Current Concepts

Current Concepts in
Ophthalmology
Andrzej Grzybowski
Editor
123
Current Concepts in Ophthalmology
Andrzej Grzybowski
Editor
Current Concepts
in Ophthalmology
Editor
Andrzej Grzybowski
Department of Ophthalmology
University of Warmia and Mazury
Poznan
Poland
ISBN 978-3-030-25388-2 ISBN 978-3-030-25389-9 (eBook)

https://doi.org/10.1007/978-3-030-25389-9
© Springer Nature Switzerland AG 2020

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Contents
1 Updates in Refractive Surgery�� 1

M. Joan T. D. Balgos and Jorge L. Alió
2 Recent Developments in Cornea and Corneal Transplants�� 35
Caterina Sarnicola, Enrica Sarnicola, Paolo Perri, and
Vincenzo Sarnicola
3 Recent Developments in Cataract Surgery�� 55
Andrzej Grzybowski and Piotr Kanclerz
4 Recent Developments in Glaucoma�� 99
Nathan M. Kerr and Keith Barton
5 Recent Advances in Uveitis�� 121
Xia Ni Wu, Lazha Ahmed Talat Sharief, Roy Schwartz, Þóra
Elísabet Jónsdóttir, Anastasia Tasiopoulou, Ahmed Al-Janabi,
Noura Al Qassimi, Amgad Mahmoud, Sue Lightman,
and Oren Tomkins-Netzer
6 Recent Developments in Maculopathy�� 141
Francesco Bandello, Marco Battista, Maria Brambati,
Vincenzo Starace, Alessandro Arrigo, and Maurizio Battaglia Parodi
7 Recent Developments in Vitreo-Retinal Surgery�� 165
Sana Idrees, Ajay E. Kuriyan, Stephen G. Schwartz,
Jean-Marie Parel, and Harry W. Flynn Jr
8 Clinical Updates and Recent Developments
in Neuro-Ophthalmology�� 201
Amrita-Amanda D. Vuppala and Neil R. Miller
v
vi Contents
9 Recent Advances in Pediatric Ophthalmology�� 251

Ken K. Nischal
10 Recent Developments in Ocular Oncology�� 275
Bertil Damato
Index�� 295
Chapter 1
Updates in Refractive Surgery
M. Joan T. D. Balgos and Jorge L. Alió
Introduction
The correction of refractive errors—hyperopia, myopia, astigmatism, and presby-

opia—is of interest to eye practitioners worldwide. Functionally, good vision allows
one to do his activities of daily life without assistance. Cosmesis and convenience,
especially for people who live active lifestyles, require a decrease or elimination in
dependency on spectacles and contact lenses. Refractive surgery aims to improve the
refractive state of the eye caused by ammetropia—whether due to the globe’s axial
length or through a difference in the refractive power of the cornea and the lens—or
by pathologies such as keratoconus. Modern means for achieving this include topi-
cal medications, surgical remodeling of the cornea, intraocular lens implantation,
and crystalline lens extraction and replacement with an intraocular implant.
Pharmacologic Treatment of Presbyopia
Several classes of eyedrops that address presbyopia are being developed or are cur-
rently under clinical evaluation [1]. One such type of eyedrop involves parasympa-
thomimetics. Whether in combination with a non-steroidal anti-inflammatory drug
or with tropicamide, these drops have been reported to stimulate parasympathetic
innervation and induce ciliary body stimulation and miosis, resulting in an increased
M. J. T. D. Balgos
Vissum, Alicante, Spain
J. L. Alió (*)
Vissum, Alicante, Spain
Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain
e-mail: [email protected]
© Springer Nature Switzerland AG 2020 1

A. Grzybowski (ed.), Current Concepts in Ophthalmology,
https://doi.org/10.1007/978-3-030-25389-9_1
2 M. J. T. D. Balgos and J. L. Alió
depth of focus [2]. Pilot studies have reported improvement of both uncorrected dis-
tance visual acuity (UDVA) and uncorrected near visual acuity (UNVA), and some
are currently in phase IIb trials. Most of the effect diminished after several hours;
adverse effects include headache, ocular stinging, and nausea [3–5].
Another set of eyedrops targets the crystalline lens to treat presbyopia. Pirenoxine
eyedrops have been shown to suppress crystalline lens hardening in rats. The same
effect was also reported in a small randomized controlled study on 18 Japanese
males with early presbyopia—no improvement was noted in patients with advanced
presbyopia [6]. A 1.5% lipoic acid choline ester-based eyedrop is also in develop-
ment. It is said to reduce crystalline protein disulfide bonds—softening the lens and
preserving its shape-changing ability during accommodation. Phase I and II studies
have reported good outcomes [7].
Corneal Inlays
Corneal inlays are implanted in the non-dominant eye, under a stromal flap or within
a corneal pocket made by femtosecond laser [8]. Inlays that alter corneal curvature
are implanted more superficially and inlays with small aperture or those that have
a different index of refraction are implanted deeper to avoid changes in the cornea
curvature and to allow a proper diffusion of nutrients in the corneal stroma [9]. The
material used in corneal inlays allows for sufficient nutrient flow into the stroma
[9–12]. Table 1.1 enumerates the advantages and disadvantages of corneal inlay
implantation for presbyopia treatment.
Corneal reshaping inlays enhance near and intermediate vision through a mul-
tifocal effect, changing the shape of the anterior curvature of the cornea and making
it hyper-prolate to increase power. Refractive inlays alter the refractive index with
a bifocal optic. Small aperture inlays improve depth of focus [9, 12].
The Raindrop™ (ReVision Optics, Lake Forest, California, USA), is a
reshaping inlay that is no longer commercially available. It changes the ante-
rior corneal surface and creates a hyper-prolate region, resulting in a multifocal
Table 1.1 Advantages and disadvantages of corneal inlays

Advantages Disadvantages
Minimally invasive Requires monovision
Reversible Decreased distance visual acuity
No need to remove corneal tissue Decreased contrast sensitivity
Quick recovery Perception of halos
Does not affect visual field testing Corneal topography changes
Can be combined with other refractive procedures (long-term)
Enables normal visualization of central and peripheral Induces HOAs
fundus Corneal haze (with long-term
implantation)
Dependent on inlay centration
Dry eye
1 Updates in Refractive Surgery 3
cornea [9, 12, 13]. In emmetropic presbyopes, the Raindrop has been shown to
improve monocular and binocular UNVA [8, 14]. UIVA was also said to improve
[14], however both UDVA and CDVA were found to decrease [8, 14]. It was asso-
ciated with significant increases in total RMS, coma-like RMS and spherical-like
RMS for a 4 mm pupil size. The Raindrop has been associated with monocular
contrast sensitivity loss, but with no binocular loss. Common reasons for inlay
explantation were vision dissatisfaction, inlay misalignment, decreased visual
acuity, epithelial ingrowth, and recurrent central corneal haze.
The Flexivue Microlens™ (Presbia Cooperatief U.A., Amsterdam, Netherlands)
is a transparent hydrophilic refractive inlay (Fig. 1.1) [13, 15, 16]. Its central zone
is plano and its peripheral zone has powers ranging from +1.25 to +3D for read-
ing. A central opening facilitates the transfer of nutrients and oxygen through the
cornea [ 9, 12, 13, 16, 17]. Light rays are designed to pass through the central zone
during distance vision, and rays pass through the peripheral refractive zone during
near vision [15, 16]. In emmetropic presbyopes the Flexivue has been found to
improve UNVA [16]. UDVA is said to decrease in the operated eye, although bin-
ocular UDVA and CDVA is not significantly affected [15, 16]. Higher order aberra-
tions [16] and mean spherical aberration [15] increased after surgery, and contrast
sensitivity decreased in the operated eye [16].
The Icolens™ (Neoptics AG, Huenenberg, Switzerland) is a refractive inlay
made of a copolymer of hydroxyethyl methacrylate and methyl methacrylate [13,
18] (Fig. 1.2). It has a bifocal design with a peripheral positive refractive zone for
near and a central zone for distance vision. This implant improves UNVA, albeit
with a decrease in UDVA and CDVA [18].
The Kamra Inlay™ (Acufocus Inc., Irvine, CA, USA) is a small aperture inlay
made of carbon nanoparticles, whose microperforations allow nutritional flow
through the cornea (Fig. 1.3). It is implanted in the non-dominant eye, in a lamellar
pocket. [9, 12, 13, 19] The Kamra improves near vision by increasing the depth of
field through the principle of small aperture optics [9, 12, 13].
The Kamra can be implanted simultaneously with LASIK for hyperopes,
myopes and emmetropes [20, 21]. Improvement in near and intermediate visual
Fig. 1.1 Flexivue
Microlens® inlay
Fig. 1.2 Icolens® inlay [18]
Fig. 1.3 Kamra® inlay [26]
acuity have been reported [20, 21], with some compromise in uncorrected monocu-
lar distance visual acuity [22] and corrected distance visual acuity.When implanted
in pseudophakic patients with monofocal IOLs—there is also improvement in NVA,
and decrease in DVA [23]. Monocular contrast sensitivity is mildly reduced after
implantation of the KAMRA inlay [24]. Halos, glare, and night-vision disturbance
are also associated with the KAMRA [20, 21]. An advantage of Kamra inlays is
their removability—with no permanent changes in corneal topography and aber-
rometry, and recovery of preoparative corrected and uncorrected NVA and DVA up
to 6 months after removal [25].
Conclusion
The idea of using intracorneal inlays to obtain multifocality is interesting, it is an

active subject in ophthalmologic research. However these inlays have never gained
full popularity due to issues of corneal immune reaction and centration during
implantation. Other concerns that need to be addressed include late complications

of corneal stromal opacity, hyperopic shift, and corneal irregularity—all of which
have led to high explantation rates. As other technology for establishing multifocal-
ity is being developed, we believe that the use of these inlays will decline.
seudophakic Presbyopic IOL’s: Conceptual Issues

P
and Optical Profiles
Presbyopia is the loss or insufficiency of the accommodative ability of the eye, and
it causes difficulties with reading and performing tasks that require near vision. It
affects individuals at the peak of their professional and creative activity, and as such,
there is an increasing demand for correcting presbyopia and eliminating the need
to use spectacles or contact lenses. This has been further bolstered by advances in
cataract and refractive surgery and implant design.
Multifocal IOL’s provide pseudoaccomodation—they are designed to focus light
onto multiple foci and do not change power with ciliary body contraction as with
accommodation [27, 28]. Bifocal IOL’s focus light onto two discrete focal points,
and trifocal IOL’s focus light onto three focal points [27, 29, 30]. Multifocal IOL’s
may also be classified according to their design. Rotationally symmetrical IOL’s
can be further divided into diffractive, refractive, or combined IOL designs [27, 31].
Rotationally asymmetric or varifocal IOLs are characterized by an inferior seg-
mental near add [32, 33]. There is a larger section for distance vision, and a smaller
reading segment with only one transition zone [34]. Extended depth of focus lenses
(EDOF) focus incoming light waves in a continuous and extended longitudinal
plane in order to give good vision at all distances [35, 36]. Accommodative lenses
have monofocal optics which, through several mechanisms, change power with
accommodative effort [37].
Several obstacles that need to be overcome by presbyopic IOL implants include
visual symptoms. Glares, haloes, starbursts, dysphotopsia and shadows occur due
to the effect of the lens design on light [38–40]. A large angle kappa, leading to
temporal IOL decentration, has been implicated as a contributor to photic phenom-
ena in refractive multifocal lenses [41]. Decreased contrast sensitivity is due to the
splitting of available light—especially by multifocal IOLs [41]. Neuroadaptation
is a phenomenon in which patients implanted with multifocal IOL implants learn
to adapt to image perception changes and visual symptoms induced by the lens
design. This may take several months [42]. A case series on the causes of mul-
tifocal IOL explantation and exchange reported that while uncorrected distance
visual acuity may have been 20/20 or better, the visual side effects were signifi-
cant enough to warrant lens exchange. The most common reasons for explantation
were decreased contrast sensitivity, photic phenomena, neuroadaptation failure,
incorrect IOL power, excessive preoperative expectation, IOL decentration, and
anisometropia [43]. Careful preoperative evaluation and planning is also necessary
for implantation of pseudophakic presbyopic implants, as lens selection should be
based on a multifactorial approach. The inherent anatomy and physiology of the
eye, and the pertinent ophthalmic history –especially a previous refractive sur-
gery, irregular astigmatism, or ocular surface disease- should be considered, along
with the patient’s lifestyle, visual needs, and expectations [41]. Hence a thorough
knowledge and understanding of the optical qualities and profiles of each presby-
opic pseudophakic lens is necessary in order to aid the surgeon in pre-operative
planning and implant selection, and in advising the patient about subsequent post-
operative expectations.
Optical Profiles of Presbyopic Pseudophakic Lenses
Diffractive Multifocal IOL’s
Diffractive IOLs have rings on the surface, forming a discontinued optical den-
sity, such that light particles that hit these rings are directed equally towards dis-
crete focal points [27, 31]. Apodized diffractive IOL’s have a gradual and uniform
decrease in diffractive step heights from the center to the periphery [30]. These
ensure that light is equally distributed in both focal points independently of pupil
size, and theoretically creates a smooth transition of light between the focal points
[41]. Apodized diffractive lenses have a gradual decrease in refractive step heights
from center to periphery, resulting in distance-dominant good vision for people with
large pupils [41].
The AT LISA® tri 839 MP (Carl Zeiss Meditec, Jena, Germany) is a one-
piece trifocal diffractive aspheric IOL [31] (Fig. 1.4). Patients who were bilaterally
implanted with the AT LISA Tri showed significant reduction in sphere, cylinder,
and spherical equivalent. There was continuous and acceptable visual acuity for all
distances. The defocus curves for the AT LISA tri show that it provides excellent
near VA between 33 and 40 cm, with the ideal distance for near vision at 36 cm.
Intermediate VA is excellent between 67 and 100 cm, and the ideal distance is at
80 cm [31]. Contrast sensitivity improved within the first month post-surgery, espe-
cially for medium spatial frequencies [31]. Ocular aberrometric analysis showed
Fig. 1.4 AT LISA® tri

839 mp IOL [31]
significant decrease in RMS total aberrations, RMS tilt, primary coma and RMS
spherical aberration. There was a significant mean decrease in total internal aberra-
tions. Most importantly, no significant changes were found in internal aberrations
between 1, 3, and 6 months post-surgery—signifying the rapid restoration of visual
function as early as the first month after surgery. The AT LISA tri induced negative
values of internal spherical aberration—more negative than that previously induced
by the crystalline lens—cancelling out the corneal spherical aberrations and result-
ing in lower ocular spherical aberration values [31].
The FineVision® Micro F (PhysIOL, Liège, Belgium) is a one-piece, pupil-
dependent, trifocal IOL. It has an aspheric posterior surface, with a convoluted dif-
fractive anterior surface (Fig. 1.5). By varying the height of the diffractive step the
amount of light distributed to the near, intermediate and distant foci are adjusted
according to the pupil aperture. The IOL distributes 43% of light energy to far vision,
28% to near vision, and 15% to intermediate vision [31]. Binocular defocus curve at
6 months for this lens showed a wide range of useful vision, with excellent contrast
sensitivity under scotopic conditions. There was statistically insignificant reduction
of HOA, yet statistically significant increase in Strehl ratio after 6 months [31].
The SeeLens (Hanita Lenses, R.C.A. Ltd., Kibbutz Hanita, Israel) is an
apodized diffractive IOL with an asymmetrical light distribution. It has concen-
tric rings located 4 mm from the the middle, and is independent of pupil size. Its
design theoretically allows for an optimum distribution of energy in different light
conditions and minimizes spherical aberrations [31]. Our experience with bilateral
implantation of this lens in 20 patients resulted in statistically significant improve-
ments in UDVA, CDVA, UNVA and CNVA within the first post-operative month.
Mean defocus curves for the SeeLens showed that there are two peaks of maximum
vision, one at distance and one at near. Defocus of −1.5D was needed to provide
aceptable intermediate vision. Contrast sensitivity function was within physiologic
levels, albeit reduced in scotopic conditions. Only the RMS of the internal high-
order aberrations, coma aberration, third-order and fourth-order aberrations were
significantly decreased. Visual quality measured with the Hartmann-Shack aber-
rometer showed an increase in Strehl ratio [31].
Fig. 1.5 FineVision®
Micro F IOL [31]
Refractive Multifocal IOL’s
Refractive IOLs use concentric zones of different dioptric powers to achieve

multifocality. They are pupil dependent and may be affected by decentration,
thus the number of zones that redistribute the light for distance and near vision
vary [41].
The Rezoom (AMO, Santa Ana, CA) uses a refractive design which has differ-
ent zones within the concentric rings for focusing at varying distances (Fig. 1.6).
Studies using an eye model with a 3 mm pupil showed that its near MTF did not
change in spite of decentration up to 1 mm. Clinical experience with the Rezoom
has shown that it provides good distance and intermediate vision, however near
Distance vision
for night driving
Distance vision in
moderate to low
light conditions
Distance vision
for daytime
driving
Near vision for

full range of
light conditions
Near vision
for moderate
to low light
conditions
Zone transitions
provide intermediate
vision
Fig. 1.6 A diagram of the Rezoom and a display of the focal points for each zone [31]
vision tasks require spectacle use especially with small pupil size, and it is still
associated with photic phenomena [31].
The M-Flex 630F (Rayner, East Sussex, UK) is a center distance dominant lens
with five refractive zones that alternate between two powers (Fig. 1.7) [44]. Reports
from clinical studies showed good monocular and binocular UIVA and UDVA, with
fair UNVA. Contrast sensitivity was at par with that of monofocal IOL’s, and the
incidence of visual disturbances was low. These did not change even after 12 months
of follow up, and neither was there the occurrence of posterior capsular opacifica-
tion requiring Nd:YAG laser capsulotomy [45].
Extended Depth-of-Focus Lenses
Extended depth-of-focus or EDOF lenses comprise a relatively more recent class

of presbyopia correcting IOL implants. These focus incoming light waves in an
extended longitudinal plane and not onto discrete points as with traditional multifo-
cal lenses. The elongated focus eliminates the overlapping of near and far images
caused by traditional multifocal IOLs—improving intermediate vision while leav-
ing far vision unaffected [35, 36, 46]. Strategies used to achieve extended depth-of-
focus include the induction of spherical aberration in specific portions, the echelette
design, or the use of small apertures [35]. Several of these lenses are in clinical use,
and some of the new generation of multifocal IOL’s induce extended depth-of-focus
to a certain extent. In 2017, the American College of Ophthalmology Task Force
published a consensus statement which outlines criteria for defining an EDOF IOL
and serve as a guide for appraising studies that evaluate EDOF lenses [47].
The MiniWell (SIFI, Italy) is a progressive multifocal aspheric EDOF IOL
(Fig. 1.8). It has a monofocal outer zone, and the inner and middle zones have
spherical aberrations with opposite signs in order to induce depth of focus and gen-
erate multifocality [48]. In vitro testing for this lens showed a comparable perfor-
mance with the Symfony in terms of far and intermediate-near vision at a 3.0 mm
pupil diameter [49]. HOA levels were also found to be maintained regardless of
pupil size [50]. Published clinical results on the Miniwell presented good perfor-
mance at intermediate. There were no relevant differences in near visual acuity
between this lens and multifocal IOL’s, with few visual disturbances at night and
similar contrast sensitivity as diffractive multifocal lenses [48, 51]. The personal
experience of the authors, however, conflict with these results. Our own results in
Fig. 1.7 The M-Flex

630-F [31]
FP FP
LSA
NEGATIVE
FP FI FM
FM FI FP
LSA
POSITIVE
FM FM
Fig. 1.8 A diagram of the MiniWell IOL design and mode of action [48]
10 bilaterally implanted patients have been poor near and distance vision, even
requiring lens exchange. We think that this is because a huge number of patients
in the reported studies so far had undergone Miniwell implantation blended with a
monofocal IOL, and so it would be interesting to find large-scale studies reporting
outcomes with bilateral implantation.
The Wichterle Intraocular Lens-Continuous Focus (WIOL-CF; Medicem,
Kemenné Zehrovice, Czech Republic) is a single haptic-less, full-optic hydrogel lens
with a meniscoid anterior surface and a polyfocal hyperbolic posterior surface that cre-
ates a refractive gradient towards the optic center. This was said to be enhanced with
pupil constriction during accommodative effort—making this lens both an accommoda-
tive and an EDOF lens hybrid [52]. While this lens had aceptable outcomes for UNVA
and UDVA, MTF and HOA [53], it was recently withdrawn from the market [54].
Small-aperture IOL’s achieve an extended and continuous range of vision
due to an embedded opaque annular mask. This mask blocks unfocused paracen-
tral light rays and allows the entry of paraxial light rays, similar to a pinole [36,
55]. The IC-8 small-aperture IOL (Acufocus, Inc), has a 3.2 mm central mask
with a 1.36 mm central aperture (Fig. 1.9). It is commercially available in Europe,
Australia and New Zealand. When implanted bilaterally, an extended range of
focus is attained with excellent intermediate and near vision albeit with higher
scores for halos [56]. Unilateral implantation in the non-dominant eye, with micro-
monovision or monovision as the target, has good near and intermediate visual
outcomes, with lower halo scores and higher patient satisfaction [56, 57]. Another
such device on the market is the Xtrafocus Pinhole Implant (Morcher, GmbH),
which is a black hydrophobic acrylic implant (Fig. 1.10) that is placed as a pig-
gyback lens in the ciliary sulcus. This implant has no dioptric power—it is purely
a diaphragm-pinhole and its occluder has a concave-convex design to prevent con-
tact with the primary IOL [55]. The IC-8 has demonstrated good tolerance to defo-
cus and induced astigmatism [58]; both the IC-8 and Xtrafocus have been used for
patients with highly-aberrated corneas with irregular astigmatism [59, 60]. Long-
term follow-up data is pending, and would be interesting to see, for these implants.
Fig. 1.9 The IC-8 Small

Aperture IOL [55]
Fig. 1.10 The Xtrafocus

Pinhole Implant [60]
Hybrid Lenses
It is important to note that there are overlaps between focality classes, and a refrac-
tive bifocal IOL may also be an EDOF IOL as well as a diffractive IOL. Some
IOL’s are considered hybrids as they are designed with either diffractive or refrac-
tive surfaces with an additional design in order to induce chromatic aberrations.
Other IOL’s use both diffractive and refractive technology.
The AcrySof® Restor® SN6AD3 (Alcon Laboratories, Inc., Fort Worth, Texas)
is a one-piece multifocal IOL that uses both apodized diffractive and refractive tech-
nology. The central 3.5 mm of the optic zone has 12 concentric steps with gradually
decreasing step height. This diffractive apodized region is surrounded by the refrac-
tive area (Fig. 1.11). The Restor is an aspheric lens, and provides negative spheri-
cal aberration in order to improve contrast sensitivity. The SN6AD3 model comes
with a near add of 4D, and the SN6AD1 comes with a near add of 3D for improved
intermediate vision, as has been found by De Vries et al. [31, 61] Defocus curve
outcomes for the SN6AD3 also show two peaks of maximal vision at far and near,
with a trough for intermediate vision. Mean intraocular aberrations after implanta-
tion of the SN6AD3 resulted in higher values of total and tilt RMS compared to a
monofocal IOL, while there were lower values of total, spherical and spherical-like
RMS [62]. The SN6AD1 has an apodized diffractive center to focus light for near
distance while the peripheral refractive zone focuses light for distance vision. Mean
defocus curves for this leans shows two peaks of maximum vision for distance
and near, like the SN6AD3, although an acceptable intermediate vision is main-
tained. Normal photopic and low mesopic contrast sensitivity was reported for both
ReSTOR lenses. The SN6AD1 induced lower values of spherical aberration [31].
The Panoptix® (Alcon Laboratories, Fort Worth, Texas, USA) is a single-piece,
aspheric, pupil-dependent apodized IOL. This IOL has a 4.5 mm unapodized dif-
fractive area in the center with 15 diffractive zones and an outer refractive rim. Light
is then distributed to four focal points—half to the distance focus and half to the
near focus. An additional feature is a negative spherical aberration on the anterior
face, in order to compensate for the positive spherical aberration of the human cor-
nea [63]. Optical bench studies of this lens showed pupil-independent good inter-
mediate distance performance, with distance and near resolution comparable to that
of a traditional multifocal IOL [64, 65]. This was in agreement with clinical studies.
Furthermore, with the Panoptix there was no significant decrease in contrast sensi-
tivity, HOA values and halo perception. Significant changes with these results were
encountered in mesopic or photopic conditions [66–68].
The Lentis® Mplus LS-313(Oculentis GmbH, Berlin, Germany) is a single-piece,
refractive rotationally asymmetric, varifocal, IOL. This is a pupil-dependent IOL with
an inferior surface-embedded segment (Fig. 1.12). It has two definite corrective zones
for far and near vision, with a seamless transition between each zone [69]. The Lentis
Fig. 1.11 AcrySof® Restor

SN6AD3 [31]
Fig. 1.12 Lentis® Mplus

LS-313 IOL [31]
MPlus had significantly better CDVA than other multifocal IOL’s, and comparable
UDVA and CDVA to that of a monofocal lens. Its defocus curve also showed good
visual acuity from −4D to −1D. Ex vivo studies with an optical bench analysis cor-
roborates these findings [70] There are also less reports of photic phenomena with
this lens [71]. A large magnitude intraocular primary vertical coma has been reported
with this lens [69], probably due to its vertically asymmetric optical geometry. This,
however, confers an extended depth-of-focus which gives good vision at all distances,
as evidenced by its defocus curves [69, 72]. Caution is advised, however, when mea-
suring for higher order berrations as some machines and measuring tools used might
not accurately predict through-focus optical quality [69].
The Tecnis® Symfony (Abbot Medical Optics, Inc., Santa Ana California, USA)
is a diffractive non-apodized achromatic IOL. This IOL has a biconvex wavefront-
designed anterior aspheric surface and a posterior achromatic diffractive surface
featuring an echelette design (Fig. 1.13) [63], thus it elongates the focus and cor-
rects the corneal chromatic and spherical aberration [63, 73]. Ex vivo evaluation of
this lens with a USAF target showed a pupil-dependent good range of vision from
far to 50 cm albeit with a drop at near [74], and pupil-dependent MTF degradation
[75]. Furthermore, the lens itself showed a higher absolute value of spherical aberra-
tion compared to trifocal IOL’s [74, 76]. Clinical studies found that, while bilateral
implantation of Symfony resulted in good UDVA, UIVA and UNVA, better UIVA and
UNVA was found when targeted for monovision [73]. When compared with other
lenses- such as the Panoptix or FineVision- the other lenses had better near vision,
equivalent distance vision. The Panoptix and Symfony had similar results for inter-
mediate vision. This lens showed no statistically significant improvement in terms of
light distortion, visual symptoms, contrast sensitivity and aberrometry [63, 77].
Accommodating IOLs
Accommodating IOLs supposedly undergo a progressive dioptric power change in

response to active ciliary body contraction during an accommodative effort [78].
Several designs have been used in order to achieve the required power change but
presently there is still no conclusive evidence of the targeted dioptric power change
in any of the IOLs that are available or in development.
Position-changing IOL’s have a single optic which provides near and intermedi-
ate vision by anterior axial movement [37]. One such example is the CrystaLens®
a b c
Fig. 1.13 The appearance of the concentric rings for the Symfony (a), compared with a trifocal
IOL (b) and bifocal IOL (c) [74]
(Bausch & Lomb, Rochester, NY, USA), the first FDA-approved accommodating
IOL, and has gone through several different designs [79]. Its optic is biaspheric
to increase depth of focus, and hinges transmit ciliary body contraction to enable
axial movement (Fig. 1.14). The anterior surface also changes its radius of curva-
ture to improve near vision [80]. Significantly better UNVA was reported with the
Crystalens® HD over a monofocal IOL, although there was no significant difference
in CNVA. No difference was noted in intraocular aberrometric coefficient between
the two lens types [80]. When compared with a low-addition-power (+1.5D) rota-
tionally asymmetric trifocal IOL, the Lentis® M-Plus, both had comparable postop-
erative UNVA and CNVA. In the defocus curve, there was significantly better visual
acuity with the multifocal IOL at several defocus levels. There were, however, less
reports of lens tilting with the Crystalens® HD, with statistically insignificant dif-
ferences in mean ocular higher order aberrations [17]. The Crystalens is, however,
associated with a higher risk of posterior capsular opacity [81, 82]. Capsular con-
traction syndrome, or Z-syndrome, is a post-operative complication that is uniquely
associated with the Crystalens®. Asymmetric capsular contraction causes the plate
haptics to vault in opposite directions, inducing astigmatism [83, 84].
The 1CU® (Human Optics, Erlangen, Germany) is a single piece biconvex
IOL with four flexible haptics (Fig. 1.15) that bend to allow anterior movement
of the optic during accommodative effort [86]. It was discontinued due to poor
near vision outcomes [87] and significant reports of glare [82]. Another single-optic
lens is the TetraFlex® (Lenstec Inc, St. Petersburg, Fla, USA), which has flexible
angulated closed-loop haptics (Fig. 1.16) that also allow forward movement within
the capsular bag [86]. This lens has also been found to increase HOA’s within the
capsular bag [88]. The BiocomFold 89A (Morcher GmbH, Sttgart, Germany) is a
Fig. 1.14 A schematic

diagram of the
Crystalens® IOL [97]
bag-in-the-lens implant. However, it has been found to produce limited and clini-
cally insignificant axial movement compared to standard bag-implanted accommo-
dating implants [89]. Other accommodating single-optic position-changing IOL’s
that have been developed include the C-Well (Acuity Ltd, OrYehuda, Israel), OPAL
(Bausch&Lomb, Rochester, NY, USA) and Tek-Clear (Tekia, Irvine, CA, USA).
There is, however, little published clinical data on these lenses [82]. The main lim-
itation with single-optic accommodating IOL’s is that there is limited amplitude
of accommodation, which is further impeded by capsular fibrosis. There are also
reports of higher association with posterior capsular opacity, especially with the
1CU®—necessitating Nd:YAG capsulotomy. The YAG procedure had no effect on
accommodative amplitude [82, 90].
Dual optic IOL’s have a mobile front optic connected to a stationary rear optic
by a spring-type haptic [86]. The now-discontinued Synchrony® (Visiogen Inc,
Abbott Medical Optics, Santa Ana, California, USA) had an anterior biconvex
optic with a high plus power and a posterior concave optic with a low minus power
Fig. 1.15 Schematic diagram

of the 1CU IOL [82]
Fig. 1.16 Schematic
diagram of the Tetraflex®
IOL [82]
(Fig. 1.17). Tension caused by the capsular bag compresses the optics and an attempt
to accommodate releases this strain energy [81, 91]. The Synchrony® has similar
outcomes as the Crystalens® HD—with no statistically significant differences in
UDVA, CDVA, near or intermediate visual outcomes between the 2 IOLs [81]. The
Sarfarazi (Bausch & Lomb, Rochester, NY, USA) has 2 optic lenses connected by
three haptics (Fig. 1.18). The change in dioptric power is also brought about by the
displacement of the anterior optic. Ex vivo testing has shown that this is capable of
attaining an amplitude of accommodation of up to 4.0D [82]. This lens has never
been released commercially and there is no published paper on its clinical results.
Dual-optic lenses, specifically the Synchrony Lens, completely occupy the cap-
sular bag, leading to a lower incidence of PCO. This also theoretically facilitates
lens movement during accommodative effort and has been clinically shown with a
wider range of defocus curves compared to single-optic lenses [81]. Studies have
shown that there is no reduction in accommodative ability over a year-long follow-
up period [92], and so it would be interesting to see long-term results with these
lenses. While dual-optic accommodating IOL’s have significantly better ocular
quality than single-optic lenses, with comparable distance-vision outcomes, their
near-vision outcomes are still limited [81] and patients may require training in order
to attain good visual performance [92]. Yet another significant finding with dual-
optic lenses is magnification of the viewed image, because of the increased distance
between the retina and the image space nodal point during accommodative effort
and movement of the anterior lens [93].
Shape-changing IOL’s can change lens curvature to change dioptric power.
The FluidVision® (Powervision, Belmont, California, USA) has optics filled with
silicone oil. During accommodation, this oil is pushed into the optic through fluid
channels that connect the haptics to the optic, inflating the lens and increasing the
Fig. 1.17 Schematic
diagram of the
Synchrony® IOL [97]
Fig. 1.18 Schematic
diagram of the Sarfarazi®
IOL [97]
Fig. 1.19 Nulens IOL [149]
dioptric power for near vision [94]. The NuLens® (DynaCurve, Herzliya Pituah,
Israel) is a conceptual sulcus-implanted lens that consists of PMMA haptics, a
PMMA anterior reference plane that provides distance vision correction, a small
chamber that contains a solid silicone gel, and a posterior piston with an aperture
in the center (Fig. 1.19). When pressure is applied on the posterior piston, the
gel-filled chamber bulges to increase or decrease optical power [95]. The Juvene
accommodating IOL (LensGen, Irvine, CA) is a 2-component IOL with a fixed
foldable lens—consisting of a base optic similar to that of an aspheric monofocal
lens and a 360-degree haptic (Fig. 1.20). The foldable lens is injected through a
3.2 mm incision after which another fluid-based shape-changing lens is inserted

and secured to the first with 3 tabs. The fluid lens has a flexible anterior suface
which can change curvature in response to capsular forces with accommodation
[52]. Clinical trials involving this lens are anticipated to start soon, and these
would be interesting to see.
Power-changing IOL’s dynamically change in refractive power. The Lumina®
(Akkolens International, Breda, Netherlands) is a conceptual sulcus-implanted,
continuous variable, lens design that has 2 partially overlapping aspherical optics.
Each optic has an elastic U-shaped loop with a spring function, and non-elastic
connections to the main body of the lens (Fig. 1.21). The anterior optic has a fixed
power of 5.0D, and the power of the posterior optic depends on the required cor-
rection of the eye. The IOL’s focal length changes as the optics shift in opposite
directions in a plane that is perpendicular to the optical axis [52]. When the IOL
is compressed by ciliary muscle contraction, as with accommodation, the optics
a b
Fig. 1.20 The Juvene IOL. One part is the base optic (a). The modular second implant (b) con-
tains a silicone optic which changes curvature when the ciliary muscles contract and the zonules
relax [52]
Fig. 1.21 Lumina IOL.

(Image courtesy of Mr.
Aleksey Simonov,
Akkolens International b.v.
Breda, The Netherlands)
move centripetally in opposite directions to increase optical lens power. Ciliary

muscle relaxation forces the elements back to their original state to decrease optical
power [96]. Preliminary clinical tests with a monofocal IOL control have shown
that the Lumina IOL significantly improves near, intermediate and far vision with-
out a ffecting contrast sensitivity, with an accommodative power between 1.5 and
6.0D. Defocus curves showed improved near vision between −4.5 and −0.5D [96].
Nd:YAG capsulotomy did not adversely affect visual acuity and accommodation.
Furthermore, the location of the IOL in the sulcus would also in theory avoid the
effect of capsular fibrosis and contraction.
Other experimental IOL concepts are still in development. Magnet-driven active
shift IOL’s involve the implantation of magnets under the superior and inferior rec-
tus muscles and in the capsular bags with the lens. The repellent action of these
magnets are expected to drive the lens and capsular bag forward during accommo-
dation—decreasing the effect of PCO and capsular fibrosis [97]. While implantation
of this design has been reported in human eyes, no published data have been found.
The LiquiLens (Vision Solutions Technologies, Inc, Rockville, MD) contains two
solutions with different refractive indices. These solutions are inmiscible, and the
current prototype has a bifocal effect which is driven by gravity [52]. An electroad-
aptive accommodating IOL is also in the works. It contains nematic liquid crystals
sandwiched between transparent electrodes. Physiologic changes in light are trig-
gered by accommodative effort and this activates microsensors [52].
Conclusion
Presbyopic lenses are approached with optical multifocality based on refractive and
diffractive optical principles, or monofocality which enables progressive dioptric
power change in response to an active accommodative effort—as with the accom-
modating. Multifocality always requires neuroadaptation, which is the main rea-
son for inadequate patient satisfaction and should significantly improve with the
most recent models. Accommodating lenses are mostly in the experimental and
pre-clinical development. Some of them, especially the sulcus-based lenses, have
published consistent results that seem to be promising for future use in cataract and
lens surgery. Experimental lenses are still in development but with no clinical trial
to date.
Refractive Laser Procedures
The advent of refractive corneal surgery was ushered by the emergence of the excimer
and later the femtosecond laser. Ablative refractive surgery aims to change refraction
through the removal of small amounts of tissue from the anterior surface of the cor-
nea [98]. The development and evolution of the excimer laser, and the emergence of
diagnostic wavefront technology, has made possible the execution of corneal surface
ablation with increasingly accurate and predictable results [99]. The excimer laser
emits photons at 193 nm, resulting in ablative photodecomposition which breaks the
peptide backbone and vaporizes corneal collagen molecules. It can ablate corneal tis-
sue without causing significant damage to adjacent tissue due to low tissue penetration
and short pulse duration. The femtosecond laser, on the other hand, has a solid-state
Nd:Glass laser source and uses ultra-fast focused pulses at near-infrared wavelenghts to
create photo disruption at their focal point. A high-intensity electric field is generated,
which forms a mixture of free electrons and ions called the plasma state. This plasma
state expands and displaces the surrounding tissue, forming a cavitation bubble in the
focal volume of the laser beam. Cutting is completed when these bubbles fuse [100].
Photorefractive keratectomy (PRK), the oldest excimer laser procedure,
involves the removal of the central corneal epithelium—achieved mechanically
after a brief application of alcohol in order to loosen the epithelium. The exposed
anterior stroma is then reshaped using the excimer laser. Myopia is treated with
central corneal flattening, hyperopia with steepening, and astigmatism with an
astigmatic pattern [100]. Epithelium removal leads to significant post-operative
pain. There is relatively slow visual recovery and risk of haze development with
PRK. However, PRK is still performed in corneas with superficial scarring, epithe-
lial dystrophies, recurrent erosions, thin corneas, in post-keratoplasty patients, and
for keratorefractive treatment of low to moderate myopia [100, 101] or hyperopia
[102]. The use of mitomycin C coupled with the introduction of more improved sur-
face ablation techniques and machines have both increased the range of treatment,
and lowered the risk of corneal haze and regression after PRK [100]. Long-term
studies on PRK outcomes report good safety and satisfaction with this procedure
[78, 101]. Targeted refraction within ±1.00D is reached in 55–81% of eyes, and
refractive stability is attained within one year. The treatment of low to moder-
ate myopia was associated with night-time visual disturbances and haze [100].
Refractive predictability is lower, and the occurrence of haze higher, for treatment
of eyes with high myopia [101]. PRK for low to moderate hyperopia is marked by
an initial temporary myopic overshoot, with a subsequent hyperopic regression
over a 24-month follow-up [102].
Laser-assisted in situ keratomileusis (LASIK) was first reported in 1990 by
Pallikaris, who initially used a microkeratome to cut a hinged corneal flap, followed
by excimer ablation of the stromal bed and subsequent flap repositioning [100, 103].
It is arguably the most-used refractive surgical procedure. LASIK is associated with
high safety and refractive predictability, even on long-term follow-up, and excellent
patient satisfaction rates [78, 100, 104]. The advantages of LASIK over PRK include
faster visual recovery, less post-operative discomfort, better and more predictable
wound healing, and less risk for corneal haze. Although there is faster improvement in
UDVA with LASIK than with PRK, long-term efficacy outcomes are comparable for
both procedures [105]. The advantages of flap creation with the femtosecond laser, as
opposed to the conventional microkeratome assisted LASIK, has increased the safety,
precision and predictability of performing LASIK—with better planning of flap diam-
eter and depth. There is reduced risk of flap button hole or free cap formation, better
flap stability, reduced post-operative dry eye symptoms [106, 107]. Studies on LASIK
for myopia and myopic astigmatism show good post-operative unaided visual acuity,
with goodsafety outcomes and refractive stability [78, 104, 107]. Myopic regression,
however, has been reported in a study with a 12-year observation period [108]. LASIK
for treating for treating low to moderate hyperopia was also found to have good safety
and refractive outcomes. However, regression has been reported even up to follow-up
periods of 5 years [109, 110]. Ectasia after corneal refractive surgery is character-
ized by a progressive increase in myopia and loss of UDVA or CDVA, with or with-
out increasing astigmatism, with keratometric steepening of the cornea, topographic
asymmetric inferior corneal thinning, and central or paracentral thinning. While
corneal ectasia after refractive surgery is rare, with reported estimates ranging from
0.4 to 0.6%, it is potentially devastating and occurs more commonly after LASIK
[111]. LASIK results in a weakening of the cornea’s biomechanical strength, mainly
because the creation of the flap affects the integrity of the corea. Patients should be
carefully screened for pre-operative risk factors for ectasia, which include abnormal
topographic patterns (such as in forme fruste keratoconus), corneal thickness and cal-
culated residual stromal bed thickness [111]. Management of symptomatic corneal
ectasia involves visual rehabilitation, conservative management with glasses or rigid
gas permeable contact lenses and scleral lenses, corneal cross-linkting to halt progres-
sion, and surgical management with penetrating keratoplasty (PKP) or deep anterior
lamellar keratoplasty (DALK) [111].
The development of more advanced diagnostic machines and wavefront tech-
nology have enabled an increased knowledge of optical aberrations. This, in turn,
has allowed for the customization of the laser refractive procedure with the end
goal being minimized degradation of visual quality compared to conventional laser
corneal refractive surgery. In wavefront-guided refractive procedures, the excimer
laser ablates a customized spatially variant pattern based on measurements taken
with an aberrometer. Wavefront-guided LASIK and PRK have been performed
clinically and have shown effectivity in treating myopia with and without astig-
matism. There was significant improvement in UCVA at 1 year, with good safety
profiles—although faster recovery was noted with LASIK as opposed to PRK [99].
Customized refractive procedures utilize information on the ocular aberrations and
the topography of the patient as well as the refractive error in order to plan the
ablation pattern to be executed. Clinical reports on outcomes with customized PRK
and Femtosecond assisted LASIK have found that higher order and spherical aber-
rations increased with both procedures moreso with PRK than with LASIK, while
total aberrations decreased. Sphere and cylinder were decreased from pre-operative
values, and UDVA showed similar improvement for both procedures [112]. As more
information is being gathered on the impact of optical aberrations on vision and
visual quality, more understanding will be gained on the utility and effectivity of
these procedures for treating ammetropia. In the meantime, careful patient selection
is advised with pre-operative counselling as to the details of both wavefront-guided
and customized refractive procedures.
Small Incision Lenticule Extraction (SMILE) is an all-femtosecond laser flapless

procedure—it involves the creation of a lenticule after which a dissector is passed
through a small incision to mobilize the lenticule and allow its removal (Fig. 1.22).
It is approved to treat myopic sphere up to −10.00D, cylinder up to −5.00D and
spherical equivalent up to −12.50D. This procedure came about as a result of the
improvement in precision and technical design of the femtosecond laser such that
the creation of lenticules of adequate dimension have been made possible [113, 114].
SMILE is a keyhole or flapless procedure, thus it has a reduced risk of traumatic cap
or flap dislocation—albeit it may be more surgically demanding and require a higher
learning curve. There is less disruption of the anterior stromal nerve plexus leading to
faster dry eye recovery [100]. Preservation of the anterior stromal lamellar, and avoid-
ance of vertical cuts contribute to better corneal biomechanics—and less propensity
to develop corneal ectasia [100, 101, 113]. Reports of outcomes for SMILE showed
good results—with a high percentage of eyes with good UDVA and CDVA and within
±1.00D or ± 0.50D of intended correction, regular corneal topography, no induced
spherical aberration, and good patient satisfaction [100, 114–117]. Several studies
have reported no significant differences in post-operative UDVA and CDVA, nor in
post-operative refraction between SMILE and LASIK [118, 119]. Higher refractive
correction in the corneal periphery was achieved with SMILE rather than with LASIK
[118], which has been postulated to explain lower values of spherical, coma, and total
HOA’s with SMILE [118]. One disadvantage of SMILE, compared to LASIK, is its
slightly slower visual recovery. Lenticule dissection and extraction is the most chal-
lenging step and intra-operative complications associated with SMILE include epithe-
lial abrasions, incision tears, difficult lenticule extraction, cap perforation, and suction
a b c
d e f
Fig. 1.22 Small incision lenticule extraction (SMILE). A femtosecond laser is used to create a
lenticule with a superior incision. The dissector is used to define the inferior and then the superior
edges of the lenticule, and to release any adhesions from the cap and the underlying cornea. (a–e)
Once the lenticule has been released, it is extracted with a pair of forceps (f) [124]
loss. These complications were not significantly associated with visual or refractive
sequelae [100, 117, 120]. Post-operative complications include trace haze, some epi-
thelial dryness, interface inflammation, retained lenticular fragments, and epithelial
ingrowth [114, 121]. In spite of the current limitations for SMILE in terms of its treat-
ment range, it has plenty of potential uses in the future all of which are being currently
investigated– including the treatment of a higher range of myopia and hyperopia, as
well as the transplantation of the preserved SMILE lenticule [122, 123].
Phakic Intraocular Lenses
Laser keratorefractive procedures have limited use in the correction of high refrac-
tive errors—wound healing and biochemical responses can lead to poor refractive
predictability, visual recovery may be prolonged and refraction unstable, and corneas
are prone to scarring or haze and irregularity. High refractive errors also require the
ablation of more corneal tissue, which may induce progressive ectasia. Intraocular
refractive procedures have several advantages over laser refractive procedures—they
can treat a broader range of ametropía with more stable post-operative refraction and
faster visual recovery, and lead to better visual quality. Phakic Intraocular Lenses
(pIOL) may be removed surgically hence any refractive result is potentially reversible,
and the procedure does not require expensive or special devices [125]. Implantation
of pIOL’s is reserved for eyes with thin corneas or abnormal topographic findings,
and may be classified according to the site of implantation. Refractive multifocal
pIOL’s have also been devised and pilot studies showed promising results for near,
intermediate and distance visual acuity—with good patient satisfaction [126, 127].
Implantation of these lenses, however, is not routinely performed due to the higher
rate of cataract formation and endothelial cell loss.
Anterior-chamber pIOL’s may be angle fixated or iris fixated. Posterior chamber
pIOL’s are implanted posterior to the iris. A pIOL’s design and location generally
predicts its safety profile. A lens closer to the corneal endothelium, angle structures,
or crystalline lens is more likely to lead to endothelial cell loss, iris complications
or cataract. Anterior chamber pIOL’s are more associated with elevated intraocular
pressure and endothelial cell loss, whereas posterior chamber pIOLs are associated
with cataract formation and lens subluxation [128, 129]. Comprehensive preopera-
tive evaluation is required and measurement of the anterior chamber depth is critical
as a shallow anterior chamber can complicate the insertion of the pIOL as well as lead
to increased endothelial cell loss. The minimum required anterior chamber depth is
between 3.0 and 3.2 mm as measured between the central anterior lens capsule and
the endothelium. A patient’s age and preoperative refraction should be taken into
account as a predictive model as the safety zone between the endothelium and lens
becomes much less than the recommended 1.5 mm over time—more than 20 years—
due to age-related changes in the anatomy of the anterior segment structures [130,
131]. This has significant effects in the decision to use pIOL’s for young patients
with very high myopia [131]. A normal anterior chamber angle is necessary for the
placement of anterior-chamber angle lenses. The corneal endothelium should also be
evaluated, as there is a need to preserve the endothelial cell density to accommodate

aging. Correct pIOL sizing avoids postoperative complications such as spinning,
decentration, and cataract formation due to an inadequate vault over the crystalline
lens. Peripheral iridotomies are required in order to prevent a pupillary block [125].
Angle fixated pIOL’s were the first to be designed. The ZB5M lens had a z-flex
haptic with four support points, a thin optic and small vaulting angle. It is placed
at the angle of the anterior chamber. A study on this lens showed good refractive
stability compared to LASIK, with superior improvement in CDVA—possibly
due to a magnification of the retinal image. However, a high rate of endothelial
cell loss per year was also reported, along with pupil ovalization, uveitis and glau-
coma [132]. This lens has already been taken of the market. The ZSAL4 (Morcher
GmbH, Stuttgart, Germany) was designed with longer haptics to decrease pressure
on the angle structures and a larger optical zone—with less night halos and glare.
Pupil ovalization was reported with the ZSAL4 and the ZB5M [133]. The Kelman
Duet Implant Phakic IOL (Tekia Inc., Irvine, CA) featured a separate optic and
haptic to enable optic exchange in case of poor fit or changes in refraction. The
AcrySof Cachet pIOL (Alcon Laboratories, Inc., Fort Worth, TX) had reported
long-term outcomes of good UDVA 20/40 or better in more than 90% of eyes, mean
IOL rotation of 10.6°, spherical equivalent of −0.17D, and residual refractive error
within ±1.00D for more than 90% [129, 134].
The iris-fixated or “iris claw” lens was developed due to an increasing number
of reported complications with angle-supported pIOL’s—although it was initially
intended for the correction of aphakia. Several advantages include one size that fits
all eyes, optimal distance from the crystalline lens and corneal endothelium, mainte-
nance of the iris vascular supply and good iris function, and excellent stability with
good lens centration. The Artisan (Ophtec BV, Groningen, the Netherlands) has a
convex-concave optic with an 0.87 mm vault anterior to the iris (Fig. 1.23), and is
available in powers ranging from −3.00 to −23.5D. The Artiflex was later developed
Fig. 1.23 The Artisan

phakic IOL [141]
based on the Artisan, but with a flexible, convex-concave silicone optic (Fig. 1.24). It
requires a smaller (3.2 mm) self-sealing incision, allowing for rapid visual recovery
[125]. Studies on outcomes with the Artisan for both myopia and hyperopia report
good UCVA, increased contrast sensitivity, good patient satisfaction rates, and sta-
ble long-term refraction [135, 136]. The Artisan has also been used for patients with
stable keratoconus [137]. It was found to have a superior safety index when com-
pared prospectively with LASIK for myopia −8 to −10D. For patients with myopia
greater than -15D, LASIK was found to be an effective enhancement treatment. As
the Artiflex is a foldable lens, clinical trials have reported a faster visual recovery
with better UCVA compared to the Artisan [136, 138, 139]. Post-operative anterior
chamber measurements for the Artiflex show that the minimum distance between
the endothelium and the lens center should be maintained at 1.7 mm to minimize
endothelial cell loss [130]. The Artisan/Verisyse toric pIOL is less likely to rotate
due to its fixation to the iris stroma. It has excellent refractive outcomes—3-year
results show UCVA better than 20/40 in 84% of 662 eyes [140].
Posterior-chamber pIOL’s are placed behind the iris, and as such are cosmeti-
cally appealing and only noticeable upon careful examination. They are far from the
anterior-chamber angle and the corneal endothelium, hence they are associated with
less changes in intraocular pressure and endothelial cell density. The Visian ICL
(STAAR Surgical CO., Monrovia, CA) is one such lens (Fig. 1.25). It is approved
for myopia from −3 to −15D and for myopia −15 to −20D with astigmatism less
than or equal to 2.5D [125]. Studies on outcomes for the Visian ICL showed good
UDVA and good contrast sensitivity for hyperopia [142], and low-to-moderate to
high myopia [143, 144]. Patients with lower levels of preoperative myopia were
found to have better uncorrected visual acuity and better satisfaction rates with less
overall reports of complications. Pupillary block was more likely to occur for hyper-
opic eyes [145]. The Visian ICL offered better safety, efficacy and predictability
when compared with LASIK [143, 146] and PRK [147] for high myopes.
Fig. 1.24 The Artiflex

phakic IOL [141]
Fig. 1.25 The Visian ICL

[148]
Conclusion
In the last century we have seen leaps and bounds in the development and evolu-
tion of modern refractive surgery. The increasing availability of new technology
for diagnosis and assessment of the ocular structures—the wavefront aberrome-
ters and topographers, the optical coherence tomographers—have allowed for an
increased understanding in what constitutes good visual quality. The capacity to
develop new biocompatible materials have enabled the conception and production
of increasingly varied intraocular implants that can be safely delivered into the eye
and provide good unassisted vision at all distances. The latest machines used in
refractive surgery—the phacoemulsification platforms, the femtosecond laser and
excimer laser—have allowed for an unprecedented increase in the safety, precision,
reproducibility and efficacy of modern-day refractive procedures. The currently
available literature supports this with information on the outcomes of refractive
procedures for a large number of patients over a long follow-up time. There is still
plenty of knowledge, however, to be gained regarding the intricacies of the differ-
ent factors that influence visual quality. Furthermore, there is a need to determine
how to harness this knowledge in order to improve the available options as well as
to select the appropriate refractive procedure for the correct indications in order
to give improved vision at all distances. It would be interesting to see how this is
addressed by the results of the ongoing and future studies—and the future seems to
be promising.
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Chapter 2
Recent Developments in Cornea
and Corneal Transplants
Caterina Sarnicola, Enrica Sarnicola, Paolo Perri, and Vincenzo Sarnicola
Cornea
NGF Treatment for Neurotrophic Keratopathy
Neurotrophic Keratopathy (NK) results from impaired corneal innervation which

may lead to persistent epithelial defect, corneal melting and perforation. The risk
factor for NK are numerous and can coexist. To date, the available treatments has
been working in maintaining a proper lubrication and protecting the integrity of
the ocular surface. Medical management includes preservative free artificial tears,
serum/plasma drops, and anti-inflammatory agents. Contact lenses, punctal plugs,
and lid closure with botulinum toxin has been proven to be helpful. Severe cases can
require surgical intervention as amniotic membrane transplantation, conjunctival
flaps and tarsorrhaphy.
Recently a human recombinant nerve growth factor (Cenegermin) has been
approved as topical treatment for NK. This medication promotes epithelial heal-
C. Sarnicola (*) · E. Sarnicola

Clinica degli Occhi Sarnicola, Grosseto, Italy
Ophthalmology Department II, Ospedale San Giovanni Bosco and Ospedale Oftalmico,
Turin, Italy
P. Perri
Department of Biomedical and Specialty Surgical Sciences, University of Ferrara,
Ferrara, Italy
V. Sarnicola
Clinica degli Occhi Sarnicola, Grosseto, Italy

36 C. Sarnicola et al.
Fig. 2.1 NGF treatment (Cenegermin) in corneal ulcer due to radiation exposure
ing and nerve health addressing for the first time the underlying pathology of NK
(Fig. 2.1).
Two independent, multicentre, randomised, double-masked, vehicle-controlled
clinical studies demonstrated the efficacy and safety of Cenegermin in patients
affected by moderate or severe NK that were refractory to other non-surgical treat-
ments. In both studies patients received Cenegermin 6 times daily in the affected
eye for 8 weeks [1, 2].
Highlights on Corneal Infections
Infectious keratitis are a major cause of blindness and visual impairment globally.
The prompt identification of the pathogen organism and an early targeted therapy
are crucial to control the infection, but often difficult to obtain. New tools in diag-
nosis and treatment are the following.
Diagnostic Investigation
Cultural exam remains the prevalent diagnostic procedure. However other

approaches can be effective to identify the causative organism or to have a faster
response.
In vivo confocal microscopy is helpful to identify fungal hyphae or Acanthamoeba
cysts [3].
PCR (Polymerase Chain Reaction) is useful especially to identify Acanthamoeba
and Herpesviridae DNA [4]. Ultimately, the use of Next Generation Sequencing
(NGS) has been suggested. NGS includes a number of different modern sequencing
technologies that allow to sequence DNA and RNA very quickly. These techniques
can be advantageous particularly for organisms that are difficult to culture such as
atypical or anaerobic bacteria [5].
2 Recent Developments in Cornea and Corneal Transplants 37
Collagen Cross-Linking (CXL) for Corneal Infections
CXL is a procedure which uses UV light and a photosensitizer (riboflavin) to

strengthen chemical bonds in the cornea. The main indication for CXL is to pre-
vent the progression of keratoconus or other ectatic disorders, however, it has been
recently proposed to treat corneal infections. In fact, several study has shown that
CXL has some antimicrobial effects and has the potential to inhibit enzymatic deg-
radation and corneal melting [6].
There is no agreement yet about when and how to employ CXL to treat keratitis,
however, several papers showed the efficacy in bacterial cases whereas there is less evi-
dence in fungal and Acanthamoeba cases [7, 8]. Furthermore, CXL should be avoided in
patient with history of herpes because the virus can be activated by ultraviolet light [9].
Further studies are needed to determine the optimized CXL protocol and define
the indications in corneal infections treatment.
Povidone-Iodine (PVI) and Corneal Infections
PVI is a well known disinfectant and antiseptic agent. Thanks to its broad spectrum
of microbicidal activity with no reports of resistance or anaphylaxis, and its reason-
able cost, it is widely used in ophthalmic surgery [10]. In addiction, PVI has been
shown to be active against Acanthamoeba in vitro and it does not induce resistance
or cross-resistance to antibiotics [11].
A recent study conducted in India and Philippines on 172 patients affected by
bacterial keratitis, showed no significant difference between the effect of topical
PVI 1.25% and topical antibiotics available in developing countries (0.3% cipro-
floxacin or neomycin-polymyxin b-gramicidin) [12].
Suggesting that PVI (widely available and inexpensive) should be considered for
treatment of bacterial keratitis in countries with limited access to antibiotic therapy.
Additionally, povidone iodine contact lens disinfection systems has been proven
effective against a variety of pathogenic microorganisms and may aid in the preven-
tion of potentially sight threatening microbial keratitis [13, 14].
Dry Eye Disease
Dry eye disease (DED) is a common ocular condition that can be the result of insuf-
ficient production and/or evaporation of the aqueous tears (Table 2.1).
The definition of dry eye is still under continual revision. According to the
2017 Report of International Dry Eye Workshop, DED is a multifactorial disease
of the ocular surface characterized by a loss of homeostasis of the tear film, and
accompanied by ocular symptoms, in which tear film instability and hyperosmo-
Table 2.1 Dry eye etiology

Aqueous deficient Evaporative
Sjogren Syndrome Non-Sjogren Syndrome Intrinsic: Extrinsic:
DED: DED: Meibomian oil Vitamin A deficiency
Primary Lacrimal deficiency deficiency Topical drugs
Secondary Lacrimal gland duct Disorders of lid preservatives
obstruction aperture Contact lens
Reflex block Low blink rate Ocular surface disease
Systemic drugs Drug action
Accutane
DED dry eye disease
larity, ocular surface inflammation and damage, and neurosensory abnormalities

play etiological roles.
Classic clinical tests are tear break-up time, Schirmer test, corneal esthesiometry,
and dye staining.
Newer diagnostic tests measure tear film osmolarity, matrix metalloproteinases
levels, and lipid composition. Advanced imaging has also allowed us to measure
tear film meniscus height (by OCT), ocular surface health (epithelium and nerve
quality by in vivo confocal microscopy), and tear film evaporation (by noninvasive
tear break-up time).
There are numerous treatments for DED, depending on the causes. The more
common include artificial tears, gel or oinments, tear conserving interventions such
as punctal plugs, topical ophthalmic steroids and tetracycline.
Topical cyclosporine-A inhibits T cell activation and decrease IL-6 and
HLA-DR. It has been the only pharmacologic treatment specifically approved for
DED by the Food and Drug Administration (FDA), but it is discontinued by most
patients as it causes burning sensation in the eye.
In 2016 lifitegrast has been approved by the FDA as therapeutic option for dry
eye too, as it affects the T-cell-mediated inflammatory pathways, inhibiting the
release of cytokines, interferon d, tumor necrosis factor alpha (TNF-α), and other
interleukins [15, 16].
Neurostimulation is another important addition to our armamentarium in DED
treatment to stimulate natural tear production using electrical stimulation. The intra-
nasal neurostimolator was shown to be safe and effective for temporarily increasing
tear production in adult patients [17].
Corneal Transplants
Corneal transplantation has developed dramatically in the last 25 years. The surgery
moved from full-thickness grafts (penetrating keratoplasty—PK) toward lamellar
keratoplasties, anatomically targeted procedures that avoid the removal of healthy
corneal tissue and replace only the diseased layer (Fig. 2.2).
Fig. 2.2 Evolution from penetrating keratoplasty to lamellar corneal transplant
Deep anterior lamellar keratoplasty (DALK) is replacing penetrating kerato-

plasty for disorders affecting the corneal stromal layers, while eliminating the risk
of endothelial rejection, providing longer graft survival, avoiding an open sky pro-
cedure and offering stronger postoperative wound resistance.
Endothelial keratoplasty selectively replaces the corneal endothelium in patients
with endothelial disease and results in more rapid and predictable visual outcomes.
Other emerging therapies are ocular surface reconstruction and artificial cornea
(keratoprosthesis) surgery, which have become more widely performed because
of the advances in these techniques. Together, these advances have resulted in
improved outcomes, and have expanded the number of cases of corneal blindness
that can now be treated successfully.
A comparison between different corneal transplant techniques is shown in
Table 2.2.
DALK: Deep Anterior Lamellar Keratoplasty
DALK is now the procedure of choice for corneal stromal diseases with a healthy
endothelium.
The most common indication to perform a DALK is Keratoconus, other indi-
cations are other corneal ectasia [18–21], corneal stromal dystrophies when
the endothelium is not affected, corneal scarring [22, 23], corneal melting [24],
Descemetoceles [24], penetrating corneal wound without loss of substance [25]. In
very experienced hands of surgeons with a low conversion rate to PK, DALK should
also be considered in case of dangerous infectious stromal keratitis unresponsive to
medical treatment (fungi or Acanthamoeba infections) [26, 27].
Table 2.2 Comparison between corneal transplant techniques

Indications Advantages Disadvantages
PK Suitable for all indications – Fast learning – Open-sky surgery
curve related risks
– Relatively fast – Progressive endothelial
procedure cell loss
– Less expensive – High glaucoma risk
procedure
– Considerable rejection
rate
– High postoperative
astigmatism
DALK – Corneal ectasia (Keratoconus, – Spares the host – Steep learning curve
pellucid marginal degeneration, endothelium
keratoglobus, post-laser-assisted in
situ keratomileusis ectasia,
recurrence of ectasia in previous
PK)
– Corneal stromal dystrophies – Less rejection – Stroma interface can
when the endothelium is not risk affect the visual
affected (macular corneal outcome (manual
dystrophy, granular corneal dissection techniques)
dystrophy, lattice corneal dystrophy
and Avellino dystrophy)
– Corneal scarring (secondary to – No endothelial – Time consuming
trauma, infection, chemical injury) rejection procedure
– Corneal melting (autoimmune, – Long term graft – Postoperative
neurotrophic or infectious) survival astigmatism similar to
PK
– Descemetoceles – Less
intraoperative
complications
– Penetrating corneal wound – Early suture
without loss of substance removal
– Fungi or Acanthamoeba stromal – Stronger
keratitis unresponsive to medical postoperative
treatment wound
resistance
EK – Endothelial dystrophy (Fuchs – Spares the – More difficult learning
endothelial dystrophy, posterior healthy stroma curve
polymorphous dystrophy and
congenital hereditary endothelial
dystrophy)
– Iridocorneal endothelial – Less rejection – Donor selection and
syndrome risk manipulation
Table 2.2 (continued)
Indications Advantages Disadvantages
– Bullous keratopathy (iatrogenic, – Early and better – Stroma interface can
post-traumatic or post-infective) visual recovery affect the visual
outcome in DSAEK
– Endothelial failure of a prior – No induced
corneal transplant astigmatism
– Fewer suture
and wound
complications
PK penetrating keratoplasty, DALK deep anterior lamellar keratoplasty, EK endothelial kerato-
plasty
Peeling off (Malbran, 1966) Manual dissection

Divide and conquer-dissection (Tsubota, 1998) techniques
Hydrodissection (Sugita, 1997)
Viscoelastic dissection (Melles, 2000)
(needle) Big-Bubble dissection (Anwar, 2002)
Cannula Big Bubble (Sarnicola, Tan, Fogla, 2009)
Air/visco-Bubble dissection (Sarnicola, 2010)
Fig. 2.3 DALK surgical techniques
Over the years different techniques to perform a DALK have been described.
DALK techniques still adopted are listed in Fig. 2.3. The most critical step in this
surgery is to achieve separation between Descemet membrane and the remaining
stroma. To facilitate this step Anwar and Teichmann in 2002 described the Big
Bubble technique, this represented an epochal change that has allowed the spread
of this surgery [28].
Needle Big Bubble Technique
This is the most used DALK procedure. A suction trephine is used to perform a partial
thickness corneal trephination at a depth of about 60–80%. A 27- or 30-gauge needle
attached to an air-filled syringe is inserted deep into the paracentral stroma through the
bottom of the trephination groove and is advanced so that the bevel remains parallel
to Descemet membrane (DM) and faces down. At this point, air is injected, forming
a large air bubble between DM and the corneal stroma in most cases (60–70%). The
stromectomy must be completed then the donor can be sutured [28, 29].
Cannula Big Bubble
The use of a special blunt cannula has been proposed to let surgeons go as deep
as possible into the corneal stroma, without being afraid of DM perforation
(Fig. 2.4).
It is common opinion that the deeper the air is injected, the higher the chances
of generating a BB. Sarnicola and Toro described the surgical steps for achieving
a Big Bubble (BB) using a blunt cannula [30]. After a partial corneal trephination,
a smooth spatula is inserted as deep as possible into the peripheral trephination
groove. The spatula is moved forward in the attempt to reach the predescemetic
plane, deeper and deeper toward the center of the cornea. Once the predesce-
metic plane is reached, two important signs are frequently observed: reduced
resistance of the advancement of the spatula and the appearance of DM folds.
The spatula can then be removed, leaving a corneal tunnel into which a 27-gauge
cannula attached to a 5 cc air-filled syringe is inserted. The cannula has a port
that faces down so that air can push DM posteriorly. After advancing the cannula
to the center of the cornea, air can be injected. The literature shows that using a
cannula to inject air provides the highest rate of successful BB accomplishment
[29, 31].
Air-Viscobubble Dissection
AVB is a technique designed to manage those cases in which BB formation has

failed.
Fig. 2.4 Cannula Big

Bubble. Tunnel formation
in the deep stroma using a
27 G spatula (a), air
insufflation using a 27 G
cannula achieving the Big
Bubble formation (b)
When air dissection does not result in big-bubble formation, superficial kera-
tectomy is performed with a Golf knife. A new deeper tunnel is created into the
stroma using the same spatula. The same cannula used for the air injection is then
attached to a viscoelastic material-filled syringe, and viscodissection is tried as a
second approach to separate DM from the corneal stroma. Sarnicola et al. reported
the percentage of DALK obtained with this combined technique: AVB helped to
attain DM separation from the stroma in 7% of cases that together with the 86%
of cases in which DM separation from the stroma had been achieved with the Big
Bubble technique using a cannula, resulted in a total achievement of DALK in 93%
of cases [29, 32].
Results and Complications
The visual outcome after a DALK is similar to PK if the residual stromal bed thick-
ness is less then 100 microns. Compare to PK, DALK provides tremendous advan-
tages in terms of rejection rate, graft survival, and intraoperative and postoperative
complications.
After a DALK procedure, rejection is extremely rare and is easily treatable
because it does not involve the endothelium. Epithelial rejection is usually very
mild, always reversible with steroid drops, and occurring within the initial postoper-
ative weeks. Subepithelial rejection is a belated complication that generally happens
within the first postoperative year; this complication is successfully reversible with
topical steroids most of the time. Stromal rejection is a more dangerous complica-
tion because it can lead to the necrosis of the stroma. It is usually very rare [33, 34].
The endothelium cells count becomes stable after 2 years post-op, this allow a
long term graft survival, probably lifetime [34]. Moreover DALK is not an open sky
surgery and there are less intraoperative complications.
The most frequent complications of DALK are DM ruptures and double anterior
chamber formation. The ability to solve these complications generally improves
when surgeons gradually become more expert.
Endothelial Keratoplasty (EK)
Endothelial keratoplasty is the procedure of choice for endothelium disfunction

treatment, including endothelial dystrophy (such as Fuchs endothelial dystrophy,
posterior polymorphous dystrophy and congenital hereditary endothelial dystro-
phy), iridocorneal endothelial (ICE) syndrome, iatrogenic or post-traumatic bullous
keratopathy and endothelial failure of a prior corneal transplant [35].
Compare to PK, EK provides tremendous advantages in terms of rejection
rate, graft survival, visual outcome and intraoperative and postoperative compli-
cations [36].
Several EK procedures have been described, nowadays the most adopted are
DSAEK and DMEK (Table 2.3).
Table 2.3 Advantages and disadvantages of DMEK over DSAEK

Advantages – Restores the corneal anatomy
– Less rejection risk
– Better and faster visual recovery
– Higher quality of vision
Disadvantages – Steeper learning curve
– More difficult donor preparation
– Not indicated in case of aphakia and aniridia
– Challenging in case of vitrectomized eyes, eyes with ACIOL or tube shunt
DMEK descemet membrane endothelial keratoplasty, DSAEK descemet stripping automated endo-
thelial keratoplasty, ACIOL anterior chamber intraocular lens
Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)
DSAEK was first described by Gorovoy in 2006, he modified the original technique
described by Melles using a microkeratome to prepare a more thin and uniform
donor tissue [37, 38].
The DSAEK graft includes corneal endothelium, Descemet’s membrane and a
thin amount of posterior stroma. In the ultrathin-DSAEK the graft thickness is less
then 150 μm, the nanothin-DSAEK graft is less then 50 μm. Thinner graft allows a
better visual outcome and less rejection risk [39, 40].
The DSAEK procedure involves creation of a 3–5 mm corneal/scleral incision
in the recipient eye. A descemetorhexis under cohesive viscoelastic or air removes
the endothelium and Descemet’s membrane of the recipient eye. Viscoelastic use
advantages are a more stable anterior chamber and a better visibility; it is important
to use a cohesive viscoelastic that can be easily fully removed from the anterior
chamber before graft insertion. Several techniques have been described to insert
the graft in the AC. A noncompression forceps was originally used to insert a 60/40
folded graft. Then donor inserters and several glides were suggested to pull the
donor tissue in the anterior chamber.
A suture pull-through insertion was even described using a double-armed 10-0
polypropylene, nonabsorbable suture, particularly useful in case of shallow anterior
chamber or floppy iris syndrome. An asymmetric 60/40 taco graft, with the endo-
thelial side inward protected by a small amount of viscoelastic (endo-on), is pulled-
through the AC [41].
Once the donor is centered, air is injected into the anterior chamber to facilitate
the adhesion between the donor stroma and host stroma. Pupillary block risk can be
prevented performing an inferior peripheral iridectomy and/or with postoperatively
mydriatic drops. Close patient monitoring is needed in the 4–5 h post-op. Air drain-
age from the paracentesis has to be performed if pupillary block occurs.
Intraoperative complications may be due to the incorrect graft orientation,
air management, bleeding and IOL dislocation. Postoperative complications of
DSAEK surgery are graft dislocation, pupillary block, primary failure, second-
ary failure for endothelial cell loss and rejection (which occurs in about 4% of
cases) [42].
Descemet Membrane Endothelial Keratoplasty (DMEK)
The DMEK graft includes corneal endothelium and Descemet’s membrane only,
allowing the perfect corneal anatomical restoration (Fig. 2.5) [43].
Literature finally showed several advantages of DMEK compared to DSAEK,
including better and faster visual outcome, lower rejection rate and higher quality
of vision, despite a more difficult surgical technique and a steep learning curve [36].
Aniridia and aphakia still are not indicated cases because of graft con be lost in
the vitreous chamber. Vitrectomized eyes, eyes with ACIOLs or tube shunt should
be evaluated with caution.
The DMEK graft can be stripped by the surgeon or the eye bank [35].
The initial surgery phases, until the descemetorhexis, are similar to DSAEK.
Then the surgery become completely different because DMEK graft has a particular
shape: a scroll with endothelium always facing outward (endo-off). This graft fea-
ture is very important and has to be always in the mind of the surgeon. It consents
to avoid the most frequent complication: the upside down positioning of the graft,
the principal graft failure cause.
Fig. 2.5 DMEK post-op. The transplant edge can be detected at the slit lamp examination.
AS-OCT shows a restoration of the normal corneal anatomy
Before injecting the graft into the AC it has to be stained with trypan blue to
improve tissue visualization and managing. Several injectors have been suggested
such as IOL cartridges or glass injectors. Once the graft is inside the AC the main
corneal incision must be promptly sutured. Asses the correct orientation of the graft
it’s a critical step of this procedure. Techniques to determine orientation include
pre-stamp the graft with an “S” or “F”, the assessment of the Moutsouri’s sign,
and intraoperative OCT [44, 45]. Unfold the tissue is the challenging step of this
surgery. Many techniques have been described, the most adopted are: tapping tech-
niques, air, hydro or mechanical ab interno unfolding techniques, etc. [46–48]. At
the end of the surgery air is injected in the AC.
Complications of DMEK can be the upside-down positioning of the graft, graft
detachment (which is treated with rebubbling), graft dislocation, primary failure,
pupillary block, and rejection (in about 1% of the cases) [49].
uture Directions: Rho Kinase (ROCK) Inhibitor for Corneal Endothelial

F
Dysfunction
ROCK inhibitor Y-27632 is approved in Japan for the treatment of glaucoma.

Kinoshita et al. have largely investigated the role of Y-27632 for corneal endothe-
lium therapy, since it has been shown to promote endothelial cell adhesion and
proliferation and to suppress apoptosis [50, 51].
Interesting, ROCK inhibitor has been proved to enhance corneal endothelium
wound healing and to decrease the incidence of bullous keratopathy following
severe endothelial damage (as in cataract surgery, one of the leading causes of cor-
neal transplantation) [52, 53].
Research has also focused on ROCK inhibitor as adjunct drugs for cell-based
therapy. In fact, the injection in anterior chamber of cultured human endothe-
lial cells supplemented with a ROCK inhibitor was followed by an increase in
endothelial density and corneal clearance in 11 persons with bullous keratopa-
thy [54].
Recently a novel approach to treat Fuchs endothelial corneal dystrophy
(FECD) without endothelial transplantation has been investigated. A 4 to 5 mm
area of central endothelium and Descemet membrane is removed without endo-
thelial transplantation. Clinic evidence supports the idea that the corneal endo-
thelium in FECD may be capable of self-regeneration [55]. In about 75% of
selected patient with central guttae but a healthy peripheral endothelium, pri-
mary descemetorhexis without transplant was successful in restoring corneal
transparence [56].
The use of Y-27632 postoperatively seems to facilitate corneal clearance after
descemetorhexis without transplantation in FECD [57, 58]. Further investigation is
needed to identify appropriate patient selection for this procedure and the optimal
descemetorhexis size.
imbal Stem Cell Deficiency and Ocular Surface

L
Transplantation
The corneal epithelium is entirely regenerated about every seven days. In case of
limbal stem cell deficiency (LSCD) the limbal stem cell population located in the
limbus is compromised and the cornea loses its ability to regenerate itself, which
may result in persistent epithelial defects, chronic inflammation, conjunctivaliza-
tion, scarring, and loss of transparency.
The causes of LSCD are numerous and various (Table 2.4).
Currently, the diagnosis is based on the history and the clinical features.
Corneal impression cytology may reveal the presence of conjunctival goblet cells
in the corneal epithelium and confocal microscopy can detect loss of the palisades
of Vogt [59].
In case of mild LSCD, mechanical debridement of the conjunctival epithelium
and, if needed, an amniotic membrane transplantation, could be sufficient to restore
an healthy corneal epithelium. Management of patients with severe or total LSCD
has always been challenging because corneal transparency cannot be restored with
a keratoplasty; these patients need limbal stem cell transplantation or prosthesis.
In the past few decades tremendous advances in the understanding of stem cells
pathophysiology and in the use of immunosuppressive regimens have encouraged
the development of several ocular surface transplant procedures. However, before
proceeding with a stem cells transplant, causative factors and comorbid condi-
tions must be managed (i.e. autoimmune diseases, ocular inflammation, infections,
removal of any ocular surface tumor and iatrogenic insults, eyelid disfunction, inad-
equate tear film) [60].
Selection of the ocular surface transplant procedure depends on the cause and
the extent of LSCD, unilaterality or bilaterality of the deficiency, patient age, living
related donor availability, and comorbidity.
Furthermore, in order to asses the best treatment and the prognosis, the staging
of the severe ocular surface diseases must consider the condition of both the limbal
stem cells and the conjunctiva. According to the classification in Table 2.5, patient
with stage I can usually restore a normal epithelium and have localized vascular-
ization that usually do not affect the visual acuity. Patient with more than 50% of
limbal stem cells loss and inflamed conjunctiva (stage IIC), as in case of severe
Table 2.4 LSCD causes

Congenital Aniridia, ectodermal dysplasia
Traumatic Alcali or acid burns, thermal injuries, physical or
iatrogenic trauma
Autoimmune disorders Stevens-Johnson syndrome, mucous membrane
pemphigoid
Table 2.5 Ocular surface diseases classification

Limbal stem Normal conjunctiva Previously inflamed Inflamed conjunctiva
cells lost (%) (stage A) conjunctiva (stage B) (stage C)
<50% Iatrogenic, OSSN, History of chemical or Mild SJS, MMP, recent
(Stage I) contact lens (Stage IA) thermal injury (Stage IB) chemical injury (Stage IC)
>50% Aniridia, severe contact History of severe Severe SJS, MMP, recent
(Stage II) lens and iatrogenic chemical or thermal chemical or thermal injury
(Stage IIA) injury (Stage IIB) (Stage IIC)
Reproduced from Holland EJ, Mannis MJ, Lee WB, editors. Ocular surface disease: cornea, con-
junctiva and tear film. Elsevier; 2013. Ch. 38, Table 38.1, p. 318
OSSN ocular surface squamous neoplasia, SJS Stevens-Johnson syndrome, MMP mucous mem-
brane pemphigoid
Stvens-Jhonson Syndrome (SJS), severe Mucous Membrane Pemphigoid (MMP)

and recent chemical or thermal injury, have the poorest prognosis for surgical
treatment.
Surgical Options for the Ocular Surface Reconstruction
Conjunctival Limbal Autograft (CLAU)
The conjunctival limbal autograft is the procedure of choice for unilateral limbal
stem cell deficiency. Two limbal grafts about 6 mm of limbal arc length, extending
about 1 mm into the cornea and 5–8 mm in the conjunctiva, are harvested from the
healthy eye and transplanted to the diseased eye. No rejection can occur and no
immunosuppression is required. It provides both healthy stem cells and conjunctiva.
The procedure only has one chance for the fellow eye to be the donor [61, 62].
Simple Limbal Epithelial Transplant (SLET)
SLET is indicated in unilateral stem cell deficiency. Compared with CLAU, a lim-
ited number of stem cells and minimal conjunctiva are transplanted. This technique
seems to be less effective in case of severe LSCD or conjunctival disease, but it may
potentially be repeated.
In this technique a 2 × 2 mm graft is excised from the superior limbus of the
healthy eye, cut in small pieces, glued to the recipient cornea and covered with
amniotic membrane [63, 64].
Keratolimbal Allograft (KLAL)
The keratolimbal allograft procedure uses one or two cadeveric donor corneo-
scleral rims as stem cell source. This technique is indicated for bilateral LSCD
and provides an excellent number of stem cells. The disadvantages include no
tissue typing, increased risk of rejection, need for immunosuppression, and no

supply of healthy conjunctiva. This procedure is most suited for disease with
minimal involvement of conjunctiva (i.e. aniridia, contact lens induced LASC,
etc.) [65].
Living Related Conjunctival Limbal Allograft (lr-CLAL)
This procedure use a patient’s living relative as donor of limbal stem cell and
conjunctiva. The technique is similar to CLAU, but systemic immunosuppres-
sion are required to minimize the risk of rejection. HLA matching and tissue
typing help to identify the best donor possibly reducing the rejection risk and
the amount of systemic immunosuppression. This technique is indicated in case
of bilateral LSCD and, compared to KLAL, it supplies both stem cells and con-
junctiva, which is extremely important for patients affected by cicatrizing con-
junctivitis (Fig. 2.6).
On the other hand lr-CLAL does not supply 360° of stem cells. Interesting,
Holland and al described the Cincinnati procedure, a combined living-related con-
junctival limbal allografts and keratolimbal allografts in severe ocular surface fail-
ure. This technique provides a significant amount of conjunctiva and an encircling
ring of stem cells; it should be considered in case of SJS, cicatricial pemphigoid and
chemical injuries with severe conjunctival involvement [66].
Fig. 2.6 Lr-CLAL in mucous membrane pemphigoid

Ex-Vivo Cultured Graft
Tissue engineering approaches for corneal epithelium reconstruction utilize

adult stem cells derived from a small tissue biopsy from either the patient
(autologous) or a donor (allogeneic), followed by their ex vivo expansion in
culture on a natural scaffold, generating a three-dimensional epithelial con-
structs for transplantation. Indications are unilateral or partial bilateral stem
cell deficiencies.
Currently, cultivated limbal epithelial transplantation (CLET) and cultivated
oral mucosal epithelial transplantation (COMET) are the only clinically validated
techniques.
These techniques are very expensive, provides a limited number of stem cells,
cannot manage conjunctival deficiency, and the literature is lacking of long term
results [67, 68].
Keratoprosthesis (K-pro I, K-pro II; OOKP)
Keratoprosthesis is a surgical option for patient with bilateral LSCD that cannot
be treated with systemic immunosuppression or who have failed a limbal stem cell
allograft.
In patients with a wet ocular surface and good eyelid function a Boston Kpro
type I can be used to restore a visual rehabilitation.
Boston Kpro type I is made of a polymethyl methacrylate (PMMA) front plate,
a corneal graft and a locking titanium or PMMA back plate. Additional procedures
such as lensectomy, glaucoma shunt placement or vitrectomy may be required at the
time of surgery [69].
Patients with severe bilateral autoimmune ocular surface disease, such as
severe SJS and MMP have a greater risk of extrusion and melting; they can
be treated with a Boston Kpro type II, with an osteo-odonto-keratoprosthesis
(OOKP).
Boston Kpro type II design is similar to the type I except for an anterior extension
to allow implantation through surgically closed eyelid. It is associated with significant
complications, long postoperative care and it alters the cosmetic appearance [70].
The OOKP utilizes an autologous canine tooth and adjacent bone as support for
a PMMA Kpro and it is a very complex surgical procedure indicated in end-stage
blindness [71, 72].
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Chapter 3
Recent Developments in Cataract
Surgery
Andrzej Grzybowski and Piotr Kanclerz
Introduction
Cataract surgery is the most common surgical procedure performed in medicine.

In the 2015 over 20 million surgeries were carried out worldwide, of which 3.6
million in the United States of America [1] and 4.2 million in the European Union
[2]. The progress in technology enabled cataract surgery to be the safest and
most predictable eye surgery. On the other hand, the increase in life expectancy
and quality of life result in higher surmises regarding the outcomes. Currently,
individuals over 70 years of age might be declared inactive or retired, however,
still wish to maintain an active lifestyle, including driving a car and performing
sports. Subsequently, there is a demand for techniques that are even more perfect.
New encounters include surgeries performed on patients with dementia and other
comorbidities related with ageing. The anticipated duration of intraocular lens
(IOL) in the eye has significantly increased. Thus physico-chemical characteristics
and IOL endurance should allow the lens to keep its’ optical properties for up to
three decades. The most significant advances in cataract surgery will be briefly
discussed within this chapter.
A. Grzybowski (*)
Department of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland
Institute for Research in Ophthalmology, Foundation for Ophthalmology Development,
Poznan, Poland
P. Kanclerz
Department of Ophthalmology, Hygeia Clinic, Gdańsk, Poland

56 A. Grzybowski and P. Kanclerz
Preoperative Considerations
Preoperative Examinations
Patients undergoing phacoemulsification cataract surgery (PCS) should have a scru-

pulous ophthalmic evaluation, preferably by the operating ophthalmologist [3]. This
allows the surgeon to formulate the treatment plan and establish a relationship with
the patient. Biometry might be conducted on the preoperative visit, particularly if
intraocular lens (IOL) banking is not available or if a specific IOL type is required.
Routine preoperative non-ophthalmic medical testing is not recommended in
patients undergoing low-risk surgery. However, such examinations commonly take
place before PCS and other ambulatory procedures [4]. Almost two decades ago
Schein et al. presented that performing tests such as electrocardiograms, blood cell
count, radiographic examinations, serum chemical analysis or urea nitrogen, creati-
nine, and glucose, does not increase the safety of cataract surgery [5]. Consecutively,
the Cochrane Database of Systematic Reviews confirmed that routine preoperative
examinations do not improve the safety of PCS [6]. On the other hand, adverse
medical events precipitated by cataract surgery remain a concern, as commonly
elderly patients with multiple medical comorbidities undergo surgery [6]. Self-
administered health questionnaires could be concerned as a substitute, nevertheless
they might be useless in developing countries where some people have ever been to
a physician [6].
The problem is not trivial; the unneeded tests and procedures in the United States
are appraised to be as high as 30% of all health care expenditures [7]. Up to 97.1%
clinicians believe that the frequency of unnecessary tests and procedures is a serious
problem [8]. Rationing and elimination of wasteful, non-beneficial interventions
was proposed to be ethically mandated [9]. The annual cost of routine preoperative
screening before cataract surgery solely in Medicare beneficients was estimated
as $45.4 million [4], and it might reach up to $150 million in the whole United
States. Interestingly, the patient’s probability of undergoing preoperative screening
was found to be associated mainly with the ophthalmologist who conducted the
preoperative evaluation, rather than his medical characteristics [10].
Anticoagulants and Cataract Surgery
Preventive antiplatelet use is one of the preventive strategies to decrease mortal-

ity due to heart attacks and strokes, which are the leading causes of mortality
in the United States. Antiplatelet or anticoagulant medications are commonly
used for prevention of venous thromboembolism, in atrial fibrillation or valvu-
lar heart disease. It is estimated that one third of adults aged 40 years or older
take preventive antiplatelet medications. The use increases with age and reached
54% of those ≥80 years of age [11].
3 Recent Developments in Cataract Surgery 57
Routine clear corneal incision (CCI) PCS carries a very small risk of clinically
significant bleeding [12]. Benzimra et al. reported that the incidence of subconjunc-
tival hemorrhage is increased in patients taking clopidogrel or warfarin compared to
controls [13]. In their study patients underwent local anaesthetic block with a sharp
needle or subtenon’s cannula. It should be underlined that subconjunctival hem-
orrhage cannot be considered as a potentially life-threatening or sight-threatening
complication, but rather a minor complication that should be reported. Furthermore,
with the CCI PCS surgeries are commonly performed under topical anesthesia, and
such an administration method should be considered without the use of a sharp
needle. The review by Grzybowski et al. showed that PCS can be performed safely
in high-risk patients, taking both anticoagulants and antiplatelet agents if the proce-
dure is performed by a skilled surgeon, through a CCI and in topical anesthesia [14].
This was further referenced by the American Academy of Ophthalmology Preferred
Practice Pattern as a strong recommendation [3].
Importantly, discontinuation of antiplatelet agents or anticoagulants may
increase the risk of thrombotic events such as myocardial infarction or stroke in
patients undergoing PCS [12]. A scrupulous risk/benefit analysis and patient selec-
tion should be performed. For example perioperative circumstances—small pupils,
floppy iris syndrome, iris neovascularization, pseudoexfoliation or phacodone-
sis—may increase the risk for intraocular hemorrhage [12]. In cases requiring IOL
suturing or concomitant invasive vitrectomy, particularly in diabetic patients, dis-
continuation of antiplatelet agents or anticoagulants might be considered [12].
Methods for Assessing Corneal Power
The corneal power can be assessed with the diagnostic procedures of keratometry
and topography/tomography. Keratometry is a measurement of the anterior central
corneal curvature and is performed with a manual keratometer, or more commonly
automatically. The two basic manual keratometers are the Javal-Schiotz type and
the Helmholtz type [15]. Automated keratometry measures the radius of the curva-
ture of the anterior surface of the cornea from four reflected points approximately
3 mm apart. Topography derives from the Greek words “to place” (topo) and “to
write” (graphein), which means to describe a place. This is classically related to the
study of Earth’s surface shape [16]; corneal topography is the study of the shape
of the corneal surface [17]. Corneal topographers include the videokeratoscope or
Placido-based devices, e. g., Topographic Modeling System (Tomey Corporation,
Nagoya, Japan), Keratron (Optikon 2000 S.p.A., Rome, Italy), Zeiss Atlas (Carl
Zeiss Meditec AG, Jena, Germany). Tomography derives from the Greek words
“to cut or section” (tomos) and “to write” (graphein). In medicine the classic term
computed tomography scanning is used for referring to the radiographic technique
for imaging a section of an internal solid organ, producing a three-dimensional
image. Corneal tomography presents a three-dimensional image of the cornea and
is used for the examination of the front and back surfaces of the cornea along with
pachymetric mapping. Currently, the corneal tomography might be assessed with:
(1) Scanning slit devices, e. g. Orbscan IIz (Bausch & Lomb, Rochester, NY) (2)
The Scheimpflug devices, e.g. Pentacam (OCULUS Optikgeräte GmbH, Wetzlar,
Germany), Sirius (CSO, Firenze, Italy), and the Galilei (Ziemer Ophthalmic Systems
AG, Port, Switzerland). The latter two have and additional large cone Placido disc
incorporated in them. (3) OCT-based devices e.g. Visante (Carl Zeiss Meditec AG,
Jena, Germany).
A significant problem in determining the true corneal power is the difficulty
to assess the posterior corneal surface. In most keratometric devices the rela-
tionship between the anterior and posterior corneal surfaces is fixed and esti-
mated based on an empiric “keratometric index”. A recent study by LaHood
et al. revealed that the magnitude of anterior and posterior astigmatism is greater
when the steep axis of the anterior astigmatism is oriented vertically [18]. Such
evaluation leads to overestimation of astigmatism in with-the-rule astigmatism,
whereas in eyes with against-the-rule astigmatism it could be underestimated.
Therefore, assessing the optical power of the posterior corneal surface, and spe-
cifically it’s astigmatism with corneal tomography devices could potentially
increase the refractive outcome in lens surgery [19]. This issue is particularly
important in IOL calculations of eyes that underwent corneal refractive sur-
gery. As in these procedures corneal tissue is removed for refractive purposes
changes, similarly the relationship between the front and back surfaces of the
cornea is altered, invalidating the use of this standardized index of refraction.
Currently, the optical biometers that employ corneal tomography, routinely
allow measurement of the posterior corneal astigmatism [18].
It might be concluded that corneal tomography (or topography, when evaluating
the posterior corneal surface is not neccessary) should be performed in patients with
irregular, abnormally flat or steep corneas, in eyes with significant astigmatism,
after previous corneal refractive surgery, or if it is not possible to achieve accurate
keratometric measurements [20].
Devices for Biometry
Primarily ultrasonography, which analyzed the echo delay time, was applied for
preoperative biometry. The accuracy of ultrasound biometry was about 100 μm in
older devices, and 20 μm in high precision instruments [21, 22]. This issue of accu-
racy is significant, as an error of 0.1 mm in axial length might result in a spherical
equivalent error of 0.3 D [22]. Contact A-mode biometry is an applanation method
and requires touching the cornea with an ultrasound probe. Corneal indentation,
which alters the measurement results, is a significant disadvantage of this method
[23]. In immersion ultrasound biometry a scleral cup filled with a coupling agent
is applied, and the probe is immersed in the fluid so it does not depress the cornea.
Optical methods are less invasive, more user- and patient-friendly, less depen-
dent on the examiner, show high accuracy and repeatability [24]. Optical biometry
is currently considered as the gold standard and techniques employed in this method
are presented in Table 3.1. A disadvantage of optical biometry is unattainability in
patients unable to fixate, and in dense cataracts due to light scattering. Similarly,
axial lens opacities might alter light transmission and give inaccurate results. Higher
wavelength results in improved tissue penetration and higher success rate. For exam-
ple in the study by Hirnschall et al. 78 of 1226 eyes (6.4%) were not measured suc-
cessfully with partial coherence interferometry (780 nm), while with swept-source
optical coherence tomography (1055 nm) the rate of unsuccessful scans was lower,
and expected to reach only 0.5% [25]. In these cases immersion measurements still
have a role in contemporary ocular biometry [25]. Currently, performing optical
biometry requires a particular device solely for performing the measurements and
IOL calculation. However, in future it might be employed in a standard anterior/
posterior segment OCT, and such devices are availabe commercially (Fig. 3.1) [26].
Table 3.1 Techniques employed for optical biometry

Technology Light source (wavelength) Example biometers
PCI Blue-light emitting diode (475 nm) Oculus Pentacam AXL
PCI Semiconductor diode laser (780 nm) Zeiss IOL Master 500
Nidek AL-scan
LCOR Superluminescent diode laser (820 nm) Haag-Streit Lenstar LS 900
Topcon Aladdin/Aladdin LT
Ziemer Galilei G6
OCT Superluminescent diode laser (830 nm) Optopol Revo NX
SS-OCT Rapidly tuned laser with longer wavelength Zeiss IOL Master 700
(1050–1060 nm) Movu Argos
Tomey OA-2000
Heidelberg Engineering
Anterion
Abbreviations: LCOR low-coherence optical reflectometry, OCT optical coherence tomography,
PCI partial coherence interferometry, SS-OCT swept source-OCT
Fig. 3.1 Biometry of a patient with dense posterior subcapsular cataract in a commercially avail-
able optical coherence tomography device (Revo NX, Optopol Technology Sp. z o.o., Zawiercie,
Poland). Although the visualization in the lower and temporal part of the macula is hampered
(lower parts of the retinal images), axial length measurements can be obtained
IOL Calculation Formulas
The earliest IOL calculation formula was proposed over 50 years ago by Fedorov
et al. [27]. First generation formulas were based on a thin-lens paraxial approxi-
mation, omitting factors such as lens thickness, corneal thickness or IOL design.
Second generation formulas (regression formulas) decoupled eye as an optical sys-
tem and were purely based on statistical analysis of refractive outcomes. The main
improvement of third generation formulas was based on the assumption that the
effective lens position is not a constant, but a function of axial length and corneal
power. The goal of fourth generation formulas was to develop a universal calcula-
tion method giving the best outcome in all eyes despite axial length. Fifth gen-
eration formulas consider even more input parameters including gender or race to
achieve a higher level of customization [28].
Recently, Koch et al. presented a different classification of IOL calculation for-
mulas using a logical approach [29]. The reason for creating the new classification
were difficulties with categorizing new formulas that employ ray tracing or artificial
intelligence. The first proposed group is historical/refraction based formula, which
include early attempts to calculate IOL power i.e. 18.0 Dpsh + 1.25 × preoperative
spherical equivalent. Regression formulas, such as SRK or SRK II, do not rely on
theoretical optics, but on analysis of previous data. The most numerous are vergence
formulas. They rely on Gaussian optic and the assumption that the image vergence
is equal to the sum of object and lens vergence. Certain formulas with the variables
required for IOL calculation are presented in Table 3.2.
Table 3.2 IOL calculation formulas

Logical approach Variables required
Formula Generation* classification AL K ACD LT WTW RxPre Age
SRK-I, Binkhorst I 1st V X X
SRK-II, Binkhorst II 2nd V X X
Holladay 1 3rd V X X
SRK/T 3rd V X X
Hoffer Q 3rd V X X
Holladay 2 4th V X X X X X X X
Olsen 4th V X X X X X
Haigis *
V X X X
Hill-RBF *
AI X X X X X
Barrett Universal II *
V X X X X X X
Abbreviations: AI artificial intelligence formulas, AL axial length, K keratometry, ACD anterior
chamber depth, LT Lens thickness, RxPre preoperative refraction, WTW horizontal corneal white-
to-white diameter, V vergence formulas
*
Within the traditional classification it is difficult to categorize new IOL calculation formulas
Similarly to regression-based, artificial intelligence formulas use huge data-

bases and a sophisticated statistical model to find relationship between not evident
approaches; these include the Clarke neuronal network or Hill-RBF formula (radial
basis function) [29, 30]. Another approach for improving the accuracy of IOL cal-
culation is the application of ray-tracing analysis. Ray-tracing is method for cal-
culation of every single ray passing through the optical system, and the refraction
of rays at each optical surface is calculated using Snell’s law. A map of corneal
power achieved in topography or tomography can be transformed into an array of
individual measurements representing a polygonal shape. Ray-tracing is employed
to analyze the optical properties of every element of the eye in order to establish the
performance of the entire optical system. Particularly in eyes after refractive surgery
it might help to solve the issue of higher-order aberrations of the cornea by selecting
a particular design of an IOL. Software applied for IOL calculation include Okulix
or Phacooptics (Olsen).
When choosing the formula for IOL calculation the performance depending on
the axial length of the eye should be taken into account (Table 3.3). The Haigis can
be considered as the first choice for most routine cases [31]. It possesses rather
small postoperative median absolute error and can be used with eyes of all axial
lengths. For eyes under 22 mm in axial length the Hoffer Q formula should be
applied for comparative assessment. The SRK-T formula manifests a lower predic-
tive accuracy in short eyes; for that reason it should be employed for comparative
purposes only in eyes over 22 mm of axial length. The Holladay I formula might be
the second choice for eyes with axial length of 22–26 mm. The Holladay II takes
into account the disparities in the anterior segment by adding the corneal white-to-
white diameter and lens thickness, and might facilitate estimating the effective lens
position. It shows benefits in eyes under 22 mm of axial length.
A notable percentage of patients undergoing PCS demonstrate corneal astigma-
tism. In a study by Hoffmann more than 36% of eyes had astigmatism 1 D or greater,
while over 8% over 2 D or more [32]. For toric IOLs calculations manufactur-
ers commonly provide an online calculator which employs the formerly presented
formulae, but has incorporated IOL models and constants (e.g. Alcon, Bausch and
Lomb, Johnson & Johnson Vision, Sifi). Also the Berdahl and Hardten calculator
should be mentioned, as it allows to assess if the residual astigmatism after surgery
is a result of toric IOL misalignment [33].
Table 3.3 The preferred IOL calculation formula based on the axial length of the eye
Axial length <22 mm 22–24.5 mm 24.5–26 mm >26 mm All lengths
1st choice Hoffer Q, SRK-T, SRK-T, SRK-T, Barrett Universal II,
formula Haigis Haigis Haigis Haigis Hill-RBF
2nd choice Holladay II Holladay Holladay –
formula
Benchmarking
Achieving an accurate refractive target is desired in contemporary PCS. Employing

optical biometry and proper IOL calculation formulas allows achieving ≤0.5 D
of the refractive target in 79.1% of eyes, while ≤1.0 D in 97.2% of cases [34].
Interestingly, the interocular axial length difference influences the refractive out-
come. The odds ratio (OR) of having a refractive outcome >0.5 D is 1.4, 1.6 and
1.8, for interocular axial length difference of 0.2, 0.4 and 0.6 mm, respectively [34].
If the interocular axial length differences is 0.2 mm or more it would be advised to
remeasure with the same device or, if possible, use another device to confirm the
axial length [35]. Myopic patients have a lower chance of achieving the refractive
target than non-myopic individuals (OR 1.9) [34].
Han and McGhee emphasized that in the current patient-focussed climate it
becomes difficult to establish a clear definition of a complication in contemporary
cataract surgery [36]. Thirty years ago a postoperative best correct visual acuity
of 6/12 (20/40) might have been considered as a good outcome. Currently, in the
era of postoperative visual acuity of 6/6 (20/20) and ±0.5 D of emmetropia, such a
result could be considered a complication. With proper preoperative assessment and
allocation of high-risk phacoemulsification procedures to experienced surgeons it
is possible to reduce the rate of intraoperative complications by 40% and the rate of
posterior capsule tear from 2.6 to 0.6% [37]. Within the Auckland Cataract Study the
proposed stratification system risk factors for intraoperative complications included
cataracts with no fundus view, pseudoexfoliation, phacodonesis, oral alpha-receptor
antagonist intake, high ametropia, posterior capsule cataract or plaque or corneal
scarring [37]. Moreover, it was proposed that patients after prior vitrectomy or with
only one eye should be operated by experienced surgeons only.
IOL Types
IOLs were introduced by Sir Harold Ridley, and the first successful IOL implan-
tation was performed in the 1950 [38]. IOLs can be divided based on the mate-
rial they are made of. Silicone lenses composed of polyorganosiloxane materials,
with high refractive indices, were the first available foldable IOLs. Acrylic lenses
can be made of rigid polymethyl methacrylate (PMMA), foldable hydrophilic or
hydrophobic acrylic materials [39]. Addition of a blue-light filtering chromofore or
UV-protection is employed in some IOL models.
The IOL design basically mirrors the intended location of IOL implantation.
Posterior chamber lenses can be placed in the capsular bag, in the ciliary sulcus,
or fixated to the iris. Single-piece IOLs may be open loop or overall plate lenses
(Fig. 3.2a, b). Three-piece IOLs have haptic components made of PMMA, polypro-
pylene, polyimide or polyvinylidene fluoride (Fig. 3.2c). In general, IOLs placed in
the sulcus should have rounded optic edge and thinner haptics to prevent irritating
the posterior part of iris, larger size of more than 13–14 mm (depending on the size
Fig. 3.2 IOL designs. (a) A single-piece hydrophobic acrylic toric IOL (Bausch+Lomb EnVista
Toric). (b) A single-piece hydrophilic acrylic IOL for micro-incisional cataract surgery—designed
for a 1.8 mm incision size (Bausch + Lomb Akreos AO60). (c) A three-piece IOL with silicone
optic anda haptics made of polymethylmethacrylate (Bausch + Lomb SofPort). (d) An accommo-
dating IOL designed for in-the-bag implantation (Bausch + Lomb Crystalens AO)
of the eye) and a three-piece design. Sulcus placement of standard one-piece IOLs
should be avoided as it increases the risk of postoperative complications, including
pigment dispersion, uveitis–glaucoma–hyphema syndrome, and recurrent vitreous
hemorrhages. On the other hand, IOLs implanted in the capsular bag should have a
squared, truncated posterior optic edge to prevent lens epithelial cell migration and
posterior capsule opacification [40]. Anterior chamber IOLs can be placed in the
anterior chamber angle (open-loop design is preferred) or fixated to the iris (iris-
claw IOLs).
Based on the optical properties IOLs can be divided into monofocal IOLs or
multifocal/accommodating IOLs. Both monofocal and multifocal IOLs might have
a spherical power, or toric in order to compensate astigmatism. The positive spheri-
cal aberration of the cornea can be compensated by aspheric design IOLs, having
negative or zero spherical aberration to improve the patient’s quality of vision. In
order to achieve multifocality or an extended depth-of-field different optical prin-
ciples are employed. A diffractive IOL generates multifocality making use of light
interference and is independent of pupil size. It incorporates a pattern consisting
of a series of annular concentric grooves less than one micron in depth, which are
engraved around the optical axis on either the front or the back surface of a lens
(the echelette technology). The refractive design allows to achieve depth of focus
with light refraction on the IOL surfaces based on Snell’s law. The optical power
decreases continuously from the center to the periphery of the lens creating an infi-
nite number of focal points and is derived from the smooth hyperbolic shape of its
optics. The performance of refractive design IOLs is dependent on pupil size and
IOL centration. Other optical concepts such as the pinhole effect [41] or light sword
optical element [42] might be employed. Accommodating IOLs may change their
curvature, or have a fixed-power presenting axial shift in order to restore accom-
modation (Fig. 3.2d) [43].
Ametropia following cataract surgery can be treated by performing a corneal refrac-

tive enhancement. Secondary piggyback IOLs are designed for secondary implanta-
tion in the ciliary sulcus to correct pseudophakic ametropias or pseudophakic lack
of accommodation. Another potential option for avoiding pseudophakic ametropia is
implantation of Light Adjustable Lens (LAL). A technology developed by Calhoun
Vision Inc. involves implantation of a three-piece light-adjustable silicone IOL with
silicone macrometrs containing an ultraviolet (UV) light-activated photo initiator [44].
Postoperatively, the IOL power can be adjusted by exposure to a customizable UV light
profile resulting in polymerization of the IOL macromers. Clinical studies confirmed
the safety of this technology to corneal endothelial cells [45] and to the retina [46].
Glaucoma and Cataract Surgery
Cataract surgery alone results in a modest reduction of intraocular pressure [47, 48].
The reduction is proportional to preoperative IOP and ranges from 8.5 mmHg in eyes
with preoperative IOP of 23–29 mmHg to 1.7 mmHg in eyes with IOP 5–14 mmHg
[49]. The decrease in IOP is attributed to the increase in anterior chamber depth,
flattening of the iris diaphragm, and subsequent extension of the trabecular mesh-
work. These changes are particularly advantageous in patients with angle-closure
glaucoma. In open-angle glaucoma although IOP parameters improve after cataract
surgery, glaucomatous visual field decay does not slow compared to rates measured
during the progression of cataract [50]. Another option that should be considered in
glaucoma patients is conjunction of PCS with endoscopic cyclophotocoagulation,
trabecular micro-bypass stent, ab interno trabeculectomy, and canaloplasty [51].
These procedures are associated with a lower risk of surgical complications, how-
ever, are less effective than trabeculectomy.
Many antiglaucoma agents were reported to cause pseudophakic cystoid macular
edema (PCME). Particularly prostaglandins—often the first line of treatment for
IOP lowering—were believed to increase the risk of PCME [52, 53]. Miyake et al.
presented findings suggesting that the preservatives used in these pharmaceutical
cause increases synthesis of prostaglandins, intensifies postoperative inflamma-
tion and results PCME [54]. Nevertheless, more recently no association between
prostaglandin analogue administration and PCME was reported [55]. It might be
concluded that there is no evidence to discontinue antiglaucoma medications during
cataract surgery and the risk associated with IOP elevation might be greater than
disadvantages associated with their use.
AMD and Cataract Surgery
The Beaver Dam Eye Study presented that having undergone PCS before baseline
examination was associated with age-related maculopathy and the exudative age-
related macular degeneration [56]. Some newer studies confirmed cataract surgery as
being a risk factor for AMD [57–59], while other reported conflicting results [60–63].
The Cochrane Database for Systematic Reviews revealed that it is not possible to draw
reliable conclusions from the available data as to whether cataract surgery is beneficial
or harmful in people with AMD after 12 months [64]. It was concluded that in general
cataract surgery provides short-term improvement in best corrected visual acuity in
AMD patients compared to patients with no surgery. It is unclear whether the tim-
ing of surgery has an effect on long-term outcomes in AMD [64]. As in vivo studies
demonstrated that blue light (430 nm wavelength) is harmful to retinal pigment epi-
thelium cells, some authors believe that the protective effect of UV-blocking and blue-
blocking IOLs might be greater than solely UV-blocking IOLs [65]. Nevertheless, the
application of blue-blocking IOLs in not based on clinical evidence, as there are no
studies truly confirming significant photoprotection [66].
Visual rehabilitation is necessary in patients with advanced AMD. Usually spec-
tacles, magnifying glasses or electronic devices are used as visual aids. For several
years specially designed intraocular implants have become an appealing alternative to
extraocular aids. The possible options include implantable macular telescope, an IOL-
VIP System, Lipshitz macular implant (for capsular bag or sulcus fixation), Fresnel
Prism IOL, iolAMD or Scharioth Macula Lens [67]. However, the results so far were
variable, and the available studies focused mainly on short-term outcomes [68].
Importantly, cataract surgery after previous intravitreal therapy is associated with
a higher likelihood of posterior capsule rupture (PVR); 10 or more previous injec-
tions is associated with a 2.59 higher likelihood of PCR [69].
Combined Surgeries (Efficacy vs Safety)
The efficacy and safety of combined phacoemulsification and vitrectomy was

reported in several surgical indications, including macular hole, macular pucker, and
in diabetic patients. A combined procedure eliminates the need for two operations
and enables faster visual rehabilitation. Another rationale for this approach is that
vitrectomy itself is known to induce cataract. For example, in a study by Jackson
et al. 51.8% of phakic patients after vitrectomy with gas tamponade developed cata-
ract requiring PCS in the following 6 months [70]. Lens opacification is associ-
ated with increased retrolental oxygen levels, particularly in extended vitrectomy
with surgical posterior vitreous detachment and anterior vitreous removal [71]. The
increased risk of intraoperative complications during PCS in vitrectomized eyes is
well known, and might be associated with lens touch during vitrectomy, zonular
dehiscence or intraoperative miosis [72–75]. The absence of vitreous support might
also result in increased anterior depth and a disparity between fluid inflow and out-
flow during phacoemulsification or irrigation/aspiration [76–78].
Combined phacoemulsification with intraocular lens implantation and keratoplasty
is known as the triple procedure. It is a safe and effective approach in patients with
coexisting cataract and corneal pathologies [79]. A significant problem in the triple
procedure is an unacceptable postoperative refractive error. It is a concern both in
penetrating keratoplasty (where some suggest PCS after suture removal due to the
refractive change associated with their removal) and lamellar keratoplasties. In deep
anterior lamellar keratoplasty a large proportion of the stroma is replaced giving
uncertainty of postoperative refraction, while in endothelial keratoplasties the cornea
is preoperatively swollen due to endothelial dysfunction altering its optical power.
In cases of visually significant cataract and co-existent glaucoma, combined sur-
gery (phacotrabeculectomy) can be considered. Filtration surgery presents a high risk
of intraoperative bleeding, in contrary to PCS alone [80]. With that, there is evidence
that long-term IOP is lowered by combined glaucoma and cataract surgery, however,
giving a smaller effect than trabeculectomy alone [81, 82]. This might be possibly
due to inflammation related to phacoemulsification. On the other hand, some studies
presented that PCS performed after trabeculectomy might reduce the function of a fil-
tering bleb in some eyes [83, 84]. In patients with angle-closure glaucoma, PCS alone
might be an effective treatment [85]. Interestingly, combined cataract surgery (with
corneal, glaucoma or vitreoretinal procedures) has a higher incidence of acute post-
operative endophthalmitis than stand-alone PCS (0.149% vs. 0.102%, respectively).
ettings (Ambulatory or Hospitalization, Operating Theater

S
or in Office)
Currently, almost all cataract surgeries are performed in outpatient settings. These
include a hospital-based outpatient departments or a standalone ambulatory surgical
centers. The Cochrane Database for Systematic Reviews found cost savings associ-
ated with same-day discharge cataract surgery versus in-patient cataract surgery,
however, the evidence regarding postoperative complications was inconclusive
because the effect estimates were imprecise [86]. Some patients may still require
an operative room or in-patient setting, intravenous sedation or general anaesthesia,
and particularly complex cataract cases, or in individuals with severe comorbidities.
Recently, safety and effectiveness of PCS performed in an office-based minor pro-
cedure room in a series of 21,501 eyes was presented [87]; it was efficient for sur-
geon, as well as comfortable for the patient [85]. Another study conferred the safety
of outpatient cataract surgery without presence or a dedicated access to anaesthetic
service [88]. The monitoring was limited to blood pressure and plethysmography pre-
and intraoperatively. Although office-based surgery is presently not reimbursed by
Medicare, such relocation of the procedure might occur in future as it is cost-effective.
Anesthesia (Topical vs Peribulbar vs Retrobulbar vs General)
The majority of cataract surgeries are performed under local anesthesia. General
anesthesia should be considered in pediatric patients and for adults having difficul-
ties with cooperation during surgery due to head tremor, deafness, mental retarda-
tion, neck or back problems, claustrophobia.
Retrobulbar anesthesia is performed by injecting the anesthetic drug to the intra-

conal space behind the eye [89]. In peribulbar anesthesia the drug is injected to the
extraconal space, and diffuses between the intra- and extracone space to achieve
anesthetic effect. Peribulbar and retrobulbar anaesthesia for cataract surgery show
similar akinesia and pain control in cataract surgery [90]. However, the need for
additional injections of local anaesthetic is greater with peribulbar anaesthesia.
Another option is sub-Tenon anesthesia which involves creating a conjunctival but-
tonhole, blunt dissection of the Tenon’s space and introduction of anesthetic to the
subtenonian space.
Topical anesthesia may be preferred in phacoemulsification due to lower com-
plication rates. Nevertheless, PCS under topical anesthesia may not be a completely
painless procedure [91]. In these cases another option is additional intracameral
anesthetic administration during the surgery.
Difficult Cases: Increased Risk of Complications
Preoperative definition which eyes poses a potential risk of complications

is critical, as in these eyes proper planning of the surgery is the key to suc-
cess. Anatomic difficulties including deep set eyes or a protruding brow might
impede surgical manipulations and proper instrument fitting it the operative
field. Another group of challenges are high ametropias. Small hyperopic eyes
make it difficult to perform intraocular manipulations, have increased chance of
irid injury, cyclodialysis or fluid misdirection syndrome [92]. In deep myopic
eyes the nucleus can be very large and the anterior chamber very deep. These
patients also have a lower risk of accurate IOL power prediction [34]. Corneal
opacities or scarring impede proper visualization of the operative field, which is
particularly important during the capsulotomy [93]. Hard, dense or hypermature
cataracts might be difficult to remove with phacoemulsification, and in these
cases extracapsular extraction might be required. Eyes with pseudoexfoliation,
with subluxated or dislocated lens (due to very mature lens, trauma, of Marfan’s
syndrome) have an increased chance of zonular dialysis, and might require
supplementary means to fixate the lens. Eyes with small pupils, bound down
pupil, floppy iris syndrome or a posterior pole cataract present an increased risk
for intraoperative complications. General health problems including chronic
obstructive pulmonary disease or dementia might impede proper patient posi-
tioning and cooperation [92].
The National Institute for Health and Care Excellence recommends that one
IOL should be in the theater, an additional identical one should be in stock, and
an alternative IOL (anterior chamber (AC)-IOL, sulcus IOL or iris-claw IOL) in
case the lens needs to be changed if there are complications during surgery [20].
Additional accessories such as pupil expansion rings, iris hooks or capsular tension
rings should be in stock.
Bilateral Operation
The principle of immediate sequential bilateral cataract surgery (ISBCS) is to

treat each eye as an individual and autonomous surgery during the same session
in the operating theater. Each eye requires a change of draping, gloves, gowns and
instruments [94]. Some authors recommend that instruments should come from
disparate sterilization cycles, while viscoelastics or irrigation fluids from different
companies or, at least, have different lots [95]. With these precautions employed,
the greatest potential risk of ISBCS—bilateral endophthalmitis—has never been
reported.
ISBCS is comparable with delayed sequential bilateral cataract surgery (when
the second eye is operated on days to weeks later) in long-term patient satisfaction,
visual acuity and complication rates [96]. A significant advantage of ISBCS is faster
visual rehabilitation [97]. This approach is also cost-effective: it requires fewer hos-
pital visits, allows faster return to work and only one pair of glasses. ISBCS is an
ideal solution for patients requiring general anaesthesia, in order to eliminate the
risks associated with a second intervention [98].
An argument commonly picked up by its opponents is the problem of anisome-
tropia. In delayed sequential cataract surgery it is possible to adjust the IOL power
of the second eye based on the postoperative results of the surgery. Nevertheless,
with the advances of optical biometry, and due to the fact after simultaneous sur-
gery, the errors are minor and symmetrical, ISBCS does not cause anisometropia.
Intraoperative Considerations
Intracapsular vs Extracapsular Cataract Extraction
Intracapsular cataract extraction (ICCE) involves removal of the opaque lens with
the capsule in one piece. Samuel Sharp (1709–1778) was he first to perform intra-
capsular cataract extraction (ICCE). His report was presented to the Royal Society
of London and subsequently published in the Philosophical Transactions [99]. A
significant problem encountered during ICCE was zonular resistance, which needed
to be overcome while releasing the lens. This was augmented with the develop-
ment of the erisophake—a special cup with suction apparatus introduced into the
anterior chamber—in order to hold firmly the lens with its capsule [100]. Alpha
chymotrypsin could have been applied for enzymatic zonulolysis to augment lens
liberation [101, 102]. Krwawicz proposed utilizing low temperatures with a cryo-
extractor which firmly attached to the lens capsule and subcapsular masses [103].
Cryoextraction cataract surgery led to a substantial progress in ophthalmology by
reducing the number of complications, particularly capsule rupture, and resulted
in achieving better outcome compared to other methods. Nevertheless, disadvan-
tages of ICCE included large incision size and relatively high rate complication
rate including vitreous loss, retinal detachment, endothelial cell damage or cystoid
macular edema [104]. Another problem in ICCE is the lack of the lense capsule,
which limits the possible options for IOL implantation.
Extracapsular cataract extraction (ECCE) involves removing the opaque lens,
while leaving it’s elastic capsule. Jacques Daviel (1693–1762) is believed to be the
first to perform ECCE and presented this method in 1752 to the French Academy
of Surgery [105]. Sushruta (600 BCE) might be considered as the a precursor of
ECCE, however, he only described a paracentesis, and some extraocular evacuation
of cortical masses, but not a large enough incision which could enable the extraction
of the entire lens, as it is usually required in a classic ECCE [106]. Currently, most
cataract surgeries attempt to preserve the lens capsule. The modification of ECCE,
manual small incision cataract surgery (MSICS) is the most commonly employed
form of ECCE, particularly in the developing world [107]. The principal feature
of MSICS is hydrodissection and hydrodelineation of lens lamella, followed by
hydroexpression of core nucleus into the anterior chamber [108]. An advantage of
the procedure is that is does not require an ophthalmic viscoelastic device nor com-
plex instrumentation. The Cochrane Database for Systematic Reviews presented
that the number of complications in both MSICS and phacoemulsification are low
[109]. Another conclusion was that removing cataract by phacoemulsification may
result in better uncorrected visual acuity in the short term (up to 3 months after sur-
gery) compared to MSICS, but similar best-corrected visual acuity. MSICS is faster,
less expensive and less technology-dependent than phacoemulsification. It may be a
convenient option in eyes with mature cataract in the developing world [110].
The main difference between ICCE and ECCE (particularly with preserved
intact capsule) is the complication rate. ICCE presents more wound-related compli-
cations due to larger incision size than ECCE. With that, due to breaking the anterior
hyaloid membrane, ICCE more commonly induces posterior vitreous detachments,
macular edema and macular holes [111]. Primarily ICCE gained popularity in the
twentieth century as, particularly with the cryoextractor, it was easy to completely
remove the lens. Later on, due to higher complication rates of ICCE than ECCE, it
was completely replaced by extracapsular methods.
Phacoemulsification
A critical advancement in cataract surgery was introduction of phacoemulsification

by Charles Kelman in 1967 [112]. As it was possible to divide and remove the lens
within the eye, this portended the upcoming of the “small-incision cataract surgery”.
Phacoemulsification allows exceptional anterior chamber control as the incision is
significantly reduced in size and is tightly sealed around the handpiece. IOP can be
held within normal range with improved anterior chamber maintenance, reducing
the likelihood of suprachoroidal or expulsive hemorrhage [113]. The decrease in
wound size supports omission of corneal suturing, leading to less induced astig-
matism and faster visual recovery. Finally, it is possible to significantly reduce the
complication rates. Disadvantages of phacoemulsification include a steep learning

curve, high reliability on the phacoemulsification unit and cost related to purchas-
ing and maintaining it. The size of the IOLs for some time impeded the decrease in
incision diameter, as is was necessary to extend the initial cut in order to implant
an IOL [38].
Femtosecond Laser-Assisted Cataract Surgery (FLACS)
Femtosecond lasers employ infrared light of the wavelength of 1053 nm and operate
at high energy levels and very short, femtosecond range, pulses. The initial results
of using femtosecond lasers for cataract surgery were presented in 2009 [114].
FLACS has raised a lot of hope as a mean to improve cataract surgery. The reported
benefits included increased precision of the anterior capsulotomy, improved wound
architecture and reduced ultrasound power during phacoemulsification (leading to
a lower endothelial cell loss and collateral tissue damage). FLACS was proposed
as a safe alternative for patients with Fuchs endothelial corneal dystrophy [115].
Nevertheless, in a recent study it was presented that FLACS does not lower the rate
of corneal decompensation in eyes with mild to moderate Fuchs dystrophy [116].
Disadvantages of FLACS include mainly the price of the surgery, and that it
is not cost-effective [117]. Another issue is the prevalence of PCME, which was
shown to be higher in FLACS than in conventional PCS. This might be attributed
to increased aqueous humor prostaglandin levels, possible due to increased surgical
trauma caused by the laser to ocular tissue [118]. The main trigger for prostaglandin
release was anterior capsulotomy [119], and the application of topical NSAIDs pre-
operatively could prevent this increase [120]. Another drawback is the potential of
FLACS-specific intraoperative complications, such as anterior radial tears, capsular
tags, suction break or pupillary constriction. The Cochrane Database for Systematic
Reviews did not determine the superiority of laser-assisted cataract surgery com-
pared to standard manual phacoemulsification [121].
Micro-incisional Cataract Surgery (MICS)
MICS is a modification of a standard cataract surgery with the approach of a mini-

mally invasive procedure. Coaxial or biaxial methods are employed, although with
the smallest possible incision. MICS with the final incision of 1.6–1.8 mm for IOL
implantation is believed to improve the visual and surgical outcome, and reduce
the risk of associated complications [122]. In a biaxial procedure the steepest cor-
neal meridian is marked and two incisions are executed 90° apart from each other.
Currently, 19 G (1/1.1 mm) and 21 G (0.7 mm) instrumentation is employed for
MICS. A relatively wider incisions should be made to enable unhampered manipu-
lations within the AC: a 1.2 mm internally and 1.4 mm externally for 19 G tools, and
1-mm for 21 G. One of the incisions should be located in the positive meridian of
the cornea—it will be enlarged for IOL implantation. Another approach is to create
another, third incision for IOL implantation in the positive meridian shortly before
IOL introduction into the eye. As a result of small incision size the continuous
curvilinear capsulorhexis has to be carried out with a bent capsulotomy needle or
23-gauge vitrectomy-style micro-incisional capsulorhexis forceps. Cortical cleav-
ing hydrodissection should be performed in two distal quadrants. Particularly in
refractive lens exchange the use of specially designed symmetrical prechoppers
such as Alió-Scimitar MICS (Katena Inc., Denville, NJ) might yield cutting the
nucleus in half without placing any asymmetrical pressure on the zonules, and using
high values of fluidics [123].
Following emulsification of the nuclear segments, the cortical material remain-
ing in the capsular bag is removed with irrigation/aspiration. Separation of irrigation
and aspiration in two independent handpieces prevents generating vortex currents
at the end of the phaco-tip. Another advantage of the bimanual technique is the
feasibility to remove the sub-incisional cortex without switching handpieces. It is
worth highlighting that MICS presents outstanding AC stability. One of the reasons
is that the irrigation handpiece is constantly within the AC. As well, the imperme-
ability of two smaller incisions is greater than with a larger incision. Accordingly,
the incidence of intraocular hypotony and the risk of AC collapse or posterior vitre-
ous detachment during surgery declines considerably.
The value of MICS is that it can be performed with most phacoemulsification
platforms. The parameters favour fluidics with high levels of irrigation/aspiration
pressure, rather than phaco power. As a consequence of fast reaction and great flex-
ibility, a Venturi pump system may be recommended. Standard infusion tools could
be insufficient regarding hydrodynamics, hence particular MICS high-inflow tools
should be employed. The major disadvantage of bimanual phacoemulsification lies
in the current limitations of the IOL technology.
Wound Construction
Currently cataract surgery employs CCI or scleral incisions, and their classifica-
tion is presented in Table 3.4. Superiorly placed scleral tunnel incisions are used
mainly in MSICS and by beginning cataract surgeons. Scleral incisions induce sig-
nificantly less astigmatic change compared to CCI, which constitutes a significant
advantage of this approach [124]. Creating a scleral incision is more challenging
and time consuming compared to a CCI, and peribulbar or retrobulbar anesthesia is
required. Proper tunnel incision architecture, at least 1–2 mm into the clear cornea,
has self-sealing wound properties. Disadvantages of scleral incisions is occasional
requirement of cautery, as the conjunctiva is highly vascular. If the initial groove is
too superficial, a thin scleral flap will be prone to tearing or lacerations. If the initial
groove is too deep, the anterior chamber might be penetrated too early. When the
corneal part of the tunnel is performed too anteriorly, the visualisation will be ham-
pered due to striae when the phaco tip is tilted down. Ballooning of the conjunctiva
might impede access to the tunnell and require an additional cut.
Table 3.4 Classification of scleral and corneal tunnel incisions

Scleral tunnel incisions
Conjunctival flap architecture Limbal-based flap
Fornix-based flap
Based on scleral groove shape Smile incision Following the limbus
Straight incision Straight line
Frown incision Curve opposite to the limbus
Blumental side cut Straight line with sides receding from
limbus
Chevron ‘v’ incision V-incision, sides receding from the
limbus
Corneal tunnel incisions
Based on external incision Clear corneal Entry anterior to conjunctival insertion
location incision
Limbal corneal Entry through the conjunctiva and
incision limbus
Scleral corneal Entry posterior to the limbus
incision
Based on architecture Single plane No groove
Shallow groove Below 400 μm
Deep groove Over 400 μm
Primarily CCIs were criticized because of presumed increased risk of endo-

phthalmitis due to uncertain sealability and poor wound healing (Fig. 3.3). Thus
CCIs were indicated only in patients with pre-existing filtering blebs, taking anti-
coagulants [125], with blood coagulation disorders or cicatrizing diseases i.e.,
ocular cicatricial pemphigoid or Stevens-Johnson syndrome. Afterwards, as CCI
can be performed under topical anesthesia, they became more and more com-
monly used. In general, regional blocks presented increased risk of complica-
tions compared to topical anesthesia. Other advantages of CCIs include ease of
approach to the incision site, preservation of options for future filtering surgeries,
increased stability in refractive results (neutralization of the forces from lid blink
and gravity), no need for bridle sutures and the location of the lateral canthal angle
under the incision which facilitates drainage. A disadvantage of CCI is the induc-
tion of astigmatism. In general, the main incision should be located in the steep
meridian of the cornea, particularly if the corneal astigmatism is higher than 0.50
cylindrical diopter. Interestingly, the CCI-induced astigmatism significantly dif-
ferences among surgeons. In a study conducted by Ernest et al. all of the surgeons
have performed CCIs in the same manner and using identical surgical tools, the
surgically induced astigmatism differed double-fold (mean induced astigmatism
from 0.38 to 0.88 D depending on surgeon) [126]. Furthermore, the location of the
incision influences the size of astigmatism. Incisions performed in the nasal quad-
rant induce s ignificantly higher astigmatism than the temporal ones [127, 128].
Although clear corneal and scleral incisions might engender complications by
nature of their architecture and location, some complications are unique to CCI. If
the conjunctiva is unintentionally incised at the time of creating a CCI, ballooning
a b c
Fig. 3.3 Artist’s interpretation of cross-section view of clear corneal incisions. (a) A single plane
incision. (b) The modified incision by making a shallow, perpendicular groove before incising the
cornea. (c) A deepened perpendicular groove, which was believed to lead to greater stability
of the conjunctiva can develop which may compromise visualization of anterior

structures. If this develops, the use of a suction catheter is usually required by
the assistant to aid in visualization. Early entry into the anterior chamber might
result in an incision of insufficient length to be self sealing, increased tendency
for iris prolapse, and requires placing a suture at the conclusion of the procedure.
Late entry may result in a long corneal tunnel, so that the phacoemulsification tip
would create striae in the cornea and hamper visualization of the anterior cham-
ber. Manipulation of the phacoemulsification handpiece intraoperatively may
result in tearing of the roof of the CCI, particularly at the edges, compromising
the ability to self-seal, or occasionally resulting in minor detachment or scrolling
of Descemet’s membrane. Incisional burns similarly compromise self-sealability,
result in corneal edema and severe induced astigmatism [129]. In addition, manip-
ulations in the proximity of the wound can cause epithelial abrasion.
Intraoperative Complications
The overall complication rates in PCS are presented in Table 3.5. PCR is the most
common a potentially serious complication of PCS. It is associated with the risk of
dropped nucleus, vitreous loss, difficulties in placement of the IOL, and postopera-
tive complications such as retinal detachment or PCME. Risk indicators for PCR are
Table 3.5 Intraoperative cataract surgery complication rates in selected studies

CND dataset UKHS dataset
(n = 55,567) (%) [130] (n = 20,070) (%) [130]
Posterior capsule rupture with or without 1.41 0.53
vitreous loss
Iris damage from phaco 0.55 0.06
Zonular dialysis 0.46 0.1
IOL complications (decentration, IOL in the 0.36 0.05
vitreous, lens exchange required)
Phaco wound burn 0.25 0.0
Nuclear fragment into the vitreous/dropped 0.18 0.03
nucleus
Corneal epithelial abrasion 0.17 0.12
Vitreous in the anterior chamber 0.17 0.08
Choroidal/suprachoroidal haemorrhage 0.07 0.0
Hyphema 0.07 0.0
Abbreviations: IOL intraocular lens, UKSH United Kingdom Specialist Hospitals, CND United
Kingdom Cataract National Dataset
brunescent/white cataract (adjusted odds ratio (AOR) 2.99), pseudoexfoliation syn-

drome/phacodonesis (AOR 2.92), no fundus view during surgery (AOR 2.46), dia-
betic retinopathy (AOR 1.63), doxazosin intake (AOR 1.51), axial length equal or
greater than 26.0 mm (AOR 1.47), small pupil size (AOR 1.45) as well as inability to
lie flat (AOR 1.27), presence of glaucoma (AOR 1.3) and surgery performed by train-
ees (AOR 3.73, when comparing to senior house officer) [131]. The cause of PCR
usually involves touching the posterior capsule with surgical instruments, and may
occur at any stage of the surgery. Particularly patients with congenital posterior polar
cataract are at risk of PCR, and in these cases hydrodelineation rather than hydrodis-
section should be performed [132].
When dealing with PCR it is critical to remove the vitreous from the wound
and anterior chamber [20]. This should be employed with a vitreous cutter in order
to minimize any traction on the retina. All the lens fragments and soft lens matter
should be removed, both from the posterior chamber and vitreous cavity. As visual-
ization of the vitreous body might be difficult, the use of triamcinolone for staining
is recommended.
A small pupil makes PCS technically challenging, and usually a stepwise
approach for pupil dilation is recommended. If poor dilation is surmised, mydriasis
might be achieved preoperative application of atropine, which is strongest mydriatic
agent. In these cases atropine sulfate 1% is applied three times for 1–3 days before
surgery. Additionally, intracameral sympathomimetics agents (e.g. epinephrine in a
1:2500 dilution) might be administered intraoperatively [133]. The mydriatic effect
might be also achieved with intracameral preservative-free lidocaine 1% [134, 135].
Lidocaine might be combined with sympathomimetics and/or tropicamide. Such a
preparation for intracameral administration is available commercially (Mydrane,
Thea Pharmaceuticals, Clermont-Ferrand, France). In moderate to severe cases the
use of iris expansion rings or iris hooks might be necessary.
Intraoperative floppy iris syndrome (IFIS) is a condition that significantly

increases the risk of complications. IFIS is associated with a higher rate of surgi-
cal complications, especially when the condition is not recognized or anticipated
[136]. The relationship between IFIS and the systemic use of α-blockers, particu-
larly tamsulosin, was reported almost 10 years ago [137]. Importantly, discontinu-
ation of tamsulosin prior to PCS does not decrease the severity of IFIS [138]. IFIS
can be prevented and treated by maintaining proper mydriasis and restraining the
iris from prolapsing during cataract surgery [139]. Proper wound construction is
critical, and the tunnel should be slightly longer and more anteriorly-situated than
in normal cases. Lower vacuum and aspiration would be recommended for surgery
and repeated injections of a viscoelastic agent.
Pseudoexfoliation syndrome (XFS) is an age-related disorder in which abnormal
fibrillar extracellular material is produced and accumulates in several ocular tis-
sues. No symptoms are usually associated with XFS, however, individuals have a
risk of increased IOP, glaucoma, and poor pupil dilation. With that, it was reported
that XFS cases might manifest zonular instability [140]. Thus, XFS eyes present an
increased risk of dropping the nucleus or nucleus fragment, zonular dialysis, phaco-
donesis or lens sublutaxion.
Retained Lens Fragments and Nucleus Luxation
Retained lens material is a rare complication of PCS, however, was reported in up to

0.8% of patients having undergone resident performed PCS [141]. The presence of
retained lens fragments may result in postoperative inflammation, secondary glau-
coma, corneal edema, PCME or rhegmatogenous retinal detachment. As these com-
plication might result in long-term visual impairment, proper management plays a
great role in the final visual outcome.
Small amounts of cortical material may become absorbed without surgery. In
cases with large cortical parts or fragments of the nucleus, such material should
be removed with pars plana vitrectomy (PPV). Small pieces of the nucleus can be
removed with a vitrectomy handpiece alone, while harder nuclear material should
be removed with a phacoemulsification instrument within the posterior segment
[142]. Treatment is theoretically possible during the same surgery with conversion
from PCS to pars plana vitrectomy while the patient is still draped. However, such
treatment has some disadvantages. Firstly, the anesthesia for vitrectomy and cata-
ract surgery is different. Some studies identified a substantially increased risk of
intraoperative bleeding during PPV, thus discontinuation of antiplatelet agents or
anticoagulants could be considered for vitrectomy (but is not usually done in PCS)
[12]. In some countries it is infrequent for cataract surgeons to perform PPV. A vit-
reoretinal surgeon might not be available immediately at the same setting, and even
if so he might be reluctant to perform immediate surgery in a patients with whom
he does not have a professional relationship. Not all phacoemulsification devices
are enabled to perform PPV or phacofragmentation, and endoillumination might
be required in these cases. Importantly, efforts to retrieve lens fragments without
proper posterior segment instrumentation might result in complex retinal detach-

ment and should be discouraged [143].
If performing immediate PPV is not possible, it is advocated to remove lens
fragments from the anterior chamber and capsular bag, place the IOL (into the cap-
sular bag, or alternatively to the sulcus or anterior chamber) and suture the cor-
neal incision [144]. Subsequently, it is postulated that PPV should be performed
up to 7 days after PCS [145]. Histopathologic investigations of vitreous specimens
obtained during PPV revealed that lens-induced inflammation increases with time
that retained lens material remains in the eye [146]. No macrophages, phacolytic
cells, neutrophils and multinucleated giant cells were present if vitrectomy was per-
formed with 3 days after PCS. Clinically, a delayed interval between PCS and PPV
results in higher retinal detachment rate [147], poorer visual outcome, and a higher
risk of developing persistent glaucoma [145]. Contrarily, some other studies did not
find an association between time of intervention and final outcome [148, 149]. In
a publication by Scott et al. 44% of patients had a final visual acuity of 20/40 and
worse, and the main cause of visual impairment was cystoid macular edema [148].
Posterior Capsulotomy
Performing a primary surgical capsulotomy is an option for eyes having a high

risk of developing significant posterior capsule opacification (PCO). This should
be considered in pediatric cataracts and particularly in patients under 6 years of
age [150], as well as in adults undergoing combined vitrectomy and cataract sur-
gery [151]. Similarly, posterior capsulotomy might be performed in eyes having a
dense PCO discovered intraoperatively [152]. Posterior capsulotomy is also postu-
lated in refractive lens exchange in young patients, however, no long-term studies
confirmed the safety in this cohort [153]. Opening the posterior capsule might be
supplemented with vitreous staining with preservative-free triamcinolone acetonide
and anterior vitrectomy.
Dropless Cataract Surgery
As topical antibiotics are difficult to instill and their effect is dependent on patient
compliance, dropless cataract surgery might be a viable option [154]. In a study
by An et al. 92.6% of patients after PCS demonstrated improper eye drop admin-
istration technique, including missing the eye, instilling an incorrect amount of
drops, contaminating the bottle, or failing to wash hands before instillation [155].
Consequences of poor compliance can affect both the patient (in cases of complica-
tions) and the society (by development of antibiotic resistance). TriMoxi (Imprimis
Pharmaceuticals) is a single use suspension containing 15 mg/mL of triamcinolone
and 1 mg/mL of moxifloxacin. Another formulation, TriMoxiVanc, adds 10 mg/mL
of vancomycin to the compound. At the conclusion of surgery 0.2 mL of the suspen-

sion is introduced into the posterior chamber through a transzonular injection. A dis-
advantage of this approach is the reduction of “the wow factor”, as the visible drug
affects the vision for up to 3–7 days after surgery. Over time, a dropless approach
might become universally preferred over topical post-cataract prophylaxis.
Postoperative Complications
Postoperative Follow Ups
The timing of postoperative examinations should be adjusted to ensure the expedi-

tious recognition and management of complications in order to optimize the final
outcome of surgery. The frequency of postoperative complications in recent studies
is presented in Table 3.6.
Several reviews were conducted to assess the value of early postoperative examina-
tions after PCS, not finding an increase in patient safety associated with postoperative
day 1 (POD1) [158, 162]. Deferment of the postoperative review was suggested in
low-risk patients. A closer follow-up was recommended in patients with glaucoma
Table 3.6 Prevalence of postoperative complications in selected cataract surgery studies

Greenberg et al. 2011 Syed et al. 2015 Jaycock et al. 2009
[156] [130] [157]
(n = 45,082) (n = 20,070) (n = 16,731)
Posterior capsule 4.2% 0.34% 1.22%
opacification
Cystoid macular edema 3.3% 0.22% 1.62%
Retained soft lens matter 1.7% 0.19% 0.45%
Raised IOP (>21 mmHg) N/A 0.31% 2.57%
Retinal tear or detachment 1.0% 0.03% N/A
IOL decentration/dislocation/ 0.9% N/A 0.22%
exchange
Vitreous hemorrhage 0.4% 0.01% N/A
Hyphema 0.2% N/A 0.07%
Hypopyon/endophthalmitis 0.2% 0.04% N/A
Iris prolapse/iris to wound N/A 0.04% 0.16%
Vitreous to section N/A 0.09% 0.39%
Vitreous in the AC N/A N/A 0.17%
Wound leak N/A 0.02% 0.14%
Choroidal effusion/ 0.1% N/A 0.13%
hemorrhage
TASS N/A 0.1% N/A
Complications with the prevalence rate of 1% or more are presented in bold. Abbreviations: AC
anterior chamber, IOL intraocular lens, IOP intraocular pressure, N/A not available, TASS toxic
anterior segment syndrome
in order to evaluate postoperative IOP spikes, in eyes with intraoperative complica-

tions, posterior synechiae, chronic/recurrent uveits), or in patients operated on by less-
experienced surgeons. Tan et al. suggested that the POD1 hospital visit may be safely
managed by way of a nurse-administered telephone questionnaire with patient con-
tentment achieved and the liberation of clinic resources ensured [159]. In their study,
only one of 238 patients reported a poor general condition, blurred vision, and pain,
and was asked to return for a clinic review on POD1. Tufail and associates compared
the complications seen with same-day discharge surgery (with a review occurring at
4–6 h postoperatively) with those seen with in-patient surgery (with a POD1 review)
and found that the most common complications in both groups were IOP rise, corneal
edema, and wound leaks [160]. Only one patient in each group, with an iris prolapse,
required attending to the department. It was concluded that there were no additional
risks related to same-day discharge surgery.
With that in mind, Eloranta et al. suggested that a postoperative check-up visit might
not be required in the majority of cases [161]. In the year 2006, a follow-up visit was
advised to occur 1 month after surgery, while in 2009 patients were informed that such
an postoperative complications in recent appointment is not necessary. Contacting the
department was advised if they experienced pain, vision deterioration, or ocular dis-
charge. Only patients with intraoperative complications or comorbidities influencing
postoperative recovery were selected for a follow-up visit. In the postoperative period,
4.2% of patients in 2006, and 3.9% of patients in 2009 contacted the hospital because
of symptoms. Referral was necessary in only 0.5% of patients in the 2006 cohort, and
0.3% of patients in the 2009 cohort, while a surgical or medical intervention was needed
by only one-third of the referred individuals. It was concluded that the lack of a 1-month
check-up did not influence patient’s safety, however, in cases with intraoperative prob-
lems, comorbidities influencing recovery, or postoperative symptoms, the patients
should be seen at a low threshold [162]. Moreover, eliminating POD1 follow-up could
result in significant health care savings without an increased risk to the patient.
The American Academy of Ophthalmology recommends that a POD1 visit
should be done in functionally monocular patients, following intraoperative com-
plications, or in those at a high risk of immediate postoperative complications such
as IOP spike. In patients without these risks the follow-up visit should be scheduled
within 48 h [3]. According to the Royal College of Ophthalmologists, POD1 review
is no longer in widespread use in the United Kingdom (UK). Such an examination is
recommended only in complicated surgeries, in eyes with co-existing diseases (e.g.,
glaucoma, uveitis), or in patients with only one eye [163]. Upon discharge, compre-
hensive information to identify potential complications should be provided with a
postoperative appointment date confirmed and the required medications dispensed.
Pseudophakic Cystoid Macular Edema (PCME)
PCME is one of the most common complication of PCS resulting in long-term

vision impairment (Fig. 3.4). PCME usually develops 1–6 weeks after cataract sur-
gery. It is postulated that physical trauma related to surgical manipulations within
Fig. 3.4 Optical
coherence tomography of
a patient with
pseudophakic cystoid
macular edema
Table 3.7 Risk factors for pseudophakic cystoid macular edema in eyes undergoing cataract
surgery
Risk factor Relative risk (95% CI)
Diabetes No signs of retinopathy 1.8 (1.36–2.36)
Presence of diabetic retinopathy 6.23 (5.12–7.58)
Presence of proliferative diabetic retinopathy 10.34 (5.13–20.85)
Epiretinal membrane 5.60 (3.45–9.07)
Retinal vein occlusion 4.47 (2.6–5.92)
Previous retinal detachment repair 3.93 (2.60–5.92)
Uveitis 2.88 (1.50–5.51)
Posterior capsule tear with or without vitreous loss 2.61 (1.57–4.34)
Source: Chu CJ, Johnston RL, Buscombe C, et al. Risk Factors and Incidence of Macular Edema
after Cataract Surgery: A Database Study of 81984 Eyes. Ophthalmology. 2016;123(2):316–323
the anterior chamber induces an inflammatory response. The release of arachidonic

acid from uveal tissue results in production of leukotrienes (via the lipoxygenase
pathway) and/or prostaglandins (via the cyclooxygenase pathway). These mediators
of inflammation diffuse posteriorly and ensue the disruption of the blood–aqueous
barrier. This results in increased permeability and accumulation of the extravascular
fluid within the retina. Reduced fluid reabsorption within the macula may be par-
tially explained by the absence of blood vessels within the foveal avascular zone.
Histological studies showed dilatation of retinal capillaries and gathering of serous
fluid in the outer plexiform and inner nuclear layers of the retina [164].
The risk factors of developing PCME are presented in Table 3.7. Based on the current
literature intensive use of potent corticosteroids with adequate intraocular penetration
remain the mainstay of PCME prophylaxis in uncomplicated cataract surgery, while it is
unclear if nonsteroidal anti-inflammatory drugs (NSAIDs) can offer additional benefit
[165]. Postoperative topical treatment is usually applied for 2–4 weeks after PCS [166,
167]. In patients with risk factors for PCME d evelopment an additional subconjunctival
injection of triamcinolone acetonide may prevent PCME development.
When assessing treatment options one should remember that PCME has a ten-
dency to resolve spontaneously [168]. With topical treatment it can be estimated that
about 54% of PCME cases completely resolve, while a decrease in macular thickness
is be observed in 80% of eyes within 6 weeks [169]. Higher baseline visual acuity
was found to be associated with successful treatment and PCME resolution [169], the
outcomes may also be worse in patients with hypertension [170]. For PCME a step-
wise approach is recommended, a topical strong steroid optionally supplemented with
some NSAIDs, subsequently a posterior sub-Tenon or retrobulbar steroid, and finally,
intravitreal steroid treatment or a steroid drug delivery system. Intravitreal anti-vas-
cular endothelial growth factor agents may be considered in patients unresponsive to
steroid therapy and/or at risk of elevated intraocular pressure.
Posterior Capsule Opacification (PCO)
PCO is a relatively common complication reported in up to 50% of patients after

PCS in a 5 year observation period [171]. In refractive lens exchange for high myo-
pia PCO rates are even higher with 77.89% of patients requiring neodymium:YAG
(Nd:YAG) laser capsulotomy in a 7-year follow-up [172, 173].
Advances in surgical techniques, IOL materials and designs have been employed
in order to reduce the PCO rate [174, 175]. One example is an increase of biocom-
patibility determined by the relationship of the IOL with remaining lens epithelial
cells within the capsular bag to inhibit their proliferation, migration, and epithelial-
to-mesenchymal transition. The truncated, square edge of the acrylic IOLs causes a
blockage of epithelial cells at the optic edge, preventing ingrowth over the posterior
capsule [176]. However, a complete elimination of PCO has not been achieved yet, and
with recent improvements the overall incidence of PCO was reported as less than 10%
in a 5 year follow-up [177]. The annual volume of cataract surgery is still increasing.
Currently, Nd:YAG laser capsulotomy is accepted as a standard and effective treatment
for PCO. Importantly, although cataract surgery itself is a risk factor for postoperative
retinal detachment, Nd:YAG capsulotomy does not increase this risk [178].
Endophthalmitis and Toxic Anterior Segment Syndrome (TASS)
Postoperative endophthalmitis (POE) is the most severe complication of cataract

surgery (Fig. 3.5). Although rare, infectious POE is a severe intraocular infection
that can result in devastating loss of vision or even loss of the eye [179]. Recent
reports confirmed low incidence of POE, under 0.1% [180]. POE usually devel-
ops 4–7 days after surgery; however, if caused by high-virulence microorganisms
it might occur 1 day after surgery [181, 182]. Symptoms include eye redness, pain,
ocular discharge and blurred vision, while lid swelling can be found in up to one-
third of cases [182].
TASS is a sterile anterior segment inflammatory response related to an ingress of
toxic substances (Fig. 3.6) [183]. Several outbreaks of TASS were reported in recently
[184–186]. TASS typically presents within 12–48 h after surgery, however, recent
Fig. 3.5 Postoperative
endophthalmitis is the
most severe complication
of cataract surgery
Fig. 3.6 Toxic anterior

segment syndrome
studies noted onset 38–137 days after surgery [184, 187]. TASS is characterized by
anterior chamber inflammation and other symptoms such as conjunctival injection/
chemosis, hypopyon or anterior vitreous opacities may be present. Endothelial cell
damage in TASS might lead to diffuse corneal edema, however, the incidence of cor-
neal edema in TASS in large series was reported as 15.6–19.1% [184, 185].
Symptoms of endophthalmitis and TASS are presented in Table 3.8. Distinguishing
between these two conditions is critical, as the management is different. POE treat-
ment includes administration of intravitreal antibiotics with vitreous tapping and/or
vitrectomy [179]. In contrary, TASS usually resolves with topical steroid treatment.
Antibiotics may be used before, during or after surgery in order to decrease the
rates of endophthalmitis. Due to low endophthalmitis rates after cataract surgery it
is difficult to verify prophylactic algorithms [189]. Thus, indirect risk measures are
Table 3.8 Symptoms of endophthalmitis and TASS

Prevalence in endophthalmitis Prevalence in TASS
Symptom [188] [185]
Red eye 82.1% 39.8%
Pain 74.3% 9.5%
Lid swelling 34.5% –
Hypopyon Hypopyon 85.7% 10.6%
Cells – 97.2%
Flare – 63.0%
Red reflex present 32.0% –
Vitreous opacities – 21.6%
Keratic precipitates – 21.6%
Corneal edema – 15.6%
Days from cataract surgery to 6 (1–63) 13.1 (1–88)
presentation: median (range)
frequently employed. There are wide variations in prevention practices around the
world [190]. Nevertheless, aseptic technique with application of povidone-iodine
remains the only technique supported by level I evidence to reduce the incidence
of endophthalmitis [191]. Intracameral administration of antibiotics is based on
recommendations of the European Society of Cataract and Refractive Surgeons
(ESCRS) study [192]. In their randomized controlled trial involving 16,603 cataract
surgeries the reported rate of proven POE was 0.025% in patients receiving levo-
floxacin drops and intracameral cefuroxime, 0.049% in intracameral cefuroxime
with no antibiotic drops, 0.173% in patients receiving solely topical levofloxacin,
and 0.247% in those receiving no antibiotic. Despite the criticism regarding the
methodology of ESCRS Study, the results confirmed by many later retrospective
case series showing 2–5 fold protection against endophthalmitis with the intracam-
eral antibiotic use. However, all of these studies were based on endophthalmitis rate
greater than 0.05%. Thus, it is not clear if it is possible to achieve similar results
in cases with lower endophthalmitis rate. On the other hand, some recent studies
showed that it is possible to achieve very low endophthalmitis rate with only topical
antibiotics [191]. Recent investigations underline the importance antisepsis with
povidone-iodine for POE prophylaxis, while the evidence for using topical antibiot-
ics, when intracameral agents are applied, is not compelling [189, 193].
Intraocular Pressure (IOP) Spikes
The incidence of postoperative IOP increase to 28 mmHg and above was noted
in up to 46.4% in populations of high-risk patients [194]. IOP usually peaks at
3–7 h after surgery and remains increased during the first 24 h postoperatively. Such
an early IOP elevation is a result of surgical trauma and consecutive prostaglan-
din release with consecutive anterior chamber inflammation [195]. Although the
increase generally does not influence the long-term quality of vision, IOP spikes
are potentially more dangerous in patients with preexisting optic nerve damage
i.e., in glaucoma or atherosclerosis-related ischemia [196]. Occasionally, an indi-
vidual with the pressure of 40–50 mmHg will experience pain or nausea, which will
prompt disappointment with the surgery or result a phone call to the surgeon in the
middle of the night.
It is estimated that up to 9.8% of patients manifest an IOP increase by 10 mmHg.
Risk factors for postoperative IOP spikes include residual viscoelastic material
[197–199], resident performed surgery [200–203], glaucoma [194, 204, 205], pseu-
doexfoliation syndrome [47], axial length above 25 mm [206], tamsulosin intake
[207], topical steroid application in steroid responders [208]. Patients with higher
baseline IOP were found to have a more pronounced IOP increase [209].
Several topical IOP lowering agents were appraised in order to prevent the occur-
rence of early IOP increase. Nevertheless, no protocol has completely eliminated
IOP spikes. We would recommend applying a combination of dorzolamide/timolol
and brimonidine topically in high-risk patients, particularly with preexisting optic
nerve damage. When the IOP is exceedingly elevated side-port paracentesis might be
conducted with, or without, supplemental antiglaucoma medications [194]. Usually
a 25-gauge needle is used to depress the posterior lip of the side-port incision.
Late Postoperative IOL Opacifications
Long-term alterations found in IOL materials include mainly glistening and IOL
calcification. Glistenings are small (1.0–20.0 μm) fluid-filled microvacuoles which
appear within the IOL optic when it is placed in an aqueous environment (Fig. 3.7).
Subsurface nanoglistenings (SSNGs) are fluid filled gaps, measuring <200 nm
in size and situated up to 120 microns from the surface of the optic of the IOL
Fig. 3.7 Light
photomicrograph of a
hydrophobic acrylic IOL
explanted because of error
in power calculation. The
presence of microvacuoles
(glistenings) can be seen,
within the optic substance
of the lens (original
magnification ×200).
Courtesy: Liliana Werner,
MD, PhD, University of
Utah
Fig. 3.8 Gross photograph

(macroscopic dark-field
image with a 90-degree
off-axis illumination;
hydrated) of a hydrophobic
acrylic IOL removed from a
cadaver eye (bottom) and a
control IOL of the same
model (top). The IOL on the
bottom shows an overall
white discoloration or haze
resulting from the presence
of subsurface
nanoglistenings
(“whitening”). Some
microvacuoles (glistenings)
can also be seen within the
optic substance of the lens.
Utah
(Fig. 3.8). Both glistenings and SSNG’s have been reported in most types of IOL
material and only heparin-surface-modified PMMA lenses do not manifest glisten-
ings. Glistening is most common in hydrophobic acrylic materials, and IOL models
differ in their resistance to glistening [210]. It has been argued that the optical qual-
ity of an acrylic foldable intraocular lens is not significantly affected by the glisten-
ings usually seen in the clinical setting, as glistenings usually does not adversely
affect the light transmittance, power performance of an IOL and the visual acuity
[211, 212]. With that, numerous glistenings are needed to cause significant straylight
elevation or decrease high spatial frequency contrast sensitivity [213]. However,
recent studies reported that commonly glistenings and SSNG’s increase retinal
straylight and decrease contrast sensitivity also under no glare conditions, tending
to impair subjective visual performance [213–216]. It was also proposed that glis-
tenings might impair driving ability and lead to driving accidents [217, 218]. One
should remember that glistening increases with time after IOL implantation, so with
the increased life expectancy and performing surgery in younger patients with less
advanced cataract, it might represent a significant problem in IOLs that have already
been implanted [219]. Glistening has also been reported in paediatric patients [220,
221], and in these cases there might be a concern for visual function in children with
IOL implants over their 80-year lifespan.
Calcification is more common in hydrophilic acrylic IOLs than in hydrophobic
or silicone IOLs (Fig. 3.9). Calcification deposits present as clusters o nanocrystal-
lites (500–600 μm) or dense formations (10–70 μm) situated on the surface of the
IOL [222]. Calcification might occur due to environmental circumstances, disrup-
tion of the blood-aqueous barrier and changes in the aqueous ambience. However,
in some cases no medical or surgical trigger could be determined, and the incidence
of calcification was supposedly related to manufacturing issues [223]. Importantly,
Fig. 3.9 Light
photomicrograph of a
MemoryLens IOL
(CibaVision) explanted
because of calcification.
Original magnification ×40.
Utah
the advancement of IOL opacification commonly is a progressive process, which

can develop many years after primary IOL implantation. In several cases calcifica-
tion results in a decrease in visual acuity and the need for IOL explantation.
Aphakia Management
There is a wide range of methods used for correcting aphakia. Aphakic glasses
and contact lenses have historically been a common way to correct aphakia. These
methods, however, have their downsides. Glasses are often heavy and can cause
distortion of the image at the edge of the lens. Due to anisometropia glasses cannot
be used to correct unilateral aphakia. Contact lenses might be difficult to apply, and
extended wear has risks [224].
Surgical options for correcting aphakia in eyes with a present lens capsule include
placing the IOL in the bag or in the sulcus. For a small anterior capsule rim tear, small
posterior capsule tear or longstanding traumatic tear with fibrosis it is commonly pos-
sible to place a lens in the capsule. In eyes with a posterior capsule rupture or zonular
dehiscence placing a three-piece IOL with angulated haptics into the sulcus should be
considered [225]. One-piece IOLs should not be used for sulcus placement, as they
might lead pigment dispersion, uveitis–glaucoma–hyphema syndrome, and recurrent
vitreous hemorrhage. Importantly, when placing an IOL anteriorly to the capsular
bag it is necessary to slightly reduce the power of the IOL compared to in-the-bag
implantation, usually by −0.5 D. In these cases optic capture with the capsulorhexis
might be considered. If lacking optic capture, the overall haptic diameter should be
sufficiently long to avoid lateral subluxation within the sulcus space. Another option
for severe zonular dehiscence is suturing a Cionni capsular tension ring to the sclera.
In eyes with no capsular support inserting an anterior chamber IOL can be con-
sidered, as well as iris or scleral fixation. Anterior chamber IOLs primarily had a bad
reputation due to development possible development of symptoms such as uveitis,
glaucoma or hyphema. With open-loop haptics such complications have been cur-
rently minimized, however, a deep anterior chamber is still required. Another option
in eyes with a healthy iris and deep anterior chamber is iris fixation. Commonly
the iris-claw IOL is placed in the anterior chamber, although fixing such an IOL
behind the iris is also possible [226]. In scleral fixation the IOL haptics are fixated
to the sclera by a suture, by glue or in a scleral tunnel; such an approach might be
required in eyes with poor endothelium or with major loss of the iris. A disadvan-
tage of scleral-fixation methods is the difficulty of the procedure and generating
more trauma compared to other procedures. Recently, Yamane et al. proposed a
flanged IOL fixation technique [227]. It is based on using diathermy to create a
flange from haptics of certain three-piece IOLs, and subsequently pushing them
back into scleral tunnels. An advantage of this technique is its simplicity and that it
is minimally invasive.
Conclusions
Modern cataract surgery has become a refractive procedure. Intraoperative and

postoperative complications are infrequent. Certain comorbidities increase the
complication rate and in these cases preventive measures should be employed.
Femtosecond laser-assisted cataract surgery does not provide significant benefits
for the patient, particularly if considering the additional costs.
Acknowledgements Dr. Grzybowski reports grants, personal fees and non-financial support from
Bayer; grants, non-financial support from Novartis; non-financial support from Alcon, personal fees
and non-financial support from Valeant, grants and non-financial support from Allergan, grants and
non-financial support from Pfizer, grants, and financial support from Santen. Dr. Kanclerz reports
non-financial support from Visim. No conflicting relationship exists for any author.
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Chapter 4
Recent Developments in Glaucoma
Nathan M. Kerr and Keith Barton
Introduction
Glaucoma is one of the most commonly encountered ophthalmic conditions, affect-

ing over 60 million people worldwide [1]. It is the leading cause of irreversible
blindness and is responsible for bilateral blindness in over eight million people
globally [1]. Because the condition is often asymptomatic in the early stages, over
50% of cases are undiagnosed [2]. Due to an ageing population the prevalence of
glaucoma is expected to increase substantially over the coming decades [3]. The
goal of management is to prevent vision loss from glaucoma in a patient’s lifetime
and to maintain or enhance quality of life.
The past 5 years have seen significant advances in imaging, visual field testing,
and therapeutics for glaucoma. The objective of this chapter is to provide ophthal-
mologists with an update on the developments in the field of glaucoma. It focuses
on clinically-relevant aspects including novel imaging techniques, new pharmaco-
logical approaches, and the latest in surgical treatment.
N. M. Kerr
Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia
Centre for Eye Research Australia, Melbourne, VIC, Australia
K. Barton (*)
Moorfields Eye Hospital, London, UK
UCL Institute of Ophthalmology, London, UK

100 N. M. Kerr and K. Barton
Recent Developments in Imaging
Optical coherence tomography (OCT) is now the most widely adopted imaging
modality for the management of glaucoma. New parameters, imaging protocols,
and modalities are further enhancing the ability to diagnose and monitor glaucoma.
Major developments in recent years include the introduction of three-dimensional
OCT scanning, swept-source OCT, OCT angiography, and adaptive optics.
Three-Dimensional Optical Coherence Tomography
The adoption of optical coherence tomography (OCT) has enabled highly-accurate

quantitative assessment of the optic nerve head and surrounding retinal structures to
assist in the diagnosis and monitoring of glaucoma. Traditional parameters include
assessment of optic disc area, rim area, cup-to-disc ratio, and two-dimensional mea-
surement of the thickness of the peripapillary retinal nerve fiber layer (RNFL) and
ganglion cell-inner plexiform layer (GC-IPL). These parameters have been shown
to have good reproducibility and the ability to distinguish between glaucomatous
and non-glaucomatous eyes [4]. The detection of RNFL damage is helpful in the
early detection of glaucoma, frequently preceding the development of visual field
loss [5]. However, two-dimensional parameters are susceptible to artifacts that may
adversely affect their diagnostic ability [6, 7]. This is especially problematic where
there are variations in optic disc size, optic nerve head tilt, peripapillary atrophy,
and myopia [8]. These imaging artifacts or inaccuracies may cause erroneous RNFL
measurements that may lead to inaccurate assessments [7]. The introduction of
three-dimensional volume scans enable high-density sampling of nerve tissue and
3D reconstruction of the neuroretinal rim anatomy which may assist in the diagno-
sis and monitoring of glaucoma [9].
Three-dimensional scanning of RNFL and ganglion cell layer (GCL) volumes
permits the assessment of new parameters such as the minimum distance band
(MDB) [10]. The MDB is the shortest distance between the internal limiting mem-
brane (ILM) and the optic disc margin, defined as the termination of the retinal
pigment epithelium (RPE)/Bruch’s membrane (BM) [11]. The MDB has several
advantages over standard neuroretinal rim parameters. The RPE/BM termination is
an objective, consistent, and easily-identifiable anatomic landmark on OCT com-
pared to traditional parameters that define the optic disc margin based on the clini-
cal optic disc margin [9]. Additionally MDB measurements are perpendicular to
the course of retinal ganglion cell (RGC) axons, therefore they take into account
the variable orientation of RGC axons as they approach the optic nerve head [9].
MDB has been validated as a marker for glaucoma and has been shown to have
good diagnostic performance compared to two-dimensional RNFL measurements
[9]. Shieh et al. showed that 3D MDB neuroretinal rim thickness measurements
had uniformly equal or better diagnostic performance for glaucoma in all quadrants
4 Recent Developments in Glaucoma 101
and was s ignificantly better in the nasal region compared to 2D RNFL thickness
measurements [9]. Similarly, Tsikata et al. found that 3D MDB had a higher diag-
nostic capability for glaucoma than RNFL thickness in the inferonasal, superonasal,
and nasal sectors as assessed by the area under the receiver operating characteristic
(AUROC) curves [12].
Wide-Field Swept-Source Optical Coherence Tomography
Traditionally, multiple scans are required to capture an OCT image. However, a

recently introduced technology called swept-source OCT (SS-OCT) uses a swept
laser to capture wide-angle, high-quality images of the optic nerve and macula in
a single scan [13]. This technology may provide better image quality and be less
affected by media opacities [14]. Wide-field scanning has been shown to be effec-
tive at discriminating between healthy and glaucomatous eyes with a diagnostic
accuracy comparable to spectral-domain OCT (SD-OCT) [15–17]. For the detec-
tion of early glaucoma, SS-OCT has demonstrated superior diagnostic ability over
conventional criteria analyzing peripapillary RNFL and ganglion cell layers [18].
Like 3D OCT, SS-OCT may also be less susceptible to artifacts and centering errors
[15]. In addition, a tunable wavelength of operation enables imaging of deep ocu-
lar structures such as the lamina cribrosa [19]. The lamina cribrosa has long been
presumed to be the primary site of axonal injury in glaucoma [20]. It is believed
that posterior bowing of the lamina cribrosa may cause mechanical and/or an isch-
aemic insult to RGC axons [21]. Using SS-OCT, Kim et al. showed greater poste-
rior displacement of the lamina cribrosa in eyes with primary open angle glaucoma
compared to age-matched healthy eyes [19]. SS-OCT may therefore assist in our
understanding of the mechanisms involved in glaucoma pathogenesis.
Optical Coherence Tomography Angiography
Optical coherence tomography angiography (OCT-A) is a new technology that

allows non-invasive visualization of the microcirculation of the eye without the use
of contrast dye. The technique takes advantage of improvements in OCT image
resolution and scanning speed and is gaining popularity in the assessment of retinal
vascular diseases. By comparing sequential scans at the same location, OCT-A is
able to detect change which are attributed to erythrocyte movement in perfused
vessels [22]. The technique offers several advantages over traditional angiography
including the ability to simultaneously assess the retinal and choroidal circulations,
quantitative assessment of the microcirculation, and three-dimensional assessment
of both microvasculature structure and function while avoiding the need for invasive
dye injections. Because of the possible role of reduced optic nerve head perfusion
and vascular dysregulation in glaucoma [23], OCT-A is being investigated as a tool
to help elucidate the pathophysiology of the disease as well as assist clinicians in

glaucoma detection and monitoring [24].
Optical coherence tomography angiography provides quantitative information
on both blood vessel structure, reported as blood vessel density and foveal avascu-
lar zone area, as well as microvasculature function using flow index, a dimension-
less parameter between 0 and 1. The measurements have been shown to have high
within-visit repeatability and between-visit reproducibility [25, 26]. Differences
between healthy and glaucomatous eyes have been observed with respect to ves-
sel density, foveal avascular area, and reduced blood flow index. In patients with
ocular hypertension, normal tension glaucoma, and primary open angle glaucoma
reductions in vessel density and size of the foveal avascular zone have been reported
[27–30]. These changes are associated with a reduction in optic disc flow and cor-
relate with the degree of visual field defect [25]. Jia et al. found a 25% reduction
in optic disc flow between healthy and glaucomatous eyes and this reduction corre-
lated strongly with visual field pattern standard deviation (PSD) [25]. Similarly, Liu
et al. and Yarmohammadi et al. found significant correlations between flow index
and visual field PSD in glaucomatous eyes [26, 31]. The data suggest an association
not only with the degree of visual field defect but also the location of the field defect
[32]. In a separate study, Yarmohammadi et al. examined vessel density in eyes with
visual field defects in a single hemifield and found that vessel density was lowest in
the affected hemiretina [32]. Interestingly, reduced vessel density was also noted in
the perimetrically intact hemiretina suggesting that microvasculature changes may
precede visual field loss [32]. Changes in OCT-A parameters also correlate with the
location of RNFL thinning. Mansoori et al. found a reduction in capillary density in
eyes with early glaucoma and that capillary density was lowest in areas with focal
RNFL defects [33]. This finding is consistent with other studies showing capillary
dropout in areas of RNFL thinning [25, 29, 34].
Several studies have investigated the diagnostic performance of OCT-A for
glaucoma detection. Using optic disc flow and a cut-off value of 0.1515, Jia et al.
reported a sensitivity and specificity of 100% in their study population [25]. The
same group then evaluated the ability of peripapillary flow index and vessel den-
sity to discriminate between healthy and glaucomatous eyes using AUROC curves
and found values of 0.982 and 0.938 respectively [26]. The performance of OCT-A
appears to depend on the stage of glaucoma [35]. Wang et al. investigated the corre-
lation between OCT-A parameters and glaucoma severity and found that both vessel
density and flow index performed best in advanced glaucoma [35].
There is some emerging data on the effect of IOP reduction on OCT-A param-
eters [36–38]. In patients with very high IOP who achieved a >50% reduction in
IOP with medical therapy there was a significant increase in OCT-A parameters
[37]. However, another study found no statistically significant difference in OCT-A
parameters in the peripapillary or macular regions following glaucoma filtration
surgery, despite an average IOP reduction of 44.2% [36]. Lastly, in patients present-
ing with acute angle closure, statistically significant changes in OCT-A parameters
have been observed following treatment and normalization of IOP [38].
Optical coherence angiography is not without limitations. Currently, there is a

lack of comparability between machines and studies due to an absence of stan-
dardized measurement protocols. Also, image quality is highly dependent on fixa-
tion and patient co-operation. Further longitudinal studies are needed to determine
whether OCT-A findings can predict or detect glaucoma progression. Nonetheless,
OCT-A remains a promising technology for elucidating the physiology of glaucoma
and evaluating structure and function in this disease.
Adaptive Optics
Adaptive optics (AO) is not an imaging modality, but rather a technology used in
combination with existing imaging modalities to improve their performance [39].
Initially developed to reduce ocular aberrations from ground-based telescopes, it
has been used in conjunction with fundus cameras, scanning laser ophthalmoscopes,
and most recently OCT to provide unprecedented resolution and the ability to visu-
alize structures at the cellular level in real time. Representing a major advance in
optical technology, AO uses a wavefront sensor that measures aberrations in ocular
optics and a deformable mirror or spatial light modulator to compensate for these
aberrations in vivo [40].
Because RNFL loss is one of the earliest detectable changes in glaucoma, often
preceding changes at the optic nerve head or visual field loss [41], there has been
particular interest in using AO to detect RNFL changes allowing for earlier detec-
tion, more precise diagnosis, and improved detection of progression in glaucoma
[39]. Several groups have used AO to visualize RNFL bundles and the gaps between
them [42–45]. Kocaoglu et al. proved that it was possible to measure the dimensions
of RNFL bundles in five health subjects [42]. This work was extended by Takayama
et al. who demonstrated reduced RNFL bundle dimensions in glaucomatous eyes
and that these abnormalities were associated with visual field defects [43]. Showing
the promise for early detection, Chen et al. demonstrated changes in RNFL bundles
on AO that were difficult, if not impossible, to discern with current OCT technology
[44]. Most recently, Hood et al. followed six eyes of five patients with deep glau-
comatous visual field defects using adaptive optics scanning light ophthalmoscopy
(AO-SLO) and showed progressive changes in RNFL bundles, demonstrating the
potential for AO to be used for monitoring glaucoma progression [46].
To date, it has been difficult to visualize individual RGCs with OA. This is because
RGCs are nearly transparent, an important attribute to allow light to pass through
them and reach photoreceptor cells. In spite of this property, one group has been able
to image the individual somas of neurons within RGCs using confocal AO-SLO and
showed progressive changes in RNFL bundles, demonstrating the potential for A in
both monkeys and humans [47]. This capability to noninvasively image RGC layer
neurons in the living eye without fluorescent labels may one day allow for insights
into the pathogenesis of glaucoma and a better diagnostic tool [47].
Recent Developments in Visual Field Testing
Visual field testing is essential in the detection and monitoring of glaucoma. Recent
advances in thresholding algorithms, testing frequency, and new portable perimetry
devices are showing potential to improve visual field testing in clinical practice.
Testing Strategies and Novel Thresholding Algorithms
Currently, 24-2 visual fields are the most commonly used method for investigat-
ing visual field defects in glaucoma. However, there is an increasing appreciation
that damage at the macula can be detected in even early stages of glaucoma [48].
The macula has the highest density of RGCs [49] and thinning of the ganglion
cell complex is seen early in the glaucomatous process [50]. In a recent study of
patients with early glaucoma, 16 of 26 eyes (61.5%) classified as normal on 24-2
tests were classified as abnormal on 10-2 visual fields [51]. In patients with ocular
hypertension, 28 of 79 eyes (35.4%) classified as normal on 24-2 tests were classi-
fied as abnormal on 10-2 visual fields [51]. It is therefore apparent that central visual
field damage on the 10-2 test may be missed with the 24-2 strategy alone [51].
These findings suggest that in the future it may be necessary to include 10-2 visual
field testing to reliably detect central visual field defects. However, further work is
required before this becomes the new standard of care.
In addition, novel thresholding strategies are being investigated that incorporate
spatial and structural information to improve the speed and precision of visual field
testing. Chong et al. introduced a perimetric algorithm that uses spatial information
regarding the location of a field defect to improve the characterization of field loss
without increasing testing times [52]. Using a computer simulation, Chong et al.
reported improved accuracy and precision in testing regions surrounding scotoma
edges [52]. The same group then validated the performance of the new algorithm,
called Gradient-Oriented Automated Natural Neighbor Approach; (GOANNA) in
humans and found results in agreement with earlier simulation studies [53]. Using an
alternative approach, Rubinstein et al. introduced a perimetric algorithm (Spatially
Weighted Likelihoods in Zippy Estimation by Sequential Testing; SWeLZ) that uses
spatial information on every presentation to alter visual field estimates, to reduce
test times without affecting output precision or accuracy [54]. Both of these strate-
gies have the potential for significant time savings in clinical settings but require
validation in larger scale clinical trials.
Another approach to improve thresholding procedures is to incorporate structural
information into the testing process [55]. An example of this approach is demon-
strated by Ganeshrao et al. who developed a perimetric test strategy called Structure
Estimation of Minimum Uncertainty (SEMU), that uses structural information to
drive stimulus choices [56]. One method of accelerating testing times is to make an
estimate of sensitivity at a location before any stimuli are shown, and then carefully
test around this estimate [56]. SEMU utilizes this approach and predicts sensitivity
at a location based on OCT data. Using a computer simulation, the authors tested
the performance of SEMU for three different profiles of patient reliability and found
reduced testing times while maintaining accuracy and precision [56]. This and other
strategies require formal validation before being introduced into routine clinical
practice but show progress toward a patient-tailored approach to improve perimetric
procedures.
Impact of Testing Frequency
Detecting visual field progression is a significant challenge in clinical practice. The

ability to detect progression depends on many factors including the rate of pro-
gression, testing frequency, and level of reliability/measurement variability. It is
especially important in the early follow-up period to establish a sufficient baseline
to rule out rapid progression [57]. Chauhan et al. calculated that to detect rapid
progression (defined as −2 dB/year) the time to detect change with 80% power is
5 years with annual examinations, 2.5 years with two examinations per year, and
1.7 years if examinations are performed three times per year [57]. More recently, Wu
et al. examined the impact of testing frequency on the ability to detect progression
[58]. Assuming a best-practice scenario with two baselines tests and a requirement
to replicate progression on one confirmatory test, they estimated rapid visual pro-
gression could be detected with 80% power after 3.3 years, 2.4 years, or 2.1 years
when testing was performed once, twice, and three times a year [58]. Based on the
diminishing returns from twice to three-times-a-year testing, they concluded that
twice yearly testing was a reasonable compromise for achieving sufficient power
whilst minimizing treatment burden [58].
Novel Methods of Assessing Visual Fields
Traditional perimetry requires the patient to maintain fixation throughout the dura-
tion of the test. Failure to maintain fixation can lead to poor reliability and unreliable
fields. A relatively new method of testing visual fields is fundus-tracked perimetry
or microperimetry where the fundus is tracked using a retinal imaging system and
stimuli are projected at specific retinal locations. Early perimeters evaluated only the
central macular region while newer machines now permit testing of the central 30°
radius. The performance of microperimetry has been compared with the Humphrey
Visual Field Analyzer in eyes with glaucoma and the sensitivities obtained with
microperimetry have been found to be repeatable and comparable to conventional
perimetry [59–61]. Another advantage is that microperimetry can be combined with
retinal imaging to provide stronger structure-function associations.
Recent advances in smartphone and tablet technology have seen significant

improvements in display resolution, dynamic range, and accurate calibration [62].
These devices are portable, do not require a continuous power supply, and are rela-
tively inexpensive allowing them to be used for home or community-based visual
field testing, even in remote areas [62]. The potential applications for portable perim-
etry include targeted screening in high-risk populations, especially where access to
healthcare is limited, or for home monitoring between office visits in patients with
a diagnosis of glaucoma. Johnson et al. have evaluated the use of a free tablet-based
perimetry application in Nepal and found the procedure to be portable, fast, and
effective for detecting moderate to advanced field loss [63]. The average testing
time was just over 3 min however improvements are underway to reduce testing
time, improve performance, and add head/eye tracking [63]. The performance of
this tablet perimeter has been compared against the Humphrey Field Analyzer and
the results show strong correlation as well as comparable test-retest reliability [64].
The system has also been used in a study investigating whether home-based perim-
etry can increase test frequency and allow for detection of rapid progression more
quickly than conventional perimetry [63]. Using a computer simulation, tablet-
based perimetry detected rapid visual field loss after 0.9 years with a sensitivity of
80% compared to 2.5 years for 6-monthly clinic-based testing [63]. These results
suggest that home-based perimetry may be a viable strategy to increase testing fre-
quency and allow for more timely detection of rapid visual field progression [63].
Recent Developments in Medical Therapy
The mainstay of glaucoma treatment has been medical therapy with eye drops.
However, multiple medications may be required [65], adherence is a major chal-
lenge especially if adjunctive therapy is required [66], instillation can be difficult
[67], and medical therapy alone may not always be sufficient in preventing progres-
sion [68]. There is therefore great excitement to see the introduction of novel phar-
macotherapy agents and alternative drug delivery systems that aim to effectively
lower IOP, reduce the need for frequent eye drop administration, and that are well
tolerated.
Rho Kinase Inhibitors
Rho kinase (ROCK) inhibitors are an entirely new class of glaucoma medications.
These medications work by relaxing the trabecular meshwork through inhibition
of the actin cytoskeleton contractile tone of smooth muscle [69, 70]. This results in
increased aqueous outflow, thereby lowering IOP. In addition, animal studies sug-
gest secondary effects which may be beneficial in glaucoma including improved
blood flow to the optic nerve [71], neuroprotection of retinal ganglion cells [72], and
inhibition of bleb scarring following glaucoma filtration surgery [73].
The most well-studied ROCK inhibitors are ripasudil and netarsudil. Ripasudil
has been shown to significantly lower IOP in phase I and II human clinical trials
[74, 75]. The medication has a good safety profile with the most common side
effect being mild hyperaemia, occurring in approximately 50% of patients [74, 75].
Transient corneal guttae-like findings have been seen and are believed to be due to
protrusion formation along intracellular borders caused by the reduction actomyo-
sin contractility in corneal endothelial cells [76]. These are not believed to adversely
affect vision [76]. In an open-label study of patients with ocular hypertension or
glaucoma, 51 of 388 patients had to discontinue the medication due to blepharitis
or allergic conjunctivitis symptoms [77]. Monotherapy with ripasudil 0.4% reduced
IOP by an average of 3.7 mmHg at 52 weeks [77]. The medication has also been
shown to be effective as an adjunctive agent when combined with either a beta-
blocker or prostaglandin analogue [78].
Netarsudil is both a ROCK inhibitor and norepinephrine transporter (NET) inhib-
itor [79]. This medication is believed to lower IOP by the triple action of reducing
aqueous production, increasing trabecular outflow, and decreasing episcleral venous
pressure [80]. The medication has been found to be effective and well-tolerated
for the treatment of patients with ocular hypertension and open-angle glaucoma in
two large randomized, double-masked phase 3 trials (ROCKET-1 and ROCKET-2)
[81]. Like other ROCK inhibitors, the most common side effect was conjunctival
hyperaemia (occurring in 50–89% of study participants) [79, 81]. In a double-
masked, randomized study of netarsudil versus latanoprost in patients with elevated
IOP, netarsudil was less effective than latanoprost by approximately 1 mmHg [82].
However, the fixed combination of netarsudil and latanoprost was found to be sta-
tistically superior in terms of IOP-lowering than its individual active components at
the same concentrations [83].
Latanoprostene Bunod
Latanoprostene bunod is a nitrous oxide-donating prostaglandin agonist that low-

ers IOP by increasing both trabecular and uveoscleral outflow [84]. The release
of nitric oxide relaxes the trabecular meshwork, increasing aqueous outflow [85].
In a randomized, controlled trial comparing latanoprostene bunod and latanoprost
0.005% in patients with ocular hypertension and open-angle glaucoma (VOYAGER
study), latanoprostene bunod achieved significantly greater reductions in diurnal
IOP while having comparable side effects to latanoprost [86]. The levels of hyper-
aemia were similar in both treatment arms [86]. In larger subsequent randomized,
double-masked, multi-center controlled trials comparing latanoprostene bunod and
timolol (APOLLO and LUNAR studies) there was a significantly greater reduction
in IOP with latanoprostene bunod than timolol [87, 88].
Alternative Drug Delivery Systems
Recently, a number of alternative drug delivery systems have been developed that
aim to reduce the need for daily medical therapy; helping address problems with
glaucoma eye drop administration and adherence. These devices aim to provide a
slow and controlled release of glaucoma medication to provide effective control
of IOP.
Travoprost Punctum Plug
The travoprost punctum plug (OTX-TP) is a novel sustained-release delivery system

that releases travoprost from a hydrogel punctum plug placed in the superior or infe-
rior canaliculus [89]. The active medication is contained within microspheres which
degrade via hydrolysis when they come in contact with the tear film, thereby releas-
ing the medication [89]. In an unmasked, single-arm study the OTX-TP reduced
IOP by 24% at day 10 and 15.6% at day 30. The device was tolerated by most
patients and side effects were uncommon [89]. Longer duration studies are planned.
Bimatoprost Ocular Ring
The bimatoprost ocular ring is a simple and novel sustained-release device that is
applied topically to the ocular surface by a physician and allows continuous drug
delivery for up to 6 months [90]. In a phase II doubled-masked randomized con-
trolled trial, patients with ocular hypertension or open-angle glaucoma were ran-
domized to the bimatoprost ocular insert and artificial tears or a placebo implant
and timolol twice daily [90]. The bimatoprost ring was non-inferior to timolol at
9 months, however the study was underpowered for the observed treatment effect
[90]. The ring was well-tolerated and adverse events were comparable to topical
bimatoprost or timolol exposure [90]. In a 13-month open-label extension study,
the ring remained in position without physician intervention in 95% of patients and
>97% of participants reported that the ring was comfortable or tolerable [91]. At
13 months the average IOP reduction was 4 mmHg with rescue medical therapy
required in 13 of 63 participants [91]. The overall safety profile was very good [91].
Bimatoprost Sustained-Release (SR) Intracameral Implant
The bimatoprost sustained-release (SR) implant is a biodegradable implant designed

to be implanted into the anterior chamber [92]. The implant provides a slow release
of bimatoprost overtime and is designed to reduce barriers to adherence and mini-
mize the incidence of adverse effects associated with topical bimatoprost adminis-
tration [93]. In a prospective, 24-month, phase I/II study bimatoprost SR provided
rapid and sustained IOP lowering with a mean IOP reduction of 9.5 mmHg at week
16 for the 20 μg implant [94]. This compared with a reduction of 8.4 mmHg in fel-
low eyes treated with topical bimatoprost [94]. A single administration controlled
IOP in the majority of patients for up to 6 months [94]. Rescue medical therapy was
required in 9% of eyes through week 16 and 29% of eyes by month 6 [94]. Adverse
events were uncommon and usually occurred within 2 days after implantation [94].
The most frequent adverse event was conjunctival hyperaemia which occurred in
6.7% of bimatoprost SR eyes and 17.3% of topically treated eyes [94].
iDose
The iDose is a titanium implant which is secured in the anterior chamber during a
micro-invasive procedure [95]. The implant is designed to elute therapeutic levels
of travoprost in a continuous and controlled fashion [95]. Once depleted, the device
can be removed and replaced [95]. In a multicenter, randomized, doubled-masked
phase II trial the iDose achieved sustained IOP reductions of approximately 30% in
a 12-month interim cohort of patients [95]. The safety profile was favorable with no
adverse events of hyperaemia in the iDose group [95].
Recent Developments in Glaucoma Laser and Surgery
Recent landmark studies have enhanced our understanding about laser iridotomy,
clear lens extraction, trabeculectomy, and tube surgery in the management of
glaucoma.
Laser Iridotomy
Laser peripheral iridotomy is frequently used to prevent or treat angle closure

glaucoma. This procedure is generally safe but may be complicated by visual dis-
turbances or dysphotopsias [96]. In a recent randomized prospective paired eye
trial, Vera et al. found that temporal placement of the laser iridotomy was less
likely to result in linear dysphotopsia than superior placement [97]. The authors
suggested that the ideal location for laser iridotomy was the temporal iris [97].
However, a larger multi-center randomized trial in India found that the incidence
of visual dysphotopsia was unaffected by iridotomy location, size, or amount of
energy used [98]. In this study, the onset of new dysphotopsia occurred in 8.4% of
patients undergoing nasal/temporal iridotomy compared to 9.5% of patients where
the iridotomy was placed superiorly [98]. Given data suggesting similar safety
with regard to location and dysphotopsia symptoms, it may therefore be advisable
to place the iridotomy in a crypt or superiorly which has been shown to cause less
pain and discomfort [97].
Clear Lens Extraction for Angle-Closure Glaucoma
An alternative approach to the management of angle-closure glaucoma is surgical

lens extraction [99]. A landmark trial has recently evaluated the efficacy, safety, and
cost-effectiveness of clear lens extraction compared to laser peripheral iridotomy
and topical medical treatment as first-line treatment in people with newly diagnosed
primary angle closure (PAC) with an IOP of ≥30 mmHg or primary angle-closure
glaucoma (PACG) [100]. It was found that clear lens extraction resulted in greater
reduction in IOP, less need for glaucoma medications, and higher quality life scores
than laser iridotomy [100]. Furthermore, initial lens extraction was more cost-
effective than standard of care with laser iridotomy [100]. Based on these results,
the authors suggest that clear lens extraction should be considered as first-line treat-
ment for newly diagnosed PACG or PAC where IOP is 30 mmHg or greater [100].
rimary Trabeculectomy or Tube Surgery for Medically

P
Uncontrolled Glaucoma
In eyes with glaucoma refractory to medical therapy, glaucoma surgery is frequently

required. The most commonly performed operations are trabeculectomy and tube
shunt surgery [101]. Previously, tube shunt surgery was found to have a higher suc-
cess rate compared to trabeculectomy at 5 years in eyes with prior trabeculectomy
and/or cataract surgery [102]. Recently, a landmark study compared the efficacy
and safety of tube shunt surgery and trabeculectomy in eyes without prior ocular
surgery [103].
In the Primary Tube Versus Trabeculectomy (PTVT) study patients with medi-
cally uncontrolled glaucoma and no previous incisional surgery were randomized
to treatment with a 350-mm2 Baerveldt glaucoma implant or trabeculectomy with
mitomycin C (0.4 mg/mL for 2 min). The trabeculectomy arm was found to have
a lower probability of failure (7.9% vs. 17.3%), lower IOP (12.4 ± 4.4 mmHg vs.
13.8 ± 4.1 mmHg), and less need for glaucoma medications (0.9 ± 1.4 vs. 2.1 ± 1.4)
compared to tube surgery at 1 year [103]. There was no significant difference in
the rates of intraoperative complications [103]. However, the frequency of serious
complications producing vision loss or requiring reoperation was lower for tube
shunt surgery [103].
Minimally Invasive Glaucoma Surgery
New minimally invasive glaucoma procedures that aim to lower intraocular pres-
sure with a better safety profile and faster recovery than conventional glaucoma
surgery are being increasingly used in clinical practice. Recently there have been a
number of major developments in this space.
The iStent inject received approval from the Food and Drug Administration
(FDA) in 2018 for use in mild to moderate open-angle glaucoma in patients under-
going cataract surgery [104]. The iStent inject trabecular micro-bypass system con-
sists of two titanium stents approximately 0.23 mm × 0.36 mm that are implanted
into the trabecular meshwork using a preloaded auto-injection system through a
single corneal entry [104]. The FDA approval was based on a pivotal iStent inject
US IDE pivotal study, a prospective randomized, multi-center clinical trial includ-
ing 505 participants who were randomized to receive the iStent inject with cataract
surgery or cataract surgery alone [104]. At 2 years, 75.8% of patients in the iStent
inject group had a 20% or greater reduction in unmedicated diurnal IOP compared
with 61.9% in the cataract surgery-only group [104]. The safety profile was similar
between the two arms of the study.
Another development in minimally invasive glaucoma surgery (MIGS) is the
Hydrus Microstent. The Hydrus is placed in Schlemm’s canal and helps restore
aqueous outflow by bypassing the trabecular meshwork, dilating Schlemm’s canal,
and allowing access to a number of collector channels over a 90-degree span. In
2018, the Hydrus also received FDA approval to treat patients with mild to moder-
ate primary open-angle glaucoma in conjunction with cataract surgery [105]. The
approval was based on the landmark HORIZON trail which included 556 people
with mild to moderate glaucoma undergoing cataract surgery. Patients were ran-
domized to receive cataract surgery with the Hydrus Microstent or cataract sur-
gery alone. In the Hydrus group, 77.2% of patients achieved a 20% of greater
reduction in unmedicated IOP compared to 57.8% in the cataract surgery alone
group at 2 years [105]. Patients who received the Hydrus were twice as likely to be
medication-free compared to those who underwent cataract surgery alone [106].
An international multi-center randomized trial comparing the effectiveness of the
Hydrus Microstent to two Glaukos iStents in standalone glaucoma, the COMPARE
study, is underway [107].
In 2018 the CyPass Micro-Stent was voluntarily withdrawn from sale by the
manufacturer due to safety concerns about endothelial cell loss. This voluntary recall
has since been updated to a Class 1 recall by the FDA [108]. The CyPass Micro-
Stent is a MIGS device that was implanted into the supraciliary space to increase
aqueous outflow via the uveoscleral pathway. It was approved based on the results
of the COMPASS trial which showed a significant and sustained 2-year reduction in
IOP and glaucoma medication use in mild to moderate open-angle glaucoma when
performed with cataract surgery [109]. No safety concerns were identified at 2 years
with endothelial cell loss being similar between patients who underwent cataract
surgery with the CyPass and those who underwent cataract s urgery alone [109]. A
subset of patients from the COMPASS trial were followed for an additional 3 years
in the COMPASS-XT study and based on these results the CyPass was withdrawn
from the market. The COMPASS-XT study found that at 5 years there was a higher
rate of endothelial cell loss with cataract surgery and CyPass insertion compared
to cataract surgery alone [110]. At 5 years, endothelial cell loss was 20.5% in the
CyPass group compared to 10.1% in the cataract surgery arm [110]. The rate of
endothelial cell loss was found to relate to the depth of insertion. Where the CyPass
was implanted with no retention rings visible on gonioscopy the rate of endothelial
cell loss was 1.39% per year, where 1 ring was visible the rate was 2.74% per year,
however where 2 or more rings were visible the rate increased to 6.96% per year
[110]. Surgeons have been advised to cease implanting the CyPass Micro-Stent and
to periodically monitor endothelial cell density using specular microscopy where
available [110]. The manufacturer is partnering with the FDA and other regulators
to explore labelling changes that would support the reintroduction of the CyPass
Micro-Stent in the future [111].
Subconjunctival filtration has traditionally delivered the greatest levels of IOP
reduction. Trabeculectomy, while effective in reducing IOP, requires extensive dis-
section, sclerostomy, and suturing which can lead to unpredictability and compli-
cations such as bleb leak, hypotony, suprachoroidal haemorrhage, and a reduction
in vision [112, 113]. Two new MIGS devices aim to take advantage of the power
of subconjunctival filtration while achieving a good safety profile and short surgi-
cal time. The XEN is a flexible gelatin implant, 6-mm long, with a 45 μm internal
diameter lumen, which is inserted via an ab interno approach from the anterior
chamber to the subconjunctival space [114]. The length and diameter of the implant
were chosen based on the Hagen-Poiseuille equation to provide sufficient resistance
to aqueous outflow to minimize hypotony [114]. The XEN eliminates the need for
conjunctival dissection, cutting a scleral flap, sclerosotomy, and iridectomy. The
XEN was approved by the FDA in 2016 based on a pivotal trial in patients with
refractory glaucoma. In this study, the XEN reduced IOP from a mean medicated
baseline of 25.1 ± 3.7 mmHg to 15.9 ± 5.2 mmHg at 12 months [115]. Glaucoma
medication use decreased from a mean of 3.5 ± 1.0 to 1.7 ± 1.5 medications over
the same period [115]. The effectiveness and safety of the XEN has been compared
with trabeculectomy in a retrospective interventional cohort study [112]. The base-
line characteristics were similar in both groups and there was no detectable differ-
ence in the risk of failure and safety profiles between standalone XEN insertion and
trabeculectomy with MMC [112].
The latest subconjunctival MIGS device to be introduced is the InnFocus
MicroShunt. This device is 8.5 mm long with a 70 μm lumen and is inserted via
an ab externo approach [116]. Like the XEN, the MicroShunt avoids the need for
a scleral flap, sclerostomy, iridectomy, and post-operative suturelysis, resulting in
a short surgical time and predictable post-operative recovery [117]. The device
is manufactured from an inert biocompatible material called poly(styrene-block-
isobutylene-block-styrene) or “SIBS.” This material has been shown to elicit mini-
mal foreign body reaction, inflammation, or capsule formation when implanted in
the eye [118]. Similar to the XEN, the dimensions of the MicroShunt are based
on the Hagen-Poiseuille equation in an attempt to prevent clinically significant
hypotony [116]. In a three-year prospective, non-randomised trial the MicroShunt
reduced IOP to the low teens in patients with glaucoma refractory to medical therapy
for up to 3 years with only transient adverse events in the first 3 months after surgery
[117]. In this study, mean medication IOP was reduced from 23.8 ± 5.3 mmHg to
10.7 ± 3.5 mmHg at 3 years with a reduction in the mean number of medications
from 2.4 ± 0.9 to 0.7 ± 1.1 [117]. The most common complications were transient
hypotony (13%) and transient choroidal effusions (8.7%), all of which resolved
spontaneously [117]. A prospective, randomized controlled trial comparing the
MicroShunt to trabeculectomy is underway.
Conclusion
Glaucoma remains a common and important cause of visual impairment. The devel-
opment and advancement of new diagnostic and therapeutic technologies, includ-
ing novel drugs and drug delivery systems together with new surgical options, will
ensure continued improvements in glaucoma detection and treatment.
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Chapter 5
Recent Advances in Uveitis
Xia Ni Wu, Lazha Ahmed Talat Sharief, Roy Schwartz,

Þóra Elísabet Jónsdóttir, Anastasia Tasiopoulou,
Ahmed Al-Janabi, Noura Al Qassimi, Amgad Mahmoud,
Sue Lightman, and Oren Tomkins-Netzer
Introduction
The uveitides are a collection of more than 30 diseases manifesting as intraocular

inflammation. Their prevalence is approximately 60–130 per 10,000 people, though
they remain a common cause of blindness, accounting for up to 15% of cases
[1, 2]. Because uveitis primarily affects young people of working age, it can result
in significant, long-lasting morbidity. Early diagnosis and prompt treatment can
prevent ocular complications and vision loss in many cases. With the continued
advancement of diagnostic techniques and targeted drugs, early identification and
rapid inflammatory control is increasingly possible.
The Standardization of Uveitis Nomenclature
The diagnosis of uveitis relies mainly on the combination of clinical presentation

and ancillary tests, including laboratory tests and imaging studies [3]. Most symp-
toms and signs have low specificity and can appear across different etiologies.
X. N. Wu · L. A. T. Sharief · R. Schwartz · Þ. E. Jónsdóttir · A. Tasiopoulou · A. Al-Janabi

N. Al Qassimi · A. Mahmoud · S. Lightman
Institute of Ophthalmology, University College London, Moorfields Eye Hospital,
London, UK
O. Tomkins-Netzer (*)
Institute of Ophthalmology, University College London, Moorfields Eye Hospital,
London, UK
Technion, Institute of Technology, Bnai Zion Medical Center, Haifa, Israel

122 X. N. Wu et al.
This complicates our ability to report on specific diseases or even reach an agree-
ment between treating physicians. To try and address this issue, the Standardization
of Uveitis Nomenclature (SUN) Working Group proposed diagnostic criteria and
unified nomenclature in describing uveitis [4]. The project categorized uveitis
according to anatomical location (anterior, intermediate, posterior, and panuve-
itis), temporal course (acute, recurrent, and chronic) and disease activity (cells
and flare grading). The SUN group then attempted to develop classification crite-
ria for the diagnosis of the leading 25 uveitis entities [5]. They reviewed the clini-
cal and laboratory findings of 5766 cases collected from multinational clinics and
examined the diagnostic agreement between uveitis experts. It was concluded that
agreement between uveitis experts on the diagnosis of a specific disease entity
was moderate in most cases but increased to 99% once a consensus was reached
between the experts. Expanding the use of validated and standardized classifica-
tion criteria will improve the diagnosis and reporting of uveitis.
Imaging in Uveitis
Imaging modalities continue to evolve, bringing with them new diagnostic abilities
and improving patient treatment and follow-up. Conventional fundus photography
and fluorescein angiography (FA) are limited by their narrow fields of view. Ultra-
wide-field (UWF) imaging provides a 200-degree view of the fundus that can dem-
onstrate pathologies in the retinal periphery and assist in their localization relative
to the posterior pole. This enhanced representation of retinal pathology aids in the
clinical management and treatment of posterior uveitis (Fig. 5.1a, b) [6]. Aggarwal
et al. compared findings in traditional and UWF FA in 33 eyes with posterior uveitis
related to tuberculosis (TB) and showed that UWF revealed additional areas of non-
perfusion, neovascularization, active vasculitis, and peripheral choroiditis, which
influenced treatment decisions in 45.5% of eyes [7]. Similarly, Mesquida et al
reviewed 38 eyes with active vasculitis associated with Behçet disease [8]. UWF
imaging revealed additional information that resulted in a change of management in
80% of patients and improved disease monitoring in 55%. Conversely, UWF may
reveal peripheral vasculitis in an otherwise asymptomatic eye and patient, the clini-
cal significance of which currently remains unknown.
Optical coherence tomography angiography (OCTA) is a novel and noninva-
sive technique for demonstrating the microvascular blood flow. It produces depth-
resolved evaluation of the reflectance data, providing three-dimensional volume
information and can be used to isolate vascular structures from the retinal neural
network [9]. A valuable use of this imaging modality is in the diagnosis of choroi-
dal neovascularization (CNV), which is a known complication of posterior uveitis.
Although FA remains the gold standard for the detection of CNV, it may be limited
when differentiating between active inflammatory lesions and inactive lesions with
an active CNV. Studies on patients with punctate inner choroidopathy and multifo-
cal choroiditis demonstrate that OCTA is able to depict the vascular elements and
5 Recent Advances in Uveitis 123
a b
c d e
Fig. 5.1 Infectious Uveitis. (a) Ultra-wide-field color images of a patient with occlusive vasculitis
related to tuberculosis demonstrating peripheral ghost vessels (arrows) and small retinal hemor-
rhages. (b) Fluorescein angiography showing an area of retinal ischemia in the temporal periphery
with neovascularization along the border (arrow). (c) Serpiginous-like choroiditis extending from
the optic disc. (d) Acute retinal necrosis with extensive areas of retinal necrosis, retinitis and retinal
hemorrhages. (e) Reactivation of ocular toxoplasmosis along the nasal border of an old chorioreti-
nal scar
help differentiate between active inflammation and CNV, both of which leak on
FA [10]. This informs subsequent management decisions for immunosuppression
and/or anti-angiogenic treatments. Further, the noninvasive nature of OCTA allows
its utilisation in patients where conventional FA would be contraindicated such as
allergy.
Swept-source optical coherence tomography (SS-OCT) uses a short cavity
swept laser with a tunable wavelength of operation instead of the diode laser used
in spectral-domain OCT, giving it improved image penetration using a wavelength
of 1050 nm and high axial resolution [11]. This method allows better visualization
of the choroid together with the retina, aiding in the diagnosis and management of
choroidal conditions. Dastiridou et al., analyzed SS-OCT images of 386 eyes with
birdshot chorioretinopathy (BSCR) and 59 control eyes and found higher choroidal
reflectivity and lower choroidal thickness in inactive BSCR patients compared with
active patients and controls, suggesting these as biomarkers for disease activity [12].
Another example of a useful biomarker was demonstrated in Vogt-Koyanagi-Harada
syndrome (VKH). A new SS-OCT parameter, “RPE undulation index” which quanti-
tatively describes choroidal deformations, was positively related to both choroidal and
retinal thickness, indicating it may be used as a marker of VKH severity [13].
124 X. N. Wu et al.
The diagnosis and management of uveitis is heavily reliant on imaging. The rapid

development of imaging modalities is expected to further enhance our ability to diag-
nose and manage uveitis patients. Combinations of the above modalities, including
wide-field and swept-source OCTA are promising developments in this regard.
Advances in the Management of Non-infectious Uveitis
Uveitis may be related to systemic disease in up to 20% of patients and can be the
presenting sign in many cases [1]. Ocular findings guide the workup of patients to
include tests aimed at identifying related diseases. Presence of systemic disease
may influence the management of the ocular inflammation, and inform the need
for multidisciplinary input. Diagnostic techniques are continually advancing,
establishing more exact disease etiologies and relationships to systemic diseases.
Anterior Uveitis and Spondyloarthritis
Anterior uveitis (AU) is the most common form of uveitis, accounting for up to
a third of cases [1], and up to 60% are also HLA-B27 positive [14]. HLA-B27-
associated acute AU (AAU) is the most common form of AU, and is strongly related
to underlying systemic disease such as spondyloarthritis (SpA), [15, 16] with many
patients having undiagnosed axial SpA. In a study on axial magnetic resonance imag-
ing (MRI) of young AAU patients with chronic back pain, up to a quarter were found
to have axial SpA [17]. Studies examining screening algorithms for the diagnosis
of SpA among patients with AAU found that 40–50% had undiagnosed SpA [14,
18], with patients who were HLA-B27 positive more likely to be subsequently diag-
nosed [14]. While treatment of AU is primarily based on topical corticosteroids, sys-
temic disease requires the involvement of rheumatologists and potentially systemic
immunosuppression. This can include anti-tumor necrosis factor α (TNFα) agents,
which may affect the likelihood of AU reactivation and disease control. Infliximab
and adalimumab have been shown to reduce the risk of uveitis flares and the need for
ocular treatment [19–25]. Conversely, etanercept is well-known to have little effect
on ocular inflammation, and may actually induce intraocular inflammation and result
in an increased prevalence of flares [22, 23]. Using screening algorithms to identify
previously undiagnosed SpA patients would allow early treatment and disease con-
trol, while the choice of drugs can have a direct impact on uveitis control.
Sarcoidosis
Sarcoidosis is a multisystemic chronic inflammatory disorder of unknown etiology

characterized by noncaseating granulomas. Between 30 and 60% of patients develop
ocular signs, which can be the presenting complaint in up to 30% of patients [26].
The International Workshop on Ocular Sarcoidosis (IWOS) recently presented the

revised guidelines for the diagnosis of ocular sarcoidosis [27]. Patients are consid-
ered to have definite ocular sarcoidosis with a positive biospy and compatible uveitis,
and presumed or probable disease if they had a combination of ocular signs and pos-
itive laboratory findings but no suggestive biopsy (Fig. 5.2a, Table 5.1). Presumed
disease requires the presence of bi-hilar lymphadenopathy and two additional intra-
ocular signs; probable disease is defined by three intraocular signs and two other
positive investigations. Other tests under consideration for inclusion in future con-
sensus guidelines include serum levels of soluble interleukin (IL)-2 receptor and
Krebs von den Lungen (KL)-6. Of note, elevated IL-2 receptor levels were reported
to have 98% sensitivity and 94% specificity in ocular sarcoidosis [28].
The use of angiotensin converting enzyme (ACE) levels to diagnose ocular sar-
coidosis is of particular interest. ACE can be elevated in many granulomatous pul-
monary diseases such as tuberculosis, sarcoidosis and histoplasmosis [29], and its
value in the diagnosis of these diseases is controversial. When results of elevated
ACE levels were combined with abnormal levels of serum lysozyme from patients
with ocular sarcoidosis they had a sensitivity of 61%, which suggests a limited role
in diagnosis [30]. In a recent study that examined the value of elevated ACE levels
in predicting ocular sarcoidosis from a general non-infectious uveitis population
[31], ACE had a sensitivity of 78% and a specificity of 90% for ocular sarcoidosis
among adults, with a negative predictive value of 97%. In children the test per-
formed less well and had a sensitivity of 60% and a specificity of 78.5%, but still
with a negative predictive value of 96.9%. These results suggest the greatest advan-
tage of testing ACE levels would be in ruling out sarcoidosis in suspected cases,
when the levels are within the normal range. It should also be noted that the normal
range of ACE levels can vary between laboratories but is generally accepted to be
up to 53 μL [31]. Normal ACE levels from children can be even higher and caution
should be exercised in their interpretation [32].
Following diagnosis, the treatment of sarcoidosis frequently requires the use of
long-term immunosuppression. Similar to other forms of uveitis, treatment is based
a b
Fig. 5.2 Non-infectious Uveitis. (a) A patient with ocular sarcoidosis demonstrating choroidal
granulomas and retinal vasculitis with hemorrhages. (b) A case of Behçet disease manifesting as
retinitis with occlusive vasculitis
126 X. N. Wu et al.
Table 5.1 IWOS revised diagnostic criteria for ocular sarcoidosis

Clinical signs
1. Mutton-fat KPs (large and small) and/or iris nodules at pupillary margin (Koeppe) or in
stroma (Busacca)
2. Trabecular meshwork nodules and/or tent-shaped PAS
3. Snowballs/string of pearls vitreous opacities
4. Multiple chorioretinal peripheral lesions (active and atrophic)
5. Nodular and/or segmental periphlebitis (± candle wax drippings) and/or macroaneurysm in
an inflamed eye
6. Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule
7. Bilaterality
Systemic investigations
1. Bilateral hilar lymphadenopathy on chest X-ray and/or chest CT scan
2. Negative tuberculin test or interferon-gamma releasing assays
3. Serum angiotensin converting enzyme elevated
4. Serum lysozyme elevated
5. Bronchoalveolar lavage fluid CD4/CD8 ratio elevated (> 3.5)
6. PET positive (abnormal accumulation of gallium-67 scintigraphy or 18F-fluorodeoxyglucose)
7. Lymphopenia (< 1000 cells/uL)
8. Parenchymal lung changes consistent with sarcoidosis as determined by pulmonologists or
radiologists
KP keratic precipitate; PAS peripheral anterior synechiae; CT computed tomography; PET posi-
tron emission tomography
on a drug escalation approach beginning with systemic corticosteroids [33, 34], fol-
lowed by 2nd-line immunosuppressive agents and biologics as needed. Sarcoidosis
appears to have a relatively good response to corticosteroids, and while these
patients are seen to need more corticosteroids than other causes of uveitis, they are
less likely to need 2nd-line treatment [35, 36]. The majority of patients respond to
treatment and visual acuity is maintained [37], with macular edema and cataract the
main causes of vision loss.
Behçet’s Disease
Behçet’s disease (BD) is a chronic inflammatory disorder of unknown etiology

that predominates along the ancient ‘Silk Route’ from southern Europe, Turkey
to Japan [38, 39]. The disease manifests as an immune-mediated systemic vascu-
litis involving small, medium, and large arteries and veins (Fig. 5.2b) [40]. Ocular
involvement occurs in up to 50% of patients and ranges from a chronic panuveitis
to vasculitis, resulting in vision loss in many cases [41, 42]. While the disease is
classically characterized by the triad of recurrent oral and genital aphthous ulcers,
ocular inflammation and skin lesions [43], many patients do not present with the
full set of signs and diagnosis is based on matching diagnostic criteria. HLA-B51
has some association with the disease (sensitivity 51%, specificity 71%) but is not
part of the diagnostic criteria and should mainly be used to support the diagnosis
[15, 44]. Several diagnostic criteria have been proposed; the International Criteria
for BD (ICBD) is currently the most commonly used [45]. These criteria com-
prise of a scoring system of seven items including ocular findings, genital ulcers,
oral ulcers, skin lesions, neurological manifestations, vascular manifestations and
a positive pathergy test [45]. The minimum score for a patient to be classified as
having BD is 4. The criteria demonstrate a high sensitivity (94.8%), but a lower
specificity (90.5%). Interestingly, a UK cohort study which used the newer ICBD
2014 classification in a predominantly UK population showed even lower specific-
ity and suggested reversion to older classification systems for UK populations [46].
Behçet’s disease is a potentially blinding condition, secondary to macular
ischaemia, dense vitritis, and macular edema [42, 47]. Treatment must be started
immediately and maintained long-term to prevent disease progression, second eye
involvement, ocular complications and vision loss. Treatment is based on the use
of systemic immunosuppression, and while corticosteroids are used as the 1st-line
agent, studies demonstrate that BD is particularly responsive to treatment with anti-
TNFα agents [48–51]. The recent licensing of adalimumab for the treatment of
refractory uveitis recognized this particular affinity and adalimumab is available in
some countries for most BD-related uveitis patients immediately following treat-
ment failure with corticosteroids, without the need of first attempting a 2nd-line
agent. Other studies suggest that refractory BD-related uveitis is also highly respon-
sive to interferon α2a [52–54], which can be considered for such cases. Treatment
results in visual acuity stabilization, extended disease remission and prolonged time
to relapse.
Systemic Treatment for Non-infectious Uveitis
Choice of treatment for non-infectious uveitis is influenced by the disease lat-

erality, systemic involvement, course and natural history, and tolerability to the
drugs. In many cases, long-term treatment is required to maintain disease con-
trol and issues of extended exposure and systemic side effects influence treatment
choice. Oral corticosteroids are crucial for acute management while the slower
acting immunosuppressive agents are important as 2nd-line treatment and as ste-
roid-sparing agents [55]. Conventional immunosuppressants include antimetabo-
lites (methotrexate, mycophenolate mofetil, azathioprine), calcineurin inhibitors
(cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambu-
cil). Newer biologic agents used in uveitis are the anti-TNFα inhibitors infliximab
and adalimumab.
Corticosteroids are the cornerstone of uveitis management and are delivered
either locally or systemically. They work quickly and effectively for most inflam-
matory conditions, are widely studied and generally well tolerated [55]. The aim
128 X. N. Wu et al.
of treatment is to achieve complete control of the disease with resolution of all

intraocular inflammation, while maintaining a long-term steroid dose of ≤7.5 mg
prednisolone per day, which significantly reduces the risk of systemic side effects
[56]. Use of 2nd-line immunosuppressive agents and biologics is advocated as
steroid-sparing treatment when inflammatory control is not achieved, maintained
at low corticosteroid doses, or when the side effects are intolerable. Second-line
immunosuppressive agents achieve disease control in up to 50% of cases and
while none are licensed for treating uveitis, methotrexate and mycophenolate
mofetil are commonly used [2, 57]. Treatment requires continual monitoring of
blood counts as well as hepatic function, and side effects can restrict the use of
these drugs.
The increasing understanding of the inflammatory cascade and in particular, evi-
dence supporting Th-17 cells as mediators of uveitis, has led to the identification of
cytokines that influence these cells and the development of specific biologic drugs.
Current candidate molecules for treatment include pro-inflammatory cytokines such
as TNFα, IL-6, IL-17 as well as vascular endothelial growth factor (VEGF) [58].
Most of the information on clinical use of biologics in uveitis focuses on anti-TNFα
drugs. Infliximab is a chimeric monoclonal antibody to TNFα and adalimumab is
a fully human monoclonal antibody. Both drugs appear to be effective for treating
uveitis and in particular, uveitis related to juvenile idiopathic arthritis (JIA), BD,
and HLA-B27-associated uveitis [20, 59]. In 2016 the results of two randomized,
placebo-controlled trials resulted in the U.S. Food and Drug Administration approv-
ing adalimumab for the treatment of non-infectious, intermediate, posterior or panu-
veitis. The VISUAL I & II studies demonstrated that treatment with adalimumab
resulted in an almost 50% reduction in relapse rates following a rapid tapering of
systemic corticosteroids [60, 61]. Patients with either active uveitis (VISUAL I) and
inactive uveitis (VISUAL II) had reduced rates of treatment failure and vision loss,
compared to patients given placebo. A follow-up study (VISUAL III) demonstrated
that 60% of patients with active uveitis at baseline were able to achieve quiescence
by week 78, with 66% of them steroid-free [62]. 74% of patients who were inactive
at baseline also maintained quiescence at week 78. Adalimumab was further demon-
strated to be an effective adjunctive treatment to methotrexate for the management
of patients with JIA-related uveitis. Those receiving adalimumab had a 27% treat-
ment failure rate compared to 60% among placebo-treated patients [63]. Several
studies have attempted to compare the effect of treating uveitis between infliximab
and adalimumab and did not find a significant difference [64–66]. Adalimumab is
currently indicated as a 3rd-line agent for refractory uveitis that failed corticoste-
roids and at least one other immunosuppressive agent, although it is licensed as
2nd-line for BD in some countries.
Studies on tocilizumab, an IL-6 receptor antagonist, suggest that repeat infu-
sions can result in effective control of intraocular inflammation over 6–12 months
[67–70]. Currently, treatment with tocilizumab is not licensed for uveitis and is con-
sidered only in cases that failed anti-TNFα agents. Sarilumab, another IL-6 receptor
antibody, demonstrated less efficacy at controlling intraocular inflammation, though
it demonstrated a more pronounced effect on macular edema [71]. Secukinumab, an

anti IL-17A antibody, has demonstrated mixed results. Three randomized controlled
studies failed to demonstrate a significant effect for subcutaneous drug adminis-
tration [72], while a trial examining intravenous infusions *resulted in* showed
improved inflammatory control and remission rates [73].
Use of Local Treatment for Non-infectious Uveitis
Local treatment for uveitis includes the use of topical drops as well as periocu-
lar and intraocular injections. Intraocular steroids are used as monotherapy or as
an adjunctive to systemic immunosuppression [74, 75]. Intravitreal injections of
triamcinolone acetate (2–4 mg) are routinely used for controlling posterior uve-
itis, vitritis, and macular edema [76]. The injections are effective in controlling the
intraocular inflammation, reducing macular edema, and improving vision, with few
systemic side effects. A single injection can last up to three months and can be
repeated as needed. However ocular side effects are common, predominantly raised
intraocular pressure and cataract progression [76, 77]. The bioerodible dexametha-
sone implant Ozurdex (Allergan, Irvine, CA) is licensed for use in non-infectious
non-anterior uveitis to control intraocular inflammation, reduce vitreous haze and
macular edema, and improve vision [78].
Long-term corticosteroid implants are also used for controlling uveitis and
there are currently two commercially available intravitreal fluocinolone aceton-
ide implants (0.59 mg), a surgically inserted implant (Retisert; Bausch & Lomb,
Bridgewater, NJ) and an injectable insert (Iluvien; Alimera Sciences, Aldershot,
UK). These implants continually release a steady dose of steroids into the vitre-
ous up to 2.5 years. The Multicenter Uveitis Steroid Treatment (MUST) trial and
follow-up study (MUST-FS) was a prospective, randomized, multicenter study
designed to compare conventional systemic therapy with oral corticosteroids and
immunosuppression against the surgically inserted fluocinolone acetonide implant
[79]. The study randomized 255 patients (479 eyes with uveitis) to either treatment
arm and by 2 years found there was no difference with regards to visual acuity,
though the implant was superior in inflammatory control [80]. Patients who com-
pleted the study were followed up to 7 years with the results remaining steady for
an additional 30 months and only lost at the 7 years timepoint, when the group
receiving systemic treatment achieved an average visual benefit of 7.1 letters [79]. It
is thought that inflammatory relapses once the steroid implant wears out results in
chorioretinal scarring and visual penalty. Ocular side effects were greater in the
implant group, with 45% of eyes requiring glaucoma surgery and 90% requiring
cataract surgery. However, visual function improved following cataract surgery and
remained comparable [81], with many patients remaining disease free for many
years, without the need for additional systemic treatment. The injectable fluocino-
lone acetate insert is currently under investigation as a treatment for non-infectious
130 X. N. Wu et al.
uveitis and preliminary results form a prospective, randomized, multicenter study

comparing it to sham injections suggest that by 12 months the risk of disease recur-
rence was significantly reduced (38% vs. 98%), though the risk of cataract develop-
ment was higher (33% vs. 12%) [82].
To identify the preferred local treatment approach to uveitic macular edema,
the Periocular and Intravitreal Corticosteroids for Uveitis Macular Edema (POINT)
trial compared the relative efficacy of periocular triamcinolone, intravitreal triam-
cinolone and the intravitreal dexamethasone implant [83]. The study randomized
192 patients (235 eyes with uveitic macular edema) to one of the three treatment
arms and followed them for 6 months. The primary endpoint was the change in cen-
tral subfield thickness (CST) at 8 weeks. The study found that while all treatment
arms resulted in improved CST, for those receiving intravitreal triamcinolone injec-
tions or the dexamethasone implant the change was greater than for those receiving
periocular triamcinolone (39%, 46% and 23%, respectively). Both intravitreal treat-
ment arms were superior in resolving macular edema and improving visual acuity,
though there was no difference between them.
Other options for local treatment include the use of intravitreal methotrex-
ate injections (400 μg/0.1 mL), which may be effective for up to 4 months in
refractory cases [84, 85], or intravitreal biologic agents such as sirolimus. A study
examining the effect of an intravitreal injection of 440 μg of sirolimus demon-
strated a significant improvement in intraocular inflammation and vitreous haze,
while maintaining visual acuity and allowing up to 77% of patients to taper their
systemic immunosuppression [86]. The follow-up study did not reach primary
outcomes and was therefore not approved by the FDA. Other small cohort studies
suggest that while visual acuity may improve, in some eyes the treatment induced
inflammation [87, 88]. The current available data is not sufficiently robust to con-
clude about the role of intravitreal anti-TNFα agents for the treatment of non-
infectious uveitis.
Anti-vascular endothelial growth factor agents are routinely used for the treat-
ment of macular edema secondary to diabetic retinopathy and retinal vein occlu-
sions [89, 90]. While its role in these diseases is well established, the evidence
in ocular inflammation is less clear and relies mainly on small case series. A
recent study of uncommon causes of macular edema compared monthly injections
of ranibizumab to sham treatment and included 21 patients with uveitis-related
macular edema. At two months, the treated group had a greater gain in visual
acuity and CST, however by 12 months the effect on CST was lost [91]. A sec-
ond study comparing repeated monthly injections of bevacizumab to intravitreal
triamcinolone for the treatment of refractory CME in eyes with inactive uveitis
found that by 24 months, both treatments resulted in improvement in CST and
visual acuity [92]. The study suggests bevacizumab may have a role in the man-
agement of refractory CME in quiescent eyes. The Macular Edema Ranibizumab
vs. Intravitreal Anti-inflammatory Therapy (MERIT) trial is currently recruiting
and will attempt to compare the efficacy of ranibizumab and intravitreal steroids
in treating uveitic macular edema.
Advances in the Management of Infectious Uveitis
When considering infectious causes of uveitis, damage to ocular structures is

caused by both the pathogen and the immune system. In many instances, ophthal-
mologists are required to begin treatment before a firm diagnosis is reached and
therapy is routinely initiated with a combination of anti-microbial and immunosup-
pressive drugs. Once a definitive diagnosis is reached, the unnecessary treatments
are stopped. While anti-microbial treatment is guided by pathogen sensitivity, the
unique structure of the eye, in particular the function of the blood-ocular and blood
retinal barriers, further complicates the choice of treatment.
Identifying possible infectious pathogens is primarily based on serum serology
and cultures obtained from ocular biopsies. Polymerase chain reaction (PCR) is a
method used to identify genetic material and is used in the diagnosis of infectious
uveitis. It is both sensitive (85–90.2%) and highly specific (67–93.9%) and can be
used to test for the DNA or RNA of a pathogen [93–95]. It can be applied to small
volume samples, such as are obtained from the anterior chamber or vitreous biop-
sies, is suitable for diagnosing ocular infectious diseases and is comparable to the
results of cultures [95–97]. The method can be applied to the diagnosis of infec-
tious endophthalmitis, ocular toxoplasmosis and herpetic-related uveitis [98–100].
In cases of anterior uveitis with sectoral iris atrophy, distinguishing the causative
agent particularly between herpes simplex virus, varicella zoster virus and cyto-
megalovirus, influences the choice, dose, and length of antiviral treatments [101].
Acute Retinal Necrosis
Acute retinal necrosis (ARN) is a retinal infection occurring in either immunocom-

petent or immunocompromised patients caused by viruses from the herpesviridae
family, particularly herpes simplex virus and varicella zoster virus. The infection
results in extensive retinal necrosis, typically beginning in the retinal periphery and
progressing towards the posterior pole (Fig. 5.1d). Patient visual outcome is gener-
ally poor and early, aggressive treatment is warranted to prevent vision loss and
retinal complications, such as retinal detachment [102]. Treatment includes the use
of systemic antivirals, particularly intravenous (IV) aciclovir with systemic cor-
ticosterois and adjunctive intravitreal injections of antiviral drugs. Alternatively,
intravenous aciclovir can be substituted with oral valaciclovir, a prodrug of aciclo-
vir, which has good bioavailability and results in comparable intravitreal concen-
trations of the active drug. Pharmacokinetic modeling predicted equivalent vitreal
concentrations between valaciclovir 1.5/2.0 g three times a day and IV aciclovir
700 mg every 8 h. Intravitreal drug levels exceeded the 50% inhibitory concentra-
tion for varicella zoster virus [103]. Using oral drugs allows patients to be man-
aged in an outpatient setting, though strict monitoring is still required. While severe
vision loss still occurs in up to 50% of eyes [104, 105], a study comparing both
132 X. N. Wu et al.
treatment approaches found no difference in final visual acuity [106]. Vision loss is
most commonly related to the development of retinal detachment that occurs in up
to 60% of eyes [98, 106, 107]. The concurrent use of intravitreal injections, either
foscarnet 2.4 mg/0.1 mL or ganciclovir 2–5 mg/0.05–0.1 mL, may have a greater
therapeutic effect and several case series suggest that rates of retinal detachment
and vision loss may be reduced [108, 109]. The value of early prophylactic barrier
laser remains unclear with conflicting results from retrospective case series. The
American Academy of Ophthalmology recently concluded that initial oral or IV
antiviral treatment with adjunctive intravitreal foscarnet is an effective therapeutic
approach, and that the role of prophylactic laser retinopexy remains unclear [98].
Tuberculosis-Related Uveitis
Tuberculosis (TB) is a worldwide problem caused by Mycobacterium tuberculo-

sis, and results in extensive morbidity and mortality [110]. The majority of people
exposed to tuberculosis remain asymptomatic and the disease is described as latent
TB. Diagnosis relies on positive testing, such as the Mantoux test or interferon
gamma release assays, amongst other investigations [111]. Ocular involvement
classically presents as choroidal granulomas, chronic panuveitis, and/or occlu-
sive retinal vasculitis (Fig. 5.1a, b). The mechanism of ocular disease in latent
TB remains unclear. Serpiginous choroiditis accounts for up to half the cases
associated with TB [112, 113], particularly in endemic regions (Fig. 5.1c). While
anti-TB treatment is clearly indicated in patients with signs of active pulmonary
or extrapulmonary TB infection, treatment of those with latent TB is inconsistent,
particularly if the ocular phenotype is atypical. While the ocular inflammation
is managed with local and systemic immunosuppressive drugs, several studies
have suggested that systemic anti-TB treatment may reduce uveitis recurrence
rates [114–118]. If the ophthalmologist suspects the uveitis to be related to latent
TB and decides to initiate immunosuppressive treatment, a full six month anti-
TB course is advocated and therapy should be given in coordination with infec-
tious disease specialists. In particular, patients should be treated for latent TB
prior to commencing anti-TNFα immunosuppression given the increased risk of
infection.
Toxoplasmosis
Toxoplasma gondii, an intracellular protozoan parasite, is a common pathogen

infecting approximately 30% of the global population [119]. The life cycle of
the parasite is linked to that of cats, and in regions where cats are common
up to 90% of the population are seropositive (e.g. Brazil, Paris) [120]. Ocular

infection is common and primary infection may be either congenital or fol-
lowing ingestion of contaminated food or drink. Most primary infections
are asymptomatic and cases that are brought to clinical attention are typi-
cally reactivations along the border of an old chorio-retinal scar (Fig. 5.1e).
Active infection can appear as a chorioretinitis with vitritis and occasion-
ally AU. While diagnosis is based on clinical presentation and positive serum
serology for Toxoplasma gondii, identifying the retinal lesions in the presence
of severe inflammation and dense vitritis may be difficult and a high level of
suspicion is needed [121]. Although toxoplasmosis in an immunocompetent
patient is a self-limiting disease, treatment is considered when active inflam-
mation is located near structures that are important for visual function (optic
disc, macula and main retinal blood vessels) or when symptoms affect visual
function. Treatment is based on a combination of anti-parasitic agents and
anti-inflammatory drugs [122], and while the classic triad of pyrimethamine,
sulfadiazine and folinic acid is commonly used, other treatment protocols
are also suggested. Alternative treatment approaches include the use of oral
or intravitreal clindamycin or oral trimethoprim and sulfamethoxazole [123,
124]. The latter is given twice a day and is considerably easier for patients
to follow. Several studies examined the efficacy of these different treatment
options though none demonstrated a clear advantage [123]. In a recent state-
ment, the American Academy of Ophthalmology concluded there was no
clinical evidence to support an advantage to using any particular treatment
and choice of protocol should be based on clinical experience [125]. The use
of prophylactic treatment following reactivation continues to be debated and
several studies demonstrated that antibiotic treatment for up to a year could
reduce the risk of reactivation by as much as 90% [126–129]. The risk of reac-
tivation may continue to be reduced after stopping treatment for up to three
years [130], though there is no clear recommendation for continuing prophy-
lactic treatment [125, 127]. Long-term prophylactic treatment should be con-
sidered in patients with increased risk of reactivation, immunocompromised
patients, or those with multiple previous recurrences [125, 131].
The last decade has seen an exponential increase in diagnostic and treat-
ment tools available to the ophthalmologist, with the ensuing advancement
in research, knowledge, and management. Precise imaging methods, utilizing
wide-angle imaging and combined techniques, will help identify active inflam-
mation even in the retinal periphery and will distinguish it from other retinal
lesions, such as neovascularization. The increasing use of biologic agents and
intravitreal drugs will also result in better control of intraocular inflammation
and less systemic side effects related to systemic corticosteroids. Longer acting
agents, with less ocular and systemic side effects will help manage the disease
in these otherwise healthy patients and promote their continued independence
and productivity.
134 X. N. Wu et al.
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Chapter 6
Recent Developments in Maculopathy
Francesco Bandello, Marco Battista, Maria Brambati, Vincenzo Starace,

Alessandro Arrigo, and Maurizio Battaglia Parodi
Introduction
The diagnosis and treatment of maculopathies underwent almost a complete rev-

olution over the last years, thank to the introduction of multimodal imaging and
intravitreal treatments. Furthermore, research activity is currently introducing more
advanced therapeutic and diagnostic techniques.
The aim of this chapter is to provide an overview on the recent developments
both in diagnostic and therapeutic fields of maculopathies.
Advances in Retinal Imaging Techniques
Retinal imaging benefited from a great progress in last decades and years.
Nowadays, the recent imaging techniques along with the improvement of old diag-
nostic methods allow a more and more detailed assessment of anatomy of macular
region (Fig. 6.1), a better diagnosis of macular pathologies and improved evaluation
of the response to treatment.
Fluorescein Angiography
Fluorescein Angiography (FA) has been in use in ophthalmologic practice since

1961, when two medical students from Indiana University described and demon-
strated the technique [1]. FA requires the intravenous injection of fluorescein dye,
F. Bandello · M. Battista · M. Brambati · V. Starace · A. Arrigo (*) · M. Battaglia Parodi

Department of Ophthalmology, Vita-Salute San Raffaele University, Ospedale San Raffaele,
Milan, Italy

142 F. Bandello et al.
Fig. 6.1 Multimodal imaging in a healthy subject. Multicolor (a) and fundus autofluorescence (b)
images show the integrity of posterior pole structure, with the physiologic distribution of autofluo-
rescence signal coming from the retinal pigment epithelium cells. Horizontal (c) and vertical (d)
structural OCT scans show the normal reflectivity properties of retinal and choroidal layers. OCTA
is able to accurately reconstruct retinal vascular network, namely superficial (e), deep (f) and cho-
riocapillary (g) plexa
6 Recent Developments in Maculopathy 143
Fig. 6.2 Fluorescein angiography in a case of myopic choroidal neovascularization. Multicolor

(a) image shows the characteristic features of a myopic fundus, including retinal thinning and
peripapillary atrophy. Moreover, an altered foveal reflex is also detected. FA examination clearly
shows the presence of two classic CNV, being detectable already in early phase (b), with progres-
sive leakage phenomena in intermediate (c) and late (d) phases
which rapidly reaches eye circulation. White light passes through a blue excitation
filter, and the blue light is absorbed by fluorescein molecules, which in turn emit
light in the yellow-green spectrum. A barrier filter allows capturing only light emit-
ted from the excited fluorescein, and the images are recorded. First FA images were
recorded on photographic film; nowadays images are recorded digitally, thus allow-
ing easier data analysis, storing and sharing, which can be easily stored and shared.
Newer angiography devices support also movie capturing, making the interpretation
of the vascular filling details, more identifiable.
FA has been an indispensable tool for diagnosis of macular diseases
(Fig. 6.2), but at present its use is diminishing. More recent imaging modalities
provide more comprehensive evaluation of the macular anatomy and function.
Furthermore, FA has some limitations: it requires an invasive dye injection with
a limited transit window and it has limited resolution. Still, angiography contri-
bution remains still valid to the assessment of vascular integrity: in contrast to
OCT-A, fluorescein angiography is a dynamic examination which show vessel
filling and leakage [2].
The indications of Fluorescein Angiography, Indocyanine Green Angiography
and Optical Coherence tomography Angiography are reported in Table 6.1.
Indocyanine Green Angiography
Indocyanine Green Angiography (ICGA) was originally described by Yannuzzi

in 1992 [3]. Indocyanine green is a water-soluble dye which is almost completely
bound to serum proteins (98%), thus its diffusion through choriocapillaris is lim-
ited. The retention of the dye in the choroidal circulation makes indocyanine green
angiography ideal for imaging of choroidal circulation. As well as FA, ICGA is
invasive and requires intravenous injection of the dye.
Nowadays, ICGA is recommended only for a small group of chorioretinal disor-
ders, including some forms of neovascularization in age-related macular degenera-
tion (Fig. 6.3) (occult choroidal neovascularization and choroidal neovascularization
with subretinal hemorrhage), other neovascular maculopathies, chronic central
serous chorioretinopathy, choroidal hemangiomas, and posterior uveitis [4].
Optical Coherence Tomography
Optical Coherence Tomography (OCT) is a non-invasive imaging modality which

allows to acquire retinal cross-section in vivo. Since its original introduction in
1991 [5], OCT has revolutionized the retinal imaging and the evaluation of the
macular pathologies. Diagnosis of maculopathy, previously based on fundus biomi-
croscopic examination, retinography or FA, in most of cases now relies upon OCT
detailed contribution. OCT can quantitatively measure retinal thickness and evalu-
ate qualitative anatomic changes, such as intraretinal or subretinal fluid.
Table 6.1 Indications of fluorescein angiography, indocyanine green angiography and optical
coherence tomography angiography in macular diseases
Indocyanine green Optical coherence
Fluorescein angiography angiography tomography angiography
Indications • Neovascular age • Occult choroidal • Neovascular age related
related macular neovascularization macular degeneration
degeneration • Choroidal • Diabetic retinopathy
• Diabetic retinopathy neovascularization with • Retinal vein occlusion
• Retinal vein occlusion subretinal hemorrhage • Retinal artery occlusion
• Retinal artery • Central serous • Genetical macular
occlusion chorioretinopathy dystrophy
• Genetical macular • Central serous
dystrophy chorioretinopathy
• Central serous • Uveitic macular edema
chorioretinopathy
• Uveitic macular edema
Fig. 6.3 Multimodal imaging of a choroidal neovascularization secondary to age-related macular

degeneration. Early (a) and late (b) FA phases show the presence of a CNV with the typical pin-
points alterations. ICGA is able to better detect the entire neovascular network, respectively in
early (c) and late (d) phases. Structural OCT (e) confirms the presence of a subretinal mixed reflec-
tivity lesion, together with the presence of subretinal fluid and intraretinal cysts
Fig. 6.3 (continued)
First OCT devices used time-domain technology (TD-OCT), allowing

approximately 400 A-scans per second and with a resolution of 10–15 microns.
The clinical utility of TD-OCT was inadequate until the implementation of
spectral domain technology (SD-OCT), which instead allowed 20,000–80,000
A-scans per second. SD-OCT (introduced in 2002) significantly improved the
image resolution (2–8 microns) and reduced motion artifacts [6]. The swept-
source OCT (SS-OCT) is a more recent technology allowing high spatial resolu-
tion and better tissue penetration. SS-OCT has a scan rate of 100,000 scans per
second, and some prototype models could reach up to 400,000 scans per second
(Table 6.2) [7]. The increased number of acquisitions improves the area of the
retina evaluated and the visualization of retinal structures. SS-OCT allows the
simultaneous detailed evaluation of the vitreous and the choroid, enabling to
better visualize the choroidal structures, as well as the sub-RPE pathology [8].
However, improvement of OCT technology is still ongoing. Adaptive Optics OCT
(AO-OCT) devices dynamically adjust their optical characteristics to compen-
sate for monochromatic aberrations occurring naturally in the eye. Overcoming
current AO-OCT limitations (narrow depth focus, restricted field of view) that
nowadays do not allow its widespread use, its improved resolution could achieve
a better understanding of normal and pathologic retinal function. Furthermore,
Table 6.2 Comparison between different commercially available optical coherence tomography
devices
Time domain Spectral domain Swept source
Commercialization 1996 2006 2012
Acquisition (A-scans 400 20,000–80,000 100,000–400,000
per second)
Resolution 10–15 μm 2–8 μm 2–8 μm
Characteristics A moving reference Higher sensitivity than Higher sensitivity than
mirror is required, TD-OCT TD-OCT, with very high
limiting the High scanning speed scanning speeds, and
acquisition rate of the and axial resolution minimal signal drop-off
technology and good visualization with depth
Mostly inadequate for of retinal layers It has high spatial
current clinical use It has limited resolution and better
penetration with tissue penetration (from
noticeable signal vitreous to choroid)
drop-off with depth
it could improve the quality of images from eyes with more aberrations, achiev-
ing better performance of the automated segmentation algorithms. Polarization-
Sensitive OCT (PS-OCT) is an innovative technology that detects polarization
changes in circularly polarized light; polarization of retinal structure (such as the
RPE) may improve the detection of macular disease and give the opportunity for
earlier intervention [9].
Optical Coherence Tomography Angiography
Optical coherence tomography angiography (OCTA) is a recent imaging tech-

nique based on OCT, which allows the study of blood vessels in the eye. OCTA
uses the variation in OCT signal caused by moving particles (such as red blood
cells) in order to infer blood flow. To discriminate the moving particles from
static tissue, OCTA devices perform repeated scans at the same location, and the
changes of the OCT signal in consecutive scans are employed to visualize the
microvasculature [10].
OCTA has many applications in retinal and choroidal vascular imaging, with
special focus on the macular disorders.
In age related macular degeneration (AMD), OCTA allows the detection of cho-
roidal neovascularization (CNV), and a more detailed visualization of its structure
than dye-based angiography examinations.
In diabetic retinopathy OCTA can show microaneurysms, appearing as focally
dilated saccular or fusiform capillaries in the superficial and deep retinal capillary
plexa. It is important to remark that not all microaneurysms seen on fluorescein
angiography can be detect by OCTA, and vice-versa. OCTA can also visualize the
retinal areas of non-perfusion in all the ischemic retinopathies.
OCTA is useful to confirm the clinical diagnosis of retinal vein occlusion or reti-
nal artery occlusion, as it can identify the areas of capillary nonperfusion and retinal
ischaemia, and moreover it can detect the presence of collateral vessels, capillary
telangiectasia and microaneurysms.
OCTA in also used in genetical macular dystrophy in order to evaluate the dam-
ages in retinal plexa and choriocapillaris, and also to detect the presence of CNV.
OCTA could be useful in improving the knowledge of uveitic macular edema,
even if there are few studies so far [11].
OCTA has several advantages over dye-based techniques: it is not invasive and
fast, it does not have to respect a narrow time window, it has a better vascular defini-
tion. OCTA has also some limitations, notably the frequent presence of image arti-
facts, which are similar and derived from artifacts that occur in OCT. Even if OCTA is
a new imaging technique without definitive clinical indications, it is already a funda-
mental tool in the diagnosis and management of macular pathologies. The comparison
between Fluorescein Angiography and OCTA techniques is provided in Table 6.3.
Fundus Autofluorescence
Fundus autofluorescence (FAF) imaging is a rapid and noninvasive technique. It

is used mainly to evaluate retinal pigment epithelial function, as the predominant
source of autofluorescence in the macula is lipofuscin granules.
Blue autofluorescence is the intrinsic fluorescence emitted by lipofuscin granules
when stimulated by blue light. With retinal aging, lipofuscin granules accumulate in
the RPE cells. Normal macula shows a reduced autofluorescence in its center due to
the blockage of luteal pigments (lutein and zeaxanthin), while the rest of the macula
shows a diffuse autofluorescence signal. Other structure such as the blood vessels
and the optic disc appear black because they do not have autofluorescent mate-
rial [12]. In contrast to blue autofluorescence, green-light autofluorescence imaging
is less affected by macular pigments, and it could probably allow a more precise
evaluation of small central changes [13].
FAF is extremely useful to uninvasively evaluate all types of maculopathies
(Table 6.4) (Fig. 6.4). Both augmentation or reduction of autofluorescence can be
pathological. For example, in Best vitelliform dystrophy the autofluorescence signal
is increased because of the accumulation of waste material (Fig. 6.5), while in geo-
graphic atrophy the signal is decreased because of the loss of RPE cells (Fig. 6.6).
Near-infrared autofluorescence imaging (NIR-AF) in another autofluorescence
technique, which evaluates melanin and its distribution throughout the RPE and
choroid. NIR-AF can be performed to detect melanin in different macular patholo-
gies (AMD, inherited macular dystrophies, diabetic macular edema, central serous
chorioretinopathy). This technique can extend our ways of studying the foveal
involvement in macular diseases, since the higher concentration of melanin is pres-
ent at the level of the fovea. Even if NIR-AF is easily performed with commercially
available instruments, it has some limitations, and further research is needed to bet-
ter understand and to standardize NIR-AF imaging [14].
148
Table 6.3 Comparison between fluorescein angiography and OCTA techniques

Secondary Peripheral
Ischemic Neovascularization vascular vascular Anastomotic
Techniques Microaneurysms IRMA DME areas Neovascularization growth branching arcades loops
Fluorescein Yes Yes Yes Yes Yes No No No No
angiography
OCTA Yes Yes Yes Yes Yes Yes Yes Yes Yes
F. Bandello et al.
Table 6.4 Fundus • Age related macular degeneration

autofluorescence indications – Drusen
– Neovascular age related macular degeneration
– Geographic atrophy
• Hereditary macular dystrophy
– Best macular dystrophy
– Stargardt macular dystrophy
– Rod-cone dystrophies
– Pattern dystrophies
• Areas of retinal atrophy
• Retinal areas of pigment accumulation
• White dot syndromes
• Optic disk drusen
Fig. 6.4 Fundus autofluorescence in a myopic CNV. At baseline, fundus autofluorescence shows the
presence of macular autofluorescence changes, with an increase of hypoautofluorescent signal (a);
structural OCT clearly detects the presence of a subretinal hyperreflective lesion, together with the pres-
ence of subretinal fluid (b). After anti-VEGF injections, fundus autofluorescence shows an increase of
hypoautofluorescent signal, interpretable as increased atrophy (c), confirmed also by structural OCT (d)
New Perspectives: Artificial Intelligence and Telemedicine
In this section the main features of multimodal imaging have been discussed,
showing the very useful role of these methodologies in clinical practice (Fig. 6.7).
Artificial intelligence has a great potential to improve medical activity and health
care quality. Several studies have demonstrated that artificial intelligence software
Fig. 6.5 Multimodal imaging in a case of Best disease. The vitelliform material appears hyperau-
tofluorescent (a) and it masks the signal provided by melanin in NIR-AF (b). Structural OCT (c,
d) clearly shows the vitelliform acculumation, with rarefaction of outer retinal layers and normally
reflective inner layers
can identify retinal diseases with the same or better accuracy than human special-
ists, even if their role in medical decision-making is still controversial. Nowadays,
the most encouraging results are obtained for age related macular degeneration and
diabetic retinopathy [15].
Another important implementation in maculopathy care could be portable
devices. For example, a portable and self-measuring OCT system may reduce the
cost of managing chronic maculopathy by providing easily accessible and continu-
ous retinal monitoring [16].
Fig. 6.6 Multimodal imaging in a case of geographic atrophy. FAF image (a) clearly shows the
hypoautofluorescent region, affected by the atrophic process. The hyperautofluorescent perile-
sional signal is typical of GA. The posterior pole atrophy is also confirmed by multicolor image
(b), showing a marked depigmentation. Structural OCT (c, d) clearly shows the atrophy of the
outer retinal layers, with window effect artifact interesting the choroid, the latter caused by the lack
of light absorption caused by the atrophy of the retinal pigment epithelium
Fig. 6.7 Multimodal imaging in a case of central serous chorioretinopathy. FA shows the presence
of a fugal hyperfluorescent point, increasing in dimension from early (a) to intermediate and late
phases (b, c). ICGA confirms the presence of the fugal point in all three phases (d–f); moreover, it
shows a masking effect secondary to the presence of massive fluid. This latter is accurately detected
by multicolor image (g) and structural OCT (h), accurately documenting the loss of physiologic
foveal profile. After the treatment with eplerenone, both multicolor image (i) and structural OCT
(j) document the restoration of macular features
Advances in Intravitreal Treatments
Choroidal neovascularization (CNV) due to neovascular AMD (nAMD) is the cause

of AMD-related severe vision loss among people aged 55 years or older in western
countries. Anti-vascular endothelial growth factor (anti-VEGF) agents, delivered
intravitreally, arrest the angiogenic process and stop the growth of abnormal blood
vessels in the eye (Fig. 6.8). The aim of this therapy is to prevent disease evolution,
vision loss and, in some cases, improve vision [17].
Fig. 6.8 Multimodal imaging in a case of Stargardt disease complicated by the onset of a choroi-
dal neovascularization. Blue (a) and near-infrared (b) autofluorescence images are very useful to
document the distribution and extension of atrophic alterations, hypo- and hyperautofluorescent
flecks. Early, intermediate and late phases of FA (c–e) and ICGA (f–h) exams detect the presence
of a CNV, associated with sparse diffuse alterations extended also over the vascular arcades.
Structural OCT shows an hyperreflective lesion associated with subretinal fluid (i), with complete
recovery of exudation with stabilization of lesion size after anti-VEGF intravitreal treatment (j)
Currently the two main drugs used to treat nAMD are Ranibizumab and
Aflibercept. Bevacizumab, (Avastin; Genentech/Roche), does not have approval
from the US Food and Drug Administration (FDA) and the National Institute for
Health and Care Excellence for the treatment of AMD. Clinical trials have dem-
onstrated similar efficacy of Bevacizumab and Ranibizumab. However, questions
remain regarding serious systemic and ocular side effects of Bevacizumab. Whereas
ranibizumab is provided in single-dose vials, bevacizumab requires compounding,
which may increase the risk of ocular infections [18, 19].
Ranibizumab was the first treatment for neovascular AMD that offered a realistic
hope for vision improvement.
The registration studies (ANCHOR and MARINA trials) analyzed the use of
Ranibizumab versus photodynamic therapy in classic membranes and versus pla-
cebo in occult neovascularization. These trials established vision improvement
in Ranibizumab groups and vision loss in the comparator groups. FDA approved
Ranibizumab for the treatment of AMD in 2007 [20, 21].
Aflibercept, formerly known as VEGF-Trap, is another anti-VEGF drug that was
approved for the treatment of nAMD by the FDA in 2011, after the results of VIEW
1 and 2 trials [22, 23]. These studies demonstrated that aflibercept is an effective
therapy for nAMD and it can be administered every 2 months [22].
Angiogenesis can be inhibited with different treatments, which have been studied
with excellent outcomes in the clinical trials but with less successful results using
real-world data. The targets of these new therapies are: better efficacy, longer dura-
tion of action and simultaneous effects on VEGF blockade and prevention of atrophy
and scarring. Between these new drugs, Brolucizumab and Abicipar pegol showed
positive outcomes in phase 2 trials and now are being studied in phase 3 trials [24].
Brolucizumab (RTH258) is a humanized single-chain antibody fragment that

inhibits all isoforms of VEGF-A. It was developed by ESBATech (discovery to
phase 2a), Alcon Laboratories (phase 2b) and Novartis (phase 3).This drug has a
small molecular weight (26 kDa) in comparison to Aflibercept and Ranibizumab
(respectively 115 kDa and 48 kDa). This enables Brolucizumab to penetrate tis-
sues and to be removed more rapidly from systemic circulation compared to larger
molecules. Two different trials (HAWK and HARRIER) were designed to com-
pare the efficacy and safety of Brolucizumab versus Aflibercept in subjects with
nAMD. These studies showed important results in term of visual acuity and dura-
tion of action. Moreover, Brolucizumab seemed to be superior to Aflibercept in
reducing intraretinal and subretinal fluid by OCT at different time-points [25, 26].
Abicipar pegol (Allergan) is a recombinant protein of the designed ankyrin repeat
protein (DARPin) family. DARPins are small, single-domain antibody mimetic pro-
teins that can selectively bind to a target protein with high affinity and specificity. In
comparison to Ranibizumab, Abicipar showed a higher affinity for VEGF-A and a
longer half-life. SEQUOIA and CEDAR are two clinical trials designed to evaluate
the safety and efficacy of Abicipar versus Ranibizumab in nAMD. After 52 weeks
both studies achieved non-inferiority in vision compared to Ranibizumab. However,
patients treated with Abicipar presented more ocular adverse events following the
treatment, most notably in the form of intraocular inflammation as uveitis, vitritis
and vasculitis. Most of these episodes were classified as mild or moderate and over
80% of them were treated and responded to topical corticosteroid [27].
Another interesting molecule with anti-angiogenic effects is Squalamine (OHR-
102). This drug is delivered to the eye in the form of an eye drop. IMPACT study was
performed on this new drug, comparing squalamine eye drops plus Ranibizumab
versus Ranibizumab monotherapy. This study showed positive outcomes in term of
visual acuity and, at present, a phase 3 study is ongoing to evaluate the efficacy and
safety of squalamine eye drops [24].
Diabetic macular edema (DME) is a severe complication of diabetic retinopathy
and is characterized by breakdown of the blood-retina barrier and increased vascu-
lar permeability.
Currently therapeutic strategies for DME includes focal/grid laser photocoagula-
tion, intravitreal anti-VEGF or corticosteroid treatment [28].
Fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien) is a nonbiodegrad-
able, injectable corticosteroid implant. It has been approved in 2013 as a treatment
option of DME in patients with pseudophakia who have been previously treated
with corticosteroids and didn’t have a clinically significant rise in intraocular pres-
sure. Iluvien lasts 36 months and contains 0.19 mg of fluocinolone acetonide which
is released at an average rate of 0.2 μg/day [29].
The Fluocinolone Acetonide in Diabetic Macular Edema (FAME) registration
studies consisted of two identical, double masked, sham-controlled, multicenter,
phase 3 studies— trial A and trial B—and included 956 patients with DME. Patients
were randomized to receive Iluvien or placebo. Participants who received Iluvien
showed a significantly improvement in best-corrected visual acuity (BCVA) than
sham injection. The Iluvien implant also significantly reduced foveal thickness
at 24 months. These effects last 36 months. Consistent with corticosteroid class-
specific adverse events, the most significant concerns in the use of Iluvien are ocular
hypertension and cataract. Raised IOP was treated with medical therapy in most
patients, with only <5% requiring incisional IOP-lowering surgery. These results
have been also supported by real-world studies [30].
Advances in Other Non-surgical Treatments
New perspectives for the treatment of maculopathies regard gene therapy and new
technological devices, namely artificial retinal microchips.
Many hopes dwell in gene therapy. The eye has been at the perfect candidate for
translational gene therapy because of its small, enclosed structure, immune privi-
lege, and easy accessibility. The availability of animal models and the opportunity to
take in vivo imaging techniques allows for noninvasive and sensible monitoring of
the effects of gene delivery. Two strategies have been adopted in gene therapy: gene
augmentation or gene disrupting/silencing [31]. The former consists in an insertion
of a mutant gene in the host cell through a vector. The latter employs editing tools, as
RNA interference or nucleases [32, 33], for gene suppression and many studies on
animal model are searching for possible applications in human ocular disease. Gene
augmentation may be use for AR and XL diseases and is the most experimented
strategy worldwide. The gene of interest could be delivered as DNA, or alterna-
tively as mRNA or mRNA analog. Viral vectors represent the preferred choice to
transfer nucleic acids in cells. Adenovirus and Lentivirus have the best qualities for
this task. Adeno-associated virus is the more used vector in ophthalmology due to
its efficiency, persistence and poor immunogenicity [34]. Adeno-associated virus
(AAV) belongs to capside virus with no envelope and has small dimension (19–
21 nm). AAV has low risk of mutagenesis because it remains in episomal form in the
nucleus [35]. AAV is the chosen vector for RPE65 trials [36, 37]. The limiting factor
in AAV use is the packaging capacity of 4.8 kb [38]. Moreover, regulatory elements
are necessary for the procedure and so the capacity is further reduced to 3 kb [39].
For this reason, large genes as ABCA4 and MY07A (7 kb) could not be inserted in
AAV carriers [40]. The use of dual AAV carrier has been developed to overcome the
issue [41]. The genetic material is packed as two distinct fragments and delivered to
the cell and then recombining through homologous recombination or trans-splicing
methodic [42]. The AAV serotypes more studied and used in ocular gene therapy
are AAV2, AAV5 and AAV8. Different capsid proteins confer diverse target tropism
and transduction efficiency [43–45]. The AAV2 is able to efficiently transduce RPE
cells, photoreceptors cells and retinal ganglion cells [43]. Recent studies suggest
that the antibody response triggered by a first injection could limit the transduction
in the other eye [46].
Lentiviral vectors derive form variant of human immunodeficiency virus type 1
[47]. The cargo capacity is larger than AAV viruses: 8–10 kb [48]. After transduction
the gene inserted are reverse transcribed into the host genome and then expressed
[49]. Insertional mutagenesis is a risk since the integration. In preclinical studies

lentivirus seemed effective in targeting RPE cell, but not photoreceptors [50].
Subretinal and intravitreal injection are the strategies to deliver the virus carriers
in the eye. The first method targets RPE cells, photoreceptors and Muller cells. In
almost all human clinical trials has been used to deliver RPE65 [51]. Observed com-
plications for subretinal injection are macular hole, retinal tears, inability to detach
the retina whit multiple injection attempts, cataract, long recovery time because
of large volume injected [36, 52, 53]. Intravitreal injection targets retinal ganglion
cells and the virus molecules are directly injected in the hyaloid [54]. Immunologic
and inflammatory responses, transient elevation in intraocular pressure are the main
complications [55–57].
Nanoparticles (NPs) can also be used for gene therapy alternatively to viral car-
rier [58]. NPs, usually lipid-based, were developed to be internalized by the cell and
to be capable of transferring the carried genetic material to the nucleus, escaping
from the endosome. Lipid NPs are stable, biocompatible, no inflammatory-induce
molecules [59]. Large plasmid DNA up to 20 kb could be transferred by NPs [60].
Two preclinical studies efficaciously treated a Rs1h deficient X-linked retinoschisis
in a mouse model through NPs injections [61, 62]. NPs disadvantages compared to
viral carriers are lower gene expression and lack of specificity to the different types
of retinal cells [59].
Viral vectors with subretinal/intravitreal injection, and in particular AAV, and gene
augmentation strategy have been used for the most completed and ongoing human tri-
als. Voretigene neparvovec-rzyl (trade name of Luxturna) was approved in December
2017 as the first gene therapy for inherited retinal degenerations by Food and Drug
Administration. It consists in AAV2 viral vectors carrying human RPE65 DNA driven
by a CMV enhancer targeting RPE cells through subretinal injection [63, 64].
Retinitis pigmentosa and Leber’s Congenital Amaurosis (LCA) would benefit
from Voretigene therapy. Mutations in RPE65 account for approximately 2% of
autosomal recessive RP and 16% of LCA [65]. Results from the first 2 years of this
clinical trial showed that RPE65 gene replacement therapy was not associated with
serious adverse events, and improvement in at least one measure of visual function
was observed in 9/12 subjects, with the trend for improvement being observed in
the younger patients [66]. In the 3, 4, 5 years after treatment no safety issues were
observed and progression of photoreceptors degeneration was slower in early age
patients [67].
Gene therapy must be completed before the onset of cell death caused by the
disease. Retinal degeneration progression was seen in a human LCA study with
gene therapy, despite a visual acuity improvement [58]. Perfect timing is therefore
crucial.
The first multicentre nonrandomised open-label clinical trial in choroideremia
patients reported encouraging results using an AAV2 [68]. After 2 years, the median
visual acuity increased by 4.5 letters in the treated eyes versus 1.5 letters loss in the
untreated eyes [69, 70]. Association with OCTA information may contribute to a
more precise localization of gene therapy in the attempt to maximize the functional
improvement [71].
Gene therapy approach is an exciting researching field in IRD and an actual

clinical option after Voretigene launch in RPE65 mediated diseases. Cargo capac-
ity remains a limiting factor and new researches are needed to find new vectors or
modify the current ones. We hope that new data and technological improvement
will lead to perfectionated the results in treated patients and extend gene therapy
effectiveness to other IRD.
Gene therapy approach may help maintain visual acuity in the early onset of the
disease, while electric stimulation through electrodes attempt to a partial restoration
of the vision using the remaining retinal network [72]. After photoreceptors degen-
eration the inner retinal cells may continue to survive and be operative for many
years despite neural remodeling [73].
Two different strategies of implants have been performed: implantation of
electrode arrays epiretinally in connection with retinal ganglion cells or implanta-
tion of the microchip in the subretinal space, substituting photoreceptors [74–76].
External image and data processing are necessary for the first approach to bypass
retinal image analysis, while the subretinal implants try to restore the normal con-
nections. RP has been targeted for this kind of approach from the beginning, due
to primarily photoreceptor degeneration. Microchip is constituted by photodiodes,
which convert light energy in electric energy. The electric response can be driven
and translated by still vital bipolar cells. Electrical stimulation pattern maintains
its retinotopic orientation because the normal retinal network is employed. This is
experimentally confirmed when patient read letters and combine them to words or
have is acuity assessed by presenting Landolt C-rings [77, 78]. Instead direct stimu-
lation of ganglion cells needs a learning/processing of the signal [79]. The subreti-
nal space is a privileged space and immunological reactions or scarring processes
are low into it. The epiretinal implant could lead to epiretinal membrane formation
or neural atrophy (Table 6.5) [80].
However, the electric signal must be amplified by the microchip before convey-
ing to bipolar cells, because the normal signal energy is not sufficient to stimulate
a diseased retina [81]. So, an induction coil located under the skin beneath the ear
was developed to confer relay power to the chip and is connected to the orbital part
with a subperiosteal cable [82]. The surgical procedure with subretinal approach is
complex and requires an high precision to fix the implant in an exact position. For
this reason, the scheduled time for a subretinal surgery implant is 5–8 h vs 1.5–4 h
for epiretinal implant surgery [83]. The subretinal microphotodiode-array has so far
been implanted in 64 patients (September 2017; data provided by Retina Implant
Table 6.5 Pros and cons in the choice of epiretinal and subretinal implantation
Pros Cons
Epiretinal Easier and faster surgical procedure Learning training needed,
implantation (1.5–4 h) epiretinal membrane or
strategy atrophy in situ formation
Subretinal Direct stimulation of bypolar cells, Complex and long surgical
implantation retinotopic orientation of the image, reduced procedure (5–8 h), signal
strategy scarring and immunologic responses needed to be amplified
AG, Reutlingen, Germany). Durability is a great issue: RETINA IMPLANT Alpha

AMS has significantly improved the previous results, reaching a half-life of at
least 5 years [82]. One thousand six hundred micro-photodiodes and electrodes are
located in an area of 2.8 mm × 2.8 mm. Energy and control signals are transferred
to the micro-photodiodes via a subretinal, trans-scleral polyimide foil and a subperi-
osteal silicone cable, which originates from a secondary coil in the retro-auricular
space under the skin. The coil received energy from a primary coil, attached mag-
netically behind the ear. The primary coil, in turn, receives energy and controls from
a small hand-held device, provided with controls for the user and engineers.
The implantation surgery begins with the retro-auricular part. Then intraocular sur-
gery follows with the preparation of a scleral flap, temporally closed with a suture.
Next step is the three-port complete vitrectomy and the sub-retinal bleb creation
to avoid retinal injuries from the guide foil or the implant. The retina is lifted with
41-gauge sub-retinal injection of balancer salt solution. After the bleb, the scleral flap is
re-opened and the guide foil is inserted through a choroidal incision into the subretinal
bleb and the pushed tangentially to the ocular surface. The guide foil is thus adjusted
in the correct position. The implant can easily be advanced between the RPE and the
guide foil and then this latter is carefully removed. The scleral flap is closed, and the
silicone mesh of the implant secured to the sclera over the flap. Fluid/air exchange is
performed, and the eye filled with silicone oil. Explantation was part of the first proto-
col (2005–2009). According to recent data, 4 of 64 patients underwent re-implantation
with RETINA IMPLANT Alpha AMS. All re-implantations have been performed in
the exact same locations as the primary surgery and, clearly, surgery is considerably
more difficult than explantation. A multicentered trial with RETINA IMPLANT Alpha
AMS in 15 blind patients was performed in Germany [82]. Implant-mediated visual
perception was seen in 13/15 patients. At second month, 11/13 patients passed the light
perception test, while motion detection was possible for two out of 11 patients when
the implant was switched ON at the first month. 2/13 patients were able to distinguish
Landolt C-rings up to 20/1111 and 20/546 and able to discriminate the orientation of
gratings with a spatial frequency of 0.66 and 1 cpd. Implant-mediated visual perception
was generally stable over the observation period of 12 months [82].
Microchip implants are a modern and feasible approach to IRD and new tech-
nological developments and studies are required to better understand the maximum
potential of this surgery [84–86].
Conclusion
In conclusion, the future perspectives on the diagnosis and treatment of maculopa-

thies will undergo to even more advanced methodologies and will led ophthalmolo-
gists to an optimistic era were patients will benefit from more fine and precocious
diagnosis, as well as in treatments able to act against the pathological mechanisms
of macular diseases, preventing the onset and progression of complications like
atrophy.
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Chapter 7
Recent Developments in Vitreo-Retinal
Surgery
Sana Idrees, Ajay E. Kuriyan, Stephen G. Schwartz, Jean-Marie Parel,

and Harry W. Flynn Jr
History of Vitrectomy
“Open sky” vitrectomy technique, termed diapupillary resection, was described by

Tsugio Dodo for partial removal of a vitreous hemorrhage from a patient in Japan
in 1955 [1, 2]. However, the Western world likely did not hear about this technique
until 1968 when David Kasner also described an “open sky” technique for vitreous
removal using cellulose sponges and scissors. This technique was initially used to
address vitreous loss during cataract surgery (Fig. 7.1) and subsequently used to
remove opacified vitreous in the setting of amyloidosis [3].
a b c
Fig. 7.1 (a) Dr. David Kasner demonstrating open sky technique for vitreous removal using cel-
lulose sponges and scissors on a cadaver eye. (b, c) High magnification of cadaver eye vitreous
removal
S. Idrees · A. E. Kuriyan
Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY, USA
S. G. Schwartz · J.-M. Parel · H. W. Flynn Jr (*)
Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA

166 S. Idrees et al.
Fig. 7.2 Dr. Robert

Machemer performing pars
plana vitrectomy
The introduction of modern pars plana vitrectomy (PPV) is generally credited

to Robert Machemer (Fig. 7.2) as he was responsible for developing the first
automated system for vitreous removal with controlled intraocular pressure in
1970 [4]. Machemer and Helmut Buettner initially designed a vitrectomy device
with a drill bit and tiny electric motor encased in a blunt hypodermic needle.
Suction was added to remove the vitreous more effectively, and an infusion tube
was soldered to the outside of the hypodermic needle to prevent globe collapse
[5]. Machemer performed his first PPV on April 20, 1970 on a diabetic patient
with a non-clearing vitreous hemorrhage and visual acuity improved from 2/200
to 20/50 [4]. Subsequently, a collaboration between Jean-Marie Parel (Fig. 7.3a)
and Machemer led to the development of the vitreous infusion suction cutter
(VISC, Fig. 7.3b) and the fiberoptic endoillumination used in early PPV. The
VISC was developed as an instrument which cut vitreous, removed debris from
the eye by suction, while simultaneously infusing Ringer’s solution [6, 7]. Early
vitrectomy was performed using a VISC that was 17 gauge and 1.5 mm in diam-
eter inserted through a 2.1 mm scleral incision [6, 8].
In 1971, Gholam Peyman (Fig. 7.4a) described a technique using a vitrophage
(Fig. 7.4b) to remove and replace the vitreous [9]. In 1974, Conor O’Malley and
Ralph Heintz developed the first three port 20-gauge pars plana vitrectomy system,
separating the components of vitreous cutting, infusion, and illumination [10]. In
1985, Machemer and Dyson Hickingbotham introduced the first 20-gaugetrocar/
7 Recent Developments in Vitreo-Retinal Surgery 167
a b
Fig. 7.3 (a) Dr. Gholam Peymann, who developed the vitrophage. (b) Photo of the vitrophage
a b
Fig. 7.4 (a) Dr. Jean-Marie Parel, who developed the vitreous infusion suction cutter (VISC) with
Dr. Robert Machemer. (b) Photo of the VISC
cannula system to allow for easier passage and interchangeability of instruments in

an attempt to reduce the risk of iatrogenic retinal tears or retinal detachment [11].
Subsequently, 20-gauge vitrectomy became standard treatment for decades.
In 1990, Eugene de Juan and Hickingbotham developed 25-gauge vitrectomy
instrumentation, including a vitreous cutter, microscissors, and vitreous mem-
brane dissector. At that time, use of 25 gauge instruments was limited to select
cases requiring high precision due to slow vitreous removal speeds [12]. Peyman
described a 23 gauge vitrectomy system in 1990 [13]. In 2002, Gildo Fujii intro-
duced a 25 gauge operating system, the Transconjunctival Sutureless Vitrectomy
System, allowing for self-sealing transconjunctival sclerotomies. This method pop-
ularized the widespread use of small gauge PPV [14, 15]. In 2005, Claus Eckardt
introduced 23 gauge instrumentation as an alternative to 25 gauge PPV [16]. Yusuke
Oshima pioneered a 27 gauge vitrectomy system in 2010 [17].
When PPV was first utilized it was generally reserved for the more severe,
selected cases, such as non-clearing vitreous hemorrhage and complex retinal
Table 7.1 Diseases commonly 1. Retinal or choroidal detachment

considered amenable to pars (a) Retinal detachment
plana vitrectomy • Rhegmatogenous
• Traction
• Combined traction/rhegmatogenous
(b) Choroidal detachment
• Serous
• Hemorrhagic
2. Proliferative vitreoretinopathy
3. Vitreous opacities
(a) Vitreous hemorrhage
(b) Other opacities
4. Vitreomacular interface disorders
(a) Epiretinal membrane
(b) Macular hole
(c) Vitreomacular traction
5. Inflammatory disorders
(a) Endophthalmitis
(b) Posterior segment uveitis
• Infectious
• Noninfectious
6. Complications of anterior segment surgery
(a) Retained lens material
(b) Dislocated intraocular lens
7. Trauma
(a) Intraocular foreign body
detachment [18]. However, evolution of vitreoretinal ancillary equipment and

surgical techniques has allowed increases in the utilization of vitrectomy and indi-
cations for vitrectomy surgery (Table 7.1). Today, PPV is the most commonly per-
formed surgical procedure by retinal specialists.
Perioperative Considerations
Vitrectomy can be performed with general or local anesthesia, including regional

with or without topical anesthesia [19]. Traditionally, vitrectomy was more often
performed with general anesthesia, but recently local anesthesia is also popular
[20]. General anesthesia may be used when the procedure is expected to be long
or painful. Additionally, patients with claustrophobia, anxiety, or dementia may
benefit from surgery with general anesthesia. However, use of general anesthesia
decreases turnover time, increases procedural costs, and has increased systemic
risks compared to local anesthesia with monitored anesthesia care [21].
Regional block with monitored anesthesia care allows the patient to remain awake
during the procedure. Several methods of local anesthesia may been used, including
retrobulbar, peribulbar, sub-Tenon’s, and topical anesthesia [20]. Retrobulbar anes-
thesia generally provides excellent anesthesia and akinesia but is associated with
small risks of retrobulbar hemorrhage and scleral perforation [22]. Peribulbar anes-
thesia is associated with fewer risks but is somewhat less effective than retrobulbar
anesthesia and may require a longer time to produce adequate effects. Sub-Tenon’s
anesthesia is administered in the posterior sub-Tenon’s space and provides rapid
anesthesia and akinesia [22]. Topical anesthesia involves the use of anesthetic drops
on the ocular surface. It has been reported effective in select patients for vitreoreti-
nal surgery [23]. However, due to relatively long procedure times for most vitreo-
retinal surgery, it has not been widely adopted. In-office PPV with local anesthesia
has also been reported, but is not widely practiced [24].
Vitrectomy Systems
Berkeley Bioengineering in 1974 developed the first three-port, 20G system known
as the Ocutome 800 (Fig. 7.5). It had a lightweight pneumatic probe with axial
cutting and surgeon foot pedal controlled on-off aspiration. It was followed by the
Coopervision Ocutome 8000, which had the first linear aspiration system, inte-
grated light source, and connected fragmenter. These early companies are no longer
in existence or are not involved in vitrectomy surgical instruments. Another early
vitrectomy system was the MID Labs MicroVit system, which produced the first
high-quality disposable pneumatic cutter [25]. The Daisy (Storz) (Fig. 7.6) was
introduced in 1986 and had multiple functions including irrigation/aspiration, ante-
rior and posterior vitrectomy, bipolar coagulation, automated scissors, illumination,
air exchange and phacoemulsification and fragmentation. The Daisy was followed
by the Premiere system. Storz was acquired by Bausch + Lomb in 1997, and the
combined organization produced the Millennium Microsurgical System (Fig. 7.7)
that year. Also in 1997, Alcon introduced the Accurus (Fig. 7.8).
Fig. 7.5 Ocutome 800

machine
Fig. 7.6 Storz Daisy

machine (Photo courtesy
of Bausch + Lomb)
Fig. 7.7 Bausch + Lomb

Millenium Microsurgical
System (Photo courtesy of
Bausch + Lomb)
Fig. 7.8 Alcon Accurus

of Alcon)
Currently, the most commonly used vitrectomy systems include the Constellation
(Alcon, 2008), Enhanced Visual Acuity (EVA, DORC, Zuidland, the Netherlands,
2015), and the Stellaris PC/Stellaris Elite (Bausch + Lomb, Bridgewater, NJ, USA,
2010/2017). The Constellation vitrectomy system (Fig. 7.9) has a dual pneumatic
vitreous cutter with increased cut rates up to 10,000 cpm, radiofrequency identifica-
tion recognition technology to regulate light intensity based upon the probe gauge
size, surgeon-controlled duty cycle, integrated laser, and torsional anterior segment
phacoemulsification. The Constellation has capacity for 20, 23, 25, and 27 gauge
instrumentation. The EVA vitrectomy system (Fig. 7.10) utilizes a two-dimensional
vitreous cutter with a cut rate of up to 16,000 cpm, high flow infusion cannula, and
instrumentation for 23, 25, and 27 gauge vitrectomy.
The Stellaris PC (Fig. 7.11), has vitreous cutters with cut rates of up to
5000 cpm. It also has a dual light source, color filters for differentiated viewing,
and instrumentation for 20, 23, and 25 gauge vitrectomy [26]. The Stellaris Elite
Vision Enhancement System (Bausch + Lomb, 2017), offers single port 20, 23, and
25 gauge vitreous cutters with cut rates up to 7500 cpm, and bi-blade 25 and 27
gauge vitrectomy cutters which cut in two directions per cycle with cut rates up to
15,000 cpm. The Stellaris Elite (Fig. 7.12) is also compatible with the ultrasound
vitreous cutter, which uses ultrasound energy to liquefy vitreous (instead of cutting
it with the traditional guillotine cutter) and remove it using a port that is continu-
ously open. The equivalent cut rate of the hypersonic vitrector (Fig. 7.13) is up to
1.7 million cpm.
Fig. 7.9 Alcon
Constellation machine
(Photo courtesy of Alcon)
Cannula-Trocar Systems
After the mid-1970s, PPV was largely performed with 20 gauge instrumentation,
requiring conjunctival incisions and sclerotomies measuring approximately 0.9 mm
in diameter. With 20G surgery trochars were optional. More recently, the growing
use of transconjunctival small-gauge has necessitated the use of cannulated scle-
rotomies. Fujii first reported a 25 gauge transconjunctival sutureless vitrectomy
Fig. 7.10 DORC EVA

of DORC)
system using microtrocars and cannulas in 2002 [14, 15]. The use of smaller gauge
vitrectomy instrumentation has reduced the scleral incision diameter to 0.72 mm for
23 gauge, 0.55 mm for 25 gauge, and 0.40 mm for 27 gauge (Fig. 7.14) [14, 16, 17].
Advantages of cannulas include maintaining the alignment between the conjunc-
tiva and sclera, minimizing wound border trauma and allowing easier and faster
interchangeability of instrument and infusion sites [27]. Less traumatic insertion
and removal of instruments is thought to contribute to a decreased risk of iatrogenic
retinal tears. Additional benefits of the cannula-trocar system include increased

Stellaris PC (Photo
courtesy of Bausch +
Lomb)
likelihood of self-sealing sclerotomy closure, decreased post-operative discomfort,

decreased risk of inflammatory reaction secondary to suture use, and post-operative
atrophy and thinning of the sclerotomy site [28]. However, the relatively small inter-
nal diameter of the cannula sleeve limits the radius of curvature of smaller gauge
intraocular scissors and results in decreased efficiency of intraocular scissors for
membrane cutting and dissection compared to intraocular scissors used in 20 gauge
vitrectomy [29]. Currently, most vitreoretinal procedures are performed with 23 or
25 gauge transconjunctival cannula-trocar systems, and 20G vitrectomy systems are
usually limited to select cases, such as severe posterior segment trauma or intraocu-
lar foreign body [30].

Stellaris Elite (Photo
Lomb)

hypersonic vitrector (Photo
Lomb)
Fig. 7.14 20, 23, 25, and 27 gauge vitrectomy probes
Valved cannulas have become popular since they minimize egress of fluid and elimi-
nate the need for cannula plugs during instrument exchange. The practical advantages of
valved cannulas are more stable intraocular fluidics and improved control of intraocular
pressure. Valved cannulas are reported to be comparable to their non-valved counter-
parts with regards to functional and anatomical outcomes as well as post-operative com-
plications. Valved cannulas can have the disadvantage of increased friction between the
instrument and valve and difficult insertion of soft or flexible tip instruments [31, 32].
A valved cannula design can also cause intraocular pressure build-up during air-silicone
oil exchange, and venting extensions have been introduced to prevent this.
Viewing Systems
Microscopes
Enhancements in the optics and illumination of operating microscopes contribute

to optimization of the retina surgeon’s view. In 1954, Littmann produced the earli-
est modern operating microscope with a constant working distance and the ability
to change magnification with a revolving Galilean turret, and paraxial illumination

[33]. The Galilean turret allowed for different magnifications at a constant working
distance, with lenses selected by turning a knob. Paraxial illumination utilized light
tubes with bulbs attached to the mounting of the body of the microscope to illuminate
the field of view and focus light at the working distance for the microscope, provid-
ing better depth perception for surgeons. The ability to move the microscope in the x-
and y-axis and control the movement through a foot pedal were major advancements
that improved visualization for vitreous surgery, developed by Parel and Machemer
in the 1970s (Fig. 7.15) [34]. An additional advancement was incorporating a beam
splitter to provide coaxial viewing for through additional oculars to allow for assis-
tant observation through the microscope (Fig. 7.16) [34]. Over the next several
decades, ocular microscopes continued to become more sophisticated with improved
light sources and optics to enable improved viewing of the vitreous and retina.
A recent advancement in microscopes for vitreoretinal surgery is the availability
of intraoperative real-time optical coherence tomography (OCT) integrated into the
surgical microscope. Currently, OCT-integrated microscopes are available from Carl
Zeiss Meditec (Fig. 7.17, Jena, Germany) and Leica Microsystems (Bannockburn,
Fig. 7.15 Early
microscope with foot pedal
control (Reproduced with
permission from Parel,
J-M., R. Machemer, and
W. Aumayr. “A New
Concept for Vitreous
Surgery: 5. An Automated
Operating Microscope.”
American journal of
ophthalmology 77.2
(1974): 161–168)
Fig. 7.16 Early
microscope with beam-
splitter to allow for
assistant viewing
IL, US). Potential uses advantages of intraoperative OCT include confirmation of

epiretinal and internal limiting membrane removal and potentially better visualiza-
tion of membrane peeling in select cases without using retinal dyes [35].
Lenses
Historically, vitreoretinal surgery was performed with planoconcave or biconcave

lenses under an operating microscope, which gave a limited field of view, approxi-
mately 20–35° (Fig. 7.18) [36]. Prism lenses were used to increase the field of view
to 60° [37]. Wide-angle viewing systems that are now available provide increased
visualization and access to the peripheral vitreous and retina. Wide-angle viewing
systems provide a panoramic view of the retina through the principles of binocular
indirect ophthalmoscopy and may require an image inverter mounted on the operat-
ing microscope. The two main types of wide-angle viewing systems are contact and
noncontact (Table 7.2) [38–42].
Contact lens wide-angle viewing systems provide better image resolution, con-
trast, and stereopsis than noncontact systems. With direct contact with the cornea,
they eliminate corneal aberrations and minimize reflective surfaces [38, 39]. The
lenses are either fixed into place using a ring sutured to the sclera or they are held
in place by a skilled assistant [39, 43]. The field of view and magnification vary
depending upon the lens used.
Noncontact wide-field viewing systems use a lens that is placed above the cor-
nea producing an inverted image, and they use an internal or separate prism system
Fig. 7.17 Lumera 700

with the Resight 700
intraoperative OCT (Photo
courtesy of ZEISS)
to reinvert the image. The field of view can be adjusted by changing the distance
between the lens and the corneal surface [44]. The noncontact wide-angle viewing
system does not require an assistant to hold the lens. The cornea must be coated
with a viscoelastic material or be constantly irrigated to avoid corneal dehydration.
Condensation on the lens, but this can be avoided with proper draping [39].
Three-Dimensional Viewing
Recently, three-dimensional (3-D) viewing techniques for vitreoretinal surgery

were introduced as an alternative to traditional viewing through microscope oculars.
With 3-D viewing systems, images from the microsurgical field are displayed on a
flat screen via a 3-D camera. The microscope head must still be positioned properly,
Fig. 7.18 Early contact

lens for vitrectomy surgery
Table 7.2 Wide angle viewing systems

Contact Noncontact
Magnifica Field of Manufac Field of
System Manufacturer tion view System turer view
MiniQuad Volk Optical 0.48× 106°/127° Binocular Indirect Oculus 130°
Ophthalmoscopy
(BIOM) HD
Disposable Lens
MiniQuad XL Volk Optical 0.39× 112°/134° Optic Fiber Free Topcon 130°
Intravitreal Surgery
System (OFFISS)
120 D
HRX Volk Optical 0.43× 130°/150° Merlin Wide Angle Volk Optical 120°
ASC Lens
Landers Wide Ocular 0.38× 130°/146° RESIGHT 500/700 Carl Zeiss 120°
Field 128 D
Single Use Katena 0.42× 155° Peyman-Wessels Ocular 135°
Surgical Wide Landers (PWL)
Field 132 D Upright
Vitrectomy Lens
A.V.I. Panoramic Advanced 0.48× 130° EIBOS 2 SPXL Haag-Streit 124°
Viewing System Visual 132 D
Instruments
(A.V.I.)
but visualization is independent of the oculars and requires the use of 3-D glasses
for stereopsis. The single display allows multiple observers to view the 3-D surgical
field. Through digital amplification of camera signals, lower illumination settings
can be used, which can potentially reduce risks of phototoxicity [45]. 3-D viewing
also has the potential to improve ergonomics compared to conventional binocular
microsurgery [46]. The Ngenuity (Fig. 7.19, Alcon, 2016) is the only commercially
available system currently.
Fig. 7.19 Ngenuity 3-D

viewing system (Photo
courtesy of Alcon)
Illumination and Filters
Initial vitrectomy was performed with coaxial light from the operating microscope
and later a modified slit-lamp affixed to the operating microscope (Fig. 7.20) [47].
In order to deliver intraocular illumination, Machemer and Parel placed fiberop-
tics around the VISC cutter (Fig. 7.21a) in 1974 and Peyman mounted a separate
fiberoptic light source attached to the vitrophage cutter in 1976 (Fig. 7.21b) [7,
48]. However, as early as 1974 the concept of separating the light source from the
Fig. 7.20 Ophthalmic
surgical microscope
equipped with slit lamp
(Reproduced with
permission from Parel,
J-M., R. Machemer, and
W. Aumayr. “A New
Concept for Vitreous
Surgery: 5. An Automated
Operating Microscope.”
American journal of
ophthalmology 77.2
(1974): 161–168)
Fig. 7.21 (a) Illuminated a

VISC (Reproduced with
permission from Parel, J-M.,
R. Machemer, and
W. Aumayr. “A new concept
for vitreous surgery: 4. b
Improvements in
instrumentation and
illumination.” American
journal of ophthalmology
77.1 (1984): 6–12.) (b)
Illuminated vitrophage
vitrector was introduced, by O’Malley and Heintz; this is currently standard prac-
tice for vitrectomy surgery [10]. The first light probes used halogen bulbs [49]. In
order to improve illumination, xenon light sources were introduced. Theoretically
the short wavelength of light emitted by xenon lamps could increase the rate of
photochemical damage [50]. Light-emitting diode (LED) light sources coupled
with smaller gauge instrumentation have the potential to allow reduction of the total
amount retinal light exposure and can be used without a fiber [51]. A mercury vapor
illuminator (Synergetics Inc., O’Fallon, Missouri, USA) was developed to provide
powerful illumination and uses a dual-output pathway from one mercury vapor bulb
with spherical reflectors adapted to generate homogenized illumination and sharpen
the focus light spot. Spectral filters, also known as pass filters, have been introduced
to eliminate hazardous wavelengths from the emission spectrum of light probes
[52]. Many modern endoillumination devices have built in some variant of a yellow
pass filter to screen lower wavelengths [50].
The structure of the light probes also determines the field of illumination. Straight
light probes provide a field of view of 50–80°. Mid-field light probes provide a field
of view of 90–110° [53–55]. Wide-angle light probes provide a field of view of up to
135–140°. Chandelier light sources illuminate from a greater distance than conven-
tional light probes, reducing the risk of photochemical damage. Additionally, the
use of chandeliers frees up the surgeon’s hand from having to hold the light source
and allows bimanual manipulation during surgery [56].
Chromovitrectomy
Chromovitrectomy refers to the use of dyes during vitreoretinal surgery to aid in the
identification of preretinal membranes or tissues [57]. The concept was introduced by
Kazauki Kadonosono in 2000 when he reported the use of indocyanine green (ICG)
to stain the internal limiting membrane (ILM) in macular hole surgery to improve
ILM visualization and facilitate its removal [58]. However, suspected toxicity to
the neuroretina and retinal pigment epithelium from ICG use has been reported and
observed to be dependent upon the dye concentration, osmolarity of the solvent solu-
tions, length of dye exposure time, and vitrectomy endolight illumination time [59].
Membrane Blue (trypan blue 0.15%, DORC, Zuidland, the Netherlands) is a dye that
is FDA-approved for epiretinal membrane (ERM)/ILM peeling but is generally not
as effective as ICG. Brilliant blue G is also used for this ERM/ILM peeling, but it
is not FDA-approved for this indication. Triamcinolone acetonide is used to stain
the vitreous to ensure complete removal of the vitreous during surgery and can stain
ERMs, but is not FDA-approved [60]. Triesence® (Alcon, Fort Worth, TX, USA) is
a preservative-free preparation of triamcinolone acetonide that is FDA-approved for
intraocular use including use for vitreous visualization in intraocular surgery.
Lensectomy and Phacoemulsification
Pars plana lensectomy or phacoemulsification from an anterior approach can be

performed during or prior to vitrectomy when visualization of the fundus is limited
due to dense cataract. Modern vitrectomy systems have the capability to perform
pars plana vitrectomy as well as anterior segment phacoemulsification. However,
many surgeons prefer to use pars plana lensectomy, especially when the crystalline
lens is severely subluxated or dislocated, or there is retained lens material in the
vitreous cavity. Historically pars plana lensectomy has been performed with the
use of a 20 gauge fragmatome, requiring a conjunctival peritomy, a 20 gauge scle-
rotomy, and suture-closure of wounds [61–68]. Since the advent of smaller gauge
transconjunctival vitrectomy, many retina surgeons use a combination of smaller
gauge vitrectomy instrumentation and either enlarge one sclerotomy or create a sep-
arate sclerotomy for a larger gauge fragmatome instrument [69]. The Constellation
Vision System (Alcon) uses a 20 gauge fragmatome, while both the EVA (DORC)
and Stellaris PC/Elite (Bauch + Lomb) systems now have the option of a 23 gauge
fragmatome for removal of lens material (Fig. 7.22) [70, 71]. The vitreous cutter can
also be used for lens removal but this may require a longer time for dense cataract
material.
Instrumentation
The evolution of vitrectomy surgery and its applications is closely linked to the
development of new instrumentation. While many retinal surgeons were key devel-
opers of various different instruments, Steve Charles has been one of the most influ-
ential developers of instruments and surgical techniques (Fig. 7.23).
Fig. 7.22 (a) Constellation a

20 gauge fragmatome. (b)
Bausch + Lomb 23 gauge
fragmatome. (c) DORC 23
gauge phaco/fragmatome
handpiece with
fragmentation needle b
c
Fig. 7.23 Dr. Steven

Charles who has developed
multiple vitreoretinal
surgical instruments and
techniques
Forceps
Various different forceps have been designed for different purposes in vitreoreti-
nal surgery. Internal limiting membrane (ILM) forceps are designed with a small
platform at the tip, which can be used to remove ILM through the pinch-peel tech-
nique or in combination with scrapers. Serrated forceps are designed to provide a
stronger grip on tissues, for manipulation of thick and heavy membranes, such as
those encountered in proliferative vitreoretinopathy or severe proliferative diabetic
retinopathy. Micro-textured grasping forceps are designed to provide a strong grip
on less thick or heavy membranes, while producing less tissue trauma [27].
Membrane Scrapers
Bausch + Lomb has developed multiple membrane scrapers, including the Tano and
variations on this device [72]. The Extendible Diamond Dusted Sweeper (DORC)
is a similar membrane scraper to the Tano instrument. The FINESSE Flex Loop
(Alcon) is a nitinol flexible extendible loop scraper that can be used to create an edge
to lift the ILM or an epiretinal membrane [73]. The force applied to the retina by the
can be adjusted based upon whether the loop is partially or fully extended [74].
Scissors
Horizontal scissors are used to cut retinal bands and tractional components near the
retinal surface. Illuminated horizontal scissors are available from some manufactur-
ers, which are useful during bimanual surgery and minimize the need for chandelier
placement. Vertical scissors can have a sharp anterior edge to optimize close dissec-
tion, tissue segmentation, and delamination techniques. Vertical scissors are used
in complex proliferative cases with multiplane tractional bands. Curved or angled
scissors follow the contour of the eye to minimize retinal trauma and are better for
segmentation and delamination [27, 74].
Extrusion Cannulas
Soft-tip extrusion cannulas are useful to allow a more complete removal of fluid by
enabling closer approach to the retinal tissue than the cutter. Newer soft-tip can-
nulas have retractable tips for greater ease with insertion through a valved cannula.
Backflush cannulas allow for active and passive aspiration of fluid (not vitreous).
Furthermore, the backflush feature can be used if retinal incarceration occurs at the
tip and can be used to disperse blood settled on the retina [75, 76].
Endolasers
Endolasers are used in vitreoretinal surgery to perform pan-retinal photocoagula-

tion, laser to the edges of retinal breaks, cauterize bleeding vessels, ablate retinal
and choroidal tumors, and perform endophotocyclocoagulation [77]. Early endola-
sers were straight, but newer endolasers with a curved tip are now available for
easier access to the far periphery. Articulating endolasers allow continuously adjust-
able articulation up to 45° and improves access to the far periphery. The probe
is semi-rigid, which makes insertion through a valved cannula easier. Illuminated
laser probes are available in curved or extendable forms and can potentially improve
peripheral viewing during laser and facilitate simultaneous depression and laser
without the help of an assistant or the need for chandelier illumination. Aspirating
laser probes provide the capacity for simultaneous endolaser and aspiration, which
minimizes the need for instrument exchanges and potentially decreases total surgi-
cal time.
Diathermy
The most common uses for diathermy in vitreoretinal surgery is to cauterize bleed-
ing retinal vessels for hemostasis and to create drainage retinotomies. External dia-
thermy application to a leaking sclerotomy has been reported effective in sealing the
surgical wound [78–80].
Perfluorocarbon Liquid
Stanley Chang (1987) introduced low viscosity fluorocarbons as an intraopera-

tive adjunct during vitreous surgery for retinal detachments (Fig. 7.24) [81]. The
high density and specific gravity of perfluorocarbon liquid allows reattachment
of the retina and unrolling of retinal folds without having to use operating bed
which enabled prone positioning of patients during the surgical repair (Fig. 7.25).
Perfluorocarbon liquid can also prevent the need for a drainage retinotomy to
drain subretinal fluid. For these reasons, perfluorocarbons have become used in the
treatment of giant retinal tears and proliferative vitreoretinopathy. Additionally,
the optical clarity of perfluorocarbon liquid allows for surgical manipulation
beneath it, such as “floating” crystalline lens fragments off the macula for sub-
sequent lensectomy. Its immiscibility with water provides a clear operating fluid
in the setting of intraoperative hemorrhage. Perfluorocarbons are biologically
inert, but evidence indicates that they are toxic when retained in the eye for lon-
ger periods of time [82]. Despite some concerns of toxicity, some studies have
demonstrated benefit from using perfluorocarbon liquids as short term tamponade
a b
Fig. 7.24 (a) Dr. Stanley Chang, the inventor of perfluorocarbon. (b) Perfluorocarbon used intra-
operatively to flatten the retina
Fig. 7.25 Inverted surgical

bed used for vitreoretinal
surgery
agents, ranging from 7 days to 3 months, in patients with inferior or complex

retinal detachments [83–86]. Subretinal perfluorocarbon in the fovea is visually
significant and generally requires removal.
Subretinal Injections
Subretinal injections are performed for several indications. Subretinal tissue plas-
minogen activator (tPA) with or without air has been reported to displace submacu-
lar hemorrhage [87–93]. More recently, gene therapy through subretinal delivery
of a viral vector has been performed effectively for with specific retinal dystro-
phies [94–97]. Luxturna (Voretigene neparvovec-rzyl, Spark Therapeutics Inc.,
Philadelphia, Pennsylvania, USA) is an FDA approved subretinal gene therapy for
patients with inherited retinal disease due to mutations in both copies of the RPE65
gene. Subretinal injection of human embryonic stem cell (HESC) and induced plu-
ripotent stem cell (iPSC)-derived RPE cells/sheets for macular degeneration have
been performed in clinical trials [98–101]. There are multiple reusable and dispos-
able small cannulas (as small as 41 gauge) that are available for subretinal injection
through trocars. New instruments are being developed to facilitate subretinal RPE
cell sheet delivery [102].
Scleral Buckling
Scleral buckling (SB) can be used to treat primary rhegmatogenous retinal detach-
ments, most commonly in phakic eyes [103]. Scleral buckling involves placement
of solid or porous silicone buckling elements—encircling, radial, or both—in order
to support equatorial or pre-equatorial breaks and reduce traction from the periph-
eral vitreous. The elements are either sutured to the sclera or placed through scleral
tunnels [104]. Once closure of the retinal breaks is achieved, the retinal pigment
epithelium pump removes subretinal fluid resulting in retinal reattachment [105,
106]. The breaks can be sealed with cryopexy and gas tamponade can be used to
aid retina reattachment. SB may be combined with PPV. A prospective random-
ized clinical trial of 681 eyes with medium complexity rhegmatogenous retinal
detachments showed that SB showed a benefit with regards to visual improvement
in phakic eyes, but PPV had a better anatomic outcome in pseudophakic patients
compared to SB [105]. In cases of proliferative vitreoretinopathy, the combination
allows support of the vitreous base and the ability to address membranes and/or
perform a retinectomy. One retrospective study found the combination of PPV and
SB to lead to better outcomes than PPV alone in retinal detachments that were at
risk to develop PVR [107].
Numerous intrascleral implants have been used in scleral buckling surgery,
including polyethylene, silicone, and gelatin implants. In 1985, episcleral hydrogel
implants (MIRAgel, MIRA Inc., Waltham, Massachusetts, USA) were introduced
as an alternative to silicone for treatment of rhegmatogenous retinal detachment.
The material was thought to have the potential to decrease risk of scleral erosion due
to its soft, pliable characteristics. However, after several years, it was discovered
that the hydrolytic degradation of the MIRAgel material caused progressive swell-
ing of the explant and subsequent strabismus, ptosis, scleral erosion, conjunctivitis,
and infection [108]. These implants are no longer used.
In one study of 728 eyes that underwent scleral buckling, the incidence of ero-
sion was analyzed based upon the type of implant used. The study found that ero-
sion occurred in 62.3% of eyes with polyethylene tubes compared with 3.8% in eyes
with solid silicone implants with silicone circling bands. The use of solid silicone
implants and circling bands has greatly reduced the issue of implant erosion [109].
Chandelier-assisted SB uses chandelier endoillumination and a wide-angle fun-
dus viewing system in lieu of an indirect ophthalmoscope. The advantages of this
technique are better visualization, improved ergonomics, and increased familiarity
for predominantly vitrectomy trained surgeons [110]. However, chandelier insertion
carries the risk of cataract from lens touch, and new breaks from vitreous traction
during eye manipulation [111, 112]. Use of an illuminated scleral depressor is a

novel technique to improve localization of retinal breaks. This method uses a 20G
light pipe with a bent tip as an illuminated scleral depressor to see the break in
greater detail and screen suspect areas [110].
Tamponade Agents
Tamponade agents are used to provide surface tension across retinal breaks in vit-
rectomy for rhegmatogenous retinal detachment repair. They prevent further fluid
flow into the subretinal space until the retinopexy via photocoagulation or cryopexy
provides a permanent seal. Gases and silicone oil (SO) are the most commonly
used classes of tamponade agents. The use of tamponade agents for the treatment of
retinal detachment was first described in 1911 by Joh Ohm who successfully treated
two patients with intravitreal sterile air [113]. In 1962, Paul Cibis described the use
of liquid silicone for the management of retinal detachment [114]. The use of inert
expansile gas sulfur hexafluoride (SF6) was described in 1973 by Edward Norton as
a vitreous substitute [115].
Currently, the most common gas tamponades in the US are air, SF6, and per-
fluoropropane (C3F8) [116]. Air is nonexpansile. SF6 100% expands two times over
1–2 days and C3F8 100% expands about four times over 3–4 days [117]. Small vol-
umes (0.5 cm3 or less) of undiluted gas are generally used for pneumatic retinopexy.
Diluted gas to fill the vitreous cavity is typically used for PPV at non-expansile con-
centrations (SF6 20% and C3F8 14%). Gas tamponade agents resorb s pontaneously
from the vitreous cavity over an average period of 5–7 days for air, 2 weeks for SF6
20%, and 8 weeks for C3F8 [118].
The Silicone Study was a prospective multicenter randomized clinical trial that
compared 1000 centistoke silicone oil to SF6 20% or C3F8 14% in patients with reti-
nal detachment associated with proliferative vitreoretinopathy, which reported that
anatomic and visual outcomes after 1 year was significantly better with SO compared
to SF6 and not significantly different for SO compared to C3F8 [119]. A 6-year follow
up of the Silicone Study reported that, among subjects whose macula was attached at
36 months, there were no significant anatomic or visual outcome differences among
SO, SF6, and C3F8 groups [119]. The European Vitreo-Retinal Society (EVRS)
Retinal Detachment Study reported no significant difference in failure rate between
tamponade with gas versus SO in patients with proliferative vitreoretinopathy [120].
In the USA, the most commonly used viscosities of silicone oils are 1000 and
5000 centistokes [121]. Due to the lower specific gravity of gases (0.001 g/mL) and
silicone oils (0.97 g/mL) compared to vitreous (1.005–1.008 g/mL), these tampon-
ade agents float in the vitreous cavity [122]. For this reason, gases and SO provide
less effective tamponade for inferior breaks without a full fill of the vitreous cavity.
Heavier-than-water tamponades, such as heavy silicone oils and perfluorocarbon
liquids, are used as tamponade agents for inferior retinal breaks [123–127]. Heavy
silicone oils are available for clinical use in many nations but not the United States.
Postoperative Considerations and Complications
Over the years PPV has evolved with the development of smaller and faster vit-
rectomy systems. Transconjunctival small-gauge instruments have provided the
advantages of decreased operating time, self-sealing scleral wounds, decreased
postoperative pain and inflammation, decreased astigmatism, and faster visual
recovery over traditional 20 gauge instruments [128–132]. PPV and SB are now
typically outpatient procedures with follow up 1 day after surgery. However, alter-
native postoperative visits on the same day as surgery and 3 or more days after
surgery have been reported [133, 134].
Overall, PPV has one of the lowest rates of endophthalmitis among intraocular
surgical procedures [135]. As small-gauge transconjunctival PPV gained popularity,
concerns arose about increased rates of endophthalmitis with 25 gauge transcon-
junctival sutureless vitrectomy. A retrospective study in 2007 examined 8600 PPV
patients and reported a 12-fold higher incidence of endophthalmitis in 25 gauge
PPV compared to 20 gauge PPV [136]. However, later studies reported no signifi-
cant difference in endophthalmitis rates between 20 gauge PPV and small incision
vitrectomy [137, 138].
With regards to post-operative retinal detachment complications, a retrospec-
tive study of 2432 vitrectomies reported a similar incidence of post-surgical retinal
detachment after sutureless 23 gauge and 25 gauge PPV compared to 20 gauge PPV
[139]. Another retrospective study of 4274 vitrectomies comparing intraoperative
complications of 23 gauge versus 20 gauge PPV showed that 23 gauge PPV had
a lower risk of choroidal hemorrhage and iatrogenic retinal tears compared to 20
gauge PPV, especially for eyes with rhegmatogenous retinal detachment [140].
Other post-operative complications of vitrectomy include cataract progression,
cystoid macular edema, hypotony, and sympathetic ophthalmia [141, 142].
Future Advancements in Vitreo-Retinal Surgery
Recent developments in vitreo-retinal surgery have led to advances in surgeon capa-

bilities, visual outcomes, and patient safety. Robotic vitreo-retinal surgery is a rap-
idly emerging technology within this domain. Early robotic vitreo-retinal surgical
techniques have been aimed at tremor cancellation, improved precision, enhanced
dexterity, force sensing and micron-scale distance sensing [143–147]. The use of
robotics in vitreo-retinal surgery has been limited by the lack of broad clinical expe-
rience among potential users and challenges to implementation.
Four-dimensional (4-D) OCT imaging has been introduced recently for use
intraoperatively to provide enhanced visualization of volumetric tissue deforma-
tion. It has been used in vitreo-retinal surgical cases for macular hold, ERM,
myopic foveal schisis, diabetic macular edema, and retinal detachment. 4-D OCT
imaging has the potential to provide enhanced intraoperative visualization from
multiple perspectives, precise determination of instrument distance from the ret-

ina, and visualization of retinal contour deformation during and after surgical
manipulation. This technology is presently limited by image quality and resolu-
tion [148].
Summary
Vitreoretinal surgical techniques have evolved in the last 50 years largely due to the
development and evolution of PPV. Developments include smaller gauge instru-
mentation, faster cut speeds, enhanced illumination techniques, microscopes, and
perfluorocarbon liquids. These advancements have improved the safety and efficacy
of vitrectomy and allowed surgeons to more effectively treat a wide variety of con-
ditions, including complications of diabetic retinopathy, macular holes, and retinal
detachments.
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Chapter 8
Clinical Updates and Recent Developments
in Neuro-Ophthalmology
Amrita-Amanda D. Vuppala and Neil R. Miller
Updates in Diagnostic Criteria/Clinical Presentation
The ability to diagnose efficiently and accurately neuro-ophthalmic conditions is

imperative to guiding timely intervention. In this section, we introduce new neuro-
ophthalmic diagnoses and review updates to the diagnostic criteria for previously
described conditions. These updates are intended to guide clinicians in accurate
examination, identification and management of commonly encountered neuro-
ophthalmic conditions. The updates are outlined by subspecialty to help the reader
think in terms of a differential diagnosis for conditions with similar presentations.
Updates in Neuro-immunology
Perhaps one of the most exciting areas in neuro-ophthalmology at the present time
are neuro-ophthalmic diagnoses pertaining to neuro-immunology. Over the years,
with the invention of magnetic resonance imaging (MRI) and the discovery of new
antibodies, two of the most well-known autoimmune conditions causing optic neu-
ritis, multiple sclerosis (MS) and neuromyelitis optica (NMO), were delineated as
separate entities. The diagnostic criteria for these conditions include guidelines for
clinical and imaging features as well as serum and cerebrospinal fluid (CSF) test-
ing. Revisions to these criteria have been designed to increase the sensitivity and
A.-A. D. Vuppala
University of Nebraska Medical Center, Omaha, NE, USA
N. R. Miller (*)
Johns Hopkins University School of Medicine, Baltimore, MD, USA

202 A.-A. D. Vuppala and N. R. Miller
specificity for diagnosis; the most recent criteria for MS and NMO are described
below. The mystery remains as to why some patients with clinical presentations
similar to MS or NMO are seronegative. More recently, the clinical significance of
previously described antibodies including those to myelin oligodendrocyte glyco-
protein (MOG) and glial fibrillary acidic protein (GFAP) have been identified as
separate, unique pathologies with presentations that may present with optic neuritis
and clinically may appear to be similar to MS and/or NMO. This section will review
the current literature regarding these new antibodies, the associated clinical presen-
tations and the recommended medical management.
Multiple Sclerosis (MS)
Multiple Sclerosis (MS) is a well-known inflammatory demyelinating disease and

is the single most common cause of disability in young adults, with age at onset
strongly influencing the course of progression [1]. In the 1970s, when MS was first
being diagnosed, there were no treatment options, and diagnosis was limited to
autopsy and direct tissue examination [2]. Since then, our ability to diagnose MS
has changed dramatically with the use of MRI in 2001 and subsequent updates in the
clinical diagnostic criteria. In the same way, disease-modifying therapies (DMTs)
have multiplied, with over a dozen DMTs currently approved worldwide over the
past 25 years [2]. With an improved ability to delay or halt clinical progression, the
need to diagnose and treat patients with MS earlier has become paramount [3].
The McDonald Criteria for diagnosing MS were first established in 2001 [4] but
have been revised many times over the last 17 years, resulting in an increase in the
number of patients diagnosed with the condition. The most recent revision of the
McDonald Criteria for diagnosing MS occurred in 2017 [5]. This revision included
three major changes. The first was related to the inclusion of symptomatic supraten-
torial, infratentorial and spinal cord lesions on MRI to meet the criteria for dissemi-
nation of lesions; previously, only asymptomatic lesions could be used. Second, if
enhancing and non-enhancing lesions are found on an MRI at one point in time, this
can be considered dissemination in time. Finally, a patient meeting the criteria for
a clinically isolated syndrome may be diagnosed with MS if oligoclonal bands are
present in the cerebrospinal fluid [5, 6].
Neuromyelitis Optica (NMO)
NMO is a rare autoimmune disease of the central nervous system (CNS) that pri-
marily affects the spinal cord and optic nerves, leading to optic neuritis and lon-
gitudinally extending transverse myelitis. Onset is typically in the third to fourth
decade of life. There is a strong female predominance with a female:male ratio as
high as 9–10:1 [7]. Clinical attacks may be recurrent as is the case with MS and
anti-MOG disease (see below); however, unlike MS and anti-MOG disease, it may
take only one attack of NMO-related optic neuritis and transverse myelitis to leave
8 Clinical Updates and Recent Developments in Neuro-Ophthalmology 203
a patient blind and paraplegic. In other words, the disability risk with NMO is
extremely high [8]. It was not until 2004 when NMO-IgG was identified as a spe-
cific marker autoantibody that can be used to distinguish MS from NMO [9]. These
autoantibodies target the most abundant water channel in the CSF: aquaporin-4
(AQP4), located on the astrocytic foot processes of the blood-brain barrier [10].
Over time, it was discovered that the range of clinical presentations associated with
AQP4 autoimmunity was much broader than just optic neuritis and longitudinally
extending transverse myelitis [10, 11]. Subsequently, Wingerchuck et al. outlined
new criteria and described NMO spectrum disorder (NMOSD). The new criteria
take into account the serum status of AQP4-IgG (present, absent or unknown) and
add additional requirements for patients with absent or unknown AQP4-IgG status.
These requirements include specific core clinical characteristics of optic neuritis,
acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic
narcolepsy or acute diencephalic syndrome and/or symptomatic cerebral syndrome
with typical brain lesions. There also are additional MRI requirements for this
group of patients [12].
New information regarding AQP4 antibody status and its relation to prognosis
also has become available. A large, retrospective cohort study evaluating the effi-
cacy of immunotherapy in NMOSD suggests that several factors, including age,
antibody status and the presence of previous attacks, may predict further attacks in
patients diagnosed and treated for NMOSD [8]. Indeed, the presence of AQP4 in the
serum of patients with NMOSD may predict future recurrent disease as opposed to
patients with seronegative presentations of NMOSD who are more likely to have a
monophasic course [13].
Myelin Oligodendrocyte Glycoprotein (MOG-IgG)
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein that is expressed on

the outer membrane of myelin. This glycoprotein is specifically found within the
CNS, including the brain, optic nerves and spinal cord [14]. MOG antibodies bind
to extracellular glycoprotein on the myelin sheath and to oligodendrocytes [15].
First identified in the 1990s, MOG antibodies initially were identified in patients
with relapsing autoimmune illness who were presumed to have MS [16, 17]. After
studies revealed low sensitivity of MOG in larger MS populations, skepticism arose
regarding the validity of MOG-IgG as a reliable biomarker for MS [18]. Shortly
thereafter, MOG-IgG was identified in several pediatric cases of acute disseminated
encephalomyelopathy (ADEM) and by 2011, the first report of MOG antibodies
in NMOSD was reported [19]. Recent studies have concluded that the presence
of MOG-IgG antibodies in a patient with an acute neurologic syndrome is indica-
tive of an entity separate from both MS and NMO [20, 21]. In one study, it was
stated that up to 42% of NMOSD patients who tested negative for AQP4 world-
wide tested positive for MOG-IgG [14]. In another study, MOG-IgG was found in
20% of patients with a demyelinating illness that did not fit the criteria for MS or
NMOSD [6].
The clinical manifestations of patients presenting with MOG-IgG are extremely

variable. Perhaps because of this, several studies have reported different findings
in regards to age and sex predilections as well clinical phenotype for MOG-IgG
disease. MOG-IgG likely affects both men and woman equally or has a very slight
female predominance and age of onset is 20–30 years of age [22, 23]. Clinically,
the majority of MOG-IgG patients present with optic neuritis, with or without other
accompanying neurologic symptoms. The optic neuritis may be unilateral; how-
ever, simultaneous bilateral optic neuritis can occur and may occur with higher
frequency than in NMOSD [21]. Anti-MOG antibody-related optic neuritis attacks
may be recurrent, with the reported number of attacks ranging from one to eight
[23]. Patients who develop anti-MOG antibody-related optic neuritis tend to have
an anterior optic neuritis: the fundus exam typically reveals optic disc swelling,
sometimes with associated flame hemorrhages (Fig. 8.1).
Other neurologic manifestations include atypical cerebral inflammatory lesions
(that may have been characterized as relapsing steroid-responsive autoimmune
encephalitis in the past), ADEM, atypical MS or CNS vasculitis. Aseptic meningitis
and pseudotumor cerebri (PTC)-like presentations (with elevated opening pressure)
also have been reported [24]. Finally, patients with anti-MOG-IgG-associated dis-
ease are more likely to have seizures and encephalitis as part of the presentation
compared with patients with AQP4-IgG-associated disease [20].
Data from several cohorts suggest that both visual and neurological outcome
are favorable in the majority of cases of MOG-IgG disease; only a small number of
patients are left with severe visual deficits, cognitive impairment or are wheelchair
bound [22]. Phenotype at onset may predict long-term outcome including likeli-
Fig. 8.1 Right optic disc

of a patient with MOG-
IgG-associated anterior
optic neuritis. Note diffuse
swelling associated with a
single flame-shaped
hemorrhage
Fig. 8.2 T1-weighted,
post-contrast axial MRI of
a patient with bilateral,
simultaneous anti-MOG
antibody-related optic
neuritis. Note marked
enhancement of the orbital
portions of both optic
nerves. This is not typical
of the findings in
idiopathic or MS-related
optic neuritis
hood for relapse; however, a large number prospective studies will be needed to
determine if this is the case [22]. CSF studies in the majority of cases reveal a
pleocytosis that may be mild (>5 white blood cells) to significant (≥50 white blood
cells), and the CSF protein concentration may be increased.
Neuroimaging findings in patients with anti-MOG antibody-related optic neu-
ritis include a long enhancing segment of the optic nerve including its orbital and
intracranial portions (Fig. 8.2).
Some patients have perineural enhancement with extension of the enhancement
into the surrounding orbital tissues [3]. In a cohort of 246 patients with recurrent
optic neuritis, no patient with positive MOG-IgG showed MS-like MRI lesions [21].
In general, treatment of patients with anti-MOG antibody-related disease with
systemic corticosteroids provides rapid and robust clinical improvement; however,
relapse upon withdrawal of steroids is not uncommon [25]. Thus, it is recommended
that treatment include a prolonged steroid taper to minimize chances of an early
relapse from steroid withdrawal and that close monitoring be performed once the
steroids are discontinued [14]. The finding of optical coherence (OCT) retinal nerve
fiber layer (RNFL) changes in patients with anti-MOG antibody-associated trans-
verse myelitis who have not experienced an attack of acute optic neuritis supports
the need for early and sustained immunosuppression [26].
Glial Fibrillary Acidic Protein (GFAP)
GFAP auto-antibody-positive meningoencephalitis is a newly described entity for

which the clinical phenotype has been described in only a small number of patients.
The presentation may be subacute or chronic and is characterized by encephalitis
or meningoencephalitis accompanied by bilateral optic disc swelling at initial pre-
sentation, although some variations in this presentation have been observed [27].
The cause for the bilateral optic disc swelling is unknown; however, the major-
ity of patients do not have an elevated opening pressure on lumbar puncture. The
underlying pathophysiology for GFAP autoantibody-positive meningoencephali-
tis is unknown but may be related to venous inflammation based on fluorescein
angiography showing prominent venular leakage in one patient with this entity and
the presence of radial perivascular enhancement on MRI in several patients [27].
Knock-out studies of GFAP in mice revealed local impairment in the blood brain
barrier and disruption in normal white matter architecture with late onset CNS dys-
myelination [28]. Patients with GFAP antibody-related neurologic disease typically
have evidence of inflammation and GFAP-IgG in their CSF.
GFAP antibody-positive neurologic disease tends to be very steroid responsive,
with the majority of patients showing improvement in their optic disc swelling and
MRI lesions after a course of high-dose intravenous corticosteroid treatment fol-
lowed by a prolonged oral steroid taper. The optic disc swelling in these patients
has been reported to be visually asymptomatic, although arcuate visual field deficits
after treatment and resolution have been observed [27]. It is not yet known if GFAP-
IgG occurs in isolation or if it co-exists with other demyelinating diseases such as
MS and NMO.
Recurrent Optic Neuritis
MS previously was recognized as a major cause of recurrent optic neuritis [21];

however, more recently, the glial antibodies AQP4 and MOG-IgG also have been
recognized as important contributors. AQP4 IgG has been reported to be present in
the serum in 8.3–25% of patients with recurrent optic neuritis [29, 30]. In addition,
it is known that patients with anti-MOG antibody-associated optic neuritis tend to
experience recurrent attacks. One cross-sectional cohort study of 246 patients with
recurrent optic neuritis reported that one-third of all patients had a positive glial anti-
body (either MOG-IgG or AQP4) [21]. The same study concluded that that AQP4-
IgG seropositivity predicts a worse visual outcome than MOG-IgG seropositivity,
double seronegativity (ie, idiopathic recurrent optic neuritis), or MS. Interestingly,
although the relapse rate of recurrent optic neuritis is higher in MOG-IgG-positive
patients compared with patients with MS and NMO, the visual prognosis is better
[21, 31]. Recurrent optic neuritis may behave differently in the glial antibody dis-
eases compared with MS-related recurrent optic neuritis. Although recurrent optic
neuritis in patients with MS tends to attack the same optic nerve that initially was
affected, glial antibody-associated recurrent optic neuritis appears to be randomly
distributed between the two optic nerves [32].
Chronic relapsing inflammatory optic neuropathy (CRION) is a recurrent optic
neuritis that is steroid responsive and is a rare cause of subacute and recurrent pain-
ful vision loss unrelated to demyelinating or connective tissue disease [33]. This
diagnosis should be made with extreme caution and only after extensive testing
and imaging. In the previously discussed cohort of 246 patients with recurrent
optic neuritis (see above), 4/14 patients with CRION tested positive for MOG-IgG,
whereas no patient tested positive for AQP4 or had an MS-like phenotype. Patients
with recurrent optic neuritis who have negative MOG-IgG and AQP4 but who also
do not fulfill criteria for MS pose a diagnostic and management challenge, espe-
cially as the probability of permanent vision loss is higher in this group compared
with MS or MOG-IgG-positive patients. Unfortunately, there are no specific treat-
ment recommendations for this subset of patients. Most are treated with systemic
corticosteroids, with other immunosuppressive agents used when necessary.
Conclusion and Recommendations
The differentiation of these various entities causing optic nerve and CNS inflamma-
tion and demyelination remains crucial due to the difference in optimum treatment
approach and both visual and neurological outcomes. Especially in the case of MS
and NMO, incorrect management can potentially lead to worsening of the disease
course. At this time, our recommendation would be to start with the diagnostic cri-
teria for MS and NMO. If the presentation is atypical or does not fulfill the above
criteria, proceed with MOG testing. MOG testing has a 98.5% specificity but 1.5%
of healthy controls testing positive for MOG-IgG [34]. The sensitivity for MOG
testing is much lower, ranging from 5% in MOG to about 36% in ADEM cases [14].
International guidelines for diagnosis and testing in MOG were published in 2018
and recommend testing for MOG-IgG in patients in whom at least minimal clinical
criteria are met. The minimal criteria include an attack of optic neuritis, transverse
myelitis or brainstem lesion; objective evidence of a demyelinating process detected
by MRI or optical coherence tomography (OCT); and other typical findings of
MOG-IgG disease, including a longitudinally extensive lesion in the optic nerve or
spinal cord [35]. These guidelines also give recommendations for “red flags” if the
result comes back positive in atypical presentations.
Complete neuro-ophthalmologic evaluation, MRI brain and orbits (and in appro-
priate cases cervical and thoracic spine) with and without contrast and optical coher-
ence tomography also should be performed for all patients. Treatment appropriate
for the diagnosis should be initiated early.
In regards to monitoring, we recommend that all of these patients be followed
with OCT. Optic neuritis causes substantial retinal damage and vision loss inde-
pendent of the underlying disease. Ganglion cell/internal plexiform layer damage
begins close to clinical onset and, thus, the structure-function correlations between
OCT and vision make OCT an important tool for monitoring acute optic neuri-
tis [36]. The utility of OCT to differentiate among MS, NMOSD, and anti-MOG
antibody-related optic nerve disease is still poorly understood. Various studies have
presented controversial results including equal RNFL thinning in both anti-MOG-
IgG and AQP4-related disease [37, 38], increased thinning of the RNFL in AQP4
compared with MOG disease [39]. A recent study showed RNFL thinning to be
similar in MS, MOG, and idiopathic optic neuritis [36].
Neuro-Degenerative Diseases
Parkinson Disease
The clinical diagnosis of Parkinson disease (PD) emphasizes the motor manifesta-
tions and cardinal signs of tremor, bradykinesia, rigidity and postural instability.
Perhaps because of this, visual signs and symptoms have been under-recognized. In
fact, non-motor symptoms, including visual complaints, impact a patient’s quality
of life significantly and may predict progression and disease outcomes [40].
Ophthalmic findings in PD are likely related to the loss of dopaminergic neurons
with accumulation of alpha synuclein in the retina [41], or related to a disturbance
of cortical visual processing from intracranial loss of dopaminergic neurons and
accumulation of alpha synuclein. Visual impairment has been suggested as a marker
for early diagnosis of PD [42] and can be recognized by neuro-ophthalmic exam.
Thus, the role of a neuro-ophthalmologist is very important in the early identifica-
tion of PD and other parkinsonian presentations. Below is a summary of the visual
problems seen in PD with clinical implications and influence of levodopa therapy.
Color Vision—Color vision deficiencies have been reported in PD patients who
are not treated with a dopaminergic drug [43]. The gold standard test for assessing
color deficiencies is the Farnsworth-Munsell 100 Hue Test; however the results are
influenced by cognitive difficulties and motor deficits [44, 45]. Interestingly, color
vision impairment also is present in patients with Rapid Eye Movement (REM) sleep
behavior disorder (RBD), an early manifestation of alpha synucleinopathies, In the
case of RBD, color vision deficiency is a risk factor for disease conversion to PD
[46] and also may predict rapid disease progression [44]. Patients with the LRRK2
gene mutation of PD have more color impairments compared with patients with
idiopathic PD [47]. Levodopa therapy may improve color vision in PD patients [48].
Visual Contrast Sensitivity—PD patients may experience problems with con-
trast sensitivity in relation to both static and moving stimuli [49]. Worsening con-
trast sensitivity is related to disease progression [50] and is partly reversible with
levodopa therapy [51, 52].
Saccades—Patients with PD often make hypometric reflexive (visually guided)
and voluntary (memory-based) saccades [53, 54]. Clinically, instead of making
accurate saccades to a target, the patient makes several small saccadic movements to
reach it [55]. Such patients also may have difficulty initiating memory-guided sac-
cades [56] and performing anti-saccades [57, 58]. The amplitude of voluntary more
than reflexive saccades is reduced with PD disease progression [54], whereas the
latency of visually guided saccades worsens in early disease stages but then stabi-
lizes [54]. Levodopa therapy has little to no effect on changing saccadic amplitude.
Although levodopa may shorten the latency for voluntary saccades, it also prolongs
the latency of reflexive saccades [54].
Smooth Pursuit Eye Movements—Smooth pursuit may be impaired in healthy
elderly patients in general [59] but also in patients of all ages with PD [60, 61].
Reduced pursuit gain has been identified in early and untreated patients with PD
[62]. The efficacy of dopaminergics in improving smooth pursuit is unclear, with
some authors suggesting improved pursuit gain [59, 63] and others finding no
improvement [64].
Convergence Insufficiency—Reduced convergence amplitude is a common
finding in PD [65, 66]. Such patients often have horizontal binocular diplopia when
attempting near tasks such as reading and sewing. Convergence amplitude and near
point of convergence measurements are better when evaluated in PD patients dur-
ing the “on” state compared to the “off” state, possibly suggesting that dopaminer-
gic therapy may be useful for this symptom [67]. Other patients may benefit from
convergence exercises, converging (base-in) prisms, extraocular muscle surgery, or
simply occluding the lower portion of one of their spectacle lens with tape.
Stereopsis—PD patients with abnormal stereopsis show worse motor functions,
supported by higher scores on the unified PD rating scale (UPDRS) compared with
PD patients with abnormal stereopsis [40]. Depth perception deficits correlate with
color deficiencies in patients with PD [68]. Stereopsis impairment in PD has been
associated with a faster cognitive decline [69] and suggests disease progression
[68]. It is also a predictor for dementia in PD patients at 24 months [69].
Ocular findings in PD for which there are no data regarding the utility in deter-
mining progression or prognosis include square-wave jerks and ocular tremor (ocu-
lar oscillations in antiphase to the direction of a head tremor during fixation) [70].
Visual hallucinations in PD previously were thought to correlate with levodopa
therapy; however, minor hallucinations have been reported in PD patients naive to
levodopa therapy and in premotor phases of PD as well [71]. Because visual hal-
lucinations have been associated with abnormalities in color vision and contrast
sensitivity [72], they may suggest disease progression and also may reflect impend-
ing dementia or even impending psychosis later in the course of the disease [40].
Nevertheless, caution is warranted in attributing visual hallucinations to worsening
disease, as they may be a medication side effect.
Progressive Supranuclear Palsy (PSP)
In 2017, the Movement Disorder Society put forth a new set of recommendations
for diagnostic criteria of PSP [73]. These criteria identified four functional domains,
with ocular motor dysfunction being one of the four along with postural instabil-
ity, akinesia and cognitive dysfunction. The ocular motor domain refers to several
clinical findings related to eye movements, including vertical supranuclear gaze
palsy, slowed velocity of vertical saccades, frequent macro square-wave jerks and
apraxia of eyelid opening. Although definitive diagnosis of PSP requires pathology,
the new PSP criteria suggest categories for probable, possible and suggestive PSP
based on clinical features alone. By identifying these eye movement abnormalities,
neuro-ophthalmologists can play an important role in helping to facilitate the early
diagnosis of PSP. However, it also should be emphasized that many patients with
pathologically confirmed PSP do not have eye movement abnormalities early in
their disease course. Thus, the lack of eye movement abnormalities does not exclude
the diagnosis of PSP [74].
Space Flight-Associated Neuro-Ocular Syndrome (SANS)
Both subjective and objective changes in visual function with associated structural
changes in the optic nerve are recognized to occur in astronauts spending long
periods of time in space. Previously described as visual impairment and intracra-
nial pressure (VIIP) syndrome, scientists at the National Aeronautics and Space
Exploration Administration (NASA) have more recently termed this phenomenon
“spaceflight-associated neuro-ocular syndrome” (SANS). Clinical findings associ-
ated with this syndrome include optic disc swelling of varying severity (unilateral
and/or bilateral), flattening of the posterior globe, refractive error (hyperopic shifts),
choroidal and retinal folds and nerve fiber layer (NFL) infarcts with cotton-wool
spots and, rarely, hemorrhages [75, 76]. Patients with SANS have structural changes
that can be appreciated on various imaging studies including MRI, ultrasonography
and OCT. For example, globe flattening may be appreciated on MRI on earth and by
ultrasound in space, and OCT reveals changes in the NFL.
The pathophysiology for SANS is unclear. Lumbar punctures performed on a few
astronauts with persistent optic disc swelling after their return to earth from long-
duration space flight reveal mildly elevated opening pressures (22–28.5 cm H2O), sug-
gesting that the optic disc swelling represents papilledema, similar to that observed
in patients with terrestrial pseudotumor cerebri (PTC). However, the demographics
are quite dissimilar in that SANS occurs in non-obese, middle-aged men rather than
obese young women of child-bearing age. In addition, SANS often is characterized
by asymmetric disc swelling whereas most patients with PTC have symmetric disc
swelling. Another difference is that choroidal folds are commonly seen in SANS
and often are associated with very mild optic disc swelling, whereas choroidal folds
are an uncommon finding in PTC and usually are associated with significant disc
swelling. Thus, although raised ICP may be a factor in some cases of SANS, the
most widely accepted mechanism for SANS is prolonged exposure to a microgravity
environment, with resultant microgravity fluid shifts and jugular venous distention
[75, 77, 78]. Another suggested mechanism for SANS includes compartmentaliza-
tion of CSF within the orbital subarachnoid space; however, this hypothesis has not
been confirmed. The role of lymphatics and venous flow is unknown.
Ongoing efforts to understand the pathophysiology of SANS include the use of
OCT and OCTA to study structural changes in the optic nerve, retinal tissue and
choroid. ICP measurements thus far have been limited to pre- or post-flight terres-
trial lumbar punctures. Researchers currently are trying to find a way to measure the
ICP inflight using various techniques [79].
Updates on Toxic and Nutritional Optic Neuropathies
Toxic-nutritional optic neuropathies (TNON) may occur in the setting of various

offending agents including medications, poisonous environmental exposures, illicit
substances, metabolic derangements and nutritional deficiencies [80]. The classic
clinical presentation for this group of optic neuropathies includes subacute, pro-
gressive, bilateral, painless vision loss. Visual field testing often reveals bilateral
central and cecocentral scotomas due to loss of the papillomacular bundle [81].
Patients also may experience significant deficient of color vision and contrast sensi-
tivity. Depending on when in the course of the optic neuropathy the patient is evalu-
ated, the optic discs may appear normal, there may be mild optic disc swelling and
hyperemia that mimic that sometimes seen in patients with Leber Hereditary Optic
Neuropathy (LHON), or the optic discs may be pale, particularly temporally [82].
The mechanism of injury is at least in some of these cases is thought to be related
to disruption of normal physiologic processes in the retinal ganglion cells and syn-
apses in the afferent visual pathway [83]. This hypothesis has been confirmed by
recent OCT studies showing thinning of the retinal ganglion cell/inner plexiform
layer in patients with toxic optic neuropathies [84]. It is important to note that some
patients have a combination of insults; e.g., both a toxic process and a nutritional
deficiency, resulting in a compounding injury to the optic nerve. This is referred to
as a toxic-nutritional optic neuropathy (TNON). Many TNONs share a mechanism
of injury similar to that which produces mitochondrial optic neuropathies, particu-
larly LHON, and, thus, careful evaluation should include testing for LHON in the
appropriate clinic setting, such as those patients who do not improve or worsen
despite repletion of the deficient nutrient or cessation of the toxic substance [85].
Toxins
The most commonly reported causes of toxic optic neuropathies include metha-
nol, ethylene glycol and toluene [85]. Methanol toxicity typically occurs in patients
consuming alcoholic beverages that contain excessive methanol rather than ethanol.
Toxicity in this setting is related to the accumulation of toxic metabolites (formal-
dehyde and formic acid), leading to metabolic acidosis and cellular dysfunction.
Acute demyelination of the optic nerve secondary to toxic formic acid may cause
axon degeneration [86]. Treatment includes hemodialysis, ethanol and fomepizole.
These antidotes are meant to inhibit alcohol dehydrogenase. The problem with etha-
nol is that it is not readily available in developing countries, and given the pharma-
cokinetics of ethanol, it is difficult to maintain adequate plasma concentrations.
Serial monitoring of ethanol levels is required. Ethanol also may cause liver injury
and hypoglycemia. There is no evidence for superiority of ethanol versus fomepi-
zole in the treatment of methanol toxicity; however, fomepizole may have fewer
adverse effects despite being very expensive [87, 88]. It has been suggested that
treatment with steroids (IV methylprednisolone) may inhibit the demyelination pro-
cess caused by methanol and also may prevent blindness and retinal atrophy [89];
however, this is a controversial issue and has not been proven in clinical trials [90].
There is also recent research suggesting that erythropoietin (EPO) may be useful
for methanol poisoning, with reports of improved visual acuity after treatment with
IV recombinant human EPO, but this, too, remains unsubstantiated by prospective
clinical trials [91].
Medication-Induced
As novel oral and injectable pharmacologic agents emerge for various disease pro-
cesses, the need to monitor for visual and ocular side effects becomes increasingly
important. Medication-induced optic neuropathies typically are related to the dose
of the offending agent and the length of time the patient was consuming it. We
briefly review some updates in the literature for various medications and provide a
table for commonly encountered medications causing optic neuropathy by category
(Table 8.1).
Although it was previously thought that ethambutol causes an optic neuropathy
at high doses (25 mg/kg/day), recent reports suggest that an optic neuropathy may
occur at lower doses closer to the recommended dose of 15 mg/kg/day. Particularly
in patients with renal dysfunction, progressive visual field deficits have been
reported, even in the setting of concurrent hemodialysis [93]. Aside from immedi-
ate cessation of the medication, there are no new treatments for ethambutol-induced
optic neuropathy. Rigorous monitoring with visual acuity, visual fields, color vision,
and OCT thus remain important. In particular, it has been suggested that assessment
of the thickness of the retinal ganglion cell/inner plexiform layer (rather than the
peripapillary retinal nerve fiber layer) can be used to diagnose ethambutol-induced
optic neuropathy at its earliest stage [94].
Linezolide is an antibiotic used to treat complicated, multidrug-resistant, gram-
positive skin infections and pneumonia. It is generally well tolerated when used for
up to 28 days [95]; however, it is known to cause a bilateral optic neuropathy in
some patients. Dempsey et al. recently suggest a new screening protocol for line-
zolid use in adult patients, with screening beginning within 1 month after initi-
ating linezolid, followed by a subsequent evaluation every 30–60 days beginning
3 months from initiation if needed for long-term use [96].
Amiodarone is a commonly used antiarrhythmic drug used to treat atrial fibril-
lation in cardiac patients around the world. Amiodarone-associated optic neuropa-
thy (AAON) is a somewhat controversial diagnosis in that most patients receiving
amiodarone have significant cardiac disease as well as other vascular risk factors
for NAION, which AAON mimics. The difference between the two conditions is
that AAON tends to be bilateral and mild, with optic disc swelling resolving over
Table 8.1 Commonly encountered medications causing optic neuropathy

Antimycobacterials/ Ethambutol, Isoniazid, Linezolid, Ciprofloxacin, Cimetidine,
antimicrobials Chloramphenicol, Erythromycin, Streptomycin, Dapsone, Quinine,
Clioquinol
Antidepressants Pheniprazine
Reversal agents Disulfiram
Chemotherapeutic agents Methotrexate, Cisplatin, Carboplatin, Vincristine, cyclosporine,
tamoxifen, Infliximab, Clomiphene
Cardiovascular Amiodarone, PDE-5 inhibitors, Blood pressure medications causing
medications hypotension such as amlodipine may cause bilateral optic neuropathy
[92]
4–6 months, whereas NAION tends to be unilateral, ranges in severity of optic disc

swelling from mild to severe, and generally resolves in 6–11 weeks [97]. The exact
mechanism of injury is unclear, although ultrastructural changes within in the optic
nerve axons and disruption of axoplasmic flow have been suggested [98]. Most
cases of AAON occur within the first year of taking the medication. Thus, it is rec-
ommended that patients undergo regular evaluations during the first year of treat-
ment, followed by annual evaluations thereafter [99]. Treatment is cessation of the
medication, assuming that there are other cardiac regimens available for the patient.
Thus, the decision regarding management of patients with presumed AAON should
be made in conjunction with the patient’s cardiologist.
Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, tadalafil, and var-
denafil, commonly are used to treat erectile dysfunction and pulmonary arterial
hypertension in both the pediatric and adult populations. Although it is clear that
some patients taking PDE-5 inhibitors can develop an optic neuropathy, it is unclear
if there is a cause-and-effect relationship. Favoring such a relationship are the fact
that PDE-5 inhibitors are vasodilators and, thus, may cause systemic hypotension.
Also, several challenge cases have been reported [100]. Finally, a study involving
102 centers found a twofold increased risk of an acute NAION-like optic neuropa-
thy occurring within five half-lives of the use of a PDE-5 inhibitor compared with
use in a prior time period [101] and a similar multicenter study involving 279 men
reported similar results [102]. On the other hand, a retrospective cohort study of four
million male patients prescribed PDE-5 inhibitors showed no difference in the rate
of development of an optic neuropathy compared with published rates of NAION
[103]. In addition, a pharmaco-epidemiological nested case-control study in which
1109 cases of NAION were matched to 1,237,900 controls found no significant
association with the use of PDE-5 inhibitors [104]. Having said this, there was a
report of the development of an acute optic neuropathy in a child using sildenafil
for chylothorax [105]. Other visual side effects of PDE-5 inhibitors include dose-
dependent, reversible color vision problems (cyanopsia) and photophobia [106].
Nutritional Deficiencies
Nutritional optic neuropathies often are considered a subset of toxic optic neuropa-
thies, with the clinical presentation being very similar; i.e., bilateral, subacute, and
characterized by central or cecocentral scotomas. True nutritional optic neuropathies
are rare and occur more commonly in developing countries. In the Western world,
nutritional deficiencies often occur in the setting of chronic alcoholism, following
bariatric surgery, and even in patients with severe depression resulting in a poor
diet. Once identified, replacing the deficient nutrient and removing other offending
agents may result in visual improvement, assuming that the patient does not have
contributing genetic factors or other toxic insults [82] or that there has not been
irreversible damage to the optic nerves. Vitamins B12, B1 (thiamine), and B2 (ribo-
flavin), as well as folic acid (particularly in chronic alcoholics) and copper are com-
monly encountered deficiencies that can produce an optic neuropathy. Deficiencies
in zinc and other fat-soluble vitamins (A, D, E) may also be seen, particularly after
gastric bypass surgery, and have the potential to result in various neuropathies,
including optic neuropathy [107]. When determining if a vitamin deficiency is the
cause of an optic neuropathy, the clinical history is of critical importance. Vitamin
levels in the serum may not be reliable in all cases. In particular, serum vitamin B12
levels may be falsely normal due to B12 binding transcobalamin [85], and red blood
cell folate is a better indicator of folate levels than serum folate [108].
The Role of Alcohol and Tobacco
Patients who consume large quantities of alcohol are, as noted above, at risk for
developing a bilateral optic neuropathy [83]. Although previously termed “tobacco-
alcohol amblyopia,” this term is inappropriate. Firstly, the pathology is related to
optic nerve injury and, thus, is not an “amblyopia” [109]. Secondly, there is abso-
lutely no evidence to suggest cigarette smoking causes an optic neuropathy in oth-
erwise healthy individuals who do not also consume alcohol heavily. In fact, the
bilateral optic neuropathy that occurs in patients who abuse alcohol almost always
is due not to the toxic effects of the alcohol (unless the individual is consuming
methanol, see above) but to the vitamin deficencies that occur when alcohol abusers
do not have an appropriate diet. Treatment thus is alcohol cessation combined with
vitamin and folate supplementation. As in the case of other toxic and nutritional
deficiencies, the prognosis for visual recovery is good it the diagnosis is made and
treatment is commenced before irreversible damage to the optic nerve occurs.
Glaucoma and the Role of Cerebrospinal Fluid Pressure
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide

[110]. Although elevated intraocular pressure (IOP) is commonly encountered and
can be modified, not all patients with what appears to be typical POAG have ele-
vated IOP [111]. Accordingly, other mechanisms for optic nerve damage that is
consistent with POAG have been hypothesized. In particular, the role of CSF flow
on the optic nerve in patients with so-called “normal-tension glaucoma” (NTG) has
been raised. Three main mechanisms have been proposed to describe the role of
ICP in NTG: (1) a barotraumatic phenomenon, (2) failure of CSF dynamics and (3)
ocular glymphatic system dysfunction.
The barotraumatic theory of NTG hypothesizes that low ICP causes a clinical
picture of glaucoma by inducing a high pressure gradient across the lamina cribrosa,
ultimately damaging the optic nerve head [111]. Several studies using swept-source
OCT indicate that the lamina cribrosa is the principal site where retinal ganglion
cell axon insult occurs [112]. The lamina cribrosa provides structural and func-
tional support to retinal ganglion cell axons as they go through the high-pressure
environment in the eye to the low-pressure environment of the subarachnoid space
surrounding the orbital optic nerve [113]. It is postulated that significant pressure
changes in the intraocular space or the subarachnoid space has a potential to bio-
mechanically injure the nerve through deformation of the laminar and optic nerve
head biomechanics.
Another proposed mechanism for NTG includes that of failed CSF flow dynam-
ics. The theory in this case is that low ICP leads to inadequate clearance of toxic
substances from the CSF, causing optic nerve damage [114]. It is well-known that
CSF circulation and turnover play an important role in the elimination of toxic sub-
stances from the CNS [115]. Because CSF turnover rate is directly proportional to
the formation but inversely related to the volume, decreased CSF production may
lead to decreased CSF turnover and, thus, allow for accumulation of biologically
highly active toxic substances and ultimate neurotoxicity [110].
The third and most common proposed mechanism used to explain the develop-
ment of what appears to be typical glaucomatous field and disc changes despite
normal IOP involves the ocular glymphatics. The ocular glymphatic system consists
of channels around the optic nerve and retina through which CSF is recirculated and
neurotoxic metabolites are cleared. These channels have been found paravascularly,
around the central retinal vein and central retinal artery [116]. A paravascular chan-
nel of the optic nerve has also been suggested and confirmed in studies of the optic
nerves of mice [117]. It has been suggested that CSF flow along the perivascular
space surrounding the central retinal artery into the anterior optic nerve and retina
and then back along the perivascular space surrounding the central retinal vein
into the subarachnoid space surrounding the optic nerve removes potentially toxic
metabolites. If ICP is too low, CSF flow may stop or decline due to an increased
pressure barrier. This, in turn, hinders paravascular flow from the optic nerve to
retina, resulting in suppression of the glymphatic fluid system and toxin accumula-
tion followed by glaucomatous optic neuropathy [110].
Updates in Imaging
New Imaging Sign in Multiple Sclerosis
The most recent imaging criteria by the Magnetic Resonance Imaging in MS

(MAGNIMS) committee was published in 2015 [118]. Although brain MRI is a
very sensitive test for diagnosing MS as well as for monitoring disease activity and
treatment response, MRI spine is less sensitive [119, 120]. The typical MRI find-
ings in MS include the presence of multiple focal white matter lesions and three or
more of these lesions should involve the periventricular white matter [121]. In addi-
tion, however, an addition MRI sign, the central vein sign, has been suggested to
differentiate MS from MS mimics [122, 123]. Pathologically, white matter lesions
in MS correspond with inflammatory infiltrates that develop around venules. Using
susceptibility-based MRI sequences, the association between brain white mat-
ter venules and perivenular lesions can be visualized. It has been found that the
Fig. 8.3 T2-FLAIR sequence showing the central vein sign in periventricular lesions in a patient
with multiple sclerosis (Both images courtesy of Dr. David Poage, MD)
proportion of MS lesions with a central vein is high [122, 124] and when compared
against other pathologies including CNS vasculopathies, the high frequency of peri-
venular lesions on MRI is pathologically specific for MS and, thus, important for
improving the accuracy with which MS can be diagnosed [122, 123] (Fig. 8.3). It is
important to note that the frequency of the central vein sign is the same for 1.5 and
3 T MRI machines and can be applied across the various phenotypes of MS [122].
Imaging Updates in Giant Cell Arteritis (GCA)
Evidence-based recommendations for imaging in GCA (and other large vessel dis-
ease such as Takayasu Arteritis) were suggested by the European League against
Rheumatism in May 2018 [125]. In particular, the League recommended that imag-
ing with ultrasonography, MRI or both should be performed in patients in whom
GCA is suspected, followed by temporal artery biopsy if the diagnosis is still in
question after imaging and clinical examination. Imaging should be performed as
early as possible after the initiation of therapy as glucocorticoid use may reduce
the sensitivity of imaging [126, 127]. Ultrasonography is recommended as the first
imaging test of choice in patients with GCA and predominantly cranial symptoms.
The League specifically recommended imaging of the superficial temporal and axil-
lary arteries; however, other authors also have included examination of the carotid,
vertebral, occipital and subclavian arteries when possible [128]. The two imaging
findings seen on ultrasound in patients with GCA include the “hypoechoic halo”
and the “compression sign.” The halo sign is due to homogenous, hypoechoic vessel
wall thickening that is delineated toward the luminal side and visible in longitudinal
and transverse planes [129]. The hypoechoic halo is thought to represent inflam-
mation of the vessel wall. This sign was found to have a sensitivity of 77% and
specificity of 96% in a systemic literature review where data was pooled from 43
Fig. 8.4 High-resolution,
T1-weighted, post-contrast
MRI showing vascular
mural enhancement in a
patient with biopsy-proven
giant cell arteritis (arrows).
Note the central arterial
flow void and the ragged
infiltrative appearance
around it. (Image courtesy
of Dr. Andrew G. Lee and
colleagues)
different studies [130]. The compression sign refers to continued visibility of the
hypoechoic vessel wall while the ultrasound probe is used to apply pressure to the
artery. This sign has been found to have a sensitivity of 77–79% and a specificity of
100% [125, 131]. In the event that ultrasound is inconclusive or simply is not avail-
able, the League recommended high-resolution scalp MRI of the cranial arteries—
specifically, the temporal and occipital arteries—to assess for mural inflammation
manifesting as mural contrast enhancement and arterial wall thickening (Fig. 8.4)
[125]. One prospective cohort study of 170 patients with suspected GCA found
MRI to be 93.6% sensitive and 77.9% specific in diagnosing patients with GCA
[132]. It should be noted, however, that accurate identification of abnormal ultraso-
nographic and MRI findings is highly dependent on the individual performing the
study in the case of ultrasound and on the individual interpreting the study in both
cases. Other authors have raised the question as to what to do when imaging shows
inflammation but temporal artery biopsy at the same location is negative. To date,
there is no recommendation for how to handle this situation [128, 133].
New consensus criteria for the classification and diagnosis of GCA is expected to
come out in 2019 via the Diagnostic and Classification Criteria in Vasculitis Study
(DCVAS) and will replace the initial criteria created by the American College of
Rheumatology in 1990s [134].
Updates in Testing and Diagnostic Modalities
Myasthenia Gravis (MG) Antibodies (MuSK and LRP4)
MG is an autoimmune disorder in which antibodies, primarily those to acetylcho-

line receptors, result in disruption of neuronal transmission at the neuromuscular
junction. Clinical symptoms include skeletal muscle weakness and fatigabil-
ity [135]. Ocular myasthenia gravis (OMG) refers to isolated involvement of
the extraocular muscles and typically presents as double vision, ptosis, or both.
Approximately 60% of patients with MG have ptosis and/or diplopia at onset,

and almost all patients with MG experience ocular symptoms at some point dur-
ing their disease course [136]. In some cases, it is difficult to make the diagnoses
of OMG based on clinical examination alone due to the potential for OMG to
mimic ocular motor nerve palsies or brainstem motility deficits (eg, internuclear
ophthalmoplegia) or even an ocular myopathy [137]. When the diagnosis can-
not be made from the examination alone, the role of serum antibodies becomes
important. For decades, antibody testing in MG was limited to the acetylcholine
binding, blocking and modulating antibodies, with the binding antibody being
the most frequently detected in both ocular and systemic MG [137]; however,
although the presence of an elevated acetylcholine receptor antibody is highly
specific for diagnosing OMG, these antibodies are typically positive in only half
of all patients presenting with OMG [138]. This is in stark contrast to cases of
generalized MG where seropositivity is reported to be as high as 85–90% [139–
141]. Now, two new antibodies, LDL-related receptor-related protein 4 (LRP4)
and Muscle-specific tyrosine kinase antibodies (MuSK) have been identified that
may help to increase the diagnostic sensitivity of OMG.
LRP4 antibodies are thought to play a role in maintenance of the neuromuscular
junction. During formation of the neuromuscular junction, LRP4 binds with agrin to
form a complex that promotes acetylcholine receptor clustering and differentiation
on the postsynaptic membrane by activation of MuSK. LRP4 antibodies have been
found in 1–5% of all patients with MG and 7–33% of patients who are negative for
acetylcholine antibodies and MuSK [136, 142, 143]. LRP4 positivity is more com-
mon in women than men and is associated with a mild disease course with only rare
escalation to myasthenic crisis. Most importantly for the ophthalmologist, it can be
present in patients with isolated ocular symptoms [136, 144–146]. The prevalence
of OMG is similar in patients with acetylcholine antibodies and LRP4 antibod-
ies [147]. Thus, an assay for LRP4 antibodies should be performed in patients for
whom OMG is highly suspected but in whom acetylcholine receptor antibodies are
negative [137].
MuSK antibodies cause a reduction in the postsynaptic density of acetylcholine
receptors by binding to an extracellular domain [143, 148]. MuSK antibodies are
present in 1–10% of all patients with MG [149, 150], with higher prevalence in the
female gender and patients of Mediterranean descent [139, 145]. From 20 to 40%
of patients with generalized MG but negative acetylcholine receptor antibodies will
test positive for MuSK [143, 148]; however, they are rarely found in patients with
OMG. One study found MuSK antibodies in only three of 82 patients with OMG
[151, 152]. Nevertheless, in patients with MuSK-positive OMG, the ocular mani-
festations appear to be more symmetric and less fluctuating than typical MG [152].
Given the low diagnostic yield of MuSK in isolated OMG, it is recommended that
this testing be reserved for patients with suspected MG despite negative acetylcho-
line receptor and LRP4 antibody testing [137]. A positive assay for MuSK antibody
in patients with OMG has been associated with a high risk for early generalization
[152, 153].
Optical Coherence Tomography (OCT)
The use of OCT has rapidly escalated over the years since its initial invention in the
1990s [154]. This increased usage is directly correlated with improved knowledge
of how OCT can be used for diagnosis and monitoring of various ophthalmic and
neurologic conditions. By providing high-resolution structural information about
the retina and optic nerve, OCT has become an imaging procedure that is routinely
performed in ophthalmology clinics worldwide. Below, we review OCT findings in
various neuro-ophthalmic disorders.
OCT can be useful in discerning the etiology of an optic neuropathy in a patient
with glaucoma and other comorbidities. Glaucomatous optic neuropathy typically
causes thinning in the superior and inferior quadrants of the disc, with temporal
sparing, whereas many non-glaucomatous optic neuropathies tend to affect the
papillomacular nerve fiber bundle, ultimately causing more temporal thinning in
addition to super or inferior thinning [155]. In a patient presenting with an optic
neuropathy and no visual acuity or field change, thinning on the OCT may be the
only indication that there has been damage to the optic nerve.
OCT in Optic Disc Elevation
Measurement of the RNFL by OCT may be useful in patients with PTC or other
etiologies of disc swelling such as non-arteritic anterior ischemic optic neuropathy
(NAION) to monitor improvement of the thickened RNFL [156] (Fig. 8.5). In addi-
tion, assessment of the position of the lamina cribrosa (bowed out vs bowed in) may
be useful in differentiating local swelling from papilledema. Finally, in patients
who present with an apparently elevated disc, OCT may help differentiate true disc
swelling from congenital elevation (eg, pseudopapilledema). No change in OCT
for several months after initial examination may provide reassurance that the disc
elevation is congenital rather than acquired.
OCT in Neurodegenerative Disease
Thinning of the RNFL and the ganglion cell/inner plexiform layer has been reported
in various neurodegenerative diseases such as Alzheimer disease (AD), PD, Mild
Cognitive impairment syndrome, and MS.
Alzheimer Disease: Although it has been established that there is some thinning
of the RNFL in patients with AD and that progressive thinning correlates with dis-
ease progression, it is unclear if a specific quadrant of the nerve or specific layer of
the retina is particularly susceptible [157] (Fig. 8.6). In OCT studies in patients with
AD, the AD was not confirmed with pathology, thus giving room for similar diagno-
ses like vascular dementia or other dementia subtypes to be included, confounding
the reported findings [157]. The future of OCT in patients with dementia is to learn
Fig. 8.5 OCT in optic disc elevation before (a) and after (b) treatment with Diamox
(Acetazolamide). The coinciding fundus photos showing significant papilledema before treatment
(c), with improvement after treatment (d) are also shown
if specific retinal or optic nerve changes point to a specific etiology. If this proves
to be the case, it will allow OCT to be used as a diagnostic tool for patients with
cognitive impairment.
MS: RNFL thinning and resultant optic nerve atrophy is a well-known and
accepted marker of disease burden in patients with MS, even in cases in which there
is no reported history of prior optic neuritis [158, 159]. There also have been reports
of reduced macular volume at baseline without any reduction in RNFL thickness
in patients with MS [160] as well as reduced central foveal area, all suggesting
involvement of outer retinal layers [161]. OCT thus has become an important moni-
toring tool for MS and other etiologies of optic neuritis, helping to determine pro-
gression, prognosis, and need for modification of therapy. Its utility to differentiate
MS from NMO, MOG and GFAP autoantibody disease remains poorly understood.
PD: Some studies have shown thinning of the RNFL contralateral to the side of
motor symptoms in patients with PD [162], although this finding is controversial
as there are other studies that have not shown thinning [163, 164]. Nevertheless,
macular retinal thickness and the total macular volumes are reduced in PD, and
the degree of macular thinning may correlate with disease progression and severity
[165, 166], although further studies are needed to confirm this finding. Increased
choroidal thickness on OCT was also observed in PD patients compared with unaf-
fected controls [167]. The significance of this finding is unclear.
Fig. 8.6 OCT in a patient with mild/moderate Alzheimer disease (AD). Compared with the OCT
from a normal individual (a), the OCT in a patient with AD (b) shows mild but definite thinning of
the peripapillary retinal nerve fiber layer in both the right and left eyes. (Images courtesy of Dr.
Elizabeth Couser)
Optical Coherence Tomography Angiography (OCTA)
The addition of angiography to standard OCT (OCTA) has become a new area of
interest in the evaluation of patients with optic neuropathies as well as neurologic
conditions since it was introduced commercially in 2014 [168]. Although Doppler
OCT has been used to measure retinal blood flow in the past, it assesses only the
axial component of blood flow velocity and is not sensitive to the slow, transverse
blood flow in retinal, choroidal, and optic disc capillary networks as is possible
with OCTA [169]. OCTA provides a three-dimensional motion-contrasted, cross-
sectional image that is produced by the backscattering of light in the retinal vascu-
lar and neurosensory tissue as moving red blood cells are contrasted against static
neurosensory tissue. Because OCTA uses the intrinsic contrast of moving red blood
cells, no dye is needed [168]. The benefit is that one may obtain quantitative infor-
mation about retinal vasculature using a non-invasive test. It also has been sug-
gested that the imaging resolution obtained by these photos are “histology level”
[170]. Clinical applications of OCTA in relation to neuro-ophthalmic conditions are
discussed below:
OCTA in Optic Neuropathies
Decreased peripapillary capillary density that correlates with RNFL thinning has
been found using OCTA in patients with optic neuropathies. Although this may
seem like an obvious observation in patients with ischemic optic neuropathies where
circulation is the direct cause of the insult, decreased peripapillary capillary density
also has been identified in patients with optic neuritis, traumatic optic neuropathy,
autoimmune optic neuritis, compressive optic neuropathy (chiasmal compression)
and Leber hereditary of optic neuropathy (LHON). In these cases, although isch-
emia is not the underlying cause, it has been suggested that optic nerve injury leads
to subsequent RNFL loss with associated decrease in capillary flow. The suggested
mechanism is that chronic injury to an optic nerve leads to a reduction in the num-
ber of nerve fibers that results in a decrease in metabolic demand and subsequent
reduced capillary blood flow. The decreased peripapillary capillary density is a sec-
ondary consequence [171]. Clinically, OCTA may be helpful in differentiation of
various etiologies of chronic optic neuropathy. Significant and profound peripapil-
lary capillary loss relative to RNFL thinning may suggest an ischemic etiology such
as anterior arteritic ischemic optic neuropathy (AAION) or NAION as opposed to,
for example, optic neuritis (Fig. 8.7). Other causes of optic nerve compression and
injury including chiasmal compression and optic disc drusen have been found to
have decreased retinal perfusion on OCTA [171]. Studies are still lacking to deter-
mine if OCTA can be used to determine etiologies of optic neuropathy in an acute
setting. Data regarding the influence of optic disc swelling on the measurements in
OCTA remain poorly described.
OCTA in Multiple Sclerosis
OCTA of the optic disc has revealed reduced flow index and vessel density in eyes
of patients with MS, with and without a prior history of optic neuritis compared
with normal subjects [172, 173]. Reports regarding macular OCTA changes in MS
are inconsistent and inconclusive [174].
Fig. 8.7 OCTA in non-arteritic ischemic optic neuropathy (NAION) in the left eye (a) and in
chronic optic neuritis involving the right eye (b). Note that there is reduction in the disc and peri-
papillary vessel density in both pathologies. Although there is a reduction in peripapillary vascular
density in all optic neuropathies, significant and profound peripapillary capillary loss relative to
RNFL thinning may suggest an ischemic etiology. (Images courtesy of Dr. Amanda Henderson)
OCTA in LHON
In some patients, OCTA has shown peripapillary telangiectatic blood vessels that
were not visualized with fluorescein angiography [175]. A recent small study of
six patients with LHON evaluated with OCTA (total 12 eyes) concluded that the
peripapillary microvascular network in these patients is very abnormal, thus sug-
gesting that there may be a contribution of microangiopathy to the vision loss in this
population [176]. More recently, a study of optic nerve head and macular OCTAs in
15 patients with LHON (20 eyes compared with 20 controls) showed that changes
in superficial and deep capillary plexi occur nasal and inferior to the optic disc, cor-
responding with the papillomacular bundle [177] (Fig. 8.8). The same study showed
a significant correlation between reduction in the superficial capillary plexus vessel
Fig. 8.8 OCTA of the macula (a) and optic nerve head (b) in a 27-year-old woman with acute
genetically proven LHON (11,778 mutation) 4 weeks after symptom onset. Note the increased per-
fusion of the vessels at the disc and macula, particularly on the nasal aspect which corresponds to
the papillomacular bundle. This is in contrast to the OCTA in chronic LHON (6 months after symp-
tom onset), where there is microvascular drop out in the macula (c) and atrophy of the superficial
plexus of the optic disc (d). Pictures (c) and (d) are from a 15-year-old boy with LHON associated
with the 14,484 mutation. (Images courtesy of Dr. Alfredo Sadun and Dr. William Sultan)
density an severity of vision loss measured by visual acuity. Of note, the authors
also found no association between OCT-assessed structural changes (thinning of the
retinal nerve fiber or ganglion cell layers) and best-corrected visual acuity.
Updates in Treatment
Unfortunately, large-number, prospective, controlled studies are significantly

lacking for many of the treatment and management updates in neuro-ophthal-
mology. Below we review several of the updated recommendations for various
neuro-ophthalmic problems that are based primarily on systemic reviews and

meta-analyses, with a few exceptions.
Treatment in Giant Cell Arteritis
Giant Cell Arteritis (GCA) is a vasculitis that affects medium-to-large vessels and
is an important cause of acute vision loss in neuro-ophthalmic patients over the age
of 50. Previously, GCA was diagnosed by clinical examination, serum inflamma-
tory markers (erythrocyte sedimentation rate, C-reactive protein, and platelets), and
temporal artery biopsy (the gold standard for diagnosis). Although temporal artery
biopsies may be used to may confirm the presence of GCA, a negative biopsy does
not definitively exclude it due to the potential for inflammatory lesions to skip cer-
tain arteries or segments [128, 178].
Despite our increased ability to recognize GCA, treatment continues to be a chal-
lenge. For decades, management of GCA was limited to long courses of steroids
and immunosuppressants that have debilitating side effects and do not secure a good
outcome. In a landmark clinical trial, the GiACTA Trial, the drug tocilizumab was
identified as the first non-corticosteroid agent with good efficacy for management of
GCA [179]. Tocilizumab is an IL-6 inhibitor that works by reducing and inhibiting
acute phase reactants contributing to inflammation. In the GiACTA trial, 251 patients
with newly diagnosed or relapsed GCA were treated with either tocilizumab and ste-
roids or placebo and steroids. This study was a double-blind, randomized controlled
trial. The patients were divided in a 2:1:1:1 ratio among the following treatment
regimens: weekly subcutaneous tocilizumab (162 mg) plus a 26-week prednisone
taper, every-other-week subcutaneous tocilizumab (162 mg) and 26-week predni-
sone taper; weekly placebo +26-week prednisone taper and weekly placebo +52-
week prednisone taper. Tocilizumab exhibited a marked steroid-sparing effect with
a higher rate of sustained remission at 52 weeks compared with placebo. Of note,
weekly dosing of tocilizumab was superior to every-other-week dosing. Overall,
the cumulative prednisone dose in the tocilizumab group was significantly less than
the amount used in the placebo group. No patient treated with weekly tocilizumab
developed any permanent visual deficits, and quality of life measures were improved
with tocilizumab compared with placebo. Tocilizumab was approved by the FDA in
2017, shortly after completion of this trial. The downside for the use of tocilizumab
is that at this time, long-term follow-up is lacking for its use in GCA. Also, the
high cost of this medication has led some physicians to resort to this medication
only in cases where patients cannot tolerate long-term corticosteroid treatment or
have failed corticosteroid treatment [128]. Of note, and in line with the new recom-
mendations above regarding imaging in GCA, 46% of the patients in the GiACTA
trial were diagnosed based on positive imaging rather than temporal artery biopsy.
It should also be noted that although tocilizumab clearly has efficacy as an add-on
treatment for GCA, no studies have been performed in which it has been used as a
first-line treatment.
Abatacept is a CTLA-4 inhibitor that has been shown to be effective in GCA. In a

small, randomized, placebo-controlled trial, 41 patients were treated with an induc-
tion course of abatacept 10 mg/kg intravenous with a 28-week prednisone taper. The
patients were then divided into two groups, one of which went on to receive monthly
treatment with abatacept and the other, placebo. The abatacept group showed a sta-
tistically higher rate of relapse-free survival (48% compared with 31%). One patient
from the abatacept group had a visual event related to GCA that occurred 28 weeks
after the initial induction [180].
Ocrelizumab in Multiple Sclerosis
In March 2017, the FDA approved the drug ocrelizumab for the treatment for mul-
tiple sclerosis. This medication is the first to be approved for primary progressive
MS and also is the first monoclonal antibody approved for use in secondary progres-
sive MS. Ocrelizumab is an anti-CD20 antibody that has been evaluated in phase II
and III trials and found to lower disability progression and improve radiologic and
relapse-related outcomes compared with placebo in patients with MS [181].
reatment for Optic Pathway Gliomas and Optic Nerve Sheath

T
Meningiomas
Optic Pathway Gliomas
Falsini et al. performed a randomized, double-masked, phase II clinical trial in 17

patients with optic pathway gliomas and stable visual function and imaging [182].
Patients received either a 10-day course of 0.5 mg murine nerve growth factor
(NGF) or placebo (10 NGF/8 placebo). Patients were evaluated clinically (visual
acuity, visual field), by imaging (OCT, MRI), and by electrophysiological testing
(visual evoked potentials and photopic negative responses) before therapy and at 15,
30, 90, and 180 days after therapy. There were no adverse effects from the treatment
and all patients who received NGF showed statistically significant improvements in
all parameters.
Optic Nerve Sheath Meningiomas
It has become increasingly clear that the appropriate management of an optic nerve
sheath meningioma (ONSM) for patients who require intervention because of progres-
sive visual loss is stereotactic fractionated or conformal radiation therapy (FCRT). Pandit
et al. performed a retrospective chart review with prospective follow-up of adult patients
treated with FCRT for primary ONSM at four academic medical centers between 1995
and 2007 with ≥10 years of follow-up after treatment [183]. They identified 16 patients
with mean post-treatment follow-up of 14.6 years; (range: 10.5–20.7 years). The mean
age at symptom onset was 47.6 years (range: 36–60 years). FCRT was performed at
a mean of 2.3 years after symptom onset (range: 0.2–14.0 years). At last follow-up,
visual acuity had improved or stabilized in 14 of the 16 (88%) patients, and 11 (69%)
had retained or achieved ≥20/40. Mean deviation on automated perimetry remained
stable (−14.5 dB pre-treatment vs. −12.2 dB at last follow-up; p = 0.68; n = 10). Two
(11%) patients had persistent pain, proptosis, or diplopia, compared with seven (44%)
pre-treatment (p = 0.11). Two (13%) patients developed radiation retinopathy more than
6 months after completion of therapy, one (50%) of whom had worse VA compared
with pre-treatment. No patient developed tumor involvement or radiation damage in
the fellow eye. Based on these findings, the authors concluded that FCRT stabilizes
or improves visual function in most patients with primary ONSM and is associated
with a low risk of significant ocular sequelae. We agree that this treatment should be
considered instead of surgery in patients with primary ONSM who require intervention
because of significant or progressive visual loss.
Leber Hereditary Optic Neuropathy (LHON)
LHON is a well-known mitochondrial disorder and is an important cause of heredi-

tary optic nerve-related permanent vision loss. LHON should be suspected in a
young male with subacute vision loss and a maternal family history of similar vision
loss [184]. Clinical examination findings are similar to those of other mitochon-
drial optic neuropathies and include variably reduced visual acuity, impaired color
vision, and central or cecocentral scotomas. At onset, the optic discs may appear
normal or hyperemic with telangiectatic vessels on the disc surface and in the peri-
papillary region. Eventually, optic disc pallor occurs that usually is more profound
temporally than nasally Diagnosis is confirmed by gene testing for one of the three
most common mitochondrial DNA mutations: 11778G>A/MT-ND4, 3460G>A/
MT-ND1 and 14484T>C/MT-ND6. These three mutations account for about 90%
of cases, however, if this screen is negative and there is a high suspicion for LHON
based on the clinical picture, entire mitochondrial genome sequencing should be
pursued to identify other rare mutations [144, 184].
There currently is no consistently beneficial treatment for LHON. The drug ide-
benone is the main intervention for preventing visual deterioration in LHON when
administered in the acute or subacute phase of the disorder. More recent treatment
options being evaluated are adeno-associated viral vector-based gene therapy and
mitochondrial replacement therapy.
Idebenone
LHON is the first mitochondrial disease for which a treatment has been approved by
the European Medicine Agency. The approved treatment is idebenone which has been
used empirically since 1992 [185]. Idebenone is a short-chain benzoquinone with
antioxidant properties. It carries mitochondrial electrons to complex III of the mito-

chondrion and directly promotes ATP production, ultimately activating ganglion cells
of the retina with resulting visual recovery [186]. The therapeutic benefit of idebenone
has been evaluated through a placebo-controlled randomized clinical trial [187] and a
large retrospective case series [186]. In 2016, an international consensus statement on
the clinical and therapeutic management in LHON was put forth by a panel of world
experts [184]. The consensus recommendation for therapeutic management in LHON
is to initiate idebenone as soon as possible at a dose of 900 mg/day in patients with
symptom onset of less than 1 year and to continue the treatment for 1 year. They panel
did not find evidence to suggest the use of idebenone in patients with chronic disease.
Gene Therapy
The mutations generated in LHON affect mitochondrial genome complex I of the elec-
tron transport chain and typically involve a single amino acid exchange [188]. The goal
of gene therapy in LHON is to replace the missing protein product. In the case of the
LHON 11778G>A mutation, this pertains to missing ND4 (mitochondrial encoded
NADH:ubiquinone oxidoreductase core subunit 4). Genetically modified adeno-asso-
ciated viral vectors (AAV2) have been developed to deliver a mitochondrial ND4 gene
construct either into the mitochondrial matrix compartment [189] or into the nuclear
genome [190] to compensate for the 11778G>A mutation [191]. It has yet to be deter-
mined if these modified ND4 subunits will integrate smoothly into complex 1 and be
stable enough to allow the electron transport chain to run efficiently [192]; however,
preliminary data from clinical trials have supported the safety of AAV2-based gene
therapy vectors and have found some visual improvement in eyes treated by intravitreal
injection of the vector [193–195]. Clinical trials to establish efficacy are ongoing.
Mitochondrial Replacement Therapy (MRT)
MRT is being studied with the goal of completely replacing mutated mitochondria with
normal mitochondria to prevent maternal transmission of mitochondrial DNA mutations.
This is done by reproductive technologies that allow for uncoupling of the mitochondrial
DNA from nuclear DNA [196] such that only the mitochondrial part of the DNA comes
from a donor [197]. Parental nuclear material is transferred into a mitochondrial donor
zygote carrying wild-type mitochondrial DNA to minimize or eliminate carryover of
mutant DNA. Preliminary results are promising and may pave the way for eliminating the
transmission of mutated maternal mitochondrial DNA in the future [196, 198].
Visual Restoration Therapy
The reported number of patients suffering from vision loss after stroke, either hem-
orrhagic or ischemic, ranges from 45 to 92% in the acute setting and from 8 to
25% chronically [199–201]. Although both efferent and afferent pathways may be
affected by stroke, homonymous hemianopia is the most common visual field defi-
cit occurring after stroke [200, 202]. Homonymous hemianopias often are debilitat-
ing, leaving a patient symptomatic for years [199]. Although 50% of patients with
homonymous hemianopia from a stroke may show some degree of improvement,
complete resolution is seen in only 8–12% of patients [201].
The benefit of several types of proposed visual rehabilitation after stroke con-
tinues to be a controversial topic of discussion among ophthalmologists and neu-
rologists. Proposed interventions for visual restoration include the use of prisms to
expand the area of good vision, saccadic exploration to explore the blind hemifield,
and restorative therapy to bring attention to the border between the seeing and non-
seeing area in an effort to increase the area of vision [202]. Unfortunately, none of
the prospective studies evaluating these interventions has been double blind and
controlled, and the results have been inconclusive. For example, in patients who
have undergone visual restoration therapy, there is no correlation between improve-
ment in visual field and improved ability to perform daily activities. Some patients
have reported improved daily activities despite no change in their field defect and
some patients with an apparent visual field improvement has reported no improve-
ment in their ability to perform daily activities. In addition, even when patients have
reported improvement in quality of life, when asked to draw what they perceive to
be the area of their scotoma after visual restoration therapy, there was no statically
significant change in the area of vision loss when compared with what was drawn
at baseline [203]. On the other hand, functional MRI and magnetoencephalography
studies performed after visual stimulation activities (although without a control)
have suggested there may be some plasticity contributing to visual recovery and
visual training; however, the utility of these imaging findings in the absence of evi-
dence to support retinotopic reorganization is limited [202, 204, 205].
Researchers have suggested various theoretical mechanisms for apparent visual
recovery. These mechanisms include activation of uninjured but suboptimally acti-
vated occipital cortex, bypassing damaged cortex, changes in neuronal chemistry
and sprouting of new connections to name a few [206–208]. Alternatively, it has
been suggested that the apparent visual recovery is actually due to unstable fixation.
It is hoped that with an increased theoretical understanding of visual rehabilitation,
new and reliable clinical therapies are on the horizon.
Endovascular Intervention Updates
Neuro endovascular intervention has become important in the world of neuro-

ophthalmology due to intersections in management [209]. This intersection includes
strokes, aneurysms, CNS vasculitis, and venous sinus stenting for pseudotumor cere-
bri (PTC) to name a few. Neuroendovascular intervention provides an additional
avenue to aid in diagnosis and management of vision-related problems; however, the
treatment itself may cause adverse visual events in some cases. Below we review a
few of the scenarios where neuro-ophthalmology and neuro-intervention intersect.
Aneurysms
Aneurysms are a common cause of neuro-ophthalmic referrals. Common complaints

related to aneurysm compression or rupture include double vision from ocular motor
nerve palsy, pupillary changes, visual pathway disorders and compressive chias-
mopathy or optic neuropathy [210]. Compression of the structures that comprise the
afferent and efferent visual pathways suggests a large and probably unstable aneu-
rysm, the diagnosis and treatment of which is crucial in preventing major permanent
visual and/or neurological deficits as well as death [210]. As neuroendovascular
intervention evolves as a treatment for aneurysms at risk for rupture, it is important
that ophthalmologists and neurologists understand the mechanism of treatment and
the potential adverse effects. Neuroendovascular aneurysmal repair involves endo-
luminal reconstruction. This refers to the use of a stenting devise to redirect flow
away from an aneurysmal sac or outpouching while endothelial ingrowth around
the stent leads to remodeling of the vessel lumen. In cases where a stent may not
be appropriate, usually determined by aneurysm architecture, detachable platinum
coils may be used to embolize the aneurysm outpouching [209]. Figure 8.9 below
provides an example of a coiled aneurysm, before and after coiling. Adverse events
from endovascular treatment include headaches, problems related to compression
from mass effect of the thrombosed aneurysm, and intraprocedural rupture [209].
Aneurysms located near the skull base have been noted to swell often which causes
stretching of the dura and pain. In one case report, mass effect from a repaired
anterior cerebral artery aneurysm caused optic tract edema with unilateral vision
loss and a homonymous field cut [211]. In this case, the patient was treated with
high-dose steroids with near-complete recovery. A meta-analysis of 13 retrospective
studies encompassing 477 patients compared visual outcomes of aneurysm repair
by surgical clipping with endovascular coiling [210]. Complete recovery after each
procedure reached 78% in the surgical group versus 44% in the endovascular group.
Similar findings were observed when comparing recovery rate specifically for cra-
nial neve palsies. Surgical intervention also results in improvement of visual field
deficits from anterior visual pathway compression. It must be emphasized, however,
that surgical intervention is associated with higher complication rates, longer stays
in the intensive care unit, and higher hospital costs compared with endovascular
intervention. Decision for neurovascular versus surgical approach is highly influ-
enced by location (experience of the operator in a high volume versus low volume
institution) and aneurysm architecture.
Griessenauer et al. treated 127 consecutive patients with 160 ophthalmic seg-
ment aneurysms using flow diverters [212]. In this cohort, complete occlusion of
the aneurysm was observed in 90 of 101 (89%) cases with a mean follow-up of
18 months. Of ten patients with visual symptoms, one had immediate improve-
ment in visual function. Among 117 patients without visual symptoms, two (1.6%)
experienced visual impairment following treatment. There was no mortality related
to the procedure, but, in addition to the two patients who experienced visual impair-
ment post-procedure, two developed a permanent neurological deficit (hemiplegia).
Based on their experience in this large series, the authors concluded that treatment of
ophthalmic segment aneurysms with flow diversion is a safe and effective procedure
compared with clipping. Several of the same authors participated in a two-center
retrospective cohort study of consecutively treated ophthalmic segment aneurysms
that compared stent-assisted coil embolization with flow diversion [213]. Sixty-two
aneurysms were treated with stent-coiling and 106 were treated with flow diversion.
The authors found that stent-coiling and flow diversion were equally effective in
treating these aneurysms and that there were no significant differences in procedural
complications or in angiographic, functional, or visual outcomes. In fact, in this
series, no patient with stent-coiling had a permanent visual complication whereas
only one patient in the flow diversion series had permanent visual loss.
For the efferent visual system, the issue relates to third nerve palsy recovery
after treatment of ruptured and unruptured internal carotid-posterior communi-
cating (PCom) aneurysms. [214] described the effect of endovascular treatment
of 34 patients with third nerve palsy associated with a ruptured PCom aneurysm.
At 6-month follow-up, 21 (61.8%) had experienced complete recovery of their
palsy whereas 8 (23.5%) had incomplete recovery. The mean time to resolution
was 24.5 days. As might be expected, there was a trend toward complete recov-
ery among patients with an initially incomplete palsy. No patient in this series had
post-operative worsening of an incomplete palsy. Hall et al. described the effect of
treatment of unruptured PCom aneurysms on resolution of third nerve palsy [215].
These authors reported their experience with 15 patients and provided a narrative
review of 179 patients from 31 case reports or cohort studies. Based on their expe-
rience and literature review, they concluded that surgical clipping was associated
with a higher rate of recovery than was endovascular treatment. Again, patients who
presented with a complete palsy had a lower rate of recovery than did those with a
partial palsy.
a b
Fig. 8.9 Cather angiogram imaged showing an Anterior communicating artery aneurysm, (a)
before and (b) after coiling. After coiling, there may be compression of neighboring brain tissue or
blood vessels from the coil mass. (Pictures courtesy of Dr. Michael Pichler, MD)
Venous Sinus Stenting in Primary Pseudotumor Cerebri (PTC)
Various institutions across the world have begun implementing venous sinus stent-
ing as a therapy for medically refractory pseudotumor cerebri (PTC) and, in some
cases, first-line therapy (Fig. 8.10). Liu et al. described ten patients with PTC
and venous sinus stenosis with an elevated gradient across the region of stenosis
(30.0 ± 13.2 mmHg) and elevated ICP (42.2 ± 15.9 mmHg) for whom medical
therapy had failed and who subsequently underwent venous sinus stenting [216].
Following stent placement, all patients had resolution of the stenosis and gradient
(1 ± 1 mmHg). More importantly, however, the authors monitored ICP throughout
the procedure and noted an immediate decrease in ICP following placement of the
stent (17.0 ± 8.3 mmHg) with a further decrease overnight. This publication and
another by Matloob et al. confirm the immediate effects of venous sinus stenting
on ICP in this group of patients [217]. Another prospective observational study
that consisted of 13 patients with venous sinus stenosis, visual field changes, and
medically refractory, medically intolerant or fulminant PTC also concluded that
venous sinus stenting is a safe and immediately effective method of reducing
intracranial pressure (ICP) in PTC [218]. This study also reported improvement
in headache and other associated symptoms of PTC, as well as reduction or reso-
lution of papilledema, resolution of RNFL thickness, and improvement in visual
field as measured by mean deviation using automated perimetry. A number of
other series with smaller groups of patients also have reported successful stenting
and resolution of increased ICP and associated symptoms [219]. Several recent
retrospective literature reviews, systematic reviews and meta-analyses of patients
undergoing venous sinus stenting for medically refractory PTC conclude that
stenting has high technical success and low complication rates in appropriately
selected patients [220–222]. Recommendations on the appropriate selection of
patients also have been suggested based on literature review [222]. This obvi-
ously is an important consideration for those patients who present with evidence
of optic nerve dysfunction and for whom a decision must be made regarding per-
forming immediate optic nerve sheath decompression, and/or drainage of cere-
brospinal fluid.
Despite the enthusiasm for venous sinus stenting for patients with PTC and
venous sinus stenosis, a recent single-center case series of 41 patients studied
clinical, radiological and manometric outcomes 120 days after venous sinus
stenting [223]. Although the results from this study supported prior findings
of reduced venous sinus pressure and lower complication rates compared with
shunting at 120 days, at least 20% of the patients developed restenosis and only
63.3% of patients showed improvement or resolution of papilledema. This raises
a question regarding the long-term viability and clinical outcomes of venous
sinus shunting. Ultimately, prospective, randomized controlled studies designed
to assess long-term outcomes and complications of stenting for PTC will be
required to determine if venous sinus stenting provides sufficient long-term ben-
efit to become the procedure of choice in patients with PTC and venous sinus
stenosis.
Fig. 8.10 Fundus photos and coinciding MR venogram images in a patient with Pseudotumor
Cerebri and venous sinus stenosis; (a) venous sinus stenosis seen on MR venogram; (b) fundus
photos showing papilledema prior to sinus stenting; (c) venous sinus now open after endovascular
stenting; (d) improved papilledema
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wno.0000000000000426.
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of idiopathic intracranial hypertension with stenting of the transverse sinus stenosis.
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220. Nicholson P, Brinjikji W, Radovanovic I, Hilditch CA, Tsang ACO, Krings T, et al. Venous
sinus stenting for idiopathic intracranial hypertension: a systematic review and meta-analysis.
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221. Leishangthem L, Sir Deshpande P, Dua D, Satti SR. Dural venous sinus stenting for idio-
pathic intracranial hypertension: an updated review. J Neuroradiol. 2019;46(2):148–54.
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223. Asif H, Craven CL, Siddiqui AH, Shah SN, Matloob SA, Thorne L, et al. Idiopathic intra-
cranial hypertension: 120-day clinical, radiological, and manometric outcomes after stent
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171/2017.4.Jns162871.
Chapter 9
Recent Advances in Pediatric
Ophthalmology
Ken K. Nischal
The Cornea
Corneal anesthesia can lead to neuropathic keratopathy, corneal scarring and blind-
ness [1]. In children it is a particular problem not only because of the effect on
amblyopia but also because children are more likely to cause microtrauma to the
cornea [2]. Causes of corneal anesthesia in children include congenital and acquired.
The congenital causes are rare and include trigeminal nerve agenesis, Riley-Day
syndrome, Goldenhar and Mobius syndrome. Acquired causes are often iatrogenic
e.g. after intracranial tumor resection and due to neoplasm damaging the trigeminal
nerve [3]. Some of these are unilateral and recent descriptions of the neurotization
of the cornea have changed the natural history and course of this condition [4]. Prior
to this, all therapies were aimed at keeping the cornea lubricated or protected (with a
tarsorrhaphy). Corneal neurotization entails using a sensory nerve such as the sural
nerve, as a conduit from the unaffected supratrochlear nerve to the affected cornea.
The nerve has to be divided into its fascicular bundles and each fascicle passed
under the conjunctiva so as to be equally distributed around the affected cornea at
the limbus (see Fig. 9.1). Re-innervation takes several months [4] but results are
reproducible, and the technique has been taken up world-wide. Its use in children
dramatically changes the prognosis (see Fig. 9.1). Cases where there is bilateral cor-
neal anesthesia have recently been reported and here coaptation of the sural nerve
to branches arising from the maxillary division or even the mandibular division of
the trigeminal nerves are possible as long as their function is normal or by using the
ipsilateral supratrochlear nerves [4].
Congenital corneal opacification has undergone a re-evaluation with respect to
nomenclature. The condition is better described as conditions that are due to primary
K. K. Nischal (*)
UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

252 K. K. Nischal
a b
Fig. 9.1 Shows a child with congenital corneal anesthesia due to aplasia of the trigeminal nerve.
(a) shows the child at presentation with a neurotrophic ulcer and hypopyon. (b) shows the corneal
neurotization procedure at the point where the sural nerve is divided into its component fascicles
which are then passed under the conjunctiva to the limbus.(c) shows an integrated intraoperative
OCT of one of the fascicles under the conjunctiva about 3 months after the surgery (white arrow)
corneal disease or secondary corneal disease (see Fig. 9.2) [5–9]. The only primary
corneal causes of CCO are corneal dystrophies, such as CHED, PPMD, X-L ECD,
corneal dermoids, cornea plana and CYP1B1 cytopathy. Secondary causes of CCO,
are due to kerato-irido-lenticular dysgenesis (KILD—see Fig. 9.3) and congenital
glaucoma. KILD encompasses iridocorneal adhesions (Peters anomaly I), kerato-
lenticular adhesions (Peters II) and other forms of partial or complete lenticular
dysgenesis leading to secondary corneal opacity. The importance of this classifica-
tion is that not only does it allow a more logical approach to these cases but also
allows for prognostications which are so important for parents and also the doctors
dealing with them.
Perhaps deep phenotyping of CCO allowed identification of those cases where
there were only iridocorneal adhesions or only a posterior central defect in endo-
thelium (von Hippel ulcer). It is in such cases that the use of selective endothelial
cell removal has resulted in rapid clearing of these congenital corneal opacities
9 Recent Advances in Pediatric Ophthalmology 253
PRIMARY CORNEAL DISEASE SECONDARY CORNEAL DISEASE

A DEVELOPMENTAL ANOMALIES OF CORNEA CONT’D
• i. Corneal dystrophies
– CHED,PPMD,CHSD,X-L ECD B ACQUIRED CORNEAL DISEASE
• ii. Cornea Plana (sclerocornea)
. i Metabolic
. Mucolipidoses
• iii Corneal structural defects due to dermoids . Mucopolysaccharidoses
– Isolated . Cystinosis
– Part of systemic disease eg. Goldenhar, Linear
sebaceous nevus . ii Trauma
• iv CYP1B1 Cytopathy . iii Infectious Keratitis
. Bacterial
SECONDARY CORNEAL DISEASE
. Viral
A DEVELOPMENTAL ANOMALIES OF . Protozoal
ANRERIOR SEGMENT . Fungal
• i Kerato-Irido-Lenticular Dysgenesis KILD . iv Non-infectious Keratitis
– a. Iridocorneal adhesions only . Exposure
. Neurotrophic
– b. Lens fails to separate from cornea
. Interstitial e.g. Cogan’s disease
– c. Mechanical e.g. due to PHPV . Steven-Johnson syndrome
– d. Lens separates but fails to form . Epidermolysis hullosa
thereafter . v Miscellaneous
– e. Lens fails to from . Keratoconus
. Keratoglobus
• ii Irido-trabecular Dysgenesis
. Xeroderma pigmentosa
– a. Infantile glaucoma
– b. Axenfeld-Rieger anomaly
– c. Aniridia
Fig. 9.2 Classification for congenital corneal opacities. All conditions in red have a poor prognosis
for corneal transplant
[10]. IN these subset of CCO, this procedure appears to allow a faster clearing of
the cornea than previously seen or expected (see Fig. 9.4). This report is potentially
a disruptive moment in this field of pediatric cornea. The fact that corneal opacities
in children ‘clear with time’ is well known but it has always been an issue that the
time taken to clear causes so much amblyopia that other therapies (PKP or optical
iridectomy) have been sought. IF by selective endothelial removal one is accelerat-
ing the corneal opacity clearing, then this may have tremendous benefits. However
this technique is unlikely to work if there is a keratolenticular adhesion or a marked
loss of posterior corneal stroma. Hence the need for deep phenotyping before apply-
ing this technique to a case of CCO.
The advent of intraoperative integrated OCT (i2OCT) has played an enormous
role in allowing better accuracy in delivering care for children with corneal disease
especially in difficult cases where the view may not be so easy (see Fig. 9.5).
Collagen cross linking (CXL) has been developed to increase the biomechanical
rigidity of an ectatic cornea (keratoconus). Initially the application of this technique
was in progressive keratoconus in adults but as our understanding of the technique and
its applications has improved, its use in children has spread. In children the presence
of keratoconus alone is enough to offer CXL. While arguments about epithelium on or
254 K. K. Nischal
Fig. 9.3 Shows a child with congenital corneal opacities. The right eye (a and c) shows no kera-
tolenticular adhesions but does show iridocorneal adhesions. The thick white arrow is showing a
formed anterior chamber. The left eye shows a clearing centrally but this is due to thinning of the
cornea and a keratolenticular adhesion (thin white arrows b and d)
epithelium off rage in the literature, evidence to date suggests that long-term stability
is better achieved with epithelium off using the Dresden protocol in children.
The original Dresden protocol, consists of manual epithelial debridement fol-
lowed by application of Riboflavin 0.146% with dextran instillation every 2 min
for 30 min followed by UV-A irradiation, 3 mW/cm2 for 30 min with continuing
riboflavin instillation [11] (see Fig. 9.6).
CXL induces and enhances cross-linking between collagen fibrils. Riboflavin
causes photo-sensitisation and UV-A creates cross-linking by generating oxidative
products in the presence of oxygen [12]. This process increases the corneal biome-
chanical strength arresting the progression of biomechanical weakening (ectasia).
Paediatric keratoconus is more aggressive even at presentation with an aggravated
progression compared to adults % [13] with a seven-fold increased risk of requiring
a penetrating keratoplasty compared to adults [14, 15]. Studies that include no chil-
dren with allergic eye disease show stabilization of progression with no requirement
of any further intervention [14, 16]. In those studies where patients had allergic eye
disease [17] 20% of eyes that were followed beyond 4 years showed reversal of
keratometric flattening with minimal drop in visual acuity; This regression of cross
Fig. 9.4 The image shows

a
pre-selective endothelial
removal (a), then a few
weeks later (b) and then a
few months later (c). There
is remarkable clearing of
the opacity and emphasizes
the need for deep
phenotyping in these cases
so that the correct
treatment can be used; e.g.
selective endothelial
removal could not be used
in the eye shown in (b).
Courtesy of Professor J
Mehta
c
256 K. K. Nischal
Fig. 9.5 Shows a child with Bardet Biedl syndrome with retinal dystrophy. The fundus autofluo-
rescence shows hyper fluorescence around the macula (black arrow) while the fundus picture
shows marked attenuation of the arterioles (white arrow) without any bony spicule pigmentation
a b
Fig. 9.6 Shows a child with traumatic corneal scar (a black arrow) and traumatic cataract . In
order to perform a corneal transplant, cataract removal and primary lens implantation, the inte-
grated intraoperative OCT (i2OCT) was used to cut the keratolenticular adhesion (a, b—thin white
arrow) using the simultaneous OCT view in the binoculars of the operative microscope (b, c—
thick white arrow shows the microscissors and the dashed white arrow in (b) shows the keratolen-
ticular adhesion cut
linking effect in a small subset of patients was thought to be due to persistent eye
rubbing due to allergic eye disease.
In patients of keratoconus older than 15 years, an objective study of quality of
life using NEI-VFQ 25 questionnaire by Cingu et al. has shown better quality of life
and decreased anxiety related traits 1 year following cross linking [18].
Studies have demonstrated both statistically and clinically that CXL with the
Dresden protocol arrests the progression of keratoconus, while causing corneal flat-
tening, variable visual improvement and significantly decreases the requirement of
keratoplasty for keratoconus and improves quality of life [16–23].
CXL is associated with minimal sight threatening complications which include
infectious keratitis (0.0017%), sterile infiltrates, limbal stem cell damage and an
anterior stromal haze not affecting vision with long-term studies showing a regres-
sion of CXL effect or failure of up to 8–10% [23–25].
Studies have shown significant progression of the disease in non-cross-linked
eyes. Progression is especially higher and rapid in paediatric keratoconus eyes
affecting vision significantly and leading to contact lens intolerance and eventually
acute hydrops [18, 26, 27].
Other options in moderate to severe keratoconus management include Intra cor-
neal ring segments (Intacs®) and keratoplasty. Intacs, though can partially reha-
bilitate vision and delay keratoplasty, is associated with poor outcomes with higher
grades of keratoconus and has reported risk of extrusion or need for removal [28,
29], which increases the number of procedures, especially in paediatric patients.
Pediatric keratoplasty has a higher risk of infections, graft rejection and difficult
visual rehabilitation compared to adult keratoplasties [19].
258 K. K. Nischal
Accelerated CXL (KXL) significantly reduces irradiation time and use of pulsed
UV delivery has circumvented the problem of O2 delivery. Long term comparative
studies with 48 months follow up in paediatric and adult populations have proven
safety and efficacy in halting progression compared to Dresden protocol. Further
better outcomes are reported with KXL when Riboflavin with HPMC is used instead
of Photrexa viscous [30].
Customised KXL with graded energy delivery to different zones of the cornea
with maximum energy at the cone has proven safety and better flattening of cone
and visual gain with lesser keratocyte damage in corneal periphery compared to
conventional technique [30].
For thinner corneas (less than 400 μm), epi-on trans epithelial CXL, though was
initially reported to be inferior to conventional epi-off method, is now showing
promise on safety and efficacy with use of modified Riboflavin with other agents as
EDTA and use of Iontophoresis for Riboflavin delivery [30].
Pediatric Cataract
No field in pediatric ophthalmology has advanced at as fast a rate than the area
of pediatric cataract surgery surgically. Key studies globally have contributed to
a better understanding of surgical outcomes, techniques and decision making for
intervention. In the past 5 years.
There have been outcomes of randomized controlled trials (RCT), an individual
metanalysis and a Delphi consensus statement, reflecting the integration of real-
world evidence, real world data with basic scientific rigor [31–34].
The infant Aphakia Treatment study was the first RCT to be published in the area
of pediatric cataract surgery, and specifically looked at unilateral cataract in infants.
The conclusion drawn from this study, which has had some criticisms in methodol-
ogy, were that at 5 year follow up IOL implantation resulted in greater number of
re-operations with no difference in vision between the two groups (aphakic corrected
with Contact lenses or IOL implantation group corrected with glasses). These con-
clusions hold true for unilateral cataract [31].
Bilateral cataracts are a different type of disease and extrapolations from IATS to
applications in bilateral congenital cataract are misleading and misguided. Recently
a group in India performed a randomized controlled trial for bilateral congenital cat-
aracts and have shown that the reoperation rates between aphakic and IOL groups
were the same and the visual outcomes in the bilateral group with IOL rending to be
better than those in the control group [32].
Sixty children (120 eyes) up to 2 years of age undergoing bilateral congenital
cataract surgery were randomized to aphakia (n = 30), or primary IOL implanta-
tion (pseudophakia) (n = 30). A single surgeon performed all the surgeries with
identical surgical technique. All patients were followed up regularly for 5 years.
The median age of the patients at time of surgery was 5.11 months (aphakia group)
and 6.01 months (pseudophakia group). At 5 year follow up the incidence of glau-
coma was about the same (16% aphakic and 13.8% pseudophakic). The incidence
of posterior synechiae was significantly higher in the pseudophakia group and
visual axis opacification requiring surgery was seen in 8% of the aphakes and
10.3% of the pseudophakes. Mean logMAR visual acuity at 5 years follow-up
was 0.59 ± 0.33 and 0.5 ± 0.23. However, more eyes in the pseudophakic group
started giving documentable vision earlier in their postoperative follow-ups than
the aphakic group [32].
This is understandable for two reasons: firstly almost ALL unilateral cataracts
(truly unilateral) are due to some form of persistent fetal vasculature (PFV) and
secondly, the IATS included several surgeons (some of whom had small volumes of
surgery for pediatric cataract) while the RCT for bilateral disease was performed by
a single center high volume pediatric cataract surgeon.
In the only individual metanalysis performed on infant cataract surgery [33],
having analyzed 486 eyes the authors concluded that surgery before 4 weeks of age
and multiple reoperations increased the risk of glaucoma development while place-
ment of an IOL protected against glaucoma. This last is still controversial; reasons
why this should be so, are likely hidden by the fact that each of the surgeons who
participated in this metanalysis were experienced high volume cataract surgeons,
who had specific indications to abort placement of IOL in even those eyes where
parents had been counseled that an IOL would be placed. This of course is real-
world evidence. Conducting RCTs for surgical techniques may not be appropriate
when the factors that influence a surgeon’s decision to place one are not taken into
account. In fact some authors suggest that RCTs in such circumstances are in fact
dangerous for the participants.
A Delphi process led consensus was reported for management of pediat-
ric cataract [34]. The process consisted of three rounds of anonymous electronic
questionnaires followed by a face-to-face meeting, followed by a fourth anony-
mous electronic questionnaire. The executive committee created questions to be
used for the electronic questionnaires. Questions were designed to have unit-based,
multiple choice or true–false answers. The questionnaire included issues related to
the preoperative, intraoperative and postoperative management of pediatric cata-
ract. Consensus based on 85% of panelists being in agreement for electronic ques-
tionnaires or 80% for the face-to-face meeting, and near consensus based on 70%.
Sixteen international pediatric cataract participated. Consensus or near consensus
was reached for 85/108 (78.7%) questions and non-consensus for the remaining 23
(21.3%) questions.
The first Delphi consensus statement was more valuable in determining where
consensus could not be reached rather than where it could. To this end the following
remain areas of controversy. There was no consensus on certain topics such as the
use of hydrodissection in cases where a pre-existing posterior capsule defect is not
suspected, the best formula to use while calculating IOL power and the minimum
age for primary IOL implantation.
Surgical techniques for pediatric capsule management continue to improve. While
femtosecond laser has been used to describe excellent centration and precision of
both anterior and posterior rhexis in children [35, 36], the expense of the procedure
260 K. K. Nischal
has prohibited its widespread use. The zeptosecond capsulotomy device [37] has
gained some interest but its use in small eyes is questionable. The Two incision push
pull technique continues to gain favor and allows sizing of the anterior and posterior
capsulorhexis in pediatric cataract surgery [38]. Continuing this need for precisely
sizing the anterior and posterior rhexis, a foldable capsulorhexis ring has been devel-
oped specifically for use with the bag-in the lens (BIL). This IOL is designed with
a groove around the optic, into which the anterior capsule and posterior capsule fit
after capsulorhexes are performed. The beauty of this lens is that the lens epithelial
cells are captured and cannot proliferate, resulting in clear visual axes [39].
The use of multifocal implants in children continues to be reported but studies
fail to measure contrast sensitivity in children who have had diffractive mutifocal
IOLs placed. Without this outcome measure the use of diffractive multifocal IOLs
is controversial [40].
The most important and perhaps controversial development has been the report
of using a new surgical technique which results in regeneration of the lens itself.
This group [41] showed in donor eyes that the younger the patient the greater the
ability for LEC’s to reproliferate; this is a clinical fact well known to pediatric cata-
ract surgeons. They then showed that the mere act of injury to the capsule would
result in a seven-fold increase in LEC proliferation regardless of age. Based on a
series of in vitro experiments, followed by surgeries on rabbit and then macaque
monkey eyes they described a surgical technique whereby a small peripheral cap-
sule opening was made and the lens fibers removed with as little damage to the
proliferating anterior lens epithelial cells. This technique resulted in a regrowth of
the lens fibers over a period of several weeks in the animal eyes. This technique
was repeated in 24 eyes (12 cases) with congenital cataract in human children and
compared to standard cataract surgery in 25 cases (50 eyes) with congenital cata-
ract. The results published show regeneration of the lens using the newer technique
over 3–5 months. There are of course many unanswered questions such as, how did
an opaque lens regenerate into a clear one and during the period of regeneration how
was amblyopia prevented? That said this concept is potentially disruptive if it can be
replicated once the unanswered questions are clarified.
Refractive Error
Myopia, commonly called near-sightedness, is the most common human eye dis-
order in the world, affecting 85–90% of young adults in some Asian countries such
as Singapore and Taiwan, and between 25 and 50% of older adults in the United
States and Europe. Unlike Western populations where the prevalence of myopia is
low (<5%) in children aged 8 years or younger, in Asian children there is a signifi-
cantly higher prevalence of myopia, affecting 9–15% of preschool children, 24.7%
of 7-year-olds, 31.3% of 8-year-olds, and 49.7% of 9-year-old primary school chil-
dren in Singapore [42]. In 12 year-old children, the prevalence of myopia is 62.0%
in Singapore and 49.7% in Guangzhou, China compared with 20.0% in the United
States, 11.9% in Australia, 9.7% in urban India and 16.5% in Nepal [43].
The economic cost of myopia is estimated at an annual US$268 billion world-

wide. Not only is there a socio-economic burden, there is a significant increased
odds ratios for myopic maculopathy, retinal detachment, cataracts, and glaucoma,
even for low and moderate levels of myopia and these odds ratios increase further
with higher levels of myopia [44].
Evidence supports heritability of the nonsyndromic forms of myopia, especially
for high-grade myopia (−5 D or higher) and Genome-wide association studies
(GWAS) have identified >20 associated loci for myopia. However, the majority of
recent studies show that the boom in myopia prevalence reported in different popu-
lations is related mostly to environmental factors, including excess in near work
especially in young age and low light exposure, especially as outdoor activity.
There has been much interest recently to try and retard myopic progression of
childhood. Some interventions that have been used in the past appear not to work.
For example under-correction of myopia either increases or has no effect on myopia
progression. Under correction does not slow myopia progression and should no
longer be advocated [45].
While there is some evidence that bifocal lenses may reduce myopia progression
there is some that suggests that they do not [45, 46]. Older studies (PALS, COMET,
CLAMP) have shown minimal myopia retardation effect on myopia using tradi-
tional contact lenses [45–48].
In overnight orthokeratology the patient wears reverse geometry contact lenses
overnight to temporarily flatten the cornea and provide clear vision during the
day without any glasses or contact lenses. Reduction in myopia (up to −6 D) is
achieved by central corneal epithelial thinning, midperipheral epithelial, and stro-
mal thickening. Unfortunately, more than one hundred cases of severe microbial
keratitis related to orthokeratology have been reported since 2001. Randomized
clinical trials of orthokeratology myopia control demonstrated significantly slower
axial elongation in children wearing orthokeratology lenses than children wear-
ing single vision spectacles. Orthokeratology contact lenses can be used to cor-
rect central refractive error while leaving peripheral myopic blur, which may act
as a putative cue to slow the progression of myopia. Overall, ortho-k results in an
approximately 40% reduction in the progression of myopia. There is no good con-
trolled long term study demonstrating sustained myopia control effect and there is
no washout data [49, 50].
While there is accumulating evidence for the role of the peripheral retina in the
development of refractive errors [51] with initial human studies involving mainly
Caucasians suggesting an association between relative peripheral hyperopia and
axial myopia, the Peripheral Refraction in Preschool Children (PREP) Study of
Singaporean Chinese children and Collaborative Longitudinal Evaluation of
Ethnicity and Refractive Error (CLEERE) study showed that relative peripheral
hyperopia had little consistent influence on the risk of myopia onset, myopia pro-
gression, or axial elongation [52]. Even human clinical trials with treatment strat-
egies aimed at reducing the peripheral retinal hyperopic defocus, there were no
statistically significant differences in the rates of myopia progression between chil-
dren who wore one of three novel spectacle lenses that decreased relative periph-
eral hyperopia and those who wore the conventional single-vision spectacle lenses.
262 K. K. Nischal
However, for children aged 6–12 years whose parents are myopic, one of the three
spectacle lenses was found to reduce the progression of myopia significantly when
higher rates of progression were evident [53, 54].
There has been a tremendous amount of interest in the use of topical atropine.
Atropine blocks muscarinic receptors non-selectively. Muscarinic receptors are
found in human ciliary muscle, retina and sclera. Although the exact mechanism
of atropine in myopia control is not known, it is believed that atropine acts
directly or indirectly on the retina or scleral, inhibiting thinning or stretching
of the scleral, and thereby eye growth. This was also shown that atropine acts
via non-accomodative way. Studies have shown some clinical effect on slow-
ing the progression of myopia in children. The Atropine for the Treatment of
Myopia studies (ATOM 1 and 2) were randomized, double-masked, placebo-
controlled trials each involving 400 Singapore children. The ATOM1 study sug-
gested 1% atropine eyedrops nightly in one eye over a 2-year period slowed
myopic progression by 77% and reduced the axial length elongation (mean axial
length increase of 0.39 mm in controls versus no growth in atropine group).
The ATOM2 study demonstrated a dose-related response with 0.5%, 0.1% and
0.01% atropine slowing myopia progression by an estimated 75%, 70% and
60% with SE changes of 0.30D,0.38D and 0.48D, respectively over 2-years.
However, when atropine was stopped, there was an inverse increase in myopia,
with rebound being greater in the children previously on higher doses. This
resulted in myopia progression being significantly lower in children previously
assigned to the 0.01% group at 36 months compared with that in the 0.1 and
0.5% groups. Younger children and those with greater myopic progression in
year 1 were more likely to require re-treatment. By the end of 5 years, myopia
progression remained lowest in the 0.01% group. It was estimated that, over-
all, atropine 0.01% slowed myopia progression by at least 50%. The efficacy
of lower dose atropine is corroborated by Taiwanese cohort studies. However,
there may be children who are poor responders to atropine. In ATOM1, 12.1% of
children (younger, with higher myopia, and greater tendency of myopic progres-
sion) had myopia progression of more than 0.5D after 1 year of treatment with
atropine 1%. Atropine 0.01% caused minimal pupil dilation (0.8 mm), minimal
loss of accommodation (2–3 D), and no near visual loss compared with higher
doses. Children on atropine 0.01% did not need progressive additional lenses,
and they did not need photochromatic lenses because of photophobia [55–58].
Finally, there have been many studies showing that outdoor activity, what was
shown to be exposition to natural light, decreased the onset of myopia and neutral-
ized the effect of parental myopia and near-distance work. The role of outdoor activ-
ity to myopia progression is not as clear since different studies shown conflicting
results. The recent interventional studies showed effectiveness in reducing the myo-
pia onset after increasing outdoor activity time in school. The notion that at least
2 h daylight exposure can be preventive against myopic progression of childhood
has gained favour and in some countries is influencing the design of classrooms to
increase daylight exposure while indoors [59–62].
Molecular Genetics
There is of course always something new in the field of molecular genetics but in
terms of overarching concepts the two that are the most important and relatively
new are nonsense suppression therapy and ciliopathies.
Nonsense mutations are single base pair substitutions in the DNA that create
one of three stop codon sequences, UAA, UAG, or UGA, called premature termina-
tion codons (PTC). These types of mutations often result in truncated protein prod-
ucts which may be subject to nonsense-mediated mRNA decay (NMD). NMD is
an evolutionarily-conserved surveillance pathway designed to eliminate abnormal
mRNA transcripts before abnormally truncated proteins can be synthesized [63,
64]. Interference in the NMD pathway may stabilize abnormal transcripts, promote
“read-through” of PTCs, and increase the amount of functioning protein [65].
“Read-through” is the misreading of stop codon during translation, allowing an
amino acid to be incorporated into the growing polypeptide [66, 67] and occurs at a
frequency of less than 0.1% at normally positioned stop codons and less than 1% at
PTCs [66–70]. Nonsense suppression therapy (NST) is promotion of read-through
and is potentially very impactful since nonsense mutations account for about 30%
of ocular genetic disease [71].
Ataluren is classified as an orphan drug by the European Medicines Agency and
U.S. Food and Drug Administration for treatment of Duchenne Muscular Dystrophy
and cystic fibrosis as a form of NST [72–76]. Despite its successes, the in vivo and
in vitro effectiveness of ataluren has been questioned and the potential complication
of action on non-targeted genes and stop codons has been raised [71, 77, 78].
In ophthalmology ataluren has been used to treat aniridia [79]. Aniridia is a
congenital, progressive, panocular condition characterized by partial or com-
plete absence of iris, nystagmus, corneal opacification, glaucoma, cataract, and
foveal hypoplasia. The condition is due to mutations in the PAX6 gene, which
plays a central role in early ocular development of the cornea, iris, lens, and
retina [80, 81].
Using a mouse model of aniridia with a naturally occurring nonsense mutation,
notated Gly194Term, in PAX6, Gregory-Evans et al. administered daily subcutane-
ous injections of ataluren (30 μg/g) from postnatal days 4 to 14 [79]. In untreated
mice, the baseline ocular phenotype included a thickened cornea connected to a
lenticular stalk and a thickened retina with abnormal infolding. By day 14, the phe-
notype progressed to globe distortion, further retinal infolding, and an abnormally
small lens. In ataluren-treated mice, the retinal infolding was corrected and the lens
was 70% larger compared to controls. Functional improvements were also apparent
by postnatal day 60 when measured by electroretinography (ERG), where untreated
mice had non-recordable ERG tracings at and treated mice had relatively substantial
ERG responses. Of note, the ERG responses in treated mice were improved but not
normalized. Anterior segment examinations revealed an abnormally thick corneal
stroma with epithelial thinning, which was not statistically different from untreated
mice. Extending injections to postnatal day 60 did not significantly improve the
264 K. K. Nischal
corneal phenotype. The authors concluded that systemic injection may limit deliv-
ery to the cornea and that improvement in the corneal phenotype may be also be
limited as other PAX6-independent factors contribute to anterior segment develop-
ment and would not be responsive to ataluren. Modification of the study for topical
delivery rescued the corneal abnormalities, demonstrated a greater reversal of lens
and retina defects compared to systemic injection, and improved retinal function by
ERG and behavioral optokinetic tracking. This study was the first to demonstrate
that an abnormal ocular phenotype could be subject to remodeling and rescue of a
near-normal or normal phenotype after birth in an animal model. These remarkable
research outcomes have led to the design and implementation of an ongoing clinical
trial of ataluren in children and adults with aniridia (NCT02647359).
To date, research of the read-through efficacy of aminoglycosides or ataluren in
cell and animal models has included aniridia, ocular coloboma, Usher Syndrome
Type 1C, choroideremia, and various forms of retinitis pigmentosa [82–84]. Given
the frequency of nonsense mutations in certain ocular disorders and the optimized
delivery system of ataluren that can penetrate both anterior and posterior segment
tissues, the success of nonsense suppression therapy with ataluren has the potential
to be extended and positively impact the phenotype of patients.
For optimal patient management and consideration for the ongoing clinical trial,
patients with aniridia should have a comprehensive testing including PAX6 sequenc-
ing and PAX6/WT1 deletion/duplication studies. PAX6 sequencing will allow detec-
tion of intragenic mutations, including nonsense mutations that would establish the
patient’s eligibility for the clinical trial of ataluren, and PAX6/WT1 deletion/dupli-
cation studies are essential to rule out involvement of the nearby WT1 gene that
increases the risk for Wilms Tumor to 45–57% [85, 86]. In the case of WT1 involve-
ment or in the absence of any PAX6 analyses, children with aniridia should undergo
renal ultrasound every 3 months until age 8 years when the development of Wilms
Tumor is rare. Late-onset Wilms Tumor, delayed involvement of the contralateral
kidney, and high incidence of renal failure with or without a history of Wilms Tumor
justifies a low threshold for ultrasonography, kidney function tests, and nephrology
referral [86–89].
Cilia are highly conserved organelles that exist and function as either motile or
non-motile structures. Motile cilia are primarily found in the ventricles, middle ear,
respiratory tract, and fallopian tubes, where they protrude from the cellular surface
and move in a coordinated, wave-like motion [90–93]. A dysfunction of motile cilia
result in certain diseases in these tissues, such as hydrocephalus, airway disease,
and infertility, or cause a broader effect such as situs inversus totalis [90–92]. Non-
motile, or primary, cilia are expressed in nearly every cell type and therefore have
the potential to result in multisystem dysfunction [91, 93].
The motile and non-motile cilia are structurally similar in that they are both
anchored by a basal body and have a projection, referred to as the axoneme. The
axonemes contain nine paired microtubule structures, where the motile cilia have
an additional, central pair of microtubules. These microtubule configurations are
referred to as 9 + 0 for non-motile cilia and 9 + 2 for motile cilia [94]. Within the
cilia, there are hundreds of proteins responsible for its functions. The synthesis of
these proteins does not occur within the cilium; rather, they are transported through
a process referred to as intraflagellar transport (IFT). IFT is achieved through com-

plexes within the base and along the cilium, which are essential for the protein traf-
ficking to form and maintain cilia [95, 96].
Cilia have essential mechanical, developmental, and sensory roles that, if dys-
functional, result in a spectrum of symptoms and disorders referred to as ciliopa-
thies. The following is a summary of these overlapping roles as they occur in normal
cilia and an example of their effect on a disease process.
1. Mechanosensation. External stimuli including fluid flow, osmotic pressure, heat
shock, touch, and extracellular movement can impact primary cilia [97–100]. In
response, signaling inside the cilium result in changes in length and stiffness
which alter how the cilia interact with their immediate environment. The
mechanical properties and relation to disease are most understood in the setting
of cystic kidney diseases including polycystic kidney disease and nephronophthi-
sis. The relevant proteins (referred to as cystoproteins), have been localized to
the cilia and centrioles and are mislocalized or absent in models in animal mod-
els of cystic kidney diseases [101–104]. Studies have demonstrated the mechani-
cal role of cilia in these diseases, where bending of kidney epithelial cilia initiates
a calcium-mediated response that subsequently affects several signaling path-
ways related to cell proliferation and cystogenesis [104]. As an example, muta-
tions in NPHP1 account for approximately 20% of cases nephronophthisis,
resulting in cyst formation and subsequent renal failure [105, 106].
2. Development. The role of primary cilia in various signaling pathways is still
emerging, but previous work demonstrates that primary cilia modulate Sonic
hedgehog, canonical and non-canonical Wnt, platelet-derived growth factor
(PDGFR), and mTOR pathways [91, 93]. A relevant disease model is Joubert
Syndrome. Mutations in AHI1 account for up to 10% of cases of Joubert
Syndrome and, in humans, primarily causes a neurologic and ocular phenotype
[107]. AHI1 mutations result in cerebellar vermis hypoplasia and the character-
istic “molar tooth sign” on MRI, rod-cone dystrophy, and progressive renal dis-
ease, among other symptoms [107].
3. Sensory. The sensory role of cilium is most prominent in the form of retinal pho-
toreceptors, which are modified primary cilia composed of an outer segment (OS)
and inner segment (IS) bridged by the connecting cilium (CC) and a synaptic end-
ing [108]. Phototransduction occurs in the outer segment and cascades to the CC
and inner segment, which relies on the integrity of IFT [108]. Mutations in ciliary
genes may disrupt the structure or sensory function of the photoreceptor, resulting
in nonsyndromic or syndromic retinal dystrophy [109]. As an example, mutations
in BBS2 result in Bardet-Biedl Syndrome or, rarely, nonsyndromic retinitis pig-
mentosa [110]. The BBS2 protein is localized to the basal body of the cilium and
mutations in this protein may explain BBS2-related retinitis pigmentosa as well as
offer insight to the underlying defect of other retinal ciliopathies, in humans.
Although the individual syndromes are rare, ciliopathies may affect up to 1 in
2000 individuals [111]. Syndromes now recognized as ciliopathies include Alstrom
syndrome, Bardet-Biedl syndrome (BBS) (see Fig. 9.7), Ellis van Creveld syndrome
(EVC), Jeune asphyxiating thoracic syndrome (JATD), Joubert syndrome and
266 K. K. Nischal
Fig. 9.7 Shows a child post collagen cross linking 3 months; the integrated intraoperative OCT
shows the interface where the UV light penetrated to (white arrows) This shows the cross-linking
related disorders (JSRD), Leber Congenital Amaurosis (LCA), McKusick-Kaufman

syndrome (MKKS), Meckel Syndrome (MKS), nephronophthisis (NPHP), orofa-
ciodigital syndromes (OFD), Senior-Loken Syndrome (SNLS), Sensenbrenner syn-
drome, Short-rib polydactyly syndromes (SRPS), and Usher syndrome [112, 113].
Traditionally, the syndromes now recognized as ciliopathies were diagnosed
based on the involved tissues and overall phenotype. With time, it has become
obvious that the overlap between these syndromes is striking and that mutations
in genes associated with these syndromes can even result in a nonsyndromic phe-
notype. This variability has the potential to have a profound impact on medical
management and genetic testing and counseling. Therefore, a low threshold for
pursuing relevant systemic investigations such as renal ultrasound, audiometric
testing, echocardiogram, intracranial imaging, and skeletal survey, in addition to
genetic testing should be considered in all early onset retinal dystrophies.
Retina
Recently, there have been revolutions in the development of both gene medicine
therapy and genome surgical treatments for inherited disorders. Much of this prog-
ress has been centered on hereditary retinal dystrophies, because the eye is an
immune-privileged and anatomically ideal target. Gene therapy treatments, already
demonstrated to be safe and efficacious in numerous clinical trials, are benefitting
from the development of new viral vectors, such as dual and triple adeno-associated
virus (AAV) vectors. CRISPR/Cas9, which revolutionized the field of gene editing,
is being adapted into more precise “high fidelity” and catalytically dead variants.
Newer CRISPR endonucleases, such as CjCas9 and Cas12a, are generating excite-
ment in the field as well. Stem cell therapy has emerged as a promising alternative,
allowing human embryo-derived stem cells and induced pluripotent stem cells to be
edited precisely in vitro and then reintroduced into the body [114–117].
Nystagmus
The field of nystagmus evaluation and management has enjoyed a period of

increased understanding and an expansion of the armamentarium of possible treat-
ments. The value of using drugs including topical dorzolamide, systemic gabapen-
tin and memantine has gained favor but again not all types of nystagmus benefit
from these treatments [118].The use of molecular investigation has revealed that
most cases of X-linked infantile nystagmus are due to mutations in the FRMD7
gene [118]. While surgical regimens for abnormal head posture due to eccentric
null position have been around for many years the advent of the Dell’Osso-Hertle
procedure (horizontal tenotomy and reattachment) has been shown to be as effec-
tive as retroequatorial recessions of the horizontal muscles for infantile nystagmus
without a definite null position [119]. The utility of this new horizontal four-muscle
tenotomy and reattachment his that it is an effective procedure for reducing nystag-
mus, broadening the null position, and improving visual acuity in primary position
for patients with nystagmus [120–122].
Neurophysiology
Previous visual neuroscience research with non-human animal subjects suggests that
visual deprivation early in life results in permanent visual function deficit (amblyopia)
leading to the idea of a ‘critical period’ for acquiring visual function. The implication of
this idea is that children who have been blind since early in life due to cataracts or other
conditions, will not be able to gain functional vision if treated late in childhood. Hence,
there is the belief that such treatments will not result in improvements in their quality of
life. A group from Boston examined the development of contrast sensitivity in a group
of children who had been visually deprived due to cataracts before the age of 1 year and
had had prolonged visual deprivation until their cataracts were operated upon. Contrast
sensitivity is a fundamental metric of visual performance that describes the sensitivity
of neurons and observers and its neural substrate is found in early visual cortex. It is
the primary visual limitation in a variety of tasks, including mobility, reading, and face
and object recognition. In both brain and behavior, contrast sensitivity functions exhibit
a characteristic shape and there is a direct relationship between behavioral and neu-
ral contrast sensitivity. Contrast sensitivity therefore provides a valuable barometer for
visual development and examination of its change following deprivation may provide
fundamental insights into the critical periods of neural plasticity. The group reported
marked improvements in contrats sensitivity functions of a sample of sight restoration
patients who experienced early-onset visual deprivation that remained untreated for an
268 K. K. Nischal
extended duration (the minimum age at treatment was 8 years). These patients exhibited
extremely poor presurgical acuity of, at most, finger counting at a distance of 1 m. Their
findings corroborate studies in animals, demonstrating that visual development is expe-
rience dependent and that critical periods can be extended through delayed exposure to
light [123–127].
In a follow up questionnaire study the participants of the original study reported
improved or newly acquired abilities to travel on their own. Positive improvements were
also seen in other domains, including social interactions and societal attitudes towards
the children and their families. This again showed that treatment for blindness, even at
a late age, can result in significant improvements in a child’s quality of life [124–126].
The take home message therefore is that in bilateral visual deprivation affecting
the anterior segment, it is never too late tom operate and improve visual function.
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Chapter 10
Recent Developments in Ocular Oncology
Bertil Damato
Ocular oncology is advancing rapidly thanks to accelerating progress in genetics,

pathology, ocular and systemic therapies, ocular imaging, and other fields. Because
of the exponential growth of knowledge, it is increasingly difficult for general oph-
thalmologists and other non-oncologists to keep abreast of developments in ocular
oncology especially with more common diseases prioritizing their attention. The
aim of this article is to describe recent trends and achievements in ocular oncology.
This review is not meant to be encyclopedic, as it assumes that the reader is already
reasonably knowledgeable about ocular oncology.
Uveal Melanoma
Prognostication
The most important development, in the author’s opinion, is the discovery that met-
astatic disease from uveal melanoma occurs almost exclusively in patients whose
tumor shows chromosome 3 loss, this genetic abnormality being strongly associated
with high mortality [1]. Extensive research has since revealed a variety of other
genetic aberrations that are associated with metastasis. The most important of these
are chromosome 8q gain, ‘class 2’ gene expression profile, epigenetic alteration,
aberrant expression of preferentially expressed antigen in melanoma (PRAME),
and BRCA1-associated protein 1 (BAP1) mutation [2, 3]. These abnormalities
merely indicate that the tumor has metastatic potential; however, prognostication
B. Damato, MD, PhD (*)

Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe
Hospital, Oxford, UK
https://www.ndcn.ox.ac.uk/team/bertil-damato

276 B. Damato
also requires an estimate of life expectancy. The American Joint Commission on

Cancer (AJCC) has recently updated the TNM (Tumor, Node, Metastasis) stag-
ing system for choroidal melanomas, which categorizes these tumors according to
tumor basal diameter, tumor thickness, ciliary body involvement and extraocular
spread [4]. Survival predictions based only on anatomic findings are only approxi-
mate, however, so that they are relevant only to large groups of patients, as in clinical
trials. As long ago as 2007, the author improved the accuracy of survival prediction
by performing multivariable analysis combining genetic, histologic and anatomic
data, also taking the patient’s age and sex into account [5]. He and associates have
developed predictive tools that are available on the Internet (www.ocularmelano-
maonline.org) [6]. The genetic tumor typing has become more successful thanks to
improved methods of tumor analysis, such as multiplex ligation-dependent probe
amplification (MLPA), next generation sequencing (NGS), and immunohistochemi-
cal analysis of nuclear BAP1 expression [2, 7, 8]. Highly reliable prognostication
has made it possible to confidently reassure patients with a good prognosis while
targeting more intensive systemic surveillance and counseling at high-risk indi-
viduals. These benefits have led to prognostic tumor biopsy of uveal melanoma
becoming routine in a growing number of centers. This, in turn, has resulted in
better biopsy techniques so that experienced surgeons can reliably sample choroidal
tumors with a thickness of less than 1 mm [9–12]. Some have expressed concerns
that biopsy and other surgical manipulations may disseminate tumor cells around
the body to cause metastatic disease. Although the author considers this unlikely,
he and associates have shown that genetic tumor analysis is successful even when
biopsy is performed soon after radiotherapy, at least with MLPA and NGS [13].
Surveillance for Metastatic Disease
Systemic surveillance for early detection of metastatic disease has changed dramatically
over the past few years, with liver function tests and chest x-ray being largely super-
seded by liver imaging. Many centers favor magnetic resonance imaging, which unlike
ultrasonography does not depend on the skill of the examiner for its success and which
does not expose the patient to ionizing radiation, unlike computerized tomography [14].
Magnetic resonance imaging is expensive, however, and also detects abnormalities that
are not metastases [15]. These problems are less troublesome if this investigation is
targeted at patients whose genetic tumor typing indicates a high risk of metastasis [16].
Treatment for Metastasis
Metastases from uveal melanoma are less responsive than cutaneous melanomas
to dacarbazine and other forms of chemotherapy. Interest in agents targeting the
MAPK and PI3K pathways was stimulated by the finding that in uveal melanomas
10 Recent Developments in Ocular Oncology 277
these pathways are usually activated by GNAQ and GNA11 mutations; however,
clinical trials investigating agents such as selumetinib and trametinib have proved
disappointing [17]. With cutaneous melanomas, dramatic remissions have been
achieved with immune checkpoint inhibitors, such ipilimumab and nivolumab,
which inhibit CTLA-4 and PD-1 respectively, thereby enabling cytotoxic T cells to
kill melanoma cells; however, these agents are less effective with uveal melanomas,
which are less immunogenic than cutaneous melanomas because they have fewer
mutations [17]. Encouraging results have recently been reported with Tebentafusp
(IMCgp100) (Immunocore, Abingdon, UK), a synthetic molecule that binds
T-lymphocytes to melanoma cells, causing tumor cell death [18]. Promising results
have also been reported with percutaneous isolated hepatic perfusion with melpha-
lan (Delcath Systems Inc., New York, US) [19]. Prolonged survival occurs in some
patients following partial hepatectomy for isolated liver metastases, but whether this
is the result of treatment or merely selection bias is not known [20]. Other forms of
therapy for hepatic metastases include radiofrequency ablation, radioembolization
with yttrium-90 microspheres, and adoptive transfer of tumor infiltrating lymph-
cytes (TILs) [17]. Patients receiving systemic adjuvant sunitinib have apparently
lived longer than historical controls, but randomized clinical trials are needed to
determine whether this treatment is actually beneficial [21].
Ocular Treatment
It is still not known whether ocular treatment for uveal melanoma influences sur-
vival and, if so, in whom [22]. The Collaborative Ocular Melanoma Study con-
cluded that plaque radiotherapy is as ‘safe’ as enucleation [23]. This is obviously
true in patients whose tumor has already metastasized by the time of diagnosis, and
in those who are fortunate enough never to develop lethal mutations in their tumor,
even if this is left untreated. However, failure of ocular radiotherapy to sterilize
uveal melanoma is well known to be associated with increased mortality and it is
not known whether this is because recurrent tumor actually results in metastasis or
whether tumor recurrence is merely an indicator of increased malignancy. It is also
not known whether it is safe for treatment of small uveal melanomas to be deferred
for months or years until tumor growth is documented [22]. The author had a patient
whose tumor rapidly grew after years of indolent behavior, with the older, basal part
of the tumor showing disomy 3, spindle cells and the newer, apical region showing
monosomy 3, epithelioid cells; the patient developed metastases, which might have
been prevented if she had been treated without delay [24]. The author also reported
a higher prevalence of monosomy 3 melanoma in older patients, hypothesizing that
this is the result of delayed presentation and treatment [25].
Most choroidal melanomas are treated with brachytherapy [26, 27].
Iodine-125 continues to be the preferred isotope for plaque radiotherapy in the
US, whereas ruthenium-106 plaques are more widely used in Europe. With
iodine-125 brachytherapy, collateral damage to healthy ocular tissues has
278 B. Damato
diminished with the development of highly collimated plaques, which are tailored
to each individual tumor using 3-D printing [28]. With ruthenium applicators, irra-
diation of optic nerve and fovea is reduced by positioning the plaque eccentrically in
relation to the tumor, with its posterior edge aligned with the posterior tumor margin
(Fig. 10.1) [29]. This requires a high degree of accuracy, which is achieved with the
use of a template having perforations in which the tip of a right-angled 20-gauge
transilluminator is placed while performing binocular indirect ophthalmoscopy.
Trans-scleral local resection of choroidal melanomas involves removal of the
tumour en bloc through a scleral trapdoor. This operation is not widely performed,
because of technical difficulty and because of the need for hypotensive anesthe-
sia (Fig. 10.2). In expert hands, rhegmatogenous retinal detachment has become
less common with the development of surgical techniques for preventing retinal
tears and preserving the pars plana epithelium [30]. Local tumor recurrence has
become rarer with adjunctive brachytherapy if this is administered with a 25 mm
ruthenium applicator. The author has found that iris conservation during iridocy-
clectomy are improved by administering meiotics instead of mydriatics before
Fig. 10.1 Choroidal
melanoma successfully a
treated with an
eccentrically placed
ruthenium plaque (a)
before treatment, and (b)
months after treatment.
The tumoricidal radiation
dose extends beyond the
visible choroidal atrophy
b
Fig. 10.2 Choroidal
melanoma (a) before and a
(b) after trans-scleral local
resection (also known as
‘exoresection’)
surgery and by excising the tumor postero-anteriorly or circumferentially instead

of antero-posteriorly [31]. With endoresection, the tumour is removed piecemeal
with a vitreous cutter that is passed through the retina, preventing recurrence with
adjunctive laser therapy and, in some cases, radiotherapy. Long-term studies of
endoresection of choroidal melanoma have reported good rates of local tumor con-
trol [32]; however, some authors continue to advocate neoadjuvant radiotherapy
[33]. With trans-retinal endoresection of choroidal melanoma, the most important
development is the use of heavy liquid instead of air to flatten the retina, this
change being prompted by a fatal case of air embolism, which occurred because
of the escape of air through a vortex vein [34].
In some centers, proton beam radiotherapy has replaced resection and plaque
radiotherapy for iris melanoma [35, 36]. Proton beam radiotherapy for more posterior
uveal melanomas has changed little in recent years, except in patients whose upper
eyelid margin cannot be fully retracted out of the radiation field. These cases are now
treated by trans-palpebral proton beam radiotherapy, administered through the closed
280 B. Damato
eyelid to avoid irradiating the lid margin, hence preventing keratinization of the palpe-
bral conjunctiva, which causes painful keratopathy [37]. Proton beam radiotherapy is
becoming more widely available as less expensive technology is developed.
There is growing use of stereotactic radiotherapy as an alternative to proton beam
radiotherapy and brachytherapy, and several authors have reported good results with
this modality [38].
After radiotherapy, many eyes develop macular edema and exudative retinal
detachment, with some also developing iris neovascularization and neovascular
glaucoma [39]. Several years ago, the author found that these complications can be
treated by photoablation or excision of the irradiated tumor, coining the term ‘toxic
tumor syndrome’ for this condition (Fig. 10.3) [39, 40]. Others have reported suc-
cessful prevention and treatment for less severe disease with intraocular injections of
steroids or anti-angiogenic agents, especially in patients who do not have extensive
loss of macular vascularity on optical coherence tomography angiography [41–43].
Detection and Diagnosis
Any opportunities for conserving the eye and vision, and perhaps preventing metas-
tasis are enhanced by early treatment, when the tumor is still small. Ocular oncolo-
gists have a wide range of imaging modalities to differentiate choroidal nevi from
melanomas [44]; however, these facilities are not widely available in the commu-
nity. The author has devised the acronym, MOLES (M, mushroom shape; O, orange
pigment; L, large size; E, enlargement; and S, subretinal fluid) to distinguish cho-
roidal nevi from melanomas and this is currently under evaluation. He has also
a b
Fig. 10.3 Successful treatment of toxic tumour syndrome by endoresection. (a) choroidal mela-
noma with extensive retinal detachment and (b) post-operative result, with a flat retina
developed an online atlas, which organizes tumors according to their location in the
eye and their color in the hope of enabling practitioners to diagnose conditions they
never knew existed (www.oculonco.com).
Quality of Life
A study on more than 1400 patients suggests that irrespective of type of treatment
(i.e., enucleation or radiotherapy), quality of life after treatment for choroidal mela-
noma is not significantly worse than the general population, once factors such as
general health, social support and employment are taken into account [45]. There
is scope for studies evaluating quality of life in patients who have developed severe
radiation-induced ocular morbidity to help predict which patients do better after
primary enucleation.
Further Studies
Clinical trials are under way to evaluate photodynamic therapy for choroidal mela-
noma using intravitreal injections of AU-011, which consists of a phthalocyanine
photosensitizer conjugated with a novel recombinant papillomavirus-like particle
[46]. Improved methods for detecting circulating tumor cells and DNA in the blood
are raising hopes for ‘liquid biopsy’, which if successful would avoid the need for
invasive sampling of intraocular tumors [47, 48]. As mentioned, various forms of
systemic adjuvant therapy for patients with high-risk melanoma are under evalua-
tion. These include Vorinostat, a histone deacetylase (HDAC) inhibitor, as well as
immune checkpoint inhibitors, tyrosine kinase inhibitors, and autologous dendritic
cell vaccines [17]. Studies on germline BAP1 mutation in patients with uveal mela-
noma are in progress following the discovery that some of these tumors develop as
part of the BAP1 tumor predisposition syndrome, which also causes renal cancer,
cutaneous melanoma, mesothelioma and other tumors [49, 50].
Retinoblastoma
Treatment
A major advance in the treatment of retinoblastoma is intravitreal chemotherapy

for eyes with vitreous seeds, which respond poorly to other forms of therapy [51].
This has greatly improved chances of ocular conservation in patients with advanced
disease. Tumor seeding into extraocular tissues is prevented by a variety of mea-
sures, such as using fine needle to inject the drug into the eye and administering
282 B. Damato
cryotherapy to the injection site on withdrawing the needle from the eye. A system
for classifying vitreous seeds has been developed (i.e., dust, spheres, clouds), which
helps to predict the efficacy of intra-vitreal chemotherapy [51]. There has also been
progress in intra-arterial chemotherapy, with improvements in technique and the
use of drugs other than melphalan, such as topotecan [52]. There is ongoing debate
as to how intra-arterial and systemic therapy compare with respect to preventing
pineoblastoma and metastatic disease.
Classification
There are several classification systems for retinoblastoma, the Reese-Ellsworth

method having become less relevant since external beam radiotherapy was super-
seded by chemotherapy. The most widely used is the International Retinoblastoma
Classification (IRC), which categorizes retinoblastomas according to size, extent,
proximity to disc and fovea, seeding and secondary effects; however, different ver-
sions of the IRC exist [53]. The TNM staging system has recently undergone several
refinements, one of which defines heritability of the disease. A limitation of current
staging systems is that they classify whole eyes and not individual tumors in eyes
harboring multiple lesions. There is a need for improved documentation so that clas-
sification systems can evolve in response to advances in imaging and treatment [54].
Genetic Analysis
Advances in genetic techniques makes it possible to identify RB1 mutations that

were previously undetectable [55]. This improved sensitivity has enhanced the
detection of mosicism. A relatively recent discovery is that some retinoblastomas
develop with high levels of MYC amplification in the absence of detectable RB1,
these tumors occurring unilaterally and tending to be highly aggressive, presenting
at a median age of 4 months [56].
Survival
Pineoblastoma is the most common cause of death in the first decade of life in countries
with high-quality care. Survival rates have improved greatly with the development of
aggressive treatment protocols if started early so that patients with germline retinoblas-
toma now undergo screening with 6-monthly brain MRI until the age of around 5 years.
In later life, mortality occurs because of osteosarcomas and other second malignant
neoplasms, especially in patients who have received external beam radiotherapy, which
is why this modality has been abandoned. Early results suggest that proton beam radio-
therapy does not cause second malignant neoplasms, but further studies are needed [57].
There is a need for greater efforts to detect second cancers earlier. There is also a
need for improved awareness of the late physical and emotional effects of retinoblas-
toma and its treatment so that these problems can be addressed in a timely manner.
Uveal Metastases
The epidemiology of uveal metastasis is changing with improvements in therapy

and longer survival times [58].
Diagnosis
The diagnosis of choroidal metastases has become easier with optical coherence
tomography, which shows the surface of these tumors to have a characteristic
‘lumpy-bumpy’ appearance (Fig. 10.4) [59]. Diagnosis has also been enhanced by
improvements in tumor biopsy and immunohistochemistry. In some centers, biopsy
Fig. 10.4 Inferotemporal choroidal metastasis in the left eye. (a) color photograph showing amel-
anotic tumor. (b) Optical coherence tomography (OCT) showing a lumpy appearance
284 B. Damato
is performed without delay, to confirm the diagnosis and to seek clues to the loca-
tion of the primary tumor, if this is not already known [60]. In other centers, intra-
ocular tumor biopsy is performed only as a last resort, if systemic investigations are
uninformative.
Treatment
Previously, patients underwent immediate radiotherapy whereas now there is now a

growing tendency to administer this form of treatment only if systemic therapy fails
to control the ocular tumor [61].
Drug-Induced Ocular Disease
Novel anti-cancer therapies have resulted in a wide variety of adverse effects.

Examples include: blepharitis, poliosis, eyelash trichomegaly, conjunctivitis
and keratopathy from cetuximab, a monoclonal antibody that targets epidermal
growth factor receptor; uveitis and vein occlusion from vemurafenib, a BRAF
inhibitor; conjunctivitis, scleritis and uveitis from ipilimumab, an anti-CLTA-4
monoclonal antibody, which enhances T-cell responses against cancer cells; uve-
itis from nivolumab and pembrolizumab, which are anti-PD-1/PD-L1 monoclo-
nal antibodies; and serous retinal detachment and retinal vein occlusion from
trametinib, a MEK inhibitor [62–64]. The management of patients with these
adverse effects is an expanding role in ocular oncology as is indeed the case with
paraneoplastic syndromes, such as bilateral diffuse uveal melanocytic prolifera-
tion (BDUMP), cancer-associated retinopathy (CAR) and vitrelliform maculopa-
thy, to mention but a few.
Retinal Lymphoma
Terminology
This terms ‘vitreoretinal lymphoma’ and ‘retinal lymphoma’ have replaced ‘pri-
mary intraocular lymphoma (PIOL)’, because intraocular lymphomas comprise
both retinal lymphomas, which are aggressive and highly lethal because of CNS
involvement, as well as indolent uveal lymphomas, which are associated with a
very good survival probability [65]. Retinal lymphoma is becoming more common.
Investigation
Ocular assessment has improved thanks to optical coherence tomography, which

demonstrates lymphoma deposits between the retinal pigment epithelium and
Bruch’s membrane [66]. Another useful development is fundus autofluores-
cence imaging, with hyper-autofluorescence indicating active disease and hypo-
autofluorescence corresponding to areas of inactive RPE atrophy (Fig. 10.5) [67].
Vitreous biopsy often fails to detect lymphoma cells, because these are so fragile,
but diagnosis can still be achieved by detecting immunoglobulin heavy chain rear-
rangements, measuring interleukin-10 protein levels, detecting myeloid differen-
tiation primary response 88 (MYD88) L265P mutation and measuring levels of
particular microRNAs [68, 69]. It can be difficult to differentiate lymphoma from
uveitis, but this task has become easier with the development of metagenomic deep
sequencing, which detects any non-human DNA, also identifying the species of any
infectious organism [70].
Treatment
In many centers, the standard treatment for retinal lymphoma consists of ocular radio-
therapy or intra-vitreal methotrexate and/or rituximab injections [71]. Encouraging
results have recently been reported with intravitreal melphalan injections, which
need to be administered less frequently than methotrexate [72]. Although ocular
therapy suppresses the intraocular disease, it does not prevent mortality from central
a b
Fig. 10.5 Fundus autofluorescence imaging in retinal lymphoma showing hyper-fluorescent sub-
RPE lymphoma deposits and hypofluorescent, atrophic RPE scars. (a) color photograph and (b)
autofluorescence image
286 B. Damato
nervous system disease. Some studies have concluded that systemic therapy does
not prolong survival [73]; however, the author and associates have achieved encour-
aging ocular and systemic outcomes with systemic chemotherapy combined with
maintenance therapy using immunomodulators. These include lenalidomide, which
is effective only in activated B-cell (ABC) lymphoma subtype, and CC-122, which
also induces regression of the germinal center B-cell lymphoma subtype [74, 75].
The author and associates have found that systemic therapy is relatively ineffective
for vitreous infiltrates unless combined with ‘therapeutic vitrectomy’ [76].
Conjunctival Melanoma
There is some evidence that the incidence of conjunctival melanoma is increasing [77].
Grading and Staging
As with other ocular tumors, such as uveal melanoma and retinoblastoma, the
Tumor, Node, Metastasis (TNM) staging of conjunctival melanomas has been
refined. One significant improvement is the incorporation of in-situ melanoma
in this classification (Tis). A scoring system has been developed to grade con-
junctival melanocytic intra-epithelial neoplasia (otherwise known as primary
acquired melanosis [PAM] with atypia) more objectively according to the den-
sity of melanoma cells in the epithelium and the degree of cellular atypia [78].
Sentinel lymph node biopsy is reported to improve prognostication but has yet to
be accepted widely [79].
Treatment
Many centers continue to treat invasive conjunctival melanoma by excision with

wide margins, adjunctive cryotherapy, and amniotic membrane grafting [80];
however, the author prefers excision with narrow safety margins and wound clo-
sure by primary intention without grafting, administering adjunctive radiother-
apy and, in patients with diffuse intra-epithelial disease, adjunctive mitomycin C
drops [81]. The author has found that comfort and compliance are improved by
prescribing this topical chemotherapy for only 1 week per month for 4 months,
instead of two 14-day courses over 6 weeks, as originally recommended.
Successful treatment with interferon alpha-2a has also been reported [82, 83].
BRAF mutation is found in about 40% of conjunctival melanomas, many
of which are responsive to systemic treatment with a BRAF inhibitor, such as
vemurafenib (Zelboraf) [84, 85]. As with cutaneous melanoma, metastases from
c onjunctival melanoma can respond to systemic treatment with immune check-

point inhibitors [86, 87].
Conjunctival Carcinoma
Conjunctival squamous intra-epithelial neoplasias and invasive carcinomas are

common, especially in hot, sunny climates [88].
Investigation
The development of optical coherence tomography has made it easier to differenti-

ate CISN/CCIN from other conditions; however, most surgeons continue to perform
biopsy to establish the diagnosis [89].
Treatment
Invasive conjunctival carcinomas are treated by excision, with adjunctive cryo-

therapy or radiotherapy. In many centers, the preferred treatment for primary
or secondary in-situ disease is topical interferon, administered 4 times per day
continuously for 3–6 months [90]. The author has achieved good results with
5-FU drops, administered four times daily for only 4 days a month for 4 months
[91]. The 5-FU drops are less expensive than interferon and do not require
refrigeration.
Other Developments
Increasingly, patients with ocular malignancy are being treated at specialist ocu-
lar oncology centers. This is because of the need for specialized equipment and
expertise, and also because of a greater awareness of the need for holistic care,
best provided by experienced multidisciplinary teams, which address psychologi-
cal and general health issues in addition to treating the ocular tumor. Patients’
expectations are increasing so that they are dissatisfied if they are not adequately
informed of all the risks and benefits of every management option, in a caring
manner, and if the emotional support they receive is deficient. The Internet has led
to the formation of patient advocacy groups so that patients and their families are
better informed about their condition and the standards of care being delivered in
different centers.
288 B. Damato
Conclusion
Patients expect their local, non-specialist ophthalmologist to be knowledgeable

about their disease when their tumor is first detected and during long-term follow
up after completion of their treatment at an ocular oncology center. It is hoped that
the present update will be helpful in this respect.
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Index
A Aphakic glasses, 86
Abatacept, 229 Apodized diffractive lenses, 6
Abicipar pegol (Allergan), 155 Artificial intelligence, 149
Accommodating IOLs, 63 Artiflex phakic IOL, 24, 25
Accommodative lenses, 5 Artisan, 24
Acrylic lenses, 62 Artisan/Verisyse toric pIOL, 24, 25
AcrySof Cachet pIOL, 24 AT LISA® tri 839 MP, 6, 7
AcrySof® Restor® SN6AD3, 11, 12 Ataluren, 263
Acute disseminated encephalomyelopathy
(ADEM), 203
Acute retinal necrosis (ARN), 123, 131 B
Adalimumab, 128 Bardet Biedl syndrome, 256
Adaptive optics (AO), 103 Barotraumatic phenomenon, 214
Adaptive Optics OCT (AO-OCT) devices, 145 Bausch + Lomb hypersonic
Adaptive optics scanning light vitrector, 175
ophthalmoscopy (AO-SLO), 103 Bausch + Lomb Millenium Microsurgical
Adeno-associated virus (AAV), 156 System, 170
Aflibercept, 154, 155 Bausch + Lomb Stellaris Elite, 175
Age related macular degeneration (AMD), 146 Bausch + Lomb Stellaris PC., 174
Air-viscobubble (AVB) dissection, 42, 43 Beaver Dam Eye Study, 64
Alcon Accurus machine, 171 Behcet’s disease (BD), 125, 126
Alcon Constellation machine, 172 Bevacizumab, 154
Alzheimer disease, 219 Bilateral cataracts, 258
Ametropia, 64 Bimanual phacoemulsification, 72
Amiodarone, 212 Bimatoprost ocular ring, 108
Amiodarone-associated optic Bimatoprost sustained-release (SR)
neuropathy (AAON), 212 intracameral implant, 108, 109
Aneurysms, 233 BiocomFold 89A, 14
Angiogenesis, 154 Biometry
Angiotensin converting enzyme (ACE), 125 contact A-mode biometry, 58
Angle fixated pIOL, 24 optical biometry, 58, 59
Aniridia, 263 ultrasound, 58
Anterior chamber IOL, 63, 86 Boston Kpro type I, 50
Anterior uveitis (AU), 124 Boston Kpro type II, 50
Anterior-chamber pIOL, 23 Brolucizumab, 155
Antiplatelet, 56, 57 Buettner, Helmut, 166

https://doi.org/10.1007/978-3-030-25389-9
296 Index
C Cenegermin, 35, 36
Calcification, 85 Central serous chorioretinopathy, 152
Cannula Big Bubble, 42 Chang, Stanley, 187
Capsular contraction syndrome, 14 Charles, Steven, 185
Cataract surgery Choroidal melanoma, 278, 279
AMD, 65 Choroidal neovascularization (CNV), 122
and anticoagulants, 56, 57 Chronic relapsing inflammatory optic
benchmarking, 62 neuropathy (CRION), 206
biometry Ciliopathies, 263, 265
contact A-mode biometry, 58 Clear corneal incision (CCI), 57, 72–74
corneal indentation, 58 Collagen cross linking (CXL), 37, 253
optical biometry, 58, 59 Color vision deficiencies, 208
ultrasound, 58 Congenital corneal anesthesia, 252
combined surgeries Congenital corneal opacities, 254
anesthesia, 66, 67 Conjunctival carcinoma
bilateral operation, 68 investigation, 287
combined phacoemulsification and treatment, 287
vitrectomy, 65 Conjunctival limbal autograft, 48
combined phacoemulsification with Conjunctival melanoma
intraocular lens implantation and grading and staging, 286
keratoplasty, 65, 66 treatment, 286
complications, 67 Constellation Vision System, 184
lens opacification, 65 Contact A-mode biometry, 58
settings, 66 Contrast sensitivity function, 7
corneal power assessment, 57, 58 Conventional fundus photography, 122
and glaucoma, 64 Convergence insufficiency, 209
intraoperative considerations Cornea
dropless cataract surgery, 77 corneal infections
FLACS, 71 collagen cross-linking (CXL), 37
ICCE vs. ECCE, 68–70 diagnostic investigation, 36
intraoperative complications, povidone-iodine (PVI), 37
74–76 dry eye disease, 37, 38
MICS, 71, 72 neurotrophic keratopathy,
phacoemulsification, 70 NGF treatment, 35, 36
posterior capsulotomy, 77 Corneal endothelial dysfunction, 46
retained lens fragments and nucleus Corneal inlays
luxation, 76, 77 advantages and disadvantages, 2
wound construction, 72–74 corneal curvature, 2
IOL calculation formula, 60, 61 corneal reshaping inlays, 2
IOL types, 62–64 intracorneal inlays, 4
postoperative complications multifocality, 4, 5
Aphakic management, 86 refractive inlays, 2
IOP spikes, 83, 84 Flexivue Microlens™, 3
late postoperative IOL opacifications, Icolens™, 3, 4
84–86 small aperture inlays, 2–4
PCME, 79, 80 Corneal neurotization procedure, 252
PCO, 81 Corneal opacities, 67
postoperative day 1 (POD1), 78, 79 Corneal tomography, 57, 58
postoperative endophthalmitis (POE), Corneal topography, 58
81–83 Corneal transplantation
prevalence, 78 artificial cornea (keratoprosthesis)
TASS, 82 surgery, 39
postoperative examinations, 78 DALK (see Deep anterior lamellar
preoperative examinations, 56 keratoplasty)
Index 297
endothelial keratoplasty (see Endothelial Descemetorhexis, 46

keratoplasty) Diagnostic and Classification Criteria in
limbal stem cell deficiency (LSCD), 47 Vasculitis Study (DCVAS), 217
ocular surface reconstruction, 39 Diagnostic techniques, 124
ocular surface transplantation Diathermy, 187
conjunctival limbal autograft, 48 Dodo, Tsugio, 165
ex-vivo cultured graft, 50 DORC EVA machine, 173
keratolimbal allograft, 48 Dropless cataract surgery, 77
keratoprosthesis, 50 Drug-induced ocular disease, 284
lr-CLAU, 49 Dry eye disease (DED), 37, 38
ocular surface diseases Dual optic IOL, 15, 16
classification, 47, 48 Dual-optic lenses, 16
procedure selection, 47
SLET, 48
penetrating keratoplasty (PK), 38 E
techniques comparison, 39–41 Eckardt, Claus, 167
Corneal tunnel incisions, 72 Electroadaptive accommodating IOL, 19
Corticosteroids, 127 Endolasers, 186
CrystaLens®, 13, 14 Endothelial keratoplasty (EK), 39
Cultivated limbal epithelial transplantation advantages and disadvantages, 43, 44
(CLET), 50 DMEK, 45, 46
Cultivated oral mucosal epithelial DSAEK, 44
transplantation (COMET), 50 endothelium disfunction treatment, 43
C-Well, 15 ROCK inhibitor, 46
CyPass Micro-Stent, 111, 112 European Society of Cataract and
Refractive Surgeons
(ESCRS) study, 83
D Extended depth-of-focus (EDOF) lenses, 5
de Juan , Eugene, 167 MiniWell, 9, 10
Deep anterior lamellar keratoplasty (DALK), 39 strategies, 9
advantages, 43 Wichterle Intraocular Lens-Continuous
AVB, 42, 43 Focus (WIOL-CF), 10
cannula Big Bubble, 42 Extendible Diamond Dusted
corneal stromal layer disorders, 39 Sweeper, 185
dangerous infectious stromal keratitis, 39 Extracapsular cataract extraction
Descemet membrane, 41 (ECCE), 69, 70
endothelium cells, 43 Extrusion cannulas, 186
epithelial rejection, 43 Ex-vivo cultured graft, 50
graft survival, 43
indications, 39
intraoperative and postoperative F
complications, 43 Femtosecond Laser-Assisted Cataract Surgery
Keratoconus, 39 (FLACS), 71
needle Big Bubble technique, 41 FineVision® Micro F, 7
rejection rate, 43 Flexivue Microlens™, 3
stromal rejection, 43 FluidVision®, 16
subepithelial rejection, 43 Fluorescein angiography (FA), 122, 141, 143
Dell’Osso-Hertle procedure, 267 Forceps, 185
Delphi process, 259 Four-dimensional (4-D) OCT imaging, 191
Descemet membrane (DM), 41, 45 Fuchs endothelial corneal dystrophy
Descemet Membrane Endothelial Keratoplasty (FECD), 46
(DMEK), 45, 46 Fujii, Gildo, 167
Descemet stripping automated endothelial Fundus autofluorescence (FAF) imaging,
Keratoplasty (DSAEK), 44 147, 149
298 Index
G Hybrid lenses
Ganglion cell layer (GCL), 100 AcrySof® Restor® SN6AD3, 11, 12
Ganglion cell-inner plexiform layer (GC-IPL), Lentis® Mplus LS-313, 12, 13
100 Panoptix®, 12
Gene therapy, 156, 158, 231 Tecnis® Symfony, 13
Genome-wide association studies (GWAS), 261 Hydrodelineation, 74
Giant cell arteritis (GCA), 216, 228, 229 Hydrophobic acrylic IOL
Glaucoma gross photograph, 85
bilateral blindness, 99 light photomicrograph, 84
imaging Hydrus Microstent, 111
adaptive optics, 103
OCT (see Optical coherence
tomography) I
irreversible blindness, 99 IC-8 small-aperture IOL, 10, 11
laser and surgery Icolens™, 3, 4
laser iridotomy, 109 Idebenone, 230
lens extraction, angle-closure iDose, 109
glaucoma, 110 Iluvien implant, 155
minimally invasive glaucoma surgery, Immediate sequential bilateral cataract surgery
110–113 (ISBCS), 68
primary trabeculectomy/tube surgery, 110 In vivo confocal microscopy, 36
medical therapy Indocyanine green angiography (ICGA), 143
bimatoprost ocular ring, 108 Infant Aphakia Treatment study, 258
bimatoprost sustained-release implant, Infliximab, 128
108, 109 InnFocus MicroShunt, 112, 113
iDose, 109 Internal limiting membrane (ILM) forceps, 185
latanoprostene bunod, 107 Intracapsular cataract extraction
ROCK inhibitors, 106, 107 (ICCE), 68–70
travoprost punctum plug, 108 Intraflagellar transport (IFT), 265
visual field testing Intranasal neurostimolator, 38
free tablet-based perimetry Intraocular lens (IOL)
application, 106 banking, 56
fundus-tracked calculation formula, 60, 61
perimetry/microperimetry, 105 hydrophobic acrylic IOL
home-based perimetry, 106 gross photograph, 84, 85
Humphrey Field Analyzer, 106 light photomicrograph, 84
portable perimetry, 106 late postoperative IOL opacifications,
tablet-based perimetry, 106 84–86
testing strategies and novel MemoryLens IOL,
thresholding algorithms, 104, 105 light photomicrograph, 85
Glaucomatous optic neuropathy, 219 optical properties, 63
Glial fibrillary acidic protein (GFAP), types, 62–64
205, 206 Intraocular pressure (IOP), 214
Glistening, 84, 85 reduction, 102
Gradient-Oriented Automated Natural spikes, 83, 84
Neighbor Approach (GOANNA), Intraoperative floppy iris syndrome (IFIS), 75
104 Intravitreal anti-vascular endothelial growth
factor, 80
Iris-fixated or “iris claw” lens, 24, 25
H iStent, 111
Hagen-Poiseuille equation, 112
Heintz, Ralph, 166
Hickingbotham, Dyson, 166 J
Horizontal scissors, 186 Juvene accommodating IOL, 17, 18
Index 299
K McDonald Criteria, 202

Kamra Inlay™, 3, 4 Mechanosensation, 265
Kasner, David, 165 Membrane scrapers, 185
Kelman Duet Implant Phakic IOL, 24 MemoryLens IOL, 85
Keratolimbal allograft (KLAL), 48 Methanol toxicity, 211
Keratoprosthesis, 50 M-Flex 630F, 9
Micro-incisional cataract surgery
(MICS), 71, 72
L Minimally invasive glaucoma surgery
Laser-assisted in situ keratomileusis (MIGS), 110–113
(LASIK), 20, 21 Minimum distance band (MDB), 100
Laser iridotomy, 109 MiniWell, 9, 10
Latanoprost, 107 Mitochondrial replacement therapy
Latanoprostene bunod, 107 (MRT), 231
Leber hereditary optic neuropathy (LHON), Monofocal IOLs, 63
211, 230 Multicenter Uveitis Steroid Treatment
Leber’s Congenital Amaurosis (LCA), 157 (MUST) trial, 129
Lensectomy, 184 Multifocal IOLs, 63
Lentis® Mplus LS-313, 12, 13 Multiple sclerosis (MS), 202, 215, 222, 225
Lentiviral vectors, 156 Myasthenia gravis (MG) antibodies, 217, 218
Lidocaine, 75 Myelin oligodendrocyte glycoprotein (MOG),
Light Adjustable Lens (LAL), 64 203–205
Limbal stem cell deficiency (LSCD), 47 Myopia control, 261, 262
Linezolide, 212
LiquiLens, 19
Living related conjunctival limbal allograft N
(lr- CLAL), 49 Nanoparticles (NPs), 157
Long-term corticosteroid implants, 129 Near-infrared autofluorescence imaging
Lumina®, 18, 19 (NIR-AF), 147
Needle Big Bubble technique, 41
Netarsudil, 107
M Neuroadaptation, 5
Machemer, Robert, 166 Neuro-degenerative diseases, 208
Macular Edema Ranibizumab vs. Intravitreal Neuro endovascular intervention
Anti-inflammatory Therapy aneurysms, 233
(MERIT) trial, 130 venous sinus stenting in PTC, 235
Maculopathies Neuro-immunology, 201
intravitreal treatments, 153, 155, 156 Neuromyelitis Optica (NMO), 202
non-surgical treatments, 156, 158, 159 Neurophysiology, 267, 268
retinal imaging techniques Neurostimulation, 38
fluorescein angiography (FA), 141 Neurotrophic keratopathy (NK), 35, 36
fundus autofluorescence (FAF) Ngenuity 3-D viewing system, 181
imaging, 147 NMO spectrum disorder (NMOSD), 203
indocyanine green angiography Non-infectious uveitis, 124, 125
(ICGA), 143 Nonsense suppression therapy
optical coherence tomography (OCT), (NST), 263, 264
144, 145 “Normal-tension glaucoma” (NTG), 214
optical coherence tomography NuLens®, 17
angiography (OCTA), 146 Nutritional optic neuropathies, 213
Magnet-driven active shift IOL, 19
Magnetic Resonance Imaging in MS
(MAGNIMS) committee, 215 O
Manual small incision cataract surgery O’Malley, Conor, 166
(MSICS), 69, 70 Ocular glymphatic system, 215
300 Index
Ocular myasthenia gravis (OMG), 217 Pediatric ophthalmology

Ocular surface transplantation cornea, 251, 254, 258
conjunctival limbal autograft, 48 molecular genetics, 263–265
ex-vivo cultured graft, 50 neurophysiology, 267, 268
keratolimbal allograft, 48 nystagmus evaluation and
keratoprosthesis, 50 management, 267
lr-CLAU, 49 pediatric cataract, 258, 260
ocular surface diseases classification, 47 refractive error, 260–262
procedure selection, 47 retina, 266
SLET, 48 Penetrating keratoplasty (PK), 38
1CU®, 14, 15 Perfluorocarbon, 187
OPAL, 15 Perfluorocarbon liquid, 187
Open sky technique, 165 Peribulbar anesthesia, 169
Optical biometry, 58, 59 Periocular and Intravitreal Corticosteroids for
Optical coherence tomography (OCT), 80, Uveitis Macular Edema (POINT)
144, 145 trial, 130
diagnosis and monitoring, 219 Peripheral iridotomies, 24
neurodegenerative disease, 219 Peyman, Gholam, 166, 167
OCT-A, 101–103 Phacoemulsification, 70, 184
optic disc elevation, 219 Phacoemulsification cataract surgery
three-dimensional optical coherence (PCS), 56
tomography, 100, 101 Phakic Intraocular Lenses (pIOL), 23–25
wide-field swept-source optical coherence Phosphodiesterase-5 (PDE-5) inhibitors, 213
tomography, 101 Photorefractive keratectomy (PRK), 20
Optical coherence tomography angiography Pirenoxine eyedrops, 2
(OCTA), 101–103, 122, 146 Polarization-sensitive OCT (PS-OCT), 146
in LHON, 226, 227 Polymerase chain reaction (PCR), 36, 131
in multiple sclerosis, 225 Polymethyl methacrylate (PMMA), 50
in optic neuropathies, 225 Position-changing IOL, 13, 14
Optic disc elevation, 219 Posterior capsule opacification (PCO), 81
Optic disc margin, 100 Posterior capsule rupture (PCR), 74
Optic nerve sheath meningioma Posterior capsulotomy, 77
(ONSM), 229, 230 Posterior chamber lenses, 62
Optic pathway gliomas, 229 Posterior-chamber pIOL, 25
Oral corticosteroids, 127 Postoperative endophthalmitis (POE), 81–83
Orthokeratology contact lenses, 261 Povidone-iodine (PVI), 37
Osteo-odonto-keratoprosthesis (OOKP), 50 Power-changing IOL, 18, 19
Premature termination codons (PTC), 263
Primary angle closure (PAC), 110
P Primary open-angle glaucoma (POAG), 214
Paediatric keratoconus, 254 Primary tube versus trabeculectomy
Panoptix®, 12 (PTVT), 110
Parel, Jean-Marie, 166, 167 Progressive supranuclear palsy, 209
Parkinson disease (PD), 222 Pseudoexfoliation syndrome (XFS), 76
color vision, 208 Pseudophakic ametropias, 64
convergence insufficiency, 209 Pseudophakic cystoid macular edema
progressive supranuclear palsy, 209 (PCME), 64, 79, 80
saccades, 208 Pseudophakic presbyopic IOL
smooth pursuit eye movements, 208 accommodative lenses, 5
stereopsis, 209 bifocal IOL’s, 5
visual contrast sensitivity, 208 EDOF, 5
Pars plana vitrectomy (PPV), 76, 77, 166, 168 multifocal IOL’s, 5
Pediatric capsule management, 259 neuroadaptation, 5
Pediatric keratoplasty, 257 optical profiles
Index 301
accommodating IOLs, 13–19 S

diffractive multifocal IOL’s, 6, 7 Saccades, 208
EDOF lenses, 9, 10 Sarcoidosis, 124, 125
hybrid lenses, 11–13 Sarfarazi®, 16, 17
refractive multifocal IOL’s, 8, 9 Sarilumab, 128
preoperative evaluation and planning, 5 Scleral buckling (SB), 189
rotationally asymmetric or varifocal Scleral incisions, 72–74
IOLs, 5 Scleral tunnel incisions, 72
rotationally symmetrical IOL’s, 5 Secondary piggyback IOLs, 64
trifocal IOL’s, 5 Secukinumab, 128
Pseudotumor cerebri (PTC), 236 SeeLens, 7
Sensory, 265
Shape-changing IOL, 16, 18
R Silicone lenses, 62
Raindrop™, 2 Simple limbal epithelial transplant (SLET), 48
Randomized controlled trials (RCT), 258 Single-piece IOLs, 62
Ranibizumab, 154, 155 Small Incision Lenticule Extraction
Ray-tracing, 61 (SMILE), 22
Recurrent optic neuritis, 206 SN6AD3 model, 11, 12
Refractive laser procedures Soft-tip extrusion cannulas, 186
excimer laser, 19 Space flight-associated neuro-ocular syndrome
femtosecond laser, 20 (SANS), 210
LASIK, 20, 21 Spatially Weighted Likelihoods in Zippy
photorefractive keratectomy (PRK), 20 Estimation by Sequential Testing
SMILE, 22 (SWeLZ), 104
Refractive surgery Spondyloarthritis, 124
ablative, 19 Squalamine, 155
ammetropia, 1 Standardization of Uveitis Nomenclature
Corneal inlays (see Corneal inlays) (SUN), 121, 122
laser procedure (see Refractive laser Stellaris Elite Vision Enhancement System, 171
procedure) Stereopsis, 209
phakic intraocular lenses (pIOL), 23–25 Storz Daisy machine, 170
presbyopia, pharmacologic treatment, 1, 2 Structure Estimation of Minimum Uncertainty
pseudophakic presbyopic IOL’s (SEMU), 104, 105
(see Pseudophakic presbyopic Subretinal injections, 188
IOL’s) Subretinal microphotodiode-array, 158
Retinal detachments, 187 Subsurface nanoglistenings (SSNGs), 84
Retinal ischemia, 123 Sub-Tenon’s space, 169
Retinal nerve fiber layer (RNFL), 100 Swept-source optical coherence tomography
Retinal pigment epithelium (RPE), 100 (SS-OCT), 101, 123
Retinitis pigmentosa, 157 Synchrony®, 15, 16
Retinoblastoma
classification, 282
genetic analysis, 282 T
survival, 282 Tecnis® Symfony, 13
treatment, 281, 282 Tek-Clear, 15
Retrobulbar anesthesia, 168–169 Telemedicine, 149
Rezoom, 8, 9 Tetraflex®, 14, 15
Rho kinase (ROCK) inhibitor, 46 Three-piece IOLs, 62
corneal endothelial dysfunction, 46 Time-domain technology (TD-OCT), 145
glaucoma, 106, 107 Timolol, 107
Ripasudil, 107 Tocilizumab, 228
Routine preoperative non-ophthalmic medical Topical anesthesia, 169
testing, 56 Toxic anterior segment syndrome (TASS), 82
302 Index
Toxic-nutritional optic neuropathies (TNON) Visian ICL, 25, 26

alcohol and tobacco, role of, 214 Visual rehabilitation, 65
medication-induced optic neuropathies, Visual restoration therapy, 231, 232
212, 213 Vitrectomized eyes, 45
nutritional optic neuropathies, 213 Vitreo-retinal lymphoma
toxins, 211 investigation, 285
Toxic tumour syndrome, 280 terminology, 284
Toxoplasmosis, 132 treatment, 285
Traumatic cataract, 257 Vitreo-retinal surgery
Traumatic corneal scar, 257 cannula-trocar systems, 172
Travoprost punctum plug (OTX-TP), 108 four-dimensional (4-D) OCT imaging, 191
TriMoxi, 77 history of, 165, 167
TriMoxiVanc, 77 instrumentation, 184, 187
Tuberculosis (TB), 132 lensectomy and phacoemulsification, 184
perfluorocarbon liquid, 187
postoperative considerations and
U complications, 168, 191
Ultra-wide-field (UWF) imaging, 122 robotics in, 191
Uncorrected distance visual acuity (UDVA), 2 scleral buckling (SB), 189
Uncorrected near visual acuity (UNVA), 2 subretinal injections, 188
Uveal melanoma tamponade agents, 190
detection and diagnosis, 280 viewing systems
metastatic disease, systemic surveillance chromovitrectomy, 183
for, 276 illumination and filters, 181
ocular treatment, 277, 280 lens, 178
prognostication, 275 microscopes, 176
quality of life, 281 three-dimensional (3-D) viewing
treatment for metastasis, 276 techniques, 179
Uveal metastasis vitrectomy systems, 169
diagnosis, 283 Vitreous infusion suction cutter (VISC), 167
treatment, 284 Vitrophage, 167
Uveitis Vogt-Koyanagi-Harada syndrome (VKH), 123
acute retinal necrosis (ARN), 131 Voretigene neparvovec-rzyl, 157
anterior uveitis (AU), 124 Voretigene therapy, 157
Behcet’s disease (BD), 126
imaging modalities, 122, 124
non-infectious uveitis treatment, W
127, 129, 130 Wichterle Intraocular Lens-Continuous
sarcoidosis, 124, 125 Focus (WIOL-CF), 10
spondyloarthritis, 124 Wide-field swept-source optical coherence
standardization of nomenclature, 121 tomography, 101
Standardization of Uveitis Nomenclature
(SUN), 122
toxoplasmosis, 132 X
tuberculosis (TB), 132 X-linked infantile nystagmus, 267
Xtrafocus Pinhole Implant, 10, 11
V
Valved cannulas, 176 Z
Venous sinus stenosis, 236 ZB5M lens, 24
Vertical scissors, 186 ZSAL4, 24

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ISBN 978-3-030-25388-2 ISBN 978-3-030-25389-9 (eBook)

© Springer Nature Switzerland AG 2020

1 Updates in Refractive Surgery���������������������������������������������������������������� 1

9 Recent Advances in Pediatric Ophthalmology�������������������������������������� 251

The correction of refractive errors—hyperopia, myopia, astigmatism, and presby-

Pharmacologic Treatment of Presbyopia

© Springer Nature Switzerland AG 2020 1

Table 1.1 Advantages and disadvantages of corneal inlays

Fig. 1.2 Icolens® inlay [18]

Fig. 1.3 Kamra® inlay [26]

The idea of using intracorneal inlays to obtain multifocality is interesting, it is an

implantation. Other concerns that need to be addressed include late complications

 seudophakic Presbyopic IOL’s: Conceptual Issues

Optical Profiles of Presbyopic Pseudophakic Lenses

Diffractive Multifocal IOL’s

Fig. 1.4 AT LISA® tri

Refractive Multifocal IOL’s

Refractive IOLs use concentric zones of different dioptric powers to achieve

Near vision for

Extended Depth-of-Focus Lenses

Extended depth-of-focus or EDOF lenses comprise a relatively more recent class

Fig. 1.7 The M-Flex

Fig. 1.9 The IC-8 Small

Fig. 1.10 The Xtrafocus

Fig. 1.11 AcrySof® Restor

Fig. 1.12 Lentis® Mplus

Accommodating IOLs supposedly undergo a progressive dioptric power change in

Fig. 1.14 A schematic

Fig. 1.15 Schematic diagram

Fig. 1.19 Nulens IOL [149]

3.2 mm incision after which another fluid-based shape-changing lens is inserted

Fig. 1.21 Lumina IOL.

move centripetally in opposite directions to increase optical lens power. Ciliary

Refractive Laser Procedures

Small Incision Lenticule Extraction (SMILE) is an all-femtosecond laser flapless

Phakic Intraocular Lenses

evaluated, as there is a need to preserve the endothelial cell density to accommodate

Fig. 1.23 The Artisan

Fig. 1.24 The Artiflex

Fig. 1.25 The Visian ICL

1. Renna A, Alió J, Vejarano L. Pharmacological treatments of presbyopia: a review of modern

3. Patel S, Salamun F, Matovic K. Pharmacological correction of presbyopia. In: Poster

Caterina Sarnicola, Enrica Sarnicola, Paolo Perri, and Vincenzo Sarnicola

NGF Treatment for Neurotrophic Keratopathy

Neurotrophic Keratopathy (NK) results from impaired corneal innervation which

C. Sarnicola (*) · E. Sarnicola

© Springer Nature Switzerland AG 2020 35

Highlights on Corneal Infections

Cultural exam remains the prevalent diagnostic procedure. However other

Collagen Cross-Linking (CXL) for Corneal Infections

CXL is a procedure which uses UV light and a photosensitizer (riboflavin) to

Povidone-Iodine (PVI) and Corneal Infections

Dry Eye Disease

Table 2.1 Dry eye etiology

larity, ocular surface inflammation and damage, and neurosensory abnormalities

Fig. 2.2 Evolution from penetrating keratoplasty to lamellar corneal transplant

Deep anterior lamellar keratoplasty (DALK) is replacing penetrating kerato-

DALK: Deep Anterior Lamellar Keratoplasty

1 Updates in Refractive Surgery�� 1

9 Recent Advances in Pediatric Ophthalmology�� 251

Pharmacologic Treatment of Presbyopia

seudophakic Presbyopic IOL’s: Conceptual Issues

Optical Profiles of Presbyopic Pseudophakic Lenses

Diffractive Multifocal IOL’s

Refractive Multifocal IOL’s

Extended Depth-of-Focus Lenses

Refractive Laser Procedures

Phakic Intraocular Lenses

NGF Treatment for Neurotrophic Keratopathy

Highlights on Corneal Infections

Collagen Cross-Linking (CXL) for Corneal Infections

Povidone-Iodine (PVI) and Corneal Infections

Dry Eye Disease

DALK: Deep Anterior Lamellar Keratoplasty

Needle Big Bubble Technique

Cannula Big Bubble

Endothelial Keratoplasty (EK)

Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)

Descemet Membrane Endothelial Keratoplasty (DMEK)

uture Directions: Rho Kinase (ROCK) Inhibitor for Corneal Endothelial

imbal Stem Cell Deficiency and Ocular Surface

Surgical Options for the Ocular Surface Reconstruction

Anticoagulants and Cataract Surgery

Methods for Assessing Corneal Power

IOL Calculation Formulas

Glaucoma and Cataract Surgery

AMD and Cataract Surgery

Combined Surgeries (Efficacy vs Safety)

ettings (Ambulatory or Hospitalization, Operating Theater

Anesthesia (Topical vs Peribulbar vs Retrobulbar vs General)

Difficult Cases: Increased Risk of Complications

Intracapsular vs Extracapsular Cataract Extraction

Femtosecond Laser-Assisted Cataract Surgery (FLACS)

Micro-incisional Cataract Surgery (MICS)

Retained Lens Fragments and Nucleus Luxation

Dropless Cataract Surgery

Postoperative Follow Ups