in the IVTA treatment
arms, which was highest in the 4 mg arm.
Elevated IOP requiring medical treatment was
found in 41 %, 8 %, and 2 % of the eyes in the
4 mg, 1 mg, and laser arms, respectively, while
36 %, 7 %, and 0.7 % of eyes, respectively, had
an IOP rise of 10 mmHg or more above baseline.
Severe IOP increase (above 35 mmHg) was
recorded in 10 % of the eyes treated with 4 mg
IVTA and in less than 2 % in other treatment
groups. None required glaucoma surgery by
12 months but two patients from the 4 mg group
required glaucoma surgery to lower IOP (one
tube, one trab) [21].
6.3.1.2 Cataract
In the CRVO SCORE Study, cataract progres-
sion was recorded in 18 % in the nontreatment
group, 26 % of the patients in the 1 mg IVTA,
and in 33 % of patients in the 4 mg IVTA arm. It
was found that only the 4 mg group had a signifi-
cantly higher rate of cataract surgery (27 %)
between the months 1224 of the study com-
pared to the observation (0 %) or 1 mg group
(3 %), which implies that significant cataract
may not be expected in significantly higher rates
in eyes receiving 1 mg IVTA as compared with
no treatment strategy. No events of endophthal-
mitis or retinal detachment occurred at 12 months
in this study [10].
E. Zunz and A. Loewenstein
During 12 months of follow-up in the SCORE
BRAVO study, the reported cataract formation
and progression rates were 35 % in the 4 mg tri-
amcinolone arm, 25 % in the 1 mg arm, and 13 %
in the standard care group. Only few cataract sur-
geries were performed over the first year, but by
the end of the second year, 35 of eyes in the 4 mg
group, 8 eyes in the 1 mg group, and 6 eyes in the
standard treatment group underwent cataract
extraction. Rates of cataract formation, progres-
sion, and surgery were statistically significantly
higher in the 4 mg triamcinolone arm compared
to either the 1 mg or standard treatment arms.
Since cataract side effects were not significantly
higher in the 1 mg triamcinolone group compared
to laser grid (standard care), this treatment is con-
sidered relatively safe [21].
6.3.2 Dexamethasone Intravitreal
Implant
The GENEVA trial included extensive safety
analysis concerning treatment with intravitreal
dexamethasone implants. The most frequent
adverse effects were conjunctival hemorrhage
and elevation of IOP. After 1 year, the cumulative
frequency of conjunctival hemorrhage was nearly
25 % of cases and did not differ significantly
between treatment arms. Actually, excluding cat-
aract formation, there were no statistically sig-
nificant differences in frequencies of any of the
ocular side effects between patients who received
one or two injections of dexamethasone implant
during the 12 months of the study. Endophthalmitis
was not reported in any of the study eyes.
6.3.2.1 IOP Elevation
Elevated IOP rates demonstrated peaks at days
60 and 240, namely, 60 days after each injection.
Incidence was 12.6 % after first injection and
15.4 % after second injection. Although up to
32.8 % of patients who received two dexametha-
sone implant injections experienced an IOP ele-
vation equal or larger than 10 mmHg during
some point of the study, this effect was transient
and resolved 180 days after injection of the
implant. It should be noted that those elevations
were either observed or treated topically. After
6 Intravitreal Steroids for the Treatment of Macular Edema in Retinal Vein Occlusions
the first injection, 25.5 % of eyes required IOP-
lowering medications and up to 38.8 % of the
eyes injected twice with intravitreal dexametha-
sone implant required this treatment. In total 14
eyes required laser or surgical measures to lower
the IOP. Four of those cases developed neovascu-
lar glaucoma secondary to the RVO and this was
the indication for IOP lowering [8].
A retrospective case series of 51 eyes treated
with Ozurdex implants for RVO reported that
27 % of eyes suffered from an IOP increase of
more than 25 mmHg after the first injection. IOP
in almost all of these patients was controlled
under topical treatment only [12].
6.3.2.2 Cataract
Cataract was reported in 29.8 % of eyes treated
with two injections of Ozurdex and in 10.5 % of
eyes in the delayed-treatment group. These
differences were statistically significant.
Conversely, cataract formation rates were not sig-
nificantly different between eyes that received
one or no intravitreal dexamethasone implant,
namely, between 5.7 and 7.6 % [8]. Cataract
extraction rates during study period were very
low and nonsignificantly different between treat-
ment arms.
6.3.2.3 Long-Term, Real-Life
Retrospective Data of Patients
Treated with Dexamethasone
Intravitreal Implant Monotherapy
or with Combined Treatments
Few retrospective studies are available concern-
ing long-term efficacy and safety of Ozurdex
treatment. These reports are not homogenous in
terms of the number of Ozurdex injections
received and whether combined therapy with
anti-VEGF or laser was applied. Nevertheless,
the results provide some evaluation of the data
regarding the safety and efficacy issues with the
treatment of dexamethasone intravitreal implants
combined with anti-VEGF treatments.
A multicenter retrospective review of 289
eyes treated with a mean of 3.2 Ozurdex injec-
tions (29.1 % as monotherapy) and a mean inter-
val between injections of 5.6 months reported
that 59.7 % of BRVO eyes and 66.7 % of CRVO
eyes improved two or more lines in vision. The
77
results of VA in patients who received dexameth-
asone as monotherapy were not reported. Cataract
progression was not systematically recorded in
this study, but 46 eyes out of 289 (15.9 %) under-
went cataract extraction during the study period.
Concerning IOP elevations, the study reported
that 32.6 % of eyes sustained a 10 mmHg eleva-
tion or more (at any of the visits). Despite that
29.1 % of eyes required topical IOP-lowering
agents some time during the follow-up, only
4.3 % presented with elevated IOP at final fol-
low-up visit [1].
Another long-term study assessed the fre-
quency of side effects and long-term visual prog-
nosis with dexamethasone intravitreal treatment
[15]. It included 17 patients who had participated
in the GENEVA Study. The mean follow-up was
of 50.5 months. Fourteen out of 17 patients with
BRVO demonstrated an improvement of two
lines.
Although side effects frequencies were not
mentioned per original treatment arm group in
the original GENEVA trial, this small series
reflects real-life scenario. Seven out of 17 of the
eyes had two Ozurdex injections during the origi-
nal GENEVA trial and the other ten patients had
only one injection. Regardless of the number of
injections, at the last follow-up (mean follow-up
of 50.5 months), the average IOP levels in all the
study sample was 14.7 mmHg and only one
patient required topical treatment for elevated
IOP above 21 mmHg throughout the follow-up
period. This finding may suggest a favorable
long-term rate of elevated IOP after one or two
Ozurdex injections. Long-term cataract progres-
sion rate was 58.8 % (ten eyes) and 35.2 % (six
patients) underwent cataract extraction after a
mean period of 28.3 18.7 months [15].
Conclusion
Without any doubt, intravitreal steroids have
an important place in RVO treatment arma-
mentarium. Ozurdex that received the FDA
approval for treatment of macular edema in
retinal vein occlusion was shown in the
GENEVA trials and in more recent studies to
be effective and safe in both BRVO and CRVO
and to achieve significant visual gain espe-
cially when multiple dexamethasone implants
78
were used on an as-needed basis under IOP
control. Intravitreal triamcinolone remains a
valid alternative for treatment of macular
edema if other means such as anti-VEGF or
Ozurdex have failed. This treatment, though,
is not available as preservative-free formula-
tion in Europe, and the preservative-contain-
ing formula has not been evaluated for efficacy
and safety in RVO [2].
Steroids in RVO offer effective monother-
apy and are indeed capable of upgrading other
treatment modalities by inducing a compre-
hensive and long-standing anti-inflammatory
and antiangiogenic effect and allow reduction
of burden of intravitreal anti-VEGF injec-
tions. Intravitreal steroids are also an alterna-
tive option for patients not responding to
regular anti-VEGF treatments, and there is
some evidence that their combination with
laser in BRVO may be synergistic.
Our knowledge is constantly evolving with
the new developments in the retina field. Clinical
trials have yet to answer many questions regard-
ing the way in which steroids affect the ocular
diseased structures as well as the normal eye
structures. We need more studies that will exam-
ine other combination therapies, different treat-
ment protocols such as multiple Dexamethasone
implant injections including PRN regimen, and
head-to-head efficacy investigations.
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8. Haller JA, Bandello F, Belfort Jr R, Blumenkranz MS,
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BA, Fisher M, Singerman LJ, Tolentino M, Chan CK,
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 Treatment of Uveitis
with Intraocular Steroids
Lazha Talat, Filis Ismetova, Susan Lightman,
and Oren Tomkins-Netzer
Contents
7.1 Pathophysiology of Uveitis . . . . . . . . . . . .
7.2 Steroid Treatment in Uveitis . . . . . . . . . . .
7.3 Local Steroid Treatment in Uveitis. . . . . .
7.3.1 Intravitreal Triamcinolone Acetonide
(IVTA) Injection . . . . . . . . . . . . . . . . . . . . .
7.3.2 Extended-Release Dexamethasone
Implant (Ozurdex) . . . . . . . . . . . . . . . . . . .
7.3.3 Fluocinolone Acetonide Intravitreal
Implants . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
L. Talat, MBChB, MPH, MSc (*)
F. Ismetova, MD, MPH
Department of Clinical Ophthalmology,
University College London/Moorfields Eye Hospital,
162 City Road, London EC1V 2PD, UK
e-mail: l.talat.11@ucl.ac.uk; filis.ismetova.12@ucl.ac.uk
S. Lightman, FRCP (UK), PhD FRCOphth
O. Tomkins-Netzer, MD, PhD
UCL/Institute of Ophthalmology and Moorfields Eye
Hospital, 162 City Road, London EC1V 2PD, UK
e-mail: s.lightman@ucl.ac.uk; o.tomkins-netzer@ucl.ac.uk
A.J. Augustin (ed.), Intravitreal Steroids,
DOI 10.1007/978-3-319-14487-0_7, Springer International Publishing Switzerland 2015
7
7.1 Pathophysiology of Uveitis
81
Uveitis, or inflammation inside the eye, is a
82
relatively uncommon disease with a prevalence
82 of 58.0114.5 per 100,000 persons [1, 2].
However, it accounts for 1015 % of all causes of
82
blindness among people of working age in the
85 developed world [3, 4]. Uveitis can be catego-
rized according to anatomical involvement (ante-
87
rior, intermediate, posterior, or panuveitis) or by
88 etiology (infectious, noninfectious, or neoplas-
88 tic). While the aim of the immune system is to
control exogenous infections and promote tissue
healing, in doing so it may also result in damage
to tissue structure that, in the eye, can cause sig-
nificant functional consequences for vision. The
inflammatory response involves a myriad of
immune cells that are controlled by a balance of
proinflammatory and inhibitory cytokines.
Abnormal regulation of the immune system can
result in autoimmunity, excessive inflammatory
responses, and further tissue damage.
In order to maintain normal visual function,
the eye must remain an immune-privileged site to
which immune cells have restricted access and
function. The intact blood-ocular barriers impede
the passage of blood constituents and cells into
the intraocular space. An intricate anti-
inflammatory and immunosuppressive microenvi-
ronment within the eye inhibits T-cell activation
and differentiation, suppresses macrophage acti-
vation [5], inhibits natural killer cells lysis of tar-
get cells [6], induces apoptosis of immune cells
81
82
[7], and limits antigen presentation by downregu-
lation of major histocompatibility complex
(MHC) class II and MHC class I molecules on
immune and retinal cells [8]. Ocular inflammation
is T-cell regulated and animal models have indi-
cated that marked migration of cells into the eye
leads to onset of structural damage in the retina
within 1215 days [7, 9]. In these models, inflam-
mation is mediated by T-helper-1 (Th-1) cells,
while Th-2 cells promoted immunosuppression
and remission [1013]. Other T-cell types have
been associated with intraocular inflammation
with downregulation of CD4+CD25+ regulatory
T (Treg) cells and increased Th-17 cell activity
both playing a role in the severity and resolution
of the inflammation [1416]. Dysfunction of
these immunosuppressive mechanisms results in
an uncontrolled intraocular immune response that
can lead to irreversible structural damage and loss
of visual function.
7.2 Steroid Treatment in Uveitis
Treatment of uveitis is based on the use of drugs
that are directed at suppressing clinically evident
inflammation, which can be administered either
systemically or locally. The cornerstone for
immunosuppressive treatment is corticosteroids
that act by multiple mechanisms including induc-
ing phospholipase-A2 inhibitory proteins that
control the synthesis of inflammatory mediators
such as prostaglandins and leukotrienes [17].
They inhibit vasodilatation, reduce vascular per-
meability, decrease leukocyte migration, and
reduce vascular endothelial growth factor
(VEGF) levels [18]. Corticosteroids also sup-
press T-cell proliferation and cytokine production
and decrease activation mechanisms such as
interferon production. Systemic corticosteroids
are generally considered best for use in cases of
bilateral intraocular inflammation causing a
threat to vision or uveitis with concomitant
systemic disease which requires corticosteroid
treatment. Though corticosteroids are highly
effective in controlling inflammation, they are
not without attendant side effects. When given
systemically, steroids are associated with an
L. Talat et al.
increased risk of raised blood glucose levels, sys-
temic hypertension, cushingoid effects, reduced
bone mass (steroid-induced osteopenia/osteopo-
rosis), and behavioral changes [19, 20]. In the
eye, systemic corticosteroids may cause cataract
formation/progression, central serous retinopa-
thy, or more rarely increased intraocular pressure
(IOP). In children, systemic corticosteroid treat-
ment can also rapidly result in reduced growth, as
well as delayed puberty [21]. Indeed, the risks
associated with using systemic steroids over any
period of time have led to the increased use of
locally administered steroids where possible for
the management of sight-threatening/sight-
reducing intraocular inflammation [22].
7.3 Local Steroid Treatment
in Uveitis
While systemic corticosteroids are very effective
in controlling ocular inflammation, the options
for local treatment are increasing. Their advan-
tage is achieving high concentrations of the drug
within close proximity of the target area, while
minimizing the risk of systemic side effects.
Corticosteroids can be administered around the
eye, through orbital floor or sub-tenon injections
and can be effective in controlling intermediate
or posterior uveitis using these routes [23].
Alternatively, use of intravitreal steroids or inser-
tion of slow-releasing steroid implants may prove
more effective under conditions when periocular
injections do not achieve adequate disease con-
trol [24, 25]. In this chapter, we will describe the
various intravitreal steroids used to treat uveitis
(Table 7.1).
7.3.1 Intravitreal Triamcinolone
Acetonide (IVTA) Injection
7.3.1.1 Dose and Administration
Triamcinolone acetonide (TA) is a water-
insoluble crystalline steroid in a suspension
which can be injected into the vitreous at a
therapeutic dose of typically 2 or 4 mg.
Kenalog-40 (40 mg/mL, Bristol-Myers Squibb,
7 Treatment of Uveitis with Intraocular Steroids 83

Table 7.1 Comparison of intravitreal corticosteroids used for noninfectious uveitis

Duration Uveitis Improved
Dose of effect activity vision by Cataract Glaucoma
(mg) Half-life (months) resolve 15 letters surgery surgery
Kenalog (TA) 4 18 days 35 33 % in 51 % in 29 %in 01 % in
4 monthsa 4 weeks a 2 yearsb 1 yearc
Ozurdex 0.7 5.5 h 46 47 % in 53 % in 0.4 % in 0 % in
(dexamethasone) 2 months 3 monthsd 6 months 6 months
Retisert (FAc) 0.59 1.7 h 2430 12 % in 21 % in 80 % in 26 % in
2 yearse 2 yearse 2 yearse 2 yearse
Iluvien(FAc)f 0.019 111 days 2430
TA triamcinolone acetonide, FAc fluocinolone acetonide
a
Kok et al. [24]
b
Gillies et al. [45]
c
Vasconcelos-Santos et al. [69]
d
The dexamethasone DDS phase II study group, 2009 [54]
e
Multicenter uveitis steroid treatment (MUST) trial research group, 2011 [55]
f
Based on the use of Iluvien in diabetic eyes with CME. No data available in uveitic eyes

NJ) is the most commonly used form for off-
label intravitreal injection with an advantage of
being cheap and easily available compare to
other alternative therapies. Other forms include
Trivaris TM (80 mg/mL, Allergan Inc., Irvine,
CA) and Triesence (40 mg/mL, Alcon Inc.,
Fort Worth, TX), both preservative-free TA
approved by the US food and drug administra-
tion (FDA) to treat ocular inflammatory dis-
eases, although their availability in different
countries varies.
7.3.1.2 Pharmacokinetics
Intravitreal injection can achieve a higher vit-
reous concentration of TA (1.2 g/mL) com-
pared to that following sub-tenon injection of
the same drug [26]. After the injection, the TA
gradually settles in the inferior vitreous in
most patients [27]. Once in the vitreous, it has
a half-life of approximately 18 days (3 days in
eyes that underwent previous vitrectomy) with
a therapeutic activity that lasts for approxi-
mately 3 months post injection [28]. The slow
rate of clearance gives IVTA superiority over
intravitreal injections of dexamethasone
sodium phosphate, which has a short half-life
of 5.5 h in the human eye [29] and is com-
pletely cleared from the vitreous within 72 h
post injection [30].
7.3.1.3 IVTA in Uveitis
IVTA was first administered in 1979 during reti-
nal detachment surgery to reduce cellular prolif-
eration [31]. These days it is widely used as a
therapeutic option in the management of macular
edema secondary to a variety of ocular patholo-
gies such as diabetic retinopathy [32], retinal
vein occlusion [33], and uveitis [34, 35]. In non-
infectious uveitis, IVTA has been reported as
effective in reducing cystoid macular edema
(CME) and vitritis, including CME secondary to
Behets disease [36], Vogt-Koyanagi-Harada
disease [37], non-TB-related serpiginous choroi-
ditis [38], and ankylosing spondylitis [39].
An early report of IVTA safety and efficacy
for CME in uveitis was a prospective pilot study
of six patients with chronic uveitis and visually
significant CME, which was refractory to all sys-
temic agents. Clinical and angiographic resolu-
tion of CME was evident in all patients by
6 weeks, together with improvement in visual
acuity by at least two Snellen lines [40]. In a ret-
rospective study of 65 eyes with uveitis and
refractory CME managed with IVTA injections,
the maximum vision improvement occurred at a
mean of 4 weeks during which 51 % had a sig-
nificant improvement in visual acuity of at least
two Snellen lines [24]. Additionally in pediatric
patients, a clinically significant improvement in
84
visual acuity was achieved in 56 % of 16 uveitic
eyes up to 15 months following IVTA injection
[41]. The long-term outcome of IVTA injections
has also been studied in uveitis secondary to
Behets disease where 87 % of the eyes had
complete resolution of vitritis within 6 months
post injection and 40 % had no relapse for up to
12 months [36].
A single IVTA injection was found to be supe-
rior to a single intravitreal bevacizumab injection
in improving the vision and reducing refractory
CME secondary to noninfectious uveitis 6 months
following injection [42]. A clinical trial of 31
eyes with CME in which patients were random-
ized to receive either repeat intravitreal injections
of either IVTA or bevacizumab found no signifi-
cant difference in visual improvement between
the groups up to 36 weeks. However, when
adjusted for the development of cataract, the
IVTA group had better visual outcome [43].
While IVTA injections allow for rapid and effec-
tive resolution of active uveitis and associated
macular edema, they have a relatively short half-
life [24, 28, 44], lasting several weeks to months,
limiting the duration of its therapeutic effect.
Repeat injections are required usually every
23 months, which increases the risk of develop-
ing ocular side effects.
7.3.1.4 Side Effects
and Contraindications
The main side effects following IVTA injections
include increased IOP and progression of cata-
ract. In a study examining the effect of IVTA in
eyes with uveitis, by 4 weeks following injection,
43 % of eyes had developed transient elevation in
IOP of >10 mmHg [24]. A randomized clinical
trial aimed at investigating the safety of a single
IVTA injection found increased IOP in 30 % of
cases, with almost two thirds requiring topical
antiglaucoma treatment for up to 8 months [45].
Young patients may also be vulnerable to devel-
oping increased IOP following IVTA injection
[22], shown in a study involving 16 eyes of pedi-
atric patients, where an IOP increase of
>15 mmHg occurred in 31 % of eyes [24, 41].
Other complications included progression of cat-
aract (55 %) and recurrence of CME (31 %).
L. Talat et al.
Thus, in children known to have experienced
steroid-induced raised IOP before, the use of
IVTA must be accompanied by measures to
ensure adequate IOP control, including surgical
intervention when needed.
Owing to the cataractogenic effect of cortico-
steroids as well as that induced by intraocular
inflammation, cataract progression and the even-
tual need to undergo cataract surgery are com-
mon after IVTA injection especially if multiple
injections are required. The risk of visually sig-
nificant cataract requiring surgery post IVTA
injection can vary but has been reported in one
study to occur in 29 % of uveitic eyes at an aver-
age of 2 years (1234 months) post IVTA injec-
tion compared to only 5 % of eyes that received a
placebo injection [45]. Repeat injections increase
the risk of developing significant cataract with up
to 100 % of patients requiring cataract extraction
surgery by the fourth injection [46].
Endophthalmitis is a rare, yet most serious
complication which can occur after any intravit-
real injection. With IVTA injection, the endo-
phthalmitis can be infective but can also be due to
noninfectious inflammation possibly secondary
to a toxic reaction against triamcinolone aceton-
ide or its preservatives [47]. While a systematic
review of literature from 1966 to 2004 estimated
the prevalence of all forms of endophthalmitis
post IVTA injections to be 1.4 % (0.6 % for bac-
terial endophthalmitis) [48], the use of the cur-
rent preventive strategies has resulted in a lower
incidence and recent reports found it ranging
from 0 % to 0.21 % [5, 36, 49].
Viral retinitis following IVTA injection,
although rare, has also been reported, and a litera-
ture review found 30 reported cases of viral retini-
tis within a mean of 4 months following intraocular
and periocular steroid injection [50]. Of these
cases, 70 % occurred post IVTA injection with
cytomegalovirus being the main isolated patho-
gen. Type 2 diabetes mellitus, human immune
deficiency virus (HIV) infection, and systemic
immunosuppressive therapies were considered
common comorbidities associated with the occur-
rence of viral retinitis post IVTA injection. IVTA
should always be avoided in cases where infec-
tious uveitis has not been excluded, including
7 Treatment of Uveitis with Intraocular Steroids
uveitis secondary to toxoplasmosis reactivation
that can progress to fulminant chorioretinitis fol-
lowing IVTA injection [51].
7.3.2 Extended-Release
Dexamethasone Implant
(Ozurdex)
7.3.2.1 Dose and Administration
The dexamethasone intravitreal implant
(Ozurdex, Allergan, Inc., Irvine, CA) is a biode-
gradable device that is inserted through the pars
plana into the vitreous using a 23 gauge needle
device preloaded with the implant. The implant
itself contains a therapeutic dose of 0.7 mg pre-
servative-free dexamethasone.
7.3.2.2 Pharmacokinetics
Dexamethasone is a potent, water-soluble, corti-
costeroid that is five times more potent than TA
and less toxic to the retina, but also has a shorter
half-life (3.55.5 h) and rapid clearance (72 h)
when given as an intravitreal injection [30, 52].
Inserting the drug into an implant made of a solid
bioerodable polymer allows for an extended,
dual-phase release of dexamethasone, an initial
rapid burst reaching peak concentration within
2 months, followed by a slower, sustained release
detected for up to 6 months [52].
7.3.2.3 Dexamethasone Implants
in Uveitis
Initially approved for the treatment of macular
edema following retinal vein occlusion, dexa-
methasone implants were approved by the FDA
in 2010 for the treatment of noninfectious inter-
mediate and posterior uveitis (Fig. 7.1) [53]. This
was the result of the encouraging outcomes
observed in published reports by the dexametha-
sone drug delivery system (DDS) phase II study
group [54]. In the first clinical trial, 41 eyes with
persistent macular edema secondary to uveitis or
Irvine-Gass syndrome were randomly assigned
to receive either a 0.35 mg, a 0.7 mg dexametha-
sone implant or to an observation group who
received no treatment nor sham procedures. At
3 months, there was a significant improvement in
85
visual acuity by at least 15 letters in 53.8 % of
eyes that received the 0.7 mg implant compare to
16.7 % of eyes with the 0.35 mg implant and only
7 % in the observed group. In addition, improve-
ment in macular leakage on fluorescein angiogra-
phy was observed in 58 % of eyes treated with
the 0.7 mg implant compared to 8 % of eyes
without an implant [54]. The HURON trial, a
prospective randomized trial involving 229
patients with noninfectious intermediate or pos-
terior uveitis, evaluated the efficacy of 0.35 and
0.7 mg intravitreal dexamethasone implants in
patients with significant vitreous haze over a
period of 8 weeks and then up to 26 weeks [55].
At 8 weeks, there was a significant reduction in
the vitreous haze score in 47 % of eyes receiving
the 0.7 mg implant compare to 36 % and 12 % in
those receiving the 0.35 mg implant or sham
injection, respectively. Approximately 34 % of
the eyes with the 0.7 mg implant had reduction of
vitreous haze that was maintained up to 26 weeks
postimplantation. In addition, visual acuity
improvement from baseline of 15 letters or more
was twice as likely to occur in treated eyes com-
pared to the sham-injected group.
While these studies focused on the effective-
ness of a single dexamethasone implant, a recent
observational study examined the outcome of
repeated implants in eyes with noninfectious
intermediate uveitis, posterior uveitis, and panu-
veitis [56]. In 38 eyes (63 % with repeat implan-
tations), there was an accumulating effect
resulting in continuing vision improvement and
reduced central retinal thickness when compared
to baseline. The relapse rate was 69 % within
6 months following the first implantation, and
48 % within 6 months following the second
implantation. A similar effect has also been
observed in a cohort of pediatric patients with
noninfectious uveitis [57].
7.3.2.4 Side Effects
and Contraindications
Elevated IOP and cataract progression can be
seen in eyes treated with dexamethasone implants
but are significantly less frequent when compared
to the rate seen with IVTA injections and fluo-
cinolone (Retisert) implants. In the HURON trial,
86
Fig. 7.1 Dexamethasone implant for cystoid macular
edema. (a) A 22-year-old patient suffering from interme-
diate uveitis with cystoid macular edema (CME) result-
ing in central retinal thickness (CRT) of 640 m and a
best corrected visual acuity (BCVA) of 6/24. (b) One
month following implantation, the CME resolves with
CRT of 237 m and BCVA returned to 6/6. A 62-year-
old patient suffering from chronic CME secondary to
eyes treated with the 0.7 mg dexamethasone
implants experienced increased IOP requiring
topical antiglaucoma treatment in 838 %
[5456] of eyes with none requiring glaucoma
surgery. A single case report of a child with inter-
mediate uveitis reported that he developed intrac-
table glaucoma, which continued to progress
even following removal of the implant and
L. Talat et al.
intermediate uveitis that was unresponsive to systemic
immunosuppression and intravitreal triamcinolone. (c)
Prior to the implant insertion, her CRT was 657 m with
BCVA of 6/60. (d) Four weeks following implantation,
the CME was almost completely resolved with a CRT of
183 m. Although the foveal architecture returned to
normal, visual function did not improve and remained at
6/36
required glaucoma surgery [58]. Cataract devel-
opment as an adverse effect of dexamethasone
implant was reported in a prospective random-
ized clinical trial in 15 % of 62 phakic eyes within
6 months after implantation, with one eye (1.6 %)
that required cataract extraction within the fol-
low-up period [55, 56]. Dexamethasone implants
should not be used in eyes with a compromised
7 Treatment of Uveitis with Intraocular Steroids
posterior lens capsule and in aphakic eyes due to
the high chance of implant migration into the
anterior chamber, which can result in significant
corneal decompensation requiring implant
removal [59].
7.3.3 Fluocinolone Acetonide
Intravitreal Implants
Fluocinolone acetonide (FAc) is one of the most
potent and selective glucocorticoids which does
not have a mineralocorticoid effect. FAc is avail-
able in two different intravitreal implant formula-
tions, Retisert (Bausch and Lomb, Irvine, CA)
and Iluvien (Alimera Sciences, Alpharetta, GA).
7.3.3.1 Retisert
Dose and Administration
Each Retisert implant consists of a pellet (a plas-
tic device with a flange with a semipermeable
membrane) containing 0.59 mg of FAc. The
implant is surgically implanted through a scle-
rotomy incision in the pars plana where it is
secured in position with a suture to the sclera.
The implant lasts on average up to 2.5 years
(30 months) when there is evidence of FAc deple-
tion and in some cases recurrence of uveitis,
requiring implant replacement.
Pharmacokinetics
Retisert consists of a nondegradable polyvinyl
alcohol and silicone-encased tablet that releases
FAc in low quantities over an extended period.
FAc is initially released at a rate of 0.6 g/day,
decreasing over the first month to a steady state
between 0.3 and 0.4 g/day over approximately
30 months [60].
Retisert in Uveitis
Retisert was approved by the FDA in 2005 for the
treatment of chronic, noninfectious posterior
uveitis. In a double-masked, multicenter con-
trolled clinical trial, 278 patients were random-
ized to receive either the 0.59 mg or the 2.1 mg
FAc implant. Both implants were able to stabilize
or improve the visual acuity in 87 % of eyes and
were able to reduce the rate of uveitis relapse
87
from 51.4 % in the 34 weeks preceding implanta-
tion to 6.1 % postimplantation. This was unlike
the fellow non-implanted eyes which showed an
increase in the rate of relapse from 20.3 % preim-
plantation to 42.0 % postimplantation [61].
A randomized, phase IIb/III, multicenter trial
assessed the safety and effectiveness of Retisert
in treating noninfectious uveitis compared to
standard therapy of systemic corticosteroid with
or without immunosuppressive agents. Eyes with
Retisert experienced a lower rate of recurrence of
uveitis compared to those on standard therapy
(18.2 % versus 63.5 %) [56].
The multicenter uveitis steroid treatment
(MUST) trial is an ongoing prospective study
setup to compare the visual acuity outcome in
patients with noninfectious intermediate uveitis,
posterior uveitis, or panuveitis randomized to
receive either systemic immunosuppression or
Retisert insertion, in both eyes if necessary and
withdrawal of systemic medication [62]. The
2-year results demonstrated that use of the implant
achieved similar results to systemic treatment
with regard to visual acuity but that control of the
uveitis was better at all time points in the Retisert-
treated patients. The longer-term outcome results
of the study are now awaited. Retisert has also
been reported in retrospective studies to control
inflammation and reduce the need for systemic
corticosteroids and immunosuppressives in
patients with sympathetic ophthalmia [63, 64].
Side Effects and Contraindications
Cataract is the most common side effect, with
80100 % of phakic eyes requiring cataract sur-
gery after 2 years [62, 65]. The MUST trial group
also found eyes with implants to have a fourfold
risk of developing IOP elevation of 10 mmHg
[62] and significantly higher incidence of glauco-
matous optic neuropathy over the first 2 years
compared with those assigned to systemic ther-
apy (23 % versus 6 %, respectively) [66]. Other
potential complications observed by 2 years post-
implantation include hypotony (8 %), vitreous
hemorrhage (15 %), retinal detachment (2 %),
and endophthalmitis (1.3 %) [45].
Fluocinolone implants are contraindicated in
patients who have concomitant viral diseases of
88
the cornea and conjunctiva such as epithelial her-
pes simplex, dendritic keratitis, vaccinia, vari-
cella, mycobacterial infections of the eye, and
ocular fungal disease [67].
A study comparing treatment of uveitis with
Ozurdex or Retisert implants found no superior-
ity of either treatment in terms of uveitis control
and visual acuity improvement. However, the
Retisert implant had higher rates of cataract pro-
gression compared to Ozurdex (100 % versus
50 %), as well as more need for glaucoma medi-
cations, and surgery [68].
7.3.3.2 Iluvien
Iluvien implants are approved in several European
countries for the treatment of chronic diabetic
macular edema (DME). Its effectiveness in man-
aging noninfectious uveitis has not been reported
to date.
Dose and Administration
Iluvien is a non-erodible implant which contains
FAc at a dose of 190 g and is injected into the
vitreous using a preloaded device with a 25 gauge
needle.
Pharmacokinetics
Following injection into the vitreous, the implant
releases FAc at a rate of 0.2 g/day, reaching an
intravitreal steady-state concentration of 2.2 ng/
mL, and continues to release FAc at a steady rate
for up to 36 months post injection.
Iluvien in Uveitis
No studies have been published to date.
Conclusions
Treatment of significant uveitis affecting the
posterior segment and causing visual loss has
historically required the use of systemic drugs
which can have extensive side effects. In addi-
tion, they are not always effective. The recent
advances in local treatment provide clinicians
with an increasing range of effective alterna-
tives to systemic therapy. These methods
deliver the therapeutic agent directly to the tar-
get area in the posterior segment of the eye,
providing a high intraocular concentration
L. Talat et al.
while minimizing systemic absorption. Ocular
side effects remain a significant issue espe-
cially with fluorinated steroids such as fluo-
cinolone or triamcinolone, and many patients
may require surgery for cataract and elevated
intraocular pressure. However, the visual out-
comes are good with good patient monitoring,
and these intraocularly delivered drugs provide
an effective option for management of patients
with sight threatening disease or in cases of
visual loss from the complications of uveitis.
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62. Kempen JH, Altaweel MM, Holbrook JT, et al.
Randomized comparison of systemic anti-
inflammatory therapy versus fluocinolone acetonide
implant for intermediate, posterior, and panuveitis:
the multicenter uveitis steroid treatment trial.
Ophthalmology. 2011;118:191626.
63. Rush RB, Goldstein DA, Callanan DG, Meghpara B,
Feuer WJ, Davis JL. Outcomes of birdshot chorioreti-
nopathy treated with an intravitreal sustained-release
fluocinolone acetonide-containing device. Am J
Ophthalmol. 2011;151:6306.
64. Mahajan VB, Gehrs KM, Goldstein DA, Fischer DH,
Lopez JS, Folk JC. Management of sympathetic oph-
thalmia with the fluocinolone acetonide implant.
Ophthalmology. 2009;116:5527.e1.
65. Pavesio C, Zierhut M, Bairi K, Comstock TL, Usner
DW. Evaluation of an intravitreal fluocinolone aceton-
ide implant versus standard systemic therapy in non-
infectious posterior uveitis. Ophthalmology. 2010;
117:56775, 75.e1.
66. Friedman DS, Holbrook JT, Ansari H, et al. Risk of
elevated intraocular pressure and glaucoma in
patients with uveitis: results of the multicenter uveitis
steroid treatment trial. Ophthalmology. 2013;120:
15719.
67. Inc. BL. Retisert (fluocinolone acetonide intravitreal
implant) 0.59 mg for intravitreal use: US prescribing
information. 2011. Bausch & Lomb Incorporated
Rochester, NY.
68. Arcinue CA, Ceron OM, Foster CS. A comparison
between the fluocinolone acetonide (retisert) and
dexamethasone (ozurdex) intravitreal implants in uve-
itis. J Ocul Pharmacol Ther Off J Assoc Ocul
Pharmacol Ther. 2013;29:5017.
69. Vasconcelos-Santos DV, Nehemy PG, Schachat AP,
Nehemy MB. Secondary ocular hypertension after
intravitreal injection of 4 mg of triamcinolone aceton-
ide: incidence and risk factors. Retina (Phila, Pa).
2008;28:57380.
 Steroids in a Combination
Strategy 8
Paolo Lanzetta, Daniele Veritti, and Valentina Sarao

Contents 8.6 Steroids and Pars Plana Vitrectomy. . . . . 100

8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 91 8.6.1 Diabetic Macular Edema . . . . . . . . . . . . . . . 100
8.6.2 Macular Edema Secondary to Retinal
8.2 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Vein Occlusion . . . . . . . . . . . . . . . . . . . . . . . 100
8.2.1 Neovascular AMD . . . . . . . . . . . . . . . . . . . . 92 8.6.3 Other Indications . . . . . . . . . . . . . . . . . . . . . 100
8.2.2 Macular Edema Secondary to Diabetes
and Retinal Vein Occlusion . . . . . . . . . . . . . 92 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

8.3 Steroids and Laser Photocoagulation. . . . 92 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

8.3.1 Diabetic Macular Edema . . . . . . . . . . . . . . .
8.3.2 Macular Edema Secondary to Retinal Vein
Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4 Steroids and Photodynamic Therapy
with Verteporfin . . . . . . . . . . . . . . . . . . . . .
8.4.1 Neovascular AMD . . . . . . . . . . . . . . . . . . . .
8.4.2 Other Indications . . . . . . . . . . . . . . . . . . . . .
8.5 Steroids and Anti-VEGF . . . . . . . . . . . . . .
8.5.1 Diabetic Macular Edema . . . . . . . . . . . . . . .
8.5.2 Macular Edema Secondary to Retinal
Vein Occlusion . . . . . . . . . . . . . . . . . . . . . . .
8.5.3 Neovascular AMD . . . . . . . . . . . . . . . . . . . .
8.5.4 Other Indications . . . . . . . . . . . . . . . . . . . . .
P. Lanzetta, MD (*) D. Veritti, MD
Department of Medical and Biological
Sciences Ophthalmology, University of Udine,
P.le S.M. della Misericordia, 33100 Udine, Italy
Istituto Europeo di Microchirugia Oculare IEMO,
Via M.A. Fiducio, 8, 33100 Udine, Italy
e-mail: paolo.lanzetta@iemo.eu;
verittidaniele@gmail.com
V. Sarao, MD
Department of Medical and Biological
Sciences Ophthalmology, University of Udine,
P.le S.M. della Misericordia, 33100 Udine, Italy
e-mail: sarao.valentina@gmail.com
92
94
95
95
96
96
96 8.1 Introduction
96
97 Todays retinal pharmacotherapy is the culmina-
99 tion of years of research in the fields of biology,
biotechnology, and pharmacology. Furthermore,
the advancements in the understanding of the
pathogenesis of posterior-segment diseases
allowed targeting important key points in the
pathogenic cascade more precisely. A revolution
in retinal pharmacotherapy has started with the
introduction of vascular endothelial growth fac-
tor (VEGF) inhibitors. Since then, anti-VEGF
therapy has become a paradigm in the treatment
of neovascular age-related macular degeneration
(AMD), diabetic macular edema (DME), and
macular edema secondary to retinal vein occlu-
sion (RVO).
However, while intravitreal anti-VEGF
monotherapy offers unprecedented benefit with

A.J. Augustin (ed.), Intravitreal Steroids, 91

DOI 10.1007/978-3-319-14487-0_8, Springer International Publishing Switzerland 2015
92
regard to visual outcome, it often requires mul-
tiple treatments, and a significant proportion of
patients do not respond to antiangiogenic treat-
ment alone or develop tolerance during the
follow-up.
The use of intravitreal steroids in association
with other agents allows broadening the thera-
pys spectrum of activity addressing multiple tar-
gets in the complex pathogenic pathway of
retinal diseases. This chapter reviews the ratio-
nale for combining intravitreal steroids to other
interventions and presents a synthesis of evi-
dence available.
8.2 Rationale
8.2.1 Neovascular AMD
Pathological choroidal neovascularization (CNV)
due to AMD is the result of a series of subretinal
changes in which neoangiogenesis, inflammation,
and cellular recruitment play a pivotal role [1].
The vascular component of CNV can be
advantageously targeted with anti-VEGF and
anti-platelet-derived growth factor (PDGF)
drugs. But, as in most biologic systems, inhi-
bition of one cascade upregulates alternate
pathways. Therefore, when treating neovascu-
lar AMD with antiangiogenic agents alone,
there is a theoretical risk of compensatory
upregulation of VEGF receptors and/or VEGF
production.
Corticosteroids act at numerous key points
of neoangiogenesis by altering cell behavior
and cytokine expression and have been shown
to be effective in reducing inflammation and
cellular recruitment, addressing the most
important pathogenic key points in the nonvas-
cular component of CNV development.
Therefore, combination approaches can lessen
the chance of compensatory rebound of non-
inhibited pathological pathways when directing
therapy to a single target. Additionally, com-
bined approaches may not only increase overall
efficacy but may also reduce the potential
adverse effects by allowing fewer re-treatments
needed.
P. Lanzetta et al.
8.2.2 Macular Edema Secondary
to Diabetes and Retinal Vein
Occlusion
Intraretinal accumulation of fluid is a hallmark of
DME and macular edema secondary to RVO. It is
usually accompanied by a blood-retinal barrier
(BRB) dysfunction. Steroids stabilize BRB, reduce
exudation, and downregulate inflammatory stimuli.
Steroids are believed to act by the induction of pro-
teins called lipocortins. These proteins reduce leu-
kocyte chemotaxis, control biosynthesis, and inhibit
the release of arachidonic acid from the phospho-
lipid membrane. Moreover, corticosteroids have
been shown to control gene expression of key medi-
ators. Steroids influence the expression of VEGF,
inhibit proinflammatory genes such as tumor necro-
sis factor-alpha (TNF-) and other inflammatory
chemokines, and induce the expression of anti-
inflammatory factors such as pigment-derived
growth factor (PEDF) [24]. It has been shown that,
besides inflammation and BRB breakdown, isch-
emia is a main driver of diabetic and RVO-related
macular edema. Therefore, combination therapy
with corticosteroids and anti-VEGF agents can be
used to target both the inflammatory and ischemic
drivers of macular edema (via vigorous VEGF inhi-
bition). Combining steroids with laser photocoagu-
lation and/or surgical removal of epiretinal
membrane allows a better oxygenation of the retinal
tissue and reduce hydrostatic pressure on capillaries
and venules. From a pharmacodynamic standpoint,
associating steroids with others agents has a strong
rationale to further widen the spectrum of action via
a synergistic treatment effect. From a pharmacoki-
netic point of view, combining agents with different
intravitreal half-lives may allow a rapid treatment
effect associated with prolonged duration of action
and reduced need of re-treatments.
8.3 Steroids and Laser
Photocoagulation
8.3.1 Diabetic Macular Edema
Combination therapy with intravitreal triamcino-
lone acetonide (IVTA) and laser photocoagulation
8 Steroids in a Combination Strategy
has been widely studied in many short- and long-
term clinical trials [511]. Several reports have
demonstrated that IVTA combined with macular
laser treatment produced better morphological
and functional outcomes compared with laser
treatment alone up to 6 months of follow-up
[57]. The first significant trial comparing laser
and IVTA was reported by Avitabile et al. [8] in
which patients were randomized to receive IVTA
alone or combined with grid laser at 3 months or
grid laser alone in the treatment of cystoid macu-
lar edema. At 45 days after treatment, the eyes of
the two groups receiving triamcinolone had better
visual acuity and lower central macular thickness
than those receiving photocoagulation. However,
the triamcinolone effect regressed 6 months after
injection. Lam et al. [9] reported a comparative
randomized controlled trial. Patients with DME
were randomized to grid laser photocoagulation
(37 eyes), 4 mg of IVTA (38 eyes), or 4 mg of
IVTA combined with sequential grid laser about
1 month later (36 eyes). After treatment, signifi-
cant central foveal thickness reductions were noted
in both the IVTA and combined groups at all fol-
low-up visits (p = 0.01) but not in the laser group.
The standardized reduction in macular thickening
at 17 weeks was significantly greater in the com-
bined group versus the IVTA group (p = 0.007),
suggesting that combined treatment might prolong
the effects of IVTA. The Diabetic Retinopathy
Clinical Research Network has investigated the
efficacy of intravitreal TA associated with laser
photocoagulation in eyes with DME involving the
central macula after 2 years of follow-up [11].
Patients were randomly assigned to one of four
groups: sham injection plus prompt laser, ranibi-
zumab 0.5 mg plus prompt laser, ranibizumab
0.5 mg plus deferred laser, and intravitreal TA
4 mg plus prompt laser. At 2 years, compared with
the sham + prompt laser group, mean change in
visual acuity from baseline was 3.7 letters greater
in ranibizumab + prompt laser group (p = 0.03),
5.8 letters greater in the ranibizumab + deferred
laser group (p < 0.01), and 1.5 letters worse in the
TA + prompt laser group (p = 0.35). The propor-
tion of patients that lost at least 15 letters was 10,
4, 2, and 13 % of eyes, respectively, and an
improvement in visual acuity by three or more
93
lines occurred in 18, 29, 28, and 22 % of eyes,
respectively. Compared with the sham + prompt
laser group, central retinal thickness decreased on
average by 31 m in the ranibizumab + prompt
laser group (p = 0.03), 28 m in the ranibizumab +
deferred laser group (p = 0.01), and 10 m in the
TA + prompt laser group (p = 0.37). These results
showed that patients treated with TA + prompt
laser did not experience a significant gain in
visual acuity compared to the other treatment
groups at 2 years of follow-up. However, in a sub-
group analysis, among individuals who were
pseudophakic at the baseline, TA + prompt laser
group reported an improvement in visual acuity
of more than 1.6 letters compared with the sham
+ prompt laser group. For eyes that were pseudo-
phakic at baseline in the TA plus prompt laser
group, improvement in mean visual acuity was
essentially the same as the groups treated with
ranibizumab (+0.5 letters in ranibizumab +
prompt laser group and +3.5 letters in the ranibi-
zumab + deferred laser group), suggesting that
the inferior result in eyes treated with intravitreal
TA was associated with the development of cata-
ract. Cataract surgery was performed in the 12 %
of phakic eyes in the sham + prompt laser and in
the ranibizumab + prompt laser groups, in the
13 % of phakic eyes in the ranibizumab + deferred
laser group, and in the 55 % of patients treated
with TA + laser. An IOP-lowering medication
was required in the 5 % of eyes in the sham +
prompt laser and ranibizumab + prompt laser
groups, in the 3 % of eyes in the ranibizumab +
deferred laser group, and in the 28 % of patients
of the TA + laser group [11, 12]. Other studies
have demonstrated promising results of combina-
tion therapy with intravitreal injection of TA and
laser photocoagulation for the treatment of prolif-
erative diabetic retinopathy (PDR) with clinically
significant macular edema (CSME) [1317]. In a
12-month randomized clinical trial conducted by
Maia et al. [18], 44 eyes with PDR and CSME
were randomized to receive treatment with com-
bined 40 mg of intravitreal triamcinolone aceton-
ide and laser photocoagulation (n = 22) or laser
photocoagulation alone (n = 22). On average,
best correct visual acuity (BCVA) improved sig-
nificantly (p < 0.001) in the TA and laser group
94
compared with the laser-alone group at all study
follow-up visits. An improvement of two or more
ETDRS lines was observed in 63.1 and 10.5 % of
eyes, respectively (p < 0.001). A significant
decrease in mean central macular thickness
occurred in the TA and laser group when com-
pared with the laser-alone group at all study fol-
low-up intervals (p < 0.001). At 12 months, mean
(SD) reductions in central macular thickness
were 123 68 m and 65 51 m, respectively result in synergistic effects as it targets both the
(p < 0.001). Despite the beneficial effect on visual
acuity and macular edema, especially during the
first months after initial treatment, IVTA use is
greatly limited by significant side effects, espe-
cially due to frequent re-treatment need [1921].
Therefore, the recent availability of an intravitreal
sustained-release corticosteroid device that would
be equally effective but safer was fully justified.
The results of combining dexamethasone implant
plus laser were recently examined in the PLACID
trial [22]. The purpose of this multicenter, ran-
domized study was to assess the efficacy and
safety of 0.7 mg dexamethasone intravitreal
implant associated with laser photocoagulation
compared with laser alone for treatment of diffuse
DME. Patients were randomized to treatment
with dexamethasone implant at baseline plus laser
(n = 126) or sham implant at baseline and laser
(n = 127). In this 1-year trial, patients in the dexa-
methasone group were eligible for a second
implant at 6 months and a third at 9 months if they
met re-treatment criteria. More patients with the
dexamethasone implant plus laser achieved a two-
line gain in visual acuity than with laser alone at
month 1 (p < 0.001) and month 9 (p = 0.007). After
9 months of treatment, this difference was no lon-
ger statistically significant. The mean improve-
ment in BCVA was significantly greater in
patients with diffuse DME who received the
implant plus laser than sham plus laser (up to 7.9
vs. 2.3 letters) at all time points through month 9
(p = 0.013). Areas of leakage and retinal thickness
decreased more in patients treating with dexa-
methasone and laser than those receiving laser
alone. A proportion of 1.0 % of patients at month
12 experienced elevation of IOP by 10 mg Hg or
more and no patient required surgery for IOP
management.
P. Lanzetta et al.
8.3.2 Macular Edema Secondary
to Retinal Vein Occlusion
Combining macular laser photocoagulation with
corticosteroid may increase the efficacy of treat-
ment for RVO-related macular edema in patients
who are not adequately responsive to laser
monotherapy. A combination approach of ste-
roid therapy with laser photocoagulation may
inflammatory and VEGF-related component at
multiple different points along the pathway.
Unfortunately, only a small number of studies
exploring RVO combination therapies have been
published to date. Most are short term and retro-
spective and/or involve small numbers of
patients [2325]. A case series has demonstrated
that TA combined with laser photocoagulation is
an effective treatment in eyes affected by persis-
tent macular edema after BRVO [25]. After
6 months of follow-up, the combination therapy
resulted in a significant reduction of central
foveal thickness (p = 0.001) and improvement of
visual acuity (p = 0.016) after a mean of 1.13
IVTA injections. It is known that grid photoco-
agulation has potential side effects, including
laser scar expansion, paracentral scotoma, ele-
vation of central visual field thresholds, second-
ary choroidal neovascularization, subretinal
fibrosis, and atrophy of the outer retinal layers.
In order to reduce the potential side effects due
to laser therapy, a prospective randomized clini-
cal trial has published the beneficial effects of
subthreshold grid laser photocoagulation
(SGLT) in combination with intravitreal TA in
eyes affected by macular edema secondary to
BRVO [26]. Twenty-four patients were random-
ized to the SGLT alone (13 eyes) or in combina-
tion with IVTA (11 eyes). At 12 months, the
mean number of lines gained was 3.4 in the
SGLT-TA group and 1.3 in the SGLT group. An
improvement in visual acuity by two lines
occurred in 91 and 62 %, respectively. The
authors reported a more rapid reduction in the
macular edema in the combined group in com-
parison with the SGLT group, which was main-
tained over the follow-up. The recent availability
of implants with corticosteroid has allowed
8 Steroids in a Combination Strategy
alternative approaches to treating macular
edema secondary to BRVO with combined ther-
apy [2729]. The intent of a 6-month trial was
to determine whether a sustained-release corti-
costeroid injection combined with macular grid
pattern laser could offer an additional benefit by
reducing the number of intravitreal implants
while maintaining the same visual acuity gain
and macular fluid reduction registered in patients
treated with as-needed dexamethasone [29]. In
this study, 50 patients with perfused macular
edema secondary to BRVO received an intravit-
real dexamethasone implant at the baseline and
were then randomized to dexamethasone implant
re-treatment on an as-needed basis (group 1,
n = 25 eyes) or macular grid photocoagulation
68 weeks after baseline followed by re-treat-
ment with pro re nata dexamethasone implant
(group 2, n = 25 eyes). After 6 months of follow-
up, mean BCVA improvement was 0.23 log-
MAR in group 1 and 0.15 logMAR in group 2.
Central macular thickness decreased on average
by 33.4 m in group 1 and 21.4 m in group 2 at
the end of follow-up. Re-treatment with dexa-
methasone implant was given in 12 % eyes in
group 1 and in 0 % in group 2 at the end of
follow-up.
8.4 Steroids and Photodynamic
Therapy with Verteporn
8.4.1 Neovascular AMD
A large number of publications confirmed the
positive synergic role of combining TA and PDT
therapy for the treatment of all types of CNV:
classic or predominantly classic, occult or mini-
mally classic, and RAP (retinal angiomatous
proliferation) lesions [3039]. Several uncon-
trolled studies indicate that combined PDT-V
and IVTA injection is more effective than either
treatment alone [30, 31]. Generally, these stud-
ies have shown that combination therapy might
play a role in reducing the frequency of PDT-V
sessions and improving visual outcome com-
pared with PDT alone. Spaide et al. [31] origi-
nally reported a 12-month follow-up of 26
95
patients with CNV who underwent combined
therapy with PDT and an injection of 4 mg of
TA. On average, an improvement in visual acu-
ity of 2.5 lines with a mean 1.24 combined treat-
ments was registered. Significant complications
can occur with this therapeutic combination,
including cataract (in up to 57 % of patients),
glaucoma (in up to 40 % of patients, sometimes
requiring surgical intervention), and endophthal-
mitis (<1 % of patients) [32]. The efficacy and
safety of PDT-V with IVTA in occult CNV were
investigated in a prospective and uncontrolled
study [33, 34]. A total of 41 patients were
included and followed up for 2 years. The mean
number of treatments needed was 1.8. Visual
acuity improved gradually in most patients, with
mean values of 20/133, 20/84, and 20/81 at
baseline 12 and 24 months after treatment,
respectively. A total of 11 of the 41 treated study
eyes (26.8 %) underwent cataract surgery
between 6 and 15 months after the first treat-
ment. Nine patients required local or systemic
glaucoma therapy owing to a transient steroid-
induced IOP increase. A randomized, masked,
controlled clinical trial of PDT-V and anecor-
tave acetate versus PDT and sham in 136 patients
with CNV due to AMD showed some visual
acuity benefit for the combination therapy over
the PDT and sham group (78 vs. 67 % of patients
had stable visual acuity), but the effect was not
statistically significant [35]. Chaudhary et al.
[36] reported a prospective, randomized pilot
study that demonstrated effective stabilization
of visual acuity and reduced treatment frequency
at 12 months with a combination of PDT-V and
IVTA therapy versus PDT-V alone. A total of 30
eyes with occult or minimally classic CNV due
to AMD were randomized to receive standard
PDT-V alone or combined PDT-V plus 12 mg
IVTA. The treatment rate was 1.13 in the PDT-V
plus IVTA group and 3.6 in the PDT-V-alone
group. Mean ETDRS scores for the PDT-V-
alone group at 3, 6, 9, and 12 months decreased
statistically from baseline by 5.7, 8.1, 9.1, and
13.3 letters, respectively. However, in the PDT-V
plus IVTA group, the ETDRS scores did not
decline significantly at any follow-up visit. The
mean decline in ETDRS scores at 3, 6, 9, and
96
12 months was 1.7, 3.7, 5.3, and 1.9 letters,
respectively. In the combined PDT plus IVTA
group, 60 % of patients achieved either stable or
improved vision compared with 33.3 % of cases
in the control group. A total of 13 % of patients
in the combined therapy and 53.3 % in the con-
trol group experienced moderate or severe vision
loss. However, in some clinical trials, patients
receiving IVTA and PDT-V did not show an
improvement in visual acuity, as compared to
the PDT-V-only treatment group [3739]. A
2-year, prospective, randomized study con-
ducted on 84 patients affected by new CNV sec-
ondary to AMD has confirmed that combination
of TA with PDT significantly reduced the num-
ber of PDT-V re-treatments needed to obtain
permanent inactivation of CNV [39]. However,
analysis of long- term visual outcomes revealed
that after an initial significant benefit observed
in the first year, the combination of PDT with
TA is associated with progressive visual decline
during the second year of follow-up. At the
24-month point, the combined group showed a
significant visual acuity worsening, reaching
values statistically similar to the PDT-only
group (p = 0.74). A reduction of visual function
may be explained by the increased risk of devel-
oping macular atrophy after the combination
therapy with intravitreal TA and PDT-V [39].
8.4.2 Other Indications
As reported in previous studies, IVTA reduces
the frequency of PDT-V re-treatment that could
result from combining the short-term effect of
PDT-induced CNV closure with antiangiogenic
and anti-inflammatory effects of intravitreal
corticosteroids [40]. Combination of PDT and
IVTA may reduce the need for re-treatment and
could be potentially useful for preserving vision
in some patients with CNV due to angioid
streaks or secondary to pathological myopia
[41, 42]. Possible adverse events of intrasurgical
use of TA (such as rise in IOP, endophthalmitis,
and cataract progression) have not been
described.
P. Lanzetta et al.
8.5 Steroids and Anti-VEGF
8.5.1 Diabetic Macular Edema
Various studies have reported the benefit of intra-
vitreal bevacizumab combined with corticoste-
roids for the treatment of DME [4348]. A
recently published systematic review and meta-
analysis was conducted to evaluate the short-term
effect of adding intravitreal bevacizumab to TA at
6, 12, and 24 weeks [48]. The authors have sug-
gested that combination therapy did not result in
any significant reduction in central thickness or
gain in vision compared to treatment with bevaci-
zumab alone at any point in time. However,
patients who experienced a significant gain in
vision after treatment with bevacizumab alone
did not maintain it through the following months,
showing a decrease of its beneficial effect up to
24 months of follow-up. The authors suggest that
the use of IVTA should be guarded against
because of cumulative side effects such as cata-
ract and glaucoma and potential toxicity of the
drug itself.
8.5.2 Macular Edema Secondary
to Retinal Vein Occlusion
In many studies, combination strategies with
anti-VEGF drugs have shown beneficial effects
in treating macular edema due to retinal vein
occlusion [49, 50]. Ehrlich et al. [50] reported
the 6-month results of combined treatment
using intravitreal bevacizumab and IVTA for
the treatment of macular edema secondary to
BRVO. At the end of the follow-up, the authors
concluded that combination treatment showed
beneficial effects in improving structural out-
comes such as central macular thickness, but
had no advantage over results with intravitreal
bevacizumab alone. Cekic et al. [51] compared
the three different intravitreal treatment modali-
ties, including intravitreal bevacizumab, IVTA,
and the combination of both. They concluded
that all treatment groups had similar therapeutic
effects at 1 month, but at 6 months of follow-up,
8 Steroids in a Combination Strategy
patients treated with bevacizumab alone
achieved better functional results. Recently, Lee
et al. [52] compared the long-term efficacy of
intravitreal TA, bevacizumab, and drug combi-
nation injections with focal grid laser photoco-
agulation for the treatment of macular edema
secondary to BRVO. Patients received one of
the following intravitreal treatments: 4 mg TA
monotherapy (n = 31), 1.25 mg bevacizumab
monotherapy (n = 95), or a combination of 2 mg
TA and 1.25 mg bevacizumab (n = 25). There
was no statistically significant difference in
change in visual acuity among the three groups
at 1, 3, 6, or 24 months postoperatively.
However, at the 12-month follow-up, the IVTA
group showed less visual improvement than did
the other groups, with statistical significance
(p = 0.01). A percentage of 16, 5.6, and 0 % of
participants in the three groups showed signifi-
cant visual loss of more than three lines of the
Snellen chart at the final follow-up examina-
tion. These considerations suggested that
although IVTA yielded outcomes similar to
those of standard grid photocoagulation, intra-
vitreal bevacizumab in monotherapy or a drug
combination resulted in significantly lower
visual loss and could be used as a valid alterna-
tive to grid laser photocoagulation.
Some studies were conducted to assess
whether dexamethasone intravitreal implant
0.7 mg with bevacizumab therapy can be syner-
gistic, providing further improvements in both
visual acuity and macular thickness, minimizing
the number of injections and increasing the dura-
tion of effects [5355]. In a prospective, consecu-
tive, nonrandomized interventional case series
were included 64 eyes of patients with ME asso-
ciated with RVO [54]. Patients were assigned to
two groups: group 1 in which 38 patients (22 eyes
with CRVO and 16 eyes with BRVO) were treated
using a dexamethasone implant alone and group
2 which consisted of 26 patients (14 cases with
CRVO and 12 cases with BRVO) and treated with
three consecutive intravitreal bevacizumab injec-
tions at monthly intervals followed by a dexa-
methasone implant 2 weeks later. In case of
recurrence, both cohorts received further dexa-
methasone implants. In group 1, BCVA improved
97
by 6.6 (1.7) letters in CRVO and 7.8 (2.9) in
BRVO patients and in group 2 by 9.8 (1.0) ver-
sus 9.4 (2.1) letters. A significant difference
was only seen between CRVO patients in groups
1 and 2 at 12 months (p < 0.05). Recurrence after
the first dexamethasone injection occurred after
3.8 (CRVO) and 3.5 months (BRVO) in group 1
versus 3.2 and 3.7 months in group 2. Elevated
IOP was measured in approximately 40 % and
cataract progression requiring surgery in about
50 % of eyes after three dexamethasone injec-
tions. The authors concluded that combined treat-
ment showed slightly better functional outcome
for CRVO patients at 1 year of follow-up.
Increased IOP and cataract progression were fre-
quent and should be considered when an individ-
ual treatment is planned.
8.5.3 Neovascular AMD
The combination of steroids and VEGF inhibitors
may overcome the shortcomings of anti-VEGF
monotherapy by addressing the multiple stimuli
that lead to angiogenesis, inflammation, and fibro-
sis. Data available in literature have reported that
the combined approach allows to prolong the ben-
eficial effects of anti-VEGF monotherapy and to
reduce the number of re-treatments. Some studies
have investigated the combined use of anti-
VEGFs with steroids in patients affected by CNV
secondary to AMD unresponsive to anti-VEGF
therapy. A retrospective 12-month case series has
analyzed 25 eyes with CNV due to AMD who
received a combination of intravitreal bevaci-
zumab (1 mg) and TA (4 mg) [56]. Re-treatment
with intravitreal bevacizumab or combination
therapy was considered at investigator discretion
at every follow-up visit. A trend toward progres-
sive loss of BCVA, from 1.08 to 1.31 logMAR,
had been observed in the 6 months before starting
the combination therapy, in spite of regular treat-
ment with anti-VEGFs (p < 0.0001). After combi-
nation therapy, a mean BCVA improvement of
0.18 (95 % CI: 0.05; 0.3) logMAR was reported
between baseline and the 12-month evaluation
(p < 0.01). OCT measurements showed a 139 mm
(95 % CI: 76; 203) decrease in mean central
98
retinal thickness (p < 0.01). On average, patients
required 1.8 additional treatments. Five (20 %)
cases of IOP elevation were successfully treated
with topical medications. In this study, the com-
bined approach seems to produce an inversion of
the tendency to visual loss in anti-VEGF nonre-
sponders, and, in addition, it suggests a reduced
need for re-treatment compared to those required
by anti-VEGF treatment alone. El-Matri and
coauthors [57] published the outcomes of com-
bined IVTA injection with intravitreal bevaci-
zumab in treating CNV associated with large
retinal pigment epithelial detachment (PED) in
seven eyes of five patients with AMD [53].
Triamcinolone and bevacizumab were adminis-
tered at 1-week interval. The combined treatment,
maintaining the same time interval between the
two agents, was repeated in four eyes, and the
number of intravitreal bevacizumab injection,
after combined therapy, ranged from 1 to 3. At the
end of the follow-up (914 months), FA showed
reduced or no leakage in all eyes, reduced foveal
thickness, and PED in all eyes.
A randomized controlled study evaluating the
use of the dexamethasone implant in combination
with ranibizumab in patients with treatment-
resistant neovascular AMD found that the implant
significantly delayed or reduced the need for
repeated ranibizumab injection. The treatment
also demonstrated an acceptable safety profile
[58]. The results of a 26-week multicenter open-
label trial, performed to evaluate the dexametha-
sone implant 0.7 mg as adjunctive therapy to
intravitreal ranibizumab in treatment-nave sub-
jects with subfoveal CNV secondary to AMD,
were recently reported [59]. The use of dexameth-
asone implant alone resulted in statistically signifi-
cant improvements in CRT from baseline as early
as week 1 and continued through week 4 (p < 0.01).
In addition, clinically significant improvements in
BCVA and fluorescein leakage were seen with the
implant alone. With the addition of ranibizumab,
statistically significant improvements in CRT,
BCVA, and FA leakage were seen (p < 0.001) at
every time point through the end of the study at
week 26. Most patients (84 %) did not need rescue
ranibizumab before 4 weeks. Over the course of
26 weeks, only three of the 44 patients enrolled
P. Lanzetta et al.
(6.8 %) received the maximum of six possible
ranibizumab injections, and 16 (36.4 %) received
five injections. Almost half of the patients (45.5 %)
required three or fewer injections of ranibizumab
over the study period to achieve these results, and
20.4 % needed one injection or fewer. This open-
label study provides the first demonstration of a
beneficial effect of the combination dexametha-
sone implant and ranibizumab in patients with
untreated neovascular AMD.
The benefit of adding intravitreal dexametha-
sone to the treatment of neovascular AMD with
anti-VEGF therapy was examined in the LuceDex
study [60]. This is a pilot randomized prospective
clinical trial in which 37 eyes were randomly
assigned to receive combination therapy with intra-
vitreal ranibizumab and dexamethasone implant
(group 1) or intravitreal ranibizumab monotherapy
(group 2). Visual acuity improvement was on aver-
age 11.1 and 5.9 ETDRS letters in groups 1 and 2,
respectively, at month 12. A gain of at least 15 let-
ters was achieved by six patients (35 %) in group 1
and four patients (20 %) in group 2 (p = 0.50). The
average number of treatments by month 12 was
7.1 in group 1 and 6.6 in group 2. Choroidal neo-
vascular membrane size decreased in group 1 sig-
nificantly compared with group 2 (p < 0.05).
Other studies have reported the beneficial effect
of a triple therapy strategy in which the adminis-
tration of anti-VEGF drugs was associated with
PDT-V and steroids. Augustin et al. [61] investi-
gated the efficacy and safety of triple therapy with
PDT-V (42 J/cm2), intravitreal dexamethasone
(800 g), and intravitreal bevacizumab (1.5 mg).
One hundred and four eyes were included in the
study; the baseline mean VA was 0.8 logMAR. A
mean increase in visual acuity of 1.8 lines was
reported at a mean follow-up of 40 weeks. Eighteen
eyes required an additional intravitreal bevaci-
zumab injection and five eyes necessitated a sec-
ond cycle of triple therapy. Bakri et al. [62]
reviewed retrospectively the safety and efficacy of
same-day therapy with PDT-V (25 J/cm2), intravit-
real dexamethasone (200 g), and bevacizumab
(1.25 mg) in 31 eyes. Visual acuity improved from
0.61 to 0.58 logMAR after a mean follow-up of
13.7 months. Re-treatment was given with a mean
of 2.3 anti-VEGF injections and 0.3 repeat TT
8 Steroids in a Combination Strategy
treatments. Ahmadieh et al. [63] evaluated the
functional results of triple therapy with PDT-V
(50 J/cm2; 600 mW/cm2), intravitreal triamcino-
lone (2 mg), and intravitreal bevacizumab
(1.25 mg) in 17 eyes. Mean VA at baseline was
0.74 logMAR. VA improved by 0.33 logMAR
after 24 weeks with a mean of 1.1 additional intra-
vitreal bevacizumab injections per eye. Yip et al.
[64] reported the results of triple therapy with
PDT-V (50 J/cm2; 600 mW/cm2), IVTA (4 mg),
and intravitreal bevacizumab (1.25 mg) in 36 eyes
with neovascular AMD. Mean VA at baseline was
1.22 logMAR, and the mean follow-up time was
14.7 months. At the end of the follow-up, mean
improvement in VA was 0.04 logMAR. A single
session of triple therapy led to complete resolution
of angiographic evidence of CNV in 77.8 % of
cases. Forte et al. [65] reviewed retrospectively the
efficacy of PDT-V (50 J/cm2), intravitreal dexa-
methasone, and ranibizumab or bevacizumab in 21
eyes. They reported a significant improvement of
visual acuity and foveal thickness with a mean
follow-up of 14 months. No adverse effects were
observed. Ehmann et al. [66] studied prospectively
the safety and efficacy of same-day PDT-V (25 J/
cm2) and intravitreal dexamethasone (800 g). At
1 and 7 weeks, patients received a bevacizumab
(1.25 mg) injection. Thirty-two eyes were included
and followed-up for 12 months. Visual acuity
improved from 0.74 to 0.53 logMAR. In the
RADICAL study, 162 patients were randomized
to one of four treatment arms: double therapy with
reduced fluence PDT-V (25 J/cm2) followed by
ranibizumab, reduced-fluence PDT-V (25 J/cm2)
followed by ranibizumab-dexamethasone triple
therapy, very low-fluence PDT-V (15 J/cm2) fol-
lowed by ranibizumab-dexamethasone triple ther-
apy, or ranibizumab monotherapy [67]. The
24-month results showed that mean visual acuity
change from baseline was not statistically different
among the treatment groups. Mean visual acuity in
the double-therapy group decreased by two
ETDRS letters, in the TT half-fluence group
improved by two letters, in the TT very low-
fluence group improved by 0.3 letters, and in the
monotherapy group improved by 3.8 letters.
Through 24 months, patients in the TT half-fluence
group had a mean of 4.2 re-treatments compared
99
with 8.9 for the ranibizumab monotherapy group.
The number of individual treatments was 12.6 in
the TT half-fluence group and 8.9 in the ranibi-
zumab monotherapy group. A 6-month interven-
tional case series has investigated the effects of
adjunctive use of intravitreal ranibizumab, modi-
fied juxtascleral triamcinolone acetonide, and
PDT-V with different irradiance in 25 patients
affected by CNV secondary to AMD and nonre-
sponder to anti-VEGF monotherapy [68]. The first
ten eyes (cohort 1) enrolled received triple therapy
(TT) with reduced fluence/reduced irradiance
PDT-V (25 J/cm2, 300 mW/cm2), cohort 2 (n = 10)
received TT with reduced fluence/standard irradi-
ance PDT-V (25 J/cm2, 600 mW/cm2), and the last
ten eyes included (cohort 3) were treated with TT
with standard fluence/standard irradiance PDT-V
(50 J/cm2, 600 mW/cm2). At the end of the follow-
up, mean BCVA change was 0.15, 0.13, and
0.29 logMAR, respectively. The mean number of
ranibizumab reinjections was 0.7 (cohort 1), 0.8
(cohort 2), and 0.5 (cohort 3). No patient experi-
enced a severe VA loss. In one case, a moderate
visual loss was reported among patients included
in cohort 3. Among all eyes enrolled, in five
(17 %), topical treatment was required due to IOP
25 mmHg. In all cases, the increase in IOP
resolved within 3 months, and thus the medication
was discontinued. One of the 20 phakic eyes at
baseline required cataract surgery. The authors
confirmed that triple therapy can potentially be a
safe and effective new treatment modality for
patients who fail to demonstrate an appropriate
response to anti-VEGF monotherapy. Reduced
fluence PDT seems to be safer than standard flu-
ence PDT and to warren better functional results.
8.5.4 Other Indications
Several published works reported a beneficial
role for IVTA as an adjuvant to bevacizumab for
the treatment of macular edema in patients with
astrocytic hamartomas and tuberous sclerosis
[69] and Coatss disease [70] and due to radiation
retinopathy in patients with posterior uveal mela-
noma [71]. Severe local or systemic side effects
were not observed.
100
8.6 Steroids and Pars Plana
Vitrectomy
8.6.1 Diabetic Macular Edema
Triamcinolone acetonide in combination with
pars plana vitrectomy with or without laser pho-
tocoagulation has recently shown beneficial
effects on both anatomical and functional out-
comes in eyes with nontractional DME refractory
to anti-VEGF therapy, proliferative diabetic reti-
nopathy, and proliferative vitreoretinopathy [72,
73].
8.6.2 Macular Edema Secondary
to Retinal Vein Occlusion
The benefit of combined vitrectomy (with or
without internal limiting membrane peeling) with
IVTA is unclear for the treatment of macular
edema secondary to RVO [7476]. Vitrectomy
with sheathotomy has been combined with IVTA,
showing favorable results of 13 Snellen lines for
CRVO [76, 77] and BRVO [78, 79]. RON com-
bined with vitrectomy and IVTA has also been
described with improved VA and decreased cen-
tral macular thickness [80, 81]. In the combined
treatment group, in terms of VA and macular
thickness, hemodilution treatment for CRVO has
been compared with hemodilution with IVTA
with improvement [82]. Lewis et al. [83] com-
pared maculopexy assisted by gas and/or triam-
cinolone for BRVO with macular edema. Patients
undergoing gas-assisted treatment showed
greater VA improvement than the IVTA group.
Promising results have been described for triple
therapy with IVTA, bevacizumab, and vitrec-
tomy. However, there is a lack of large, multi-
center, randomized controlled trials to support
these results [73].
8.6.3 Other Indications
Another study has investigated the efficacy of
pars plana vitrectomy with additional intraopera-
tive intravitreal TA injection on the course of
P. Lanzetta et al.
CME in patients with uveitis [84]. After
12 months, CME was improved in 44 % of patient
and worsened in 12 % of cases. A mean improve-
ment in visual acuity was noted in 28 % of eyes
after 12 months. However, development or pro-
gression of cataract and increased IOP were fre-
quent. Cataract progressed in 85 % of the phakic
patients postoperatively. Increased IOP was
detected in 11 % 12 months after surgery.
Conclusions
The aim of combining intravitreal steroids to
other treatments is to take advantage of syner-
gies among the complementary means of
action of different drugs and interventions to
provide similar or better efficacy outcomes
than approved therapies while reducing treat-
ment frequency and the proportion of nonre-
sponder patients. The results presented in this
chapter support the use of steroids in associa-
tion with anti-VEGF agents in the treatment of
neovascular AMD, DME, and macular edema
secondary to RVO. However, the level of evi-
dence is still low, and further studies are
needed to better elucidate which are the most
efficacious and safe combinations and what is
the best treatment regimen/dosage. Moreover,
it is needed to clarify which patients would
benefit the most from a combination approach
rather than monotherapy.
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 Intravitreal Steroids as a Surgical
Adjunct 9
Stanislao Rizzo, Tomaso Caporossi,
and Francesco Barca

Contents
9.1 Introduction
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 105
9.2 Preoperative Therapeutic Uses . . . . . . . . . 105 Corticosteroids are powerful tools for preserving
9.3 Intraoperative Use of Steroids ocular tissues due to their anti-inflammatory,
as Surgical Instrument . . . . . . . . . . . . . . . 106 anti-permeability, and anti-fibrotic properties.
9.4 Use During and After Vitrectomy: Steroids can be administered through topical
As an Adjuvant. . . . . . . . . . . . . . . . . . . . . . 107 application, intravitreal injection, and, more
9.4.1 Proliferative Vitreoretinopathy (PVR) . . . . . 107 recently, sustained-release delivery vehicles.
9.4.2 Macular Edema After Membrane Systemic administration of steroids is not useful
Peeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
9.4.3 Chronic Refractory Uveitic Hypotony. . . . . 108 as a long-term therapeutic approach in the man-
9.4.4 Macular Edema in Vitrectomized agement of ophthalmic diseases.
Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 This class of drugs plays key roles before,
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 during, and after ophthalmic surgery. Alone or
as part of a combined therapeutic approach,
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
corticosteroids reduce the patients ability to
mount a strong inflammatory response to
surgery.

9.2 Preoperative
Therapeutic Uses

Steroids are a mainstay in the management of a

wide range of inflammatory and vascular poste-
S. Rizzo, MD
rior segment disease including diabetic macular
Department of Neuroscience,
Azienda Ospedaliera Universitaria Pisana, edema (DME) [14], proliferative diabetic reti-
Viaparadisa n 2, Pisa 56124, Italy nopathy (PDR) [57], central retinal vein occlu-
e-mail: stanislaorizzo@gmail.com sion (CRVO) [810], branch retinal vein
T. Caporossi (*) F. Barca, MD occlusion (BRVO) [810], neovascular glau-
Chirurgia Oftalmica, Azienda Ospedaliera coma, chronic hypotony (phthisis), chronic uve-
Universitaria Pisana, via Paradisa n 2,
itis, pseudophakic cystoid macular edema
Pisa 56124, Italy
e-mail: tomaso.caporossi@me.com; (PCME), and neovascular age-related macular
barcaf@hotmail.com degeneration (AMD) [11].

A.J. Augustin (ed.), Intravitreal Steroids, 105

DOI 10.1007/978-3-319-14487-0_9, Springer International Publishing Switzerland 2015
106 S. Rizzo et al.

9.3 Intraoperative Use floating in the vitreous cavity (Fig. 9.2). The
of Steroids as Surgical absence of TA particles on the underlying retina
Instrument helped to identify areas where the ILM had been
successfully removed. Use of TA in peeling of
Triamcinolone acetonide (TA) is a water- the ERM has also been described as part of a
insoluble steroid molecule that has been used in double-staining technique with brilliant blue G
ophthalmic surgery as a stain to improve the visu- vital dye [16].
alization of ophthalmic structures such as the Staining of the vitreous with TA can facilitate
cortical vitreous and the internal limiting mem- its effective removal in a variety of surgical sce-
brane (ILM). Granules of TA are trapped on the narios. Sonoda et al. [17] used TA to identify
surface of the vitreous body, making it clearly residual vitreous cortex in a series of eyes that
visible under the surgical microscope. This prop- underwent vitrectomy for a variety of patholo-
erty is thought to be due to the integration of gies including diabetic retinopathy, diabetic mac-
insoluble white TA crystals into loosely orga- ular edema, branch retinal vein occlusion, and
nized collagen matrices in the vitreous [12]. rhegmatogenous retinal detachment (RRD). TA
The use of a corticosteroid as a surgical instru- helped to visualize residual vitreous cortex on the
ment was first suggested by Peyman et al. [12]
who described the use of TA to improve visual-
ization of the vitreous and the posterior hyaloid
during pars plana vitrectomy (PPV) (Fig. 9.1).
These authors showed that TA adheres to vitreous
fibrils, but not to the retina; when TA is injected
into the vitreous cavity, the crystals become
trapped in the vitreous gel, and the suspension
creates good visual contrast between the whit-
ened vitreous and the post-hyaloid space, which
contains a free-floating suspension of TA parti-
cles. Intraoperative injection of TA can be used to
demonstrate the vitreous anatomy, including the
highlighting of the invisible residual cortical
vitreous.
An extension of this mechanism is thought to Fig. 9.1 Posterior hyaloid stained with TA
be responsible for the staining of the superficial
portions of the ILM and epiretinal membrane
(ERM). Electron microscopy studies have shown
that a small layer of cells and collagen fibers
remains attached to the retina after manual vitre-
ous detachment. The latter residual material may
be responsible for the integration of TA crystals,
allowing the visualization of the ILM and ERM
[1315]. TA crystals entrapped in superficial col-
lagen fibrils facilitate the identification of the
ILM and ERM through the microscope [14]. TA
application can be repeated until the desired visu-
alization is achieved [1315].
Tognetto et al. [15] showed that TA staining is
useful in ILM peeling during vitreoretinal sur-
gery. Once peeled, the stained ILM could be seen Fig. 9.2 ILM visualization with TA during peeling
9 Intravitreal Steroids as a Surgical Adjunct
retinal surface after surgical posterior vitreous
separation during a PPV, especially in patients
with diabetic retinopathy.
TA can also be used during surgical repair of
proliferative vitreoretinopathy (PVR). Furino
et al. [18] described the use of TA to facilitate
removal of the posterior hyaloid and ERM in
patients undergoing PPV for RRD as a complica-
tion of PVR. Staining with TA improved visual-
ization of the posterior hyaloid and ERM,
allowing more complete ERM removal in this
critical scenario. TA was safe and well tolerated
when used in a low concentration and rapidly
removed during surgery.
The value of steroids and steroid-like factors
to visualize prolapsed vitreous was soon recog-
nized by anterior segment surgeons. Huang et al.
[19] used a precursor of cortisol without steroid
activity (11-deoxycortisol) to visualize vitreous
in the anterior chamber in an animal model of
posterior capsule rupture. The use of TA in com-
plicated cataract surgery was found to be benefi-
cial to visualize vitreous in the anterior chamber;
Yamakiri et al. [20] recommended a washout of
the anterior chamber to avoid complications such
as elevation of IOP.
9.4 Use During and After
Vitrectomy: As an Adjuvant
The use of steroids as an adjuvant during or after
vitrectomy has been suggested for numerous
indications, including control of PVR, reduction
of macular edema after membrane peeling, treat-
ment of chronic refractory uveitic hypotony, and
treatment of macular edema in vitrectomized
patients.
9.4.1 Proliferative
Vitreoretinopathy (PVR)
PVR can occur as a complication of RRD. Surgical
approaches to the management of PVR include
PPV, membrane peeling, endolaser application,
and postoperative intraocular tamponade. Despite
these measures, PVR can recur after surgery,
107
with proliferation of membranes on both the
retina and the vitreous base [21].
In 1980, Tano et al. [22] showed that intravit-
real injection of dexamethasone inhibited fibro-
blast growth in a rabbit model of intraocular
proliferation and tractional retinal detachment.
Later, in a model of PVR induced with macro-
phages, Hui and Hu [23] showed that a combina-
tion of daunomycin and TA was effective in
preventing development of PVR in rabbits.
A randomized controlled clinical trial pub-
lished in 2008 showed no benefit of adjunctive
TA injected into the vitreous cavity in eyes filled
with silicone oil after PVR surgery. The trial was
conducted to investigate the role of silicone oil
(frequently administered as a tamponade in sur-
gery for PVR) as a vehicle for long-term postop-
erative release of steroids. Ahmadieh and
colleagues [21] found no benefit in outcomes
with the injection of 4 mg TA after surgery. The
retinal reattachment rate was not statistically sig-
nificantly different between treatment and con-
trol groups at 6 months follow-up.
9.4.2 Macular Edema After
Membrane Peeling
Recently, the effects of intraoperative and post-
operative use of steroids in membrane-peeling
surgery have been investigated by several authors.
The major findings suggest that local or systemic
steroid treatment, during or after successful vit-
rectomy combined with peeling, does not
improve anatomic and functional outcomes.
TA injected during vitrectomy and membrane
peeling in patients with idiopathic ERM did not
affect postoperative foveal thickness or func-
tional recovery [24]. Similarly, there was no dif-
ference with or without the use of intravitreal TA
in long-term anatomic and visual outcomes after
vitrectomy and membrane peeling in patients
with idiopathic ERM, although there was an
increased risk of IOP elevation [25].
Ritter and colleagues [26] prospectively eval-
uated the use of systemic steroids after mem-
brane peeling in eyes with macular edema due to
idiopathic ERM. Patients undergoing 23-gauge
108
vitrectomy with ERM and ILM peeling were ran-
domly assigned to receive postoperative oral
prednisolone. No statistically significant differ-
ences in anatomic or functional outcomes were
found between treated and control group at up to
3 months postoperative.
9.4.3 Chronic Refractory Uveitic
Hypotony
Long-term intraocular delivery of the steroid
fluocinolone acetonide (FA) has been evaluated
in the treatment of refractory uveitic hypotony.
Dayani et al. [27] reported the results of com-
bined PPV, insertion of a sustained-delivery FA
implant, and silicone oil infusion in 13 eyes with
refractory uveitic hypotony with a mean baseline
IOP of 2.3 mmHg. At 6, 12, and 24 months fol-
low-up, postoperative mean IOP was 5.9 mmHg,
5.1 mmHg, and 5.0 mmHg, respectively. No
intraoperative complications were described, and
the procedure was well tolerated by patients.
9.4.4 Macular Edema
in Vitrectomized Patients
Macular edema can occur as an inflammatory
reaction after vitreoretinal surgery, including vit-
rectomy. Steroid therapy is a potential approach
to treat macular edema after vitrectomy. However,
several studies have indicated that a number of
drugs are cleared from the posterior segment
faster in vitrectomized eyes than in eyes with an
intact vitreous.
In the 1980s, Schindler and colleagues [28]
showed rapid clearance of TA from vitrectomized
rabbit eyes (average 17 days) compared with eyes
without surgery (average 41 days).
More recently, Chin et al. [29] compared the
clearance of TA between vitrectomized (n = 42)
and non-vitrectomized (n = 42) rabbit eyes. The
concentration of TA decreased 1.5 times more rap-
idly in vitrectomized than non-vitrectomized eyes.
At 30-day follow-up, TA was detected in only one
eye in the vitrectomized group (0.22 g/mL) com-
pared with four eyes in the non-vitrectomized
S. Rizzo et al.
group (mean 0.92 g/mL). The authors concluded
that faster clearance of the drug should be consid-
ered when intravitreal injection of TA is used in
vitrectomized eyes.
Similar differences in clearance rates have
been reported with VEGF [30], amphotericin B
[31], and 5-fluorouracil [32], with faster clear-
ance from vitrectomized than non-vitrectomized
rabbit eyes.
The use of sustained-release delivery modalities
may be a solution to this rapid clearance. Chang-
Lin and colleagues [33] assessed the pharmacoki-
netics of a sustained-release 0.7-mg dexamethasone
intravitreal implant in vitrectomized (n = 25) and
non-vitrectomized (n = 25) rabbit eyes, showing
that the maximum concentration of dexamethasone
in the vitreous humor of non-vitrectomized eyes
was 791 ng/mL, compared with 731 ng/mL in vit-
rectomized eyes at 22-day follow-up.
The CHAMPLAIN Study Group [34] evalu-
ated the effectiveness of the 0.7-mg dexametha-
sone intravitreal implant for the treatment of
diabetic macular edema (DME) in vitrectomized
eyes. In this prospective multicenter study, 55
patients with refractory DME (mean duration,
43 months) and history of PPV received a single
0.7-mg implant. Statistically and clinically sig-
nificant improvements in visual acuity and cen-
tral retinal thickness were shown in treated eyes
during the follow-up.
Conclusions
From its height of popularity a few years ago,
the use of intravitreal TA has exponentially
decreased due to a high rate of complication.
The association of corticosteroid therapy with
the development of posterior subcapsular cat-
aracts has been well documented. Despite
these findings, these drugs are widely used
therapeutically, principally to capitalize on
their ability to inhibit inflammatory responses
before, during, and after surgery.
For many years, an injectable intramuscu-
lar suspension of TA was adapted for ophthal-
mic use because no ophthalmic formulation
was commercially available. Recently, inject-
able suspensions have become available for
intravitreal injection, with indications from
9 Intravitreal Steroids as a Surgical Adjunct
the US FDA for use in sympathetic ophthal-
mia, temporal arteritis, uveitis, and ocular
inflammatory conditions unresponsive to topi-
cal corticosteroids. A sustained-release dexa-
methasone intravitreal implant has FDA
approval for the treatment of macular edema
following BRVO and CRVO and for the treat-
ment of noninfectious uveitis affecting the
posterior segment. A 0.59-mg FA intravitreal
implant is FDA approved for the treatment of
chronic noninfectious uveitis affecting the
posterior segment. A smaller, 190-g FA
implant is approved in some countries in
Europe for the treatment of vision impairment
associated with chronic DME insufficiently
responsive to other available therapies.
Steroids are useful to better visualize the
vitreous, as a non-colorant precipitating stain-
ing agent in uncomplicated membrane peeling
and in sustained-release delivery modes in
intraocular inflammatory diseases. Steroids
are not effective to treat macular edema in vit-
rectomized eyes or to visualize the ILM in
complex cases such as highly myopic eyes.
The therapeutic use of steroids remains invalu-
able in the treatment of inflammatory patholo-
gies such as uveitis.
Widening therapeutic indications and the
availability of new longer-lasting sustained-
release delivery modes for corticosteroids will
lead to new approaches to treat the widest pos-
sible range of ocular diseases, along with sig-
nificant lowering of health-care costs for both
patients and institutions.
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