Ke

rat
oconus
TheWholeStory

Mo
ata
zM.
Wes
sam
Keratoconus
The whole story

Moataz M. Wessam
First edition, 2021
 I
Preface

Moataz M. Wessam
Author & Editor
MD, FRCS, ICO, M.Sc.
Cornea and Cataract Consultant.
Lecturer of Ophthalmology – Ain Shams University,
Cairo, Egypt.
drmoatazwessam@gmail.com
www.drmoatazwessam.com
Dr. Moataz Wessam

Keratoconus patients are challenging to any cornea specialist, trying to apply his
best experience to get satisfactory results. The aim of any cornea specialist is not
to diagnose an established keratoconus case, but to early detect any suspicious
one during routine screening. Early detection of suspected cases gives an
opportunity for proper counseling and management. In suspect cases visual
acuity is not markedly affected so, it is a golden period to mainatin a functioning
vision.

This book will discuss keratoconus in a stepwise approach starting with

classification of ectatic corneal diseases this will be followed by detailed
information about keratoconus epidemiology including its incidence in pediatric
age group, the importance of family history and risk factors as eye rubbing and
atopy. Clinical examination of keratoconus patients may be completely normal
so, this book will discuss the most important clinical examinations that should be
done and signs that may be found either early or late. Patterns of keratoconus are
classified to the most practical classification that helps in better recognition of
keratoconus. It’s important to grade keratoconus patients in order to take the right
decision, you will find in this book most of the clinical gradings written in
literature including the old and up to date ones. Till now no gold standard criteria
present to assess the progression of keratoconus, this book collects the most
clinically accepted criteria including the up to date software available to monitor
 II
Preface

keratoconus progression. One of the most important chapters in this book is the
diagnostic tools from routine topography and tomography to studying corneal
epithelium and studying corneal biomechanics with brillouin microscopy and
ending up with artificial intelligence that plays an important role in aiding the
diagnosis not only in ophthalmology but in other medical fields. Nowadays we
are facing multiple armamentarial modalities for treating keratoconus. Corneal
cross linking is one of the main arms in treating keratoconus. This book will get
you deep to better understand cross linking from its evolution till nowadays with
the most recent protocols. Corneal cross linking in pediatric keratoconus is also
discussed with the most acceptable protocols in literature. From my readings in
literature, I found no book that collects intracorneal ring segments with the
discussion of the different nomograms and how to apply it clinically. Luckily this
book included all up to date information about ICRS available in our practice and
how to clinically apply different nomograms. Refractive surgeries in
keratoconus, one of the most debatable treatment between cornea specialists is
discussed thoroughly for better understanding. This book also will spot out
controversies between different treatment modalities. Lastly, we will end with a
step wise approach to a case with keratoconus that sums up how can we deal
with keratoconus patients in our clinic.

Although I chose the name of the book Keratoconus “The Whole Story” to give
an information for the reader that this book collects every detailed and up to date
information about keratoconus yet as a cornea specialist I know that the story
will never end, and I expect that more innovations will appear in the diagnosis
and treatment of keratoconus.

What makes this book different is that it is explained in series of videos on my

YouTube channel in both Arabic and English languages, an option that make the
reader can read and at the same time listen to every detailed information, so, I
advise readers of this book to read as well as to listen to the videos as they are
both complementary. An information that may be vague in the book will be
 III
Preface

discussed in detail in the video. Throughout the book you will find following a
subtitle or a paragraph “For an illustrative video see YouTube channel” this
refers to the importance of the video for better understanding. You will find the
link of the YouTube channel at the end of this introduction.

During editing the book, a new protocol in cross linking was released “Sub400
Protocol”, it was added to the book, but it wasn’t discussed in the videos.

This book is intended to ophthalmologists especially beginners who have an

interest in cornea although cornea specialists will find it interesting too.
Optometrists can take advantage of the book to help them suspect keratoconus
patients and their early referral to a cornea specialist, also the part of the book
discussing contact lenses would be of great help.

As an editor to this book with my colleagues, we tried our best to write this book
in a simple and easy memorizing layout with no mistakes. I will be very grateful
to receive your feedback for better improvement in further editions.

Finally, I hope this book will be useful and help you better understand and
practice keratoconus and would like to thank my colleagues and students.
without all of them this book would have never found its way to the world.

Moataz M. Wessam

The link of the YouTube channel

www.youtube.com/channel/UC6hHOUGxDtpMam5WE_psWww
 IV
Preface

Co-editors

1. Abdelrahman Abdallah Abdelhai, M.Sc. of ophthalmology – Al

Azhar University.

2. Mohamed Nabil Hamza, M.Sc. of ophthalmology - Ain Shams

University, FICO, MRCSed.

3. Front and back cover design by Afnan Abdallah Abdelhai.

 V
Abbreviations

ACD Anterior chamber depth

ACT Ablation cone thickness
AGEs Advanced glycation end products
AI Artificial intelligence
ANN Artificial neural networks
ARTmax Ambrosio relational thickness
AS-OCT Anterior segment optical coherence tomography
ATR Against the rule astigmatism
BAC Benzalkonium chloride
BAD Belin Ambrosio display
BCVA Best corrected visual acuity
BFS Best fit sphere
BFTE Best fit toric ellipsoid
BOSS™ Brillouin optical scanner system
BSS Balanced salt solution
CAIRS Corneal allogenic intrastromal ring segments
CBI Corvis biomechanical index
CCT Central corneal thickness
CFM Confocal microscopy
CH Corneal hysteresis
CKI Central keratoconus index
CL Contact lens
CRF Corneal resistance factor
CURV Customized remodeling vision
 VI
Abbreviations

CXL Corneal cross linking

Da Deviation of ARTmax
DALK Deep anterior lamellar keratoplasty
Db Deviation of back elevation difference map
DC Diopter cylinder
Df Deviation of front elevation difference map
DM Diabetes mellitus
Dp Deviation of average pachymetry progression
DS Diopter sphere
Dt Deviation of minimum thickness
ECD Ectatic corneal diseases
EDTA Ethylenediamine tetra acetic acid
FDA Food and drug administration
FFKC Forme fruste keratoconus
HOAs High order aberrations
I-S Inferior minus Superior
ICL Implantable collamer lens
ICRS Intracorneal ring segments
IHA Index of height asymmetry
IHD Index of height decentration
IL-6 Interleukin 6
IOL Intraocular lens
IOP Intraocular pressure
ISV Index of surface variance
 VII
Abbreviations

IVA Index of vertical asymmetry

IVCM In vivo confocal microscopy
KC Keratoconus
KCS Keratoconus suspect
KI Keratoconus index
Km Median keratometry
Kmax Maximum Keratometry
KMI Keratoconus match index
KMP Keratoconus match probability
LASER Light amplification by stimulated emission of radiation
LASIK Laser assisted in situ keratomileusis
MA Manifest astigmatism
MMC Mitomycin C
MMP Matrix metalloproteinases
NIR LASER Near infrared LASER
NSAID Nonsteroidal anti-inflammatory drugs
OA Oblique astigmatism
PACK-CXL Photoactivated chromophore cross linking
PiXL Photorefractive intrastromal cross linking
PK Penetrating keratoplasty
PMD Pellucid marginal degeneration
PMMA Poly (methyl methacrylate)
PPCD Posterior polymorphous corneal dystrophy
PRK Photorefractive keratectomy
 VIII
Abbreviations

PROSE Prosthetic replacement of ocular surface ecosystem

PTK Phototherapeutic keratectomy
PVA Potential visual acuity
RBF Radial basis function
RF Riboflavin
RGP Rigid gas permeable
ROS Reactive oxygen species
RST Residual stromal thickness
SMILE Small incision lenticule extraction
SRAX Skewed radial axis
Selective transepithelial ablation for regularization of
STARE-XL
ectasia with simultaneous cross linking
TA Topographic astigmatism
TBI Tomographic biomechanical index
TL Thinnest location
TNF-α Tumor necrosis factor alpha
UCVA Uncorrected visual acuity
UV Ultraviolet
UV-LED Ultraviolet light emitting devices
VAE Very asymmetrical ectasia
VIPA Virtual image phased array
VKC Vernal keratoconjunctivitis
WTR With the rule astigmatism
WTW White to white diameter
Contents IX

Chapter One, Classification of Ectatic Corneal Diseases ........................................... 1

Chapter Two, Epidemiology of Keratoconus ............................................................. 1

Chapter Three, Clinical Examination and Slit-Lamp Findings .................................. 3

Chapter Four, Patterns and Clinical Grading ............................................................. 5

Morphological Patterns .............................................................................................. 5

Curvature Based Patterns .......................................................................................... 6
1.Symmetrical Shapes....................................................................................... 6
2.Asymmetrical Shapes .................................................................................... 6
3.Skewed Shapes .............................................................................................. 7
4.Irregular Shapes ............................................................................................. 7
Elevation Based Patterns ........................................................................................... 7
1.Best Fit Sphere Mode .................................................................................... 7
2.Best Fit Toric Ellipsoid Mode ....................................................................... 9
Pachymetry Based Patterns........................................................................................ 9
Forme Fruste Keratoconus and Keratoconus Suspect ............................................. 10
Clinical Grading....................................................................................................... 11
1. Amsler – Krumeich Classification.............................................................. 11
2. Alio – Shabayek Classification ................................................................... 11
3. RETICS Classification................................................................................ 11
4. Ishii Classification ...................................................................................... 12
5. Belin ABCD Classification......................................................................... 14

Chapter Five, Progression Criteria in Keratoconus .................................................. 16

Chapter Six, Diagnostic tools in Keratoconus .......................................................... 19

Contents X

Topography and Tomography ................................................................................. 19

Segmental Tomography with Epithelial Thickness ................................................. 20
Biomechanics of Cornea ......................................................................................... 23
A. Ex-Vivo Flap Extensiometry ..................................................................... 23
B. Air Puff Deformation ................................................................................. 24
C. Brillouin Optical Scanner System .............................................................. 26
Wavefront Aberration Analysis ............................................................................... 28
Confocal Microscopy............................................................................................... 29
Spectral Microscopy ................................................................................................ 30
Artificial Intelligence and Artificial Neural Networks ............................................ 30

Chapter Seven, Treatment Modalities....................................................................... 32

1.Spectacles ............................................................................................................. 32
2.Contact Lenses ...................................................................................................... 32
Terms in Contact Lenses .............................................................................. 33
Soft Toric Contact Lens................................................................................ 33
Rigid Gas Permeable Contact Lens .............................................................. 34
Piggyback Lens ............................................................................................ 35
Scleral Lens .................................................................................................. 35
Hybrid lens ................................................................................................... 37
3.Corneal Cross Linking .......................................................................................... 39
Evolution of cross linking ............................................................................ 39
Determiners of cross linking ........................................................................ 41
1.Epithelium ............................................................................................. 41
2.Ultravilet radiation with specific intensity, dose and beam profile ...... 41
3.Adequate diffusion of riboflavin in corneal stroma .............................. 42
Contents XI

4.Availability of oxygen .............................................................................. 44

5.Time factor for ultraviolet light and riboflavin soaking time ................... 44
General reaction mechanism .......................................................................... 45
Evidence of action after cross linking ............................................................ 45
Protocols of cross linking ............................................................................... 46
1.Dresden protocol ...................................................................................... 46
2.Accelerated protocols ............................................................................... 46
3.Protocols for thin cornea ........................................................................... 46
Hypo-Osmolar riboflavin solution ............................................................ 46
Transepithelial cross linking with enhancers and femtosecond pockets .. 47
Transepithelial cross linking using iontophoresis..................................... 47
Pachymetry based accelerated cross linking “M Nomogram” ................. 48
Sub400 protocol ........................................................................................ 48
4.Topography guided protocols ................................................................... 49
5.Combined protocols................................................................................... 51
Athens protocol ......................................................................................... 51
Cretan protocol ......................................................................................... 52
LASIK-Xtra .............................................................................................. 52
Indications of cross linking ............................................................................. 53
Complications of cross linking ....................................................................... 53
Cross linking in children ................................................................................. 54
Recent trends in cross linking ......................................................................... 55
Photorefractive intrastromal Cross Linking................................................ 55
Photoactivated Chromophore Cross Linking.............................................. 55
Bullous Keratopathy .................................................................................. 56
Evolution of cross linking devices .................................................................. 56
4.Intracorneal ring segments .................................................................................... 56
Contents XII

Structure of intracorneal ring segments .......................................................... 56

Types of intracorneal ring segments ............................................................... 56
1.Kera ring ............................................................................................... 56
2.Ferrara ring ........................................................................................... 57
3.Intacs ring ............................................................................................. 57
4.Myoring ................................................................................................ 57
5.Visum ring ............................................................................................ 59
6.Corneal Allogenic Intrastromal Ring Segments ................................... 59
Mechanism of action of ICRS ........................................................................ 60
Indications of ICRS ........................................................................................ 62
Types of Keratoconus ..................................................................................... 62
1.Central keratoconus .............................................................................. 62
2.Peripheral Keratoconus ......................................................................... 62
3.Bowtie keratoconus............................................................................... 62
4.Pellucid Like keratoconus ..................................................................... 62
Nomograms of ICRS ...................................................................................... 62
Kera ring nomogram ................................................................................ 64
Asphericity based nomogram .................................................................. 65
Combined procedures ..................................................................................... 68
Improving vision after ICRS .......................................................................... 68
Complications of ICRS ................................................................................... 68
5.Refractive Surgeries in Keratoconus .................................................................... 69
Protocols ......................................................................................................... 69
1.Selective Transepithelial Ablation for Regularization of Ectasia with
simultaneous Cross Linking..................................................................... 69
2.Athens protocol ..................................................................................... 71
3.Cretan protocol ..................................................................................... 71
Contents XIII

Wavefront guided ablation ............................................................................. 72

Phakic intraocular lens .................................................................................... 73
Refractive lens exchange or cataract extraction with Toric PCIOL ............... 74
Approach to refractive surgeries in keratoconus ............................................ 74
6.Surgery in keratoconus ......................................................................................... 74
Penetrating keratoplasty.................................................................................. 75
Deep anterior lamellar keratoplasty ................................................................ 75
Bowmans membrane transplantation .............................................................. 75
Stromal lenticule addition keratoplasty .......................................................... 76

Chapter Eight, Approach to Keratoconus Case ........................................................ 77

Bibliography .............................................................................................................. 78

Index........................................................................................................................... 87
1 1. Classification of Ectatic Corneal Diseases
Classification of Ectatic
Corneal Diseases
Corneal ectasia is a chronic bio-
mechanical failure that leads to
progressive thinning and protru-
sion.
Keratoconus (KC).
Pellucid marginal degeneration
(PMD)
It is a rare bilateral, asymmetrical,
non-inflammatory, inferior cor-
neal thinning, located mostly from
4 - 8 o’clock with 1mm free zone
from the limbus. It presents be-
tween second to fifth decades.
Keratoglobus
It is a bilateral, non-inflammatory
generalized corneal thinning and
Epidemiology
Keratoconus
It is chronic, bilateral, asymmet-
rical, non-inflammatory, pro-
gressive corneal thinning and
steepening.
protrusion. It is rare and mostly
congenital.
Post LASER refractive correc-
tion ectasia
Usually seen after laser assisted
in situ keratomileusis (LASIK)
and sometimes seen also after
both photorefractive keratectomy
(PRK) and small incision lenti-
cule extraction (SMILE).
N.B.
Terms as forme fruste kerato-
conus (FFKC) and keratoconus
suspect (KCS) aren’t true ectatic
corneal diseases (ECD)
Tomographic Definition
It is abnormal elevation maps es-
pecially posterior, abnormal cur-
vature map with or without ab-
normal pachymetry map.
2. Epidemiology of Keratoconus
Incidence in general population
is about 1:2000 with high preva-
lence in Saudi Arabia, Iran, Leb-
anon and New Zealand.
It has an autosomal dominant in-
heritance with decreased pene-
trance and no sex predilection.
Pediatric keratoconus may be as-
sociated with Down syndrome,
Leber’s congenital amaurosis,
mitral valve prolapse and Marfan
syndrome.
N.B.
Recent studies that examined
tears of keratoconus patients
showed increased IL-6, MMP
and TNF-α which are known
inflammatory mediators.
The most important risk factors
are
1. Eye Rubbing
Habitual eye rubbing leads to
stromal remodeling and kerato-
cyte apoptosis.
Eye rubbing in keratoconus pa-
tients precedes the diagnosis of
keratoconus unlike patients with
allergic eye disease whom eye
rubbing is pathognomonic. This
2
may explain why the majority of
patients with allergic eye dis-
eases doesn’t develop kerato-
conus.
2. Atopy
Studies show that keratoconus is
associated with allergic tenden-
cies which promotes eye rubbing
than other related atopic pro-
cesses. This was supported when
keratoconus is associated with
non-atopic conditions as Leber’s
congenital amaurosis “Oculo-
Digital Sign”.
Keratoconus may be associated
with either atopic eye diseases
as vernal keratoconjunctivitis
(VKC) or systemic atopy as
bronchial asthma or urticaria.
It is important to identify age of
onset and age of diagnosis, la-
tency between them is unclear.
Age of Onset
It can be known from history by
rapid change in vision and fre-
quent change of glasses.
Typical keratoconus starts
around puberty and progresses
till the third decade then it takes
3 3. Clinical Examination and Slit Lamp findings
a stationary course.
Pediatric keratoconus is not un-
common, younger onset predicts
severity and faster progression.
Age of Diagnosis
Typically, between 20 - 30 years.
It’s uncommon after the age
of 35 years and if diagnosed
in older groups by chance for
example before “cataract
surgery” it implies that
Clinical Examination and
Slit-Lamp Findings
Don't forget full ophthalmolog-
ical examination.
The most common complaint is
progressive visual blur and dis-
tortion secondary to myopia and
irregular astigmatism.
A. History
Refractive instability with fre-
quent changes in glasses pre-
scription which will identify the
age of onset.
ectasia passed unnoticed due
to mild symptoms or lack of
accurate diagnostic tools.
N.B.
Studies show that the common
knowledge that keratoconus pro-
gression stops around the third
decade isn’t precise, so docu-
mented progression is required.
Ask about associated allergic eye
diseases as VKC, eye rubbing,
systemic atopy, family history to
identify FFKC or KCS and don’t
forget the medical history.
B. Visual Acuity
Perform both uncorrected visual
acuity (UCVA) and best cor-
rected visual acuity (BCVA).
For evaluation, documentation,
follow up and for selecting best
treatment modality. In early
3. Clinical Examination and Slit Lamp Findings 4

stages BCVA is minimally af- E. Slit-lamp signs

fected and can be corrected with
Early
glasses, while in late stages
Central or paracentral thinning
BCVA is more affected and can’t and easy visualization of corneal
be corrected with glasses but
nerves.
may be with contact lenses.
Late
Assessment of potential visual Fleischer ring, a brownish iron
acuity (PVA) for identifying vis- deposits around base of the cone
ual prognosis by best seen with cobalt blue light
1. Rigid contact lens “The best”. (Fig.1).
2. Pin hole, by identifying the dif-
ference between UCVA &
BCVA or improvement of
UCVA only “at least 2 lines”.

C. Scissoring Reflex
For illustrative video see YouTube
Channel
It is a very early sign which is
seen by retinoscopy. It’s not rou-
tinely done but has to be checked
in family history of keratoconus
or high astigmatism, so, it re-
quires a high index of suspicion.
Figure 1, upper and lower arrows
show corneal nerves and middle arrow
show fleischer ring.
Vogt’s Striae, are vertical stress
lines at level of the posterior
stroma, may disappear on gentle
pressure on the globe (Fig.2).

D. Rizzutti Sign
For illustrative video see YouTube
Channel

It is conical reflection on the na-

sal cornea when a penlight is di-
rected from the temporal side. Figure 2, Vogt’s striae.
5 4. Patterns and Clinical Grading

Munson sign which is a protru-

sion of the lower eyelid when
looking downward (Fig. 3).
Corneal scaring following hy-
drops due to breaks or rupture in
the Descemet membrane.

Figure 3, Munson sign.

Patterns and Clinical

Grading

Morphological Patterns

Best seen with the tangential

map, which is important also in
contact lens fitting, may be

1. Nipple Cone
Small (≤ 5 mm), cone apex ei- Figure 4, Nipple cone.
ther central or paracentral
(Fig.4).

2. Oval Cone
Larger (6 - 7 mm), cone apex
mostly displaced inferotem-
poral (Fig.5).

3. Globus Cone
The largest (> 7 mm), may in-
Figure 5, Oval cone.
volve > 75 % of cornea (Fig 6).
4. Patterns and Clinical Grading 6

Curvature Based Patterns

1. Symmetrical Shapes

- Abnormal if Km > 47.2 D in

placido-based topographers or
> 48 D in scheimpflug-based
tomographers, may be
• Rounded which is a hot spot Figure 6, Globus cone.
usually decentered and signi-
fies minimal anterior astigma-
tism (Fig. 7).
• Oval which is a hot spot that is
oval, may be centered or de-
centered and signifies minimal
Figure 7, rounded hot spot.
anterior astigmatism (Fig. 8).
• Symmetrical bowtie either
vertical “WTR”, horizontal
“ATR” or oblique “OA”, so
˚
not every symmetrical bowtie
is normal (Fig. 9 a, b, c).
Figure 8, oval hot spot.

2. Asymmetrical Shapes
For illustrative video see YouTube
Channel
- Superior steepening which is a
an isolated hot spot superiorly.
- Asymmetric bowtie superior
steep if S-I > 2.5 D on 2 op- c
b
posing points in 4 mm zone. c
Figure 9, a; with the rule astigma-
- Inferior steepening which is an tism, b; against the rule astigmatism,
isolated hot spot inferiorly. c; oblique astigmatism.
7 4. Patterns and Clinical Grading

- Asymmetrical bowtie inferior

steep if I-S > 1.5 D on 2 op-
posing points in 4 mm zone.
˚
3. Skewed Shapes
- Symmetrical bowtie with
SRAX > 22˚ (Fig.10).
Figure 10, skewed radial axis > 22 ˚,
- Asymmetric Bowtie with dashed red lines.
SRAX > 22˚.
meridian is above the refer-
- Skewing can be ignored in
ence surface.
1. Topographic astigmatism
- The most important reference
≤ 1D.
surfaces are the best fit sphere
2. Enantiomorphism.
(BFS) and the best fit toric el-
3. Misalignment.
lipsoid (BFTE).
1. Best fit sphere float mode 8
4. Irregular Shapes
mm reference surface
- Always abnormal.
“qualifies the surface”
- As crab claw or kissing birds
- Best to identify cone location
“pellucid like keratoconus”,
a) Central if the apex of the cone
butterfly pattern like crab claw
is within the 3 mm zone (Fig.
but not connected inferiorly,
12 a).
vortex pattern and irregular
b) Paracentral if the apex of the
shape (Fig. 11 a, b, c & d).
cone is within 3 – 5 mm zone
(Fig. 12 b).
Elevation Based Patterns
c) Peripheral if the apex of the
For illustrative video see YouTube cone is outside the 5 mm zone
Channel (Fig. 12 c).
- The normal cornea is toric el- - Used in screening in keratore-
lipsoid. fractive procedures.
- In astigmatism, the steeper - Shapes may be symmetrical
meridian is under the refer- hourglass either vertical
ence surface while the flat “WTR”, horizontal “ATR” or
4. Patterns and Clinical Grading 8

a b

c d

Figure 11, a; crab claw pattern or pellucid like keratoconus, b; butterfly pattern, c; vor-
tex pattern, d; irregular shape.

a b c

Figure 12, a; central cone, b; paracentral cone, c; peripheral cone.

9 4. Patterns and Clinical Grading

skewed “OA” and isolated Pachymetry Based Patterns

central island which signifies
- Normal shape is concentric.
minimal astigmatism.
- Abnormal Shapes may be
- To detect abnormality, look at
1. Oblique displacement of the
the thinnest location on the an-
thinnest location “Dome
terior and posterior elevation
Shape” (Fig. 13).
maps
2. Inferior thinning or Bell sign
1. In myopia, > 8 µm on the an-
“pathognomonic of PMD”
terior elevation map and > 18
(Fig. 14).
µm on the posterior elevation
3. Generalized thinning or kera-
map are abnormal.
toglobus (Fig. 15).
2. In hypermetropia, > 7 µm on
the anterior elevation map and
> 28 µm on the posterior ele-
vation map are abnormal.
For illustrative video see YouTube
Channel

2. Best fit toric ellipsoid float

mode 8mm reference surface
“quantifies the surface”
Figure 13, oblique displacement of
- Best to identify true cone ele- thinnest location.
vations and in irregular astig-
matism.
- To detect any abnormality,
look inside the 5 mm zone
1. Any point > 12 µm on the an-
terior elevation map is abnor-
mal.
2. Any point > 15 µm on the pos-
terior elevation map is abnor-
mal.
For illustrative video see YouTube Figure 14, inferior thinning, Bell sign
found in PMD.
Channel
4. Patterns and Clinical Grading
Figure 15, generalized thinning.
Forme Fruste Keratoconus
and Keratoconus Suspect
- The most debatable terms till
now with no widely accepta-
ble criteria for their classifica-
tion.
- The most accepted criteria are
1. FFKC is an eye with abnor-
mal anterior sagittal map with
or without abnormal pachym-
etry map or a normal eye in
which the other eye is kerato-
conus.
2. KCS is an eye with abnormal
anterior sagittal map with or
without abnormal pachymetry
map with the other eye is ei-
ther normal or abnormal.
10
- Amsler (1961) was the first to
introduce FFKC and described
it as an eye with mild ectasia
and irregular astigmatism
(Placido disc) which was not
progressive and was found
mostly in the other eye of a
unilateral keratoconus or in
families with positive history
of keratoconus.
- Holladay (2008) described
FFKC as when a HOT SPOT
coincides between
1. Tangential anterior curva-
ture map, which is more accu-
rate than the sagittal map.
2. Posterior elevation map with
the BFTE as a reference sur-
face.
3. Relative Pachymetry Map,
it’s a map that shows a thick-
ness of a point in relation to
normal thickness of the same
point in a percentage “normal
distribution” e.g. a point with +
5 µm means that its thicker than
normal distribution by 5 so,
takes 5 % while a point with - 5
µm takes - 5 %.
11
- Klyce (2009) has described
FFKC as the fellow eye in a
unilateral keratoconus which
doesn’t show any clinical find-
ings except for certain topo-
graphic changes.
- While KCS as patients who
have no keratoconus in both
eyes but have certain topo-
graphic findings in one or both
eyes as
1. Area of localized steepening
mainly inferior and may be
central and rarely superior.
2. Inferior superior asymmetry
within 1.4 - 1.9 D.
3. Keratometry values > 47 D.
4. Oblique astigmatism > 1.5 D.
- Recently, objective methods
using artificial intelligence
(AI) have been proposed to di-
agnose FFKC and KCS e.g.
Sirius CSO and Orbscan II.
Clinical Grading
- Till now, there is no clinically
adequate classification for ker-
atoconus.
4. Patterns and Clinical Grading
1. Amsler - Krumeich classifi-
cation (1998) (Table 1).
• Most commonly used.
• Not consistent in all cases as
the cornea may be clear in ad-
vanced cases.
2. Alio - Shabayek classification
(2006) (Table 2).
• It added the vertical coma and
other high order aberrations
(HOAs) due to its prevalence
in keratoconus.
3. RETICS Classification Jorge
L. Alio et.al, (2011), it in-
cluded (Table 3)
- BCVA due to its functional
implications and its direct re-
lation to the severity of kerato-
conus.
- Internal astigmatism which
is the difference between
manifest astigmatism “cal-
culated at the corneal
plane” and anterior corneal
astigmatism. It’s consid-
ered as an indirect way to
determine the contribution
of the posterior corneal
4. Patterns and Clinical Grading 12

Grade Mean Central Keratometry CCT Spherical Equivalent Cornea

1 < 48 D > 500 µm < -5 D Clear

2 48 D to < 53 D > 400 µm - 500 µm - 5 D to < - 8 D Clear

3 53 D to < 55 D > 300 µm - 400 µm >-8D Clear

4 > 55 D < 300 µm Not Measurable Scar

Table 1, Amsler - Krumeich classification.

Mean Central Keratome- Spherical

Grade CCT Coma RMS Cornea
try Equivalent

1 < 48 D > 500 µm < -5 D 1.5 µm - 2.5 µm Clear

> 400 µm - 500 > 2.5 µm - ≤ 3.5

2 48 D to < 53 D - 5 D to < - 8 D Clear
µm µm

> 3.5 µm - ≤ 4.5

3 53 D to < 55 D 300 µm - 400 µm >-8D Clear
µm

4 > 55 D < 300 µm Not Measurable > 4.5 µm Scar

Table 2, Alio – Shabayek classification.

surface to the ocular 4. Ishii and Associates Classifi-

astigmatism, assuming a cation (2012), it included (Ta-
minimal contribution of ble 4)
the crystalline lens.
- BCVA.
- Minimum radius of curvature
- Asphericity or Q-value at 8
on the anterior corneal surface
mm as keratoconus is
“Kmax”.
known to produce a prolate
or a hyperprolate surface.
I
n
13 4. Patterns and Clinical Grading

Internal
Grade BCVA Q-Value (8mm) Coma RMS Mean Central K CCT
Astigmatism

1.16 µm - 1.52
1 > 0.9 1.59 - 2.14 - 0.05 to -0.22 44.75 D - 45.4 D 495 µm - 510 µm
µm

1.82 µm - 2.31
2 > 0.6 - ≤ 0.9 2.18 - 2.79 - 0.22 to -0.48 46 D - 46.93 D 475 µm - 493 µm
µm

2.65 µm - 3.32
3 > 0.4 - ≤ 0.6 3.04 - 4.17 - 0.58 to -0.95 48.21 D - 49.27 D 451 µm - 470 µm
µm

3.45 µm - 4.42
4 ≤ 0.4 3.68 - 4.58 - 0.83 to -1.21 51.42 D - 53.12 D 433 µm - 454 µm
µm

4 Plus ≤ 0.2 > 5.5 < -1.5 > 5.5 µm > 57 D 360 µm- 420 µm

Table 3, RETICS classification.

- Indices of irregular cornea • Index of Height Decentration

(IHD) which describes the de-
• Index of Surface Variance centration of elevation in ver-
(ISV) which describes corneal tical direction.
surface irregularity.
• Keratoconus Index (KI) which
• Index of Vertical Asymmetry describes the curvature
(IVA), which describes curva- asymmetry “the ratio between
ture asymmetry between supe- the radii of curvatures of the
rior and inferior cornea “as I/S superior and inferior cornea”.
ratio”.
• Central keratoconus Index
• Index of Height Asymmetry (CKI) which describes the se-
(IHA) which describes eleva- verity of central keratoconus.
tion asymmetry between supe-
rior and inferior cornea which - Retinoscopy.
is more sensitive.
4. Patterns and Clinical Grading 14

R-min of
Grade BCVA ISV KI Other 4 Indices ACS Retinoscopy Cornea
(mm)

1.04 -
Early 1 < 30 Normal 7.8 - 6.7 Normal Clear
1.07

30 - 1.07 - Sometimes 1 value Distorted Red Reflex,

1 O.8 - 1 7.5 - 6.5 Clear , Fleisher Ring
55 1.15 abnormal mild SR

55 - 1.10 - Often 1 value Difficult Retinoscopy,

2 0.3 - 1 6.9 - 5.3 May be Clear, FR, VS
90 1.25 abnormal Clear SR

0.16 - 90 - 1.15 - At least 1 value Difficult Retinoscopy May be

3 6.6 - 4.8
0.6 150 1.45 abnormal Clear SR Clear,Thinning, FR,VS

< 0.05 - At least 1 value Difficult Retinoscopy,

4 > 150 > 1.5 < 5.00 Scarred , MS
0.2 abnormal Clear SR

Table 4, Ishii classification.

5. Belin ABCD Classification • Modifier, - “No scaring”, +

(2016) (Table 5). “Scarring not obscuring iris
details”, ++ “Scarring obscur-
- Needs a special software, ing iris details”.
mainly on the oculus pentacam
(Fig. 16), it includes - The goal was to produce a clas-
sification similar to Amsler -
• Anterior radius of curvature Krumeich classification for an-
for a 3 mm zone centered on terior data and at the same time
the thinnest location. solve the deficiencies in previ-
ous staging as
• Back “Posterior” radius of cur-
vature for a 3 mm zone cen- • Lack of posterior corneal data.
tered on the thinnest location.
• Relying on central corneal
• Corneal pachymetry at thin- thickness instead of thinnest
nest location. location.

• Distance best corrected vision. • Different parameters fall into

different stages.
15 4. Patterns and Clinical Grading

• Poor differentiation between

no Clinically
normal andAdequate Classification
abnormal corneas. for
Keratoconus
Classification (1998)

20. 7 20/20

0000000

Figure 16, Belin ABCD software on ocu-

lus pentacam.

Grade ARC PRC Thinnest Pachymetry BCVA Scaring

> 7.25 mm ≥ 20/20

0 > 5.9 mm > 490 µm -
( <46.5 D ) (≥1)

> 7.05 mm ≤ 20/20

1 > 5.7 mm > 450 µm - , + , ++
( < 48 D ) (≤1)

> 6.35 mm > 5.15 < 20/40

2 > 400 µm - , + , ++
( < 53 D) mm ( < 0.5 )

> 6.15 mm > 4.95 < 20/100

3 > 300 µm - , + , ++
( < 55 D ) mm ( < 0.2 )

< 6.15 mm < 4.95 < 20/400

4 ≤ 300 µm - , + , ++
( > 55 D ) mm ( < 0.05 )

Table 5, Belin ABCD classification.

5. Progression Criteria in Keratoconus
Progression Criteria in
Keratoconus
- Keratoconus is known to be
progressive, so documenta-
tion
) of progression is im-
(Tablein
portant -2)order to choose the
• It Added the Vertical
best treatment modality and Coma & Coma like HOA’s due to its prevalence
in KC
follow up patients before and
after treatment.
- Till now, none of the available
criteria have achieved the re-
quired level of accuracy and
reliability
Included BCVAto duebetoconsidered
its Functional
Internal Astigmatism
• Standard.
Gold
- The main reasons are the dis-
parity of diagnostic tools and
the lack of knowledge on the
kinetic progression of kerato-
conus e.g. very asymmetrical
ectasia (VAE).
- Identifiable risk factors of pro-
gression are
1. Young age at diagnosis.
2. Mechanical factors as post
LASER refractive correction
in undiagnosed cases and with
habitual eye rubbing.
16
3. Genetic factors, as when kera-
toconus is associated with syn-
dromes or positive family his-
tory of progressive kerato-
conus.
4. Hormonal factors as during
pregnancy.
- The most accepted parameters
“of which three of them should
occur concurrently” are
as implications and it
1. Increased Kmax > 1 D in 1 year.
2. Increased manifest cylinder >
1 D in 1 year.
3. Deterioration of BCVA in 1
year.
4. Thinning of thinnest location
≥ 5 % in 6 - 12 month.
5. Increased spherical equivalent
≥ 0.5 D in 1 year.
6. Increased Km > 1.5 D in 1 year.
7. Change in contact lens power
over 2 years.
- Recently Belin ABCD pro-
gression display can be used
for detecting progression (Fig.
17).
17
Figure 17, Belin ABCD progression display two.
- The four parameters A, B, C
and D are displayed side by
side to easily visually deter-
mine a trend of progression.
- Problems we face in our clinic
- Each individual exam can be
marked as baseline/reference
“first exam by default” or
treatment.
- The red lines are the confi-
dence intervals of keratoconus
patients and green lines are the
confidence intervals of normal
population.
- The Confidence Interval is a
range associated with
5. Progression Criteria in Keratoconus
confidence level in which true
parameters are present in the
confidence interval.
are
• In the first visit, most kerato-
conus patients do not have
topographic, tomographic or
refractive data history to sup-
port keratoconus progression.
• Sometimes, if patients have
some topographic and tomo-
graphic data, mostly they will
not be comparable as they
were done on different topo-
graphic systems.
5. Progression Criteria in Keratoconus 18

• What complicates the pregnancies and patients

problem more is that the
topography and tomogra-
phy in keratoconus pa-
tients aren’t reproducible
due to intra or inter test
variability.
on chronic steroid use.
• In low risk group, the expecta-
tion of rapid progression is
low, so, documented progres-
sion is required.

• We start to rely on the his-

N.B.
tory from patients or fami-
It is not recommended to per-
ly as progressive blurring,
form cross linking during preg-
frequent change in glasses
nancy, although cross linking
prescription and trying to
isn’t contraindicated in preg-
identify the age of onset.
nancy.

• We must wait for the next

follow up to document
progression, which is
sometimes may not be a
good option, so, patients
should be classified into
high risk or low risk group.

• High risk group has a

greater risk for progres-
sion, rate of progression
isn’t predictable and loss
of functional vision may
affect quality of life as pa-
tients younger than 20
years, females who are ex-
pected to have multiple
19
Diagnostic tools in Kerato-
conus
- The aim isn’t to diagnose an
established case of kerato-
conus but to have diagnostic
tools with high specificity and
sensitivity to diagnose early
cases during screening indi-
viduals.
- There are multiple tools that
aid in the diagnosis of early
cases, but none of them is 100
% diagnostic.
- The aim is getting multiple
characteristic signs from dif-
ferent diagnostic modalities
that can point out suspected
cases early.
Topography & Tomography
- As discussed before in curva-
ture, elevation and pachyme-
try based patterns.
- Belin Ambrosio enhanced ec-
tasia software may aid in early
detection which includes
6. Diagnostic Tools in Keratoconus
• Belin Ambrosio display
(BAD)
For illustrative video see YouTube
Channel
• Pachymetry data
For illustrative video see YouTube
Channel
• Numerical values (Fig. 18).
N.B.
Belin Ambrosio enhanced ecta-
sia will not diagnose early
cases with curvature map ab-
normalities.
- Progression Index “white is
normal, yellow is suspicious
and red is abnormal” (Fig 18).
For illustrative video see YouTube
Channel
• Minimum, it’s the meridian
with the smallest progression
“Green line”.
• Maximum, it’s the meridian
with the largest progression
“Blue line”.
• Average, it’s the averaged ra-
tio of progression related to
6. Diagnostic Tools in Keratoconus
Figure 18, Numerical values in Belin Ambrosio enhanced ectasia.
the normal progression “better
to be < 1.2”.
• ARTmax “Ambrosio relational
thickness”, is the ratio be-
tween thinnest location to pro-
gression index maximum.
- Deviation Parameters from
the standard deviation “White
is normal, yellow is suspicious
and red is abnormal” (Fig 18).
• Df, deviation of the front ele-
vation difference map.
• Db, deviation of the back ele-
vation difference map.
20
• Dp, deviation of the average
pachymetry progression.
• Dt, deviation of the minimum
corneal thickness.
• Da, deviation of ARTmax.
• Final D, total deviation of all
numerical values, normal <
1.6 SD, suspicious ≥ 1.6 SD
and abnormal ≥ 2.6 SD.
Segmental Tomography with
Epithelial Thickness
- Using AS-OCT for whole an-
terior chamber tomography.
21
- Normal epithelial distribu-
tion is approximately 50 -
60 µm (Fig. 19).
- It is thicker inferior than
superior and nasal than
temporal.
- This asymmetrical distri-
bution may be due to
blinking effect, upper eye
lid firm tarsus and outer
canthus being slightly ele-
vated than the medial can-
thus.
- The corneal epithelium has
active remodeling activity
to mask any underlying
stromal irregularities to
produce smooth, symmet-
rically optical outer corne-
al surface. Remodeling is
achieved by either
• Thinning over an elevated or
steep areas e.g. keratoconus
and hypermetropia.
• Thickening over flattened are-
as or where tissues are re-
moved e.g. myopia,
6. Diagnostic Tools in Keratoconus
Figure 19, normal distribution of epi-
thelial thickness.
hypermetropia or localized ef-
fects as scar
- In keratoconus, it takes either
“Focal Thinning” (Fig. 20)
or “Doughnut Pattern”
which is thinning over the
cone surrounded by an annu-
lus of thickened epithelium
(Fig. 21).
- Either doughnut pattern or
focal thinning in epitheli-
um is suggestive of kerato-
conus but not pathogno-
monic.
- To confirm the diagnosis
of keratoconus, doughnut
pattern or focal thinning
must be coinciding with
an elevation.
6. Diagnostic Tools in Keratoconus 22

- In (Fig. 22), normal an-

terior axial curvature
map with focal epitheli-
al thinning coinciding
with an elevation on the
posterior elevation map.
So, this is a case of ker-
atoconus and epithelial
thinning is a masking Figure 20, focal thinning of epithelium.
effect to the subepithe-
lial cone.

- In (Fig. 23), the anterior

axial curvature map
shows inferior superior
asymmetry > 1.5 D,
epithelial thickening
and normal posterior
elevation map. So, the
localized thickening of
epithelium is the cause Figure 21, doughnut pattern of epi-
thelium in keratoconus.
of inferior steepening.

Figure 22, a case of keratoconus with normal anterior curvature map and focal epithelial
thinning coinciding with posterior elevation.
23
Figure 23, a case with inferior-superior asymmetry on anterior curvature map and focal epi-
thelial thickening “arrow” with normal posterior elevation map.
Biomechanics of Cornea
- To increase the accuracy
for early detection of sus-
pected cases, we have to
study the cornea beyond its
geometry.
- Biomechanics is the sci-
ence that studies the equi-
librium and deformation of
tissues submitted to any
force.
- The anterior 40 % of the
cornea has twice the bio-
mechanical properties of
the posterior part.
- Cornea is viscoelastic in
which the collagen fibrils
are responsible for the
elastic component and the
matrix for the viscous
component.
6. Diagnostic Tools in Keratoconus
- Elasticity is the property of
a substance to change its
length, volume or shape in
response to a force and to
recover its original form
upon removal of the force.
- Viscosity is the resistance
of a substance to change in
shape due to internal fric-
tion between molecules.
A. Ex-Vivo Flap Extensiometry
- It’s the gold standard tech-
nique.
- It’s destructive and can’t
be applied in vivo, it com-
promises the structural in-
tegrity of the cornea in
which the collagen fibers
are cut.
6. Diagnostic Tools in Keratoconus
- A corneal flap is cut from the
central cornea and subjected to
either
• One dimensional tensile load
in which the force “stress” is
increased while the extension
“strain” is recorded. It doesn’t
reflect the natural stress distri-
bution as it doesn’t include the
whole collagen fibers (Fig. 24
a).
• Two dimensional tensile loads
in which a circular flap is sub-
jected to multiple bi-direc-
tional loads to include all col-
lagen fibers (Fig. 24 b).
• Three dimensional tensile
loads in which loads are added
a b
Figure 24, a; one dimensional tensile load, b; two dimensional tensile loads, c; three di-
mensional tensile loads.
24
that act as IOP to simulate the
natural stress (Fig. 24 c).
B. Air Puff Deformation
- Can be used in vivo as it’s
fast and non-contact.
- None of them achieved the
required level of accuracy
and reliability for being
gold standard.
- Deformation of the cornea
wasn’t related to the bio-
mechanics only but rather
to corneal thickness and
IOP. In addition, they only
give information from the
central area.
c
25
- The Two Available Devices
are
1. Ocular Response Analyzer ®
For illustrative video see YouTube
Channel
• Corneal Hysteresis (CH) is a
physical property in which sub-
stances don’t follow applied
force instantly, it is the differ-
ence between the two applana-
tion pressures and is due to vis-
cous dampening of the cornea,
normal values are 10.8 +/- 1.5
mmHg (Fig. 25).
• Corneal Resistance Factor
(CRF) is calculated from CH,
normal values are 11 +/- 1.6
mmHg.
• Both CH and CRF decrease in
keratoconus but still there is an
overlap between normal value
and keratoconus.
• Studying the deviation of the
waveform from normal made
the appearance of keratoconus
match probability (KMP) and
keratoconus match index
(KMI). Both still not validated
to be used clinically.
6. Diagnostic Tools in Keratoconus
Figure 25, show how ocular response
analyzer measures CH.
2. Corvis ST ® “Scheimpflug To-
nometer”
For illustrative video see YouTube
Channel
• It asses the dynamic response
of the cornea by a
scheimpflug camera in re-
sponse to air puff.
• Corvis Biomechanical Index
(CBI) is calculated from sev-
eral geometrical parameters.
• Tomographic Biomechanical
Index (TBI) is calculated
from both Corvis Biomechan-
ical Index and Belin Ambro-
sio enhanced ectasia “Final
D” which is the deviation of
all numerical values (Fig. 26).
6. Diagnostic Tools in Keratoconus
Figure 26, Corvis Biomechanical Index, BAD-D or Final D and Tomographic Biome-
chanical. Available on oculus pentacam.
C. Brillouin optical scanner
system (BOSS ™) or brillouin
microscopy
For illustrative video see YouTube
Channel
- It is a new method for as-
sessing the biomechanical
properties of the cornea.
- It doesn’t involve any dy-
namic or shape changing pro-
cess, in addition it’s non-con-
tact with high resolution map.
- How does it work (Fig. 27).
26
• In tissues, there is spontaneous
vibrational motion of mole-
cules known as “thermody-
namic fluctuations”, if a LA-
SER source strikes tissues, it
will interact with these me-
chanical “acoustic” fluctua-
tions and will be scattered with
characteristic manner “Bril-
louin scatter or Brillouin
spectrum”. “Léon Nicolas
Brillouin (1922), Solid State
Physics”.
• At each point the LASER hits,
brillouin spectroscopy detects
27
the spectral shift between out-
going LASER and ingoing
LASER.
• Brillouin scatter gives infor-
mation on the elastic properties
of the tissue it interacts with in
which you can perform a 3D
map of this tissue.
• The problem is that brillouin
scatter is in the gigahertz range
and has a very faint signal
strength.
• In 2007, Harvard university
made a breakthrough by com-
bining brillouin spectroscopy
to virtual image phased array
(VIPA) detector in which in-
going frequencies became high
enough with the ability to de-
tect multiple frequencies at the
same time.
• In 2016, it came to clinical use
and was named BOSS ™ “In-
telon Optics” but still not FDA
approved in USA but has re-
ceived CE mark certification
for use in the European union.
6. Diagnostic Tools in Keratoconus
780 nm
Figure 27, schematic diagram show-
ing the idea of brilloiun scatter.
N.B.
BOSS™ is a combination of
Confocal LASER scanning
microscopy +VIPA +bril-
louin spectroscopy.
• Young’s longitudinal elastic
modulus reflects biomechani-
cal properties in solid (Table,
6).
• Frequency Shift Ω “Brillouin
Frequency” = 2 x speed of me-
chanical fluctuations / wave-
length of near infrared (NIR)
light in tissue, so, velocity of
mechanical “acoustic” fluctu-
ations is directly proportional
to frequency Shift Ω.
• Velocity of mechanical fluctu-
ations is directly proportional
to longitudinal modulus.
6. Diagnostic Tools in Keratoconus 28

Velocity of Mechanical Frequency Young’s Longitudinal

“Acoustic” Fluctuations Shift Ω Elastic Moduls

Increased Increased Increased

Decreased Decreased Decreased

Table 6, correlation between velocity of mechanical fluctuations, frequency shift Ω and

Young’s longitudinal elastic modulus.

- One of the main advantages of

brillouin microscopy that it
can detect focal weakening.

- Keratoconus now is well rec-

ognized that its due to focal
weakening not generalized
weakening (Fig, 28).
Figure 28, cycle of biomechanical de-
compensation in keratoconus.
- From this cycle we can con-
clude that thinnest location
isn’t the location with high
- Using NIR LASER “780 nm”
stress, but it’s the steep part
made brillouin frequency
“cone”.
ranges from 5.69 to 5.76 GHz,
(Fig 29).
- This cycle of decompensation
also introduced the possibility
that ICRS can delay the pro- Wavefront Aberrations Anal-
gression of keratoconus, but ysis
it’s still debatable.
- Corneal HOAs are increased
- The idea of focal weakening in keratoconus due to irregular
raised up the possibility of astigmatism especially coma
customized treatments. and trefoil.
29 6. Diagnostic Tools in Keratoconus

Figure 29, Brillouin microscopy in a; normal individuals, b; mild keratoconus, c; ad-

vanced keratoconus

- Ocular HOAs may be more ac- cellular level and can also
curate as they include poste- study separate corneal layers.
rior corneal surface.
- Confocal microscopy (CFM)
- Analysis of wavefront HOAs
takes multiple 2D images at
may aid in early diagnosis and
different planes to create 3D
even follow up in keratoconus.
images.

- In advanced keratoconus cases - CFM can be used alone or in

may be helpful in refraction association with brillouin mi-
assessment as it measures the croscopy “Confocal LASER
objective refraction. Scanning Microscopy”.

- In keratoconus (Fig, 30)

Confocal Microscopy
• Decreased epithelial cell den-
- It’s a non-invasive imaging of
sity which is correlated with
a micrograph “which is mag-
the severity of keratoconus.
nified, high resolution images
of a microscope”. Which al- • Prominent thickened sub basal
lows imaging at corneal nerves.
6. Diagnostic Tools in Keratoconus 30

• Decreased stromal keratocytes

density.

• Presence of posterior stromal

folds “Vogt’s stria”.

• In addition, it may identify the

demarcation line depth after
CXL which appears as stromal
keratocyte apoptosis.

Spectral Microscopy

- In early stages, endothelium in

keratoconus appears normal
but when the disease progress
there will be increased pleo-
morphism.
- Spectral microscopy is useful
also in detection of diseases
occurring simultaneous with
keratoconus as PPCD.
Artificial Intelligence and Arti-
ficial Neural Networks
- Algorithms that through learn-
ing has enabled computers to
be intelligent.
- Learning is defined as the abil-
ity to update parameters of an
Figure 30, confocal LASER scanning mi-
croscopy of normal and keratoconus cor-
nea.
algorithm upon the availabil-
ity of data.
- One of the main advantages of
artificial intelligence is their
ability to eliminate the gap be-
tween research and clinical ap-
plication by providing a sim-
ple output parameter that can
be directly used as a risk strat-
ification tool.
31 6. Diagnostic Tools in Keratoconus

- Artificial neural networks

“ANN” are a type of artifi-
cial intelligence designed
on the concept of biologi-
cal neurons (Fig. 31).

- ANN are composed of in-

puts that receive external Figure 31, artificial neural networks based
data, circles are different on the concept of biological neurons.
cell bodies that are inter-
connected with arrows
which are connections as
nerve axon (Fig. 32).

- Input neuron receives ex-

ternal data that is delivered
to a neuron of activation
function that acts as a syn- Figure 32, schematic algorithm of ANN.
apsis to modulate data and
lastly deliver it to an out-
put neuron that accomplish 1. Software available in
the final goal. different topographers
and tomographers that
use a variety of indices
- One of the problems of
tested before in clinical
ANN that they require ex-
trials and proved effi-
tremely large clinical da-
ciency in early detec-
tasets for achieving a glob-
tion of keratoconus.
ally accepted performance.
2. Software aiding in the
- Some examples of ANN in nomogram for ICRS
the diagnosis of kerato- implantation e.g. Sirius
conus are CSO.
7. Treatment Modalities, Spectacles and Contact Lens
3. The waveform parameters in
ocular response analyzer that
produce the keratoconus
match probability index
(KMP) and the keratoconus
match index (KMI).
4. Corvis biomechanical index
(CBI) and tomographic bio-
mechanical index (TBI).
5. Belin Ambrosio enhanced ec-
tasia, Belin ABCD classifica-
tion and progression display.
Treatment Modalities
1. Spectacles
- Glasses can be used in early
stages when there is satisfac-
tory BCVA “minimal astigma-
tism”.
- It can be used following any
treatment if there is satisfac-
tory BCVA.
2. Contact Lenses
- May be used in mild to moder-
ate and some severe cases to
32
N.B.
The participation of high-tech
companies to provide the compu-
tational power needed, multi-
centric collaborations to gather
big datasets along with efficient
data sharing systems to con-
stantly train the models is a vital
step to improve the accuracy of
AI models. Don’t rely on them
solely.
correct the irregular astigma-
tism that is not corrected by
glasses.
- Contact lens can also be used
following any treatment if
there is satisfactory BCVA.
- In general, it depends on cor-
neal topography especially
tangential map to detect the lo-
cation and degree of ectasia.
- Soft toric, rigid gas permeable,
33
piggyback, scleral and hybrid
contact lenses can be used in
keratoconus.
Terms in Contact Lenses
For illustrative video see YouTube
Channel
- Diameter is the width of con-
tact lens.
- Optic zone is the area on the
front surface with refracting
power.
- Base curve is the central cur-
vature of the posterior surface
“Rc mm”.
- Sagittal depth “Vault” is a
measurement from any flat
plane of known diameter to the
highest point on base curve.
- Edge Lift is the peripheral lens
in relation to the underlying
cornea, it’s determined by the
peripheral curve “documented
with fluoresceine”.
- Dk which describes the oxygen
permeability of the lens mate-
rial “High Dk > 40, Hyper Dk
> 100”.
7. Treatment Modalities, Contact lens
- Power is determined by con-
tact lens shape.
- Lacrimal lens
For illustrative video see YouTube
Channel
• It’s an optical lens formed by
the tear film layer between the
base curve and the anterior
corneal surface, its shape de-
pends on the base curve and
the central curvature of cor-
nea.
• If the base curve is steeper
than the corneal central curva-
ture, the tear lens will act as a
converging “plus” lens.
• If the base curve is flatter than
the corneal central of curva-
ture, the tear lens will act as a
diverging “minus” lens.
Soft Toric contact lens
- Usual soft CL can’t be fitted in
keratoconus as it slips over the
cornea with failure to create
lacrimal lens to correct irregu-
lar astigmatism and HOAs.
7. Treatment Modalities, Contact Lens
- Can be used for mild “early”
cases. A new design with high
modulus is now available
which are relatively stiff that
can hold its shape over an ir-
regular cornea.
Rigid Gas Permeable (RGP)
contact lens
- Rigid to fit on irregular cor-
neas, tears fill on the space be-
tween the back of lens and the
anterior irregular surface of
the cornea forming “lacrimal
lens”, this interaction creates
an optically improved surface
correcting the irregular astig-
matism.
For illustrative video see YouTube
Channel
- The ideal fitting of a RGP is
confirmed by
1. Dynamic Fitting
- To be well centered and to
move approximately 0.5 - 1
mm with blinking and doesn’t
cross the limbus, to allow for
34
oxygen rich tears exchange
under the lens.
- Push up test, which is manu-
ally pushing the contact lens
up with the edge of lower eye-
lid and waiting for the contact
lens to be recited.
2. Static Fitting
- Three-point touch “divided
support”, it’s the best contact
lens fitting, characterized by
gentle central touch at the apex
with surrounding fluoresceine
pooling, mid peripheral touch
with pooling at lens edge ap-
proximately 0.5 - 1 mm (Fig.
33 a).
- Apical clearance, the apical
“vault” area is clear and the
lens bearing is directed to-
wards the periphery which re-
sults in decreased peripheral
tear exchange (Fig 33 b).
- Apical bearing is an old type,
in which the lens mostly bears
on the apex that caused cor-
neal scarring (Fig 33 c).
35
a b
Figure 33, dynamic fitting of RGP contact lens using fluoresceine stain, a; three-point
touch, b; apical clearance, c; apical bearing.
- The advantages of RGP are
• Simple fitting.
• Easy to insert, remove and
clean.
• High oxygen permeability as
it’s made from high Dk materi-
als.
• Relatively inexpensive.
- The disadvantages of RGP are
• Doesn’t fit some cases as in in-
ferior cone where RGP lens
will center on apex of the cone
which will make the visual
axis outside the optical zone.
• Not suitable in dusty environ-
ments as dust may enter under
the lens through the peripheral
tear exchange.
Piggyback Lens
- Sometimes patient’s epithe-
lium can’t tolerate the lens
7. Treatment Modalities, Contact lens
c
touch at the apex with recur-
rent punctate keratitis and ero-
sions, so, a disposable silicon
hydrogel with high oxygen
permeability “high Dk” may
be used under the rigid gas
permeable contact lens to in-
crease the wear time and de-
crease the discomfort.
- New designs of piggyback
lenses have a central cutout
depression to accommodate
the rigid gas permeable con-
tact lens over it, prevent it
from decentration and im-
proves the comfort because of
minimal interaction with the
lids (Fig. 34).
Scleral Lens
- Are large diameter rigid gas
permeable contact lens that
rests completely on the sclera.
7. Treatment Modalities, Contact Lens
Figure 34, new design of piggyback con-
tact lens with central cutout depression.
- Formed of the vault “optical
zone” which is over the cornea
and not touching it, transi-
tional zone “limbal clearance
area” and the edge of the lens
“landing zone” (Fig.35).
- For ideal fitting
• Choose appropriate diameter.
• Choose appropriate sagittal
depth.
• Adjustment of the landing
zone “edge lift”.
- The patient fills the lens with
saline before insertion to pro-
duce a lacrimal lens approxi-
mately 200 - 250 µm which is
relatively thick.
- Advantages of scleral lens are
• Due to presence of a vault can
fit to more severe cases.
36
• Due to its large diameter cen-
tration is good with minimal
lid interaction as the edge is
beyond the palpebral opening.
• Made from high Dk materials.
- Disadvantages are
• Fitting problems, if the vault is
shallow this will lead to cor-
neal abrasions and scarring. If
the edge is tight this will lead
to recurrent conjunctivitis,
conjunctival hypertrophy and
corneal neovascularization
from chronic ischemia.
• Difficult to insert and remove
using the suction cup.
• Fogging due to increase in
temperature of lacrimal lens or
from debris that accumulates.
This requires the patient to re-
move the lens and clean it or to
adjust the edge lift.
• Not fit for those with glau-
coma drainage device.
37
Figure 35, schematic image of scleral
lens.
- Prosthetic Replacement of Oc-
ular Surface Ecosystem
(PROSE) is a type of scleral
lens that can be customized to
each patient, but limited centers
fit it worldwide (Fig. 36).
Hybrid Lens
- It’s made from RGP center
and soft silicon hydrogel skirt
(Fig. 37).
- Advantages of hybrid Lens
• Excellent centration, fitting and
comfort due to the soft skirt.
• Possible in dusty environment.
- Disadvantages of hybrid lens
• It can’t fit severe cases due to
limited parameters and cus-
tomized design.
7. Treatment Modalities, Contact lens
• Difficult insertion and re-
moval.
• It can be torn at the junction.
• High cost.
- An overview of different con-
tact lens designs used in kera-
toconus (Table, 7).
- Aspects that must be consid-
ered when prescribing contact
lens in keratoconus are
• Contact lenses aren’t chosen
based on topography only, but
other important information
include occupation, presence
or absence of atopy and ocular
surface diseases.
• Patients must know that con-
tact lenses have no therapeutic
Figure 36, schematic image of PROSE.
7. Treatment Modalities, Contact Lens 38

effect on keratoconus and

don’t prevent progression.

• They must know that contact

lens fitting requires multiple
lengthy visits.

• Lens power or type may be

changed as keratoconus pro-
gresses.

• Patients need annual revision

to confirm stability and pre-
Figure 37, schematic image of hybrid
vent complications.
lens.

- Use of different contact lens

designs in grades of kerato-
conus (Table 8).

Lens Ease of Care Corneal

Vision Stability Comfort Cost
Design &Handling Health

RGP A A A B B +

Scleral C A A A A +++++

PROSE C A A A A ++++

Hybrid C A A A A +++

Piggyback B B B B B ++

Soft Toric A C B A A ++

Table 7, overview of different contact lens designs used in keratoconus, A; excellent, B;

good, C; fair.
39
Lens Design Mild KC
RGP
Scleral
PROSE
Hybrid
Piggyback
Soft Toric
Table 8, different contact lens designs and their use in different grades of keratoconus.
3. Cross Linking
Evolution of cross linking
- Professor Theo Seiler (1993)
in Dresden university made a
large study on corneal biome-
chanics and cross linking.
- After reading in literature and
performing CXL on porcine
eyes using advanced glycation
end products (AGEs) and ul-
traviolet (UV) light and tested
their efficiency by stress-strain
measurements, he found that
• Physiological cross linking oc-
curs by time with lysyl-oxi-
dase enzyme which explains
the decreased incidence of
keratoconus in old age.
• Cross linking by AGEs from
glucose, ribose and
7. Treatment Modalities, Cross linking
Moderate KC Severe KC
glyceraldehyde, takes a long
time, so, wasn’t chosen and
this also explains the low fre-
quency of keratoconus in dia-
betes mellites.
• Photo-Oxidative cross linking
with ultraviolet light was cho-
sen because of acceptable bio-
mechanics and its prevalence
in the field of dentistry as it
was known that it hardens the
polymers.
- The problem found in cross
linking with ultraviolet light
that its effect is weak and to
get a better effect the ultravio-
let dose should be increased
which is dangerous, so, the
idea of photosensitizer was
born that will increase the ef-
fect without increasing ultravi-
olet dose.
7. Treatment Modalities, Cross Linking
- Several photosensitizers were
found but most of them were
toxic. The best chosen photo-
sensitizer was riboflavin
which is vitamin B2 that is not
toxic and hydrophilic.
- The next step was to determine
the excitation wavelength of
riboflavin and its concentra-
tion. Two peaks were found
365 nm and 460 nm, 365 nm
was chosen after comparing
the biomechanical effect of
both and 0.1 % was found to
be the best concentration as it
produces the highest absorp-
tion coefficient “90 % of ultra-
violet light is absorbed within
the stroma for the safety of en-
dothelium, lens and retina”.
- Professor Seiler (1995) started
to test UV light 365 nm with
intensity 2 mW/cm2, 0.1 % ri-
boflavin for different time in-
tervals and found the best bio-
mechanical effect with 45 min.
- In (2000) UV-LEDs (light
emitting devices) with 365
nm and intensity 3mW/cm 2
named “double diodes” were
40
developed, so, they concluded
that this may decrease irradia-
tion time, Professor Seiler
tested 2 mW/cm2 for 45 min
and 3 mW/cm2 for 30 min and
found biomechanical effect is
better with the 3 mw/cm2 and
named it standard irradiation.
- The best soaking time for ribo-
flavin 0.1 % was 30 min which
was time dependent to get the
maximum diffusion into the
stroma with epithelium re-
moved “epi-off”.
- Further studies was done to
detect the safety of ultraviolet
radiation on the endothelium
and found a minimum corneal
thickness of at least 400 µm is
required to be safe.
- Dresden Protocol evolved us-
ing UV-LED 365 nm with in-
tensity 3 mW/cm2 for 30 min
with a total dose 5.4 J/cm2. It
was an “epi-off” protocol with
0.1 % riboflavin and soaking
time every 5 min for 30 min. It
then entered clinical study be-
tween 1998 - 2003.
41
Determiners of cross linking
1. Epithelium
- Epithelium acts as a barrier for
ultraviolet radiation “25% loss
from epithelium and Bow-
mans membrane”, riboflavin
and oxygen.
- Epi-off CXL is the standard
procedure for better results.
- Transepithelial “epi-on” CXL
is done to decrease the compli-
cations of epi-off.
- Riboflavin passes through the
epithelium by either
• Modifying epithelium permea-
bility with enhancers, but most
are epitheliotoxic e.g. Benz
Alkonium Chloride (BAC), so-
dium EDTA, proparacaine,
tetracaine and gentamycin.
• Changing the physiochemical
property e.g. iontophoresis.
• Delivering riboflavin directly
into the stroma e.g. femtosec-
ond pockets
7. Treatment Modalities, Cross linking
2. Ultraviolet radiation 365 nm
with specific intensity, dose
and beam profile
- Standard irradiation parame-
ters are intensity 3 mW/cm2
and a total dose of 5.4 J/cm2.
- Accelerated irradiation either
• Increased intensity with same
total dose 5.4 J/cm2.
• Increased Intensity with in-
creased total dose eg. 7 J/cm2,
7.2 J/cm2 and 15 J/cm.2
- For both standard and acceler-
ated irradiation, the mode may
be continuous or pulsed “1 sec
on and 1 sec off” which is bet-
ter for replenishment of oxy-
gen.
- Accelerated intensities de-
pends on Bunson-Roscoa law
of Reciprocity which states
“The same photochemical ef-
fect can be achieved by in-
creasing irradiation intensity
while correspondingly de-
creasing illumination time as
long as the total dose is not
changed”.
7. Treatment Modalities, Cross Linking
- So, it’s supposed to have the
same effect with 9 mW/cm2
for 10 min, 15 mW/cm2 for 6
min, 18 mW/cm2 for 5 min, 30
mW/cm2 for 3 min, 45
mW/cm2 for 2 min and 90
mW/cm2 for 1 min.
- This doesn’t occur clinically
(Graph 1) shows
• Up to 30 mW/cm2 had nearly
the same biomechanical ef-
fects as standard irradiation.
• After 30 mW/cm2 dramatic de-
crease in biomechanics seen.
- Bunson Roscoa principle
doesn’t apply for higher inten-
sities which may be explained
by decreased oxygen availa-
bility.
Different Beam Profiles
- Gaussian profile, which is bet-
ter in the center than periphery,
it’s not used now (Fig. 38 a).
- Top hat “flat top” profile,
which has more homogenous
distribution (Fig 38 b).
42
Bunson-Roscoe Principle
Irradiance mW/cm2 x Time in seconds = Total Dose J/cm2
Graph 1, biomechanical stiffness of dif-
ferent irradiation intensity and duration
keeping total dose constant.
- Cosine compensated profile
which has more peripheral en-
ergy to compensate for the cor-
neal curvature (Fig. 38 c).
3. Adequate diffusion of ribo-
flavin in the corneal stroma
- Riboflavin concentration is
time dependent, the ideal
soaking time is every 5 min for
30 minutes for full stromal dif-
fusion, and the best indicator
is examining the patients on a
slit-lamp to detect homoge-
nous diffusion of riboflavin
into the corneal stroma and
a green aqueous flare.
43
a b
Figure 38, beam profiles of ultraviolet radiation, a; gaussian profile, b; top hat profile, c;
cosine compensated profile.
- Epithelium acts as a barrier for
the hydrophilic riboflavin dif-
fusion.
- Different riboflavin used in
clinical practice are
Standard riboflavin which is
isotonic and used in epi-off
CXL, 0.1 % RF with 20%
dextran that may cause stro-
mal dehydration, so, check
stromal thickness before UV
irradiation, soaking time is
every 5 min for 30 min as
VibeX®, Ricrolin® and Medio-
CROSS D®.
Riboflavin for accelerated
CXL which is isotonic and
used in epi-off CXL, 0.1 %
RF with 1.1 % HPMC that im-
proves diffusion and doesn’t
7. Treatment Modalities, Cross linking
c
cause stromal dehydration,
soaking time is every 2 min for
10 min as VibeX Rapid® and
MedioCROSS M®.
Epi-on “transepithelial” ri-
boflavin “two steps”
Step one is application of TE
RF, which is isotonic, 0.25 %
RF ,1.2 % HPMC ,0.01%
BAC, soaking time is 2 drops
every minute for 4 min, aim is
opening the tight junctions.
Not more than 4 min to avoid
epithelial sloughing as Para-
cel® and MedioCROSS TE®.
Step two is application of spe-
cial RF which is isotonic,
0.22% RF, soaking time is 1
drop every 30 sec for 6 min as
VibeX Xtra®.
7. Treatment Modalities, Cross Linking
Ricrolin TE® “one step”
which is isotonic, 0.1 % RF,
15 % dextran, EDTA, tromet-
amol, soaking time is 1 drop
every 2 min for 15 min then 15
min RF within a silicon ring.
Riboflavin for thin corneas
which is hypotonic and dex-
tran free, used in epi-off
CXL, 0.1 % RF as Medio-
CROSS H®.
Special riboflavin, which is
isotonic, 0.22 % RF, used for
LASIK Xtra as VibeX Xtra®.
Special riboflavin, which is
hypotonic and dextran free,
0.1 % with EDTA and tromet-
amol, for iontophoresis and
sub400 protocol as Ricrolin®+.
4. Availability of oxygen
- Sufficient oxygen is important
in cross linking.
- Epithelium acts as a barrier for
oxygen delivery in CXL.
- In cross linking, higher inten-
sities > 30 mW/cm2 oxygen
44
Figure 39, oxygen boost googles.
consumption is rapid which
affects cross linking reaction.
- Supplemental oxygen is used
through boost googles espe-
cially in higher intensities >
10 mW/cm2, if not available
you may use the usual oxygen
line (Fig.39).
5. Time factor for ultraviolet
light and riboflavin soaking
time
- Standard irradiation intensity
is 3mW/cm2 for 30 min.
- Accelerated irradiation is de-
termined according to the in-
tensity used.
- Different riboflavin soaking
time according to the proce-
dure.
45 7. Treatment Modalities, Cross linking

Algorithm 1, chemical reactions type 1 and 2 and the importance of oxygen availability
in cross linking.

General reaction mechanism stress and healing response of

For illustrative video see YouTube
tissues. Preferred to be deep,
Channel approximately 200 - 250 µm
and to be posterior to the ante-
- Type two reaction is aerobic
rior 40 % which is already bio-
and lasts for 10 - 15 sec and
mechanically stronger. It may
it’s more important, while type
not appear in every case.
one reaction is anaerobic and
lasts longer.
- Haze, due to the oxidative
stress and dehydration. It may
- The two reactions compete
last for 1 month.
with the available oxygen, so,
oxygen depletion occurs (Al-
- Clinically
gorithm 1).
• Keratometry readings increase
Evidence of action after cross in the first 1-3 months due to
linking the masking effect of epithe-
lium then decrease.
- Demarcation line, which is a
hyper-reflective line seen by
AS-OCT and confocal micros- • Increased BCVA but not in all
copy, it is due to the oxidative cases.
7. Treatment Modalities, Cross Linking
Protocols of cross linking
1. Dresden protocol
- Topical anesthesia 10 min be-
fore the procedure.
- Mechanical epithelium re-
moval over a 9 mm area.
- Standard riboflavin, which is
isotonic, 0.1 % RF with 20%
dextran that may cause stro-
mal dehydration, so, check
stromal thickness before UV
irradiation “must be ≥ 400
µm”, soaking time is every 5
min for 30 min.
- Standard irradiation which is
3 mW/cm2 for 30 min, contin-
uous mode with a total dose
5.4 J/cm2 + riboflavin every 5
min “avoid irradiation on lim-
bal stem cells by leaving an
area of about 2 mm”.
- After finishing apply a band-
age contact lens, NSAID then
steroids after epithelial heal-
ing, antibiotics eye drops and
vitamin c tablets.
2. Accelerated protocols
- May be epi-off or epi-on,
pulsed or continuous mode.
46
- Most common used intensities
are 9mW/cm2 for 10 min,
15mW/cm2 for 6 min and 30
mW/cm2 for 3 min.
- Riboflavin for accelerated
CXL, two step transepithelial
or one step transepithelial ri-
boflavin may be used.
3. Protocols for thin corneas
- Hypo-osmolar riboflavin solu-
tion.
- Transepithelial cross linking
using enhancers, iontophore-
sis or femtosecond pockets.
- Pachymetry based accelerated
cross linking “M Nomogram”.
- Sub400 protocol.
N.B.
Other protocols used in thin
corneas but of less importance
are contact lens assisted CXL
and epithelial island CXL.
Hypo-Osmolar Riboflavin So-
lution, Hafezi et al, 2009
- Removal of the epithelium.
- Apply standard riboflavin as
Dresden protocol.
- Apply hypotonic riboflavin,
47
0.1 %, dextran free to swell
cornea to be ≥ 400 µm “1 drop
every min for 5 -7 min” then
check with pachymetry.
- UV irradiation as Dresden
protocol but don’t add ribofla-
vin during irradiation.
- After finishing, apply a band-
age contact lens, NSAID then
steroids after epithelial heal-
ing, antibiotics eye drops and
vitamin c tablets.
Transepithelial cross linking
using enhancers and femtosec-
ond pockets
- Transepithelial riboflavin
“two steps” is applied fol-
lowed by accelerated UV irra-
diations. Most studies show
inferior results than epi-off.
- Creating femtosecond pockets
and directly applying ribofla-
vin into the stroma followed
by accelerated UV irradiation.
Studies also show inferior re-
sults.
N.B.
Femtosecond pocket assisted
cross linking is combined some-
times with Myoring implanta-
tion.
7. Treatment Modalities, Cross linking
Figure 40, principles of iontophoresis.
Transepithelial cross linking
using iontophoresis
- Iontophoresis is a non-inva-
sive system that enhances de-
livery of charged molecules
“riboflavin is negative” into
tissues using small electric
current (Fig 40).
- Two involved mechanisms
1. Electro repulsion, as negatively
charged riboflavin repels.
2. Electro-osmosis, as corneal tis-
sue is positively charged in the
physiological PH.
- A recent study was published
by Mazotta, et al 2018 “En-
hanced-Fluence Pulsed-Light
iCXL” show very promising
effects. Demarcation line
7. Treatment Modalities, Cross Linking
depth is approximately 290
µm in > 80% of patients.
- Parameters used in the study
• UV irradiation 18 mW/cm2,
pulsed with a total dose opti-
mized to 30 % increase to be 7
J/cm2 to overcome loss of UV
by absorption from the epithe-
lium and Bowmans membrane
for 6.28 min. The total time is
12.56 min which is also opti-
mized to 30 % increase.
• Riboflavin used is 0.35 ml of a
special riboflavin, Ricrolin®+
• Iontophoresis suction ring
with a current 1 mA for 5 min.
Pachymetry based accelerated
cross linking “M Nomogram”,
Mazzotta et al, 2018.
- It’s an epi-off study compar-
ing the demarcation line depth
in conventional protocol and
different accelerated protocols
by in vivo confocal micros-
copy, AS-OCT and calculated
mathematical CXL models.
- There was very high correla-
tion between measured IVCM,
OCT and calculated depth of
the demarcation line.
48
- M, matching the IVCM and
OCT measurements with the
simulated CXL depth mathe-
matical models.
- All measurements include the
epithelium (Fig 41).
- All measurements include 50
µm “plus” for endothelial
safety.
- The 18mW/cm2 isn’t included
as it wasn’t superior to
15mW/cm2 in Kmax flattening
and biomechanics.
- The M nomogram allows to
set a desired depth of treat-
ment for corneas ranging from
250 µm - 400 µm.
Sub400 protocol, Hafezi et al,
2020.
- It’s an epi-off study that is
based on individualizing the
total dose during CXL,
according to the intraoperative
pachymetry.
- The irradiance is kept constant
at 3mW/cm2, continuous mode
while only the duration and the
total dose are adjusted to every
patient according to the
thinnest pachymetry after
49 7. Treatment Modalities, Cross linking

Figure 41, schematic image of a 400 µm thickness cornea showing demarcation line
depth including epithelium and 50 µm plus for endothelial safety, total dose is kept con-
stant 5.4 J/cm2 for different intensities.

riboflavin soaking and before 4. Topography guided

UV irradiation (Table 9). protocols

- It’s based on a theoretical - Customized Remodel-

model that takes into account ing Vision (CURV)
stromal riboflavin diffusion, which is done on the
oxygen and UV availability new device, MOSAIC®
during cross linking. system.
- Ricrolin®+ is soaked for 20
- It’s known from studying
min which is hypotonic, dex-
corneal biomechanics by
tran free, 0.1 % RF, with
brillouin microscopy that
EDTA and trometamol.
keratoconus is due to focal
- The advantages of this proto- weakening, so, customized
col that it can be applied on CXL over the weak areas
any CXL device and that the is better than generalized
total dose doesn’t exceed 5.4 CXL over the entire cor-
mJ/cm2. nea.
7. Treatment Modalities, Cross Linking 50

Demarcation
Minimum Stromal Thickness Duration “min”
Line depth “µm”
200 1 130
210 1:20 140
220 1:40 150
230 2 160
240 2:30 170
250 3 180
260 3:30 190
270 4 200
280 5 210
290 6 220
300 7 230
310 9 250
320 10 255
330 12 265
340 14 275
350 16 283
360 18 290
370 20 300
380 23 310
390 26 320
400 29 330

Table 9, sub400 protocol showing stromal thickness and expected demarcation line
depth, irradiance is kept constant at 3 mW/cm2 while total dose and duration is variable.

- The new MOSAIC® system of- - Different overlapping custom-

fers this advantage of custom-
ization in which the weak area
“cone” receives more intense,
localized and targeted CXL,
while the rest of the cornea
will receive less intense CXL
(Fig. 42 a, b, c and d).
izations are available with dif-
ferent shapes, energies and du-
ration (Fig. 42 e).
- There is a real time eye tracker
to overcome the cyclotorsion.
- Accelerated protocols from 9
mW/cm2 to 100 mW/cm2 with
51
total dose up to 15 J/cm2 are
also available.
- Selectively induced stiffening
in weak areas, can flatten the
cone and improve the vision.
5. Combined protocols
• Athens protocol
• Cretan protocol
• LASIK-Xtra
Athens protocol
For illustrative video see YouTube
Channel
- It involves simultaneous PTK
for epithelial removal “50 µm”
+ partial topography guided
ablation “50 µm” to regularize
the anterior corneal surface +
accelerated CXL. Riboflavin
for accelerated protocols is
used with intensity of
9mW/cm2 for 10 min, with or
without MMC application.
Simultaneous protocol shows
better results than sequential
protocol, Kanellopolous et
al,2009.
- Prerequisite
1. Stage 1 or 2 “early and mild
keratoconus”.
7. Treatment Modalities, Cross linking
a b c
d
e
Figure 42, CURV in Mosaic system, a; dif-
ferent depth of demarcation line which is
deeper in weaker areas that received higher
fluence, b; c; and d; overlapping in Mosaic
system, e; different overlapping customiza-
tion found in the Mosaic System.
2. Decreased BCVA < 0.6 “no
need to ablate progressive KC
with good BCVA, CXL is
enough”.
3. Preoperative CCT ≥ 450 µm or
≥ 400 µm before CXL.
4. Preoperative epithelial map-
ping, to avoid epithelial mask-
ing and include it from stromal
ablation over the cone.
5. Astigmatism
• If MA and TA are aligned,
the difference is ≤ 1D and ≤
15˚, correct 70% within the
limits of 50 µm.
7. Treatment Modalities, Cross Linking
• If both aren’t aligned don’t in-
clude the astigmatism and
treat as Cretan protocol.
6. Check ablation cone thick-
ness (ACT) it must be ≤ 50
µm. ACT is how much
will be ablated over the
cone, check it also with the
epithelial map.
7. Adjust optical zone e.g.
decrease optical zone to
decrease ACT and increase
RSB to be ≥ 400 µm.
8. Don’t promise patients
about glasses independ-
ence, you are just regular-
izing the corneal surface.
Cretan protocol
- Phototherapeutic keratectomy
(PTK) 50 µm for epithelium
removal.
- Standard riboflavin is used
which is isotonic, 0.1 % RF
with 20% dextran that may
cause stromal dehydration, so,
check stromal thickness before
UV irradiation, soaking time is
every 5 min for 30 min.
- Standard irradiation is used, 3
mW/cm2 for 30 min with a total
dose 5.4 J/cm2 with or without
52
riboflavin every 5 min and
MMC application “avoid irra-
diation on limbal stem cells by
leaving an area 2 mm from
limbus”.
- It has better results as it may
act as a partial topography
guided ablation due to epithe-
lium masking effect.
LASIK-Xtra
- After excimer LASIK abla-
tion, cover the corneal stroma
with VibeX Xtra® for 1 min.
Avoid soaking of the flap with
riboflavin.
- Wash riboflavin with BSS, re-
turn the flap over the stroma
then apply the UV irradiation
45 mW/cm2 for 80 seconds
with a total dose 3.6 J/cm2.
- Avoid flap CXL “as flap has
minimal stroma” to avoid de-
hydration, shrinkage, decreas-
ing UV light reaching stroma
and eventually it will not con-
tribute to corneal stability.
- My opinion about LASIK Xtra
1. LASIK is an elective surgery,
no need to apply LASER on a
moderate or high risk
53
topography for aim of prophy-
laxis against post LASIK ecta-
sia.
2. Unpredictable refractive re-
sults due to prolonged flatten-
ing effect of CXL may occur.
3. The number of published stud-
ies for combined LASIK and
CXL are few with unknown
long-term outcomes.
4. No agreement on a standard
protocol, multiple protocols
are available.
5. In the era of premiere phakic
IOLs, there is no need to put
the patient at a risk for an elec-
tive procedure.
Indications of cross linking
- Progressive keratoconus with
good BCVA.
- The standard CXL is epi-off
till long term studies of epi-on
show its effect.
- There are some indications for
epi-on, i.e., inability to per-
form epi-off as
• Young patients refusing epi-
off CXL or older patients with
inability to document progres-
sion.
7. Treatment Modalities, Cross linking
• Non-compliant children e.g.
Down syndrome.
• Advanced ocular surface dis-
ease to avoid epithelial healing
problems.
- Bilateral simultaneous CXL
isn’t a good option for fear of
rehabilitation and complica-
tions, unilateral procedure is
the best and after reaching a
functional vision, CXL is done
to the other eye.
N.B.
Once you take a decision of
epi-on CXL, you must follow
up the patient regularly.
Complications of cross linking
- Persistent epithelial defect.
- Corneal scar.
- Infectious keratitis.
- Sterile stromal infiltrates.
- Endothelial dysfunction with
corneal edema.
- Limbal stem cells damage
from excessive UV especially
in PMD, so, leave an area 1-2
mm from the limbus.
- Treatment failure with contin-
ued progression.
7. Treatment Modalities, Cross Linking 54

- Decreased BCVA in patients Dresden protocol under

with visual acuity ≥ 0.7, it’s topical anesthesia as
not a serious complication but long as the child is
must be discussed with the pa- compliant with a mini-
tients. mum stromal thickness
≥ 400 µm as adults and
Cross linking in children the use of hypotonic ri-
boflavin if minimum
- A child is a human younger stromal thickness < 400
than 18 years. µm.
- Different stages the eye passes - If the child is noncom-
through at different ages are pliant, epi-On CXL
shown in (Fig, 43). with 30 min irradiation
- Estimated collagen turnover in may take a chance un-
children is approximately 3 der topical or general
years compared to adults that anesthesia. This group
is about 6-7 years. This indi- may benefit from bilat-
cates regular short period fol- eral CXL under general
low up for increased possibili- anesthesia.
ties of retreatments. - The use of accelerated pro-
- Current evidence sug- tocols in children shows
gests epi-off CXL encouraging results.

12 – 15 Years > 15 – 18 Years

Birth – 12 Years
Increased elasticity
Increased viscosity
The transition be- Decreased elasticity
tween the two stages
were the cornea is Increased rigidity
biomechanically un-
Natural CXL
stable.

Figure 43, different stages the eye pass through in different age group.
55
N.B.
During the first 6 months after
CXL, the cornea shows topo-
graphic changes in addition to
changes in refraction and visual
acuity. After 6 months corneal
parameters stabilize and corneal
stability is judged thereafter for
any possibility of retreatment.
Recent trends in cross linking
Photorefractive intrastromal
cross linking (PiXL)
For illustrative video see YouTube
Channel
- CXL is known to decrease cor-
neal curvature by anterior cor-
neal flattening, so, we can ben-
efit from this as a refractive
tool.
- PixL is a customized application
of CXL acting by reshaping of
the cornea by means of localized
tissue strengthening (Fig. 44).
- Indicated in low refractive er-
rors ≤ 3 diopters. “John Kanel-
lopoulos the first to present
clinically”.
7. Treatment Modalities, Cross linking
- May be applied as epi-off or
epi-on.
- An ongoing study “PiXL with
Boost O2” aims to study the ef-
fect of epi-on PiXL with high
oxygen concentration, high in-
tensity and total dose on low
myopia.
- PiXL still needs more clinical
trials for standardized nomo-
grams for refractive errors.
a b c
Figure 44, principal of PiXL in a; myo-
pia, b; Astigmatism, c; hypermetropia
N.B.
Both CURV and PiXL are
customized CXL techniques
that are available on the new
device Mosaic® System.
Photoactivated chromophore
cross linking “PACK-CXL”
- CXL has microbicidal effect,
so may be used in infective
keratitis.
- It is active against bacteria,
fungi and acanthamoeba but
7. Treatment Modalities, Intracorneal Ring Segments
not active against virus and it
may activate latent viral in-
fections.
- Chromophore is the substance
used that may be riboflavin or
rose bengal stain and it is ap-
plied as Dresden protocol.
- Antimicrobial activity is due
to
1. Microbial RNA and DNA
damage by UV and reactive
oxygen species (ROS).
2. Biomechanical stiffness that
causes increased resistance to
enzymatic digestion.
3. Decreased pain due to de-
creased number of corneal
nerves.
Bullous keratopathy
- By using the corneal dehydra-
tion effect of CXL due to the
presence of dextran in ribofla-
vin.
- It’s better to dehydrate the cor-
nea before application of UV
irradiation with either glycerol
70 % or glucose 40 %.
- Ideal time of preoperative de-
hydration isn’t clinically iden-
tified, from hours to one day
before UV irradiation.
56
N.B.
Cross linking was FDA ap-
proved in Europe in 2007 and in
USA in 2016.
Evolution of cross linking de-
vices
For illustrative video see YouTube
Channel
4. Intracorneal ring segments
Structure of ICRS
For illustrative video see YouTube
Channel
- ICRS was originally devel-
oped for surgical correction of
high myopia and astigmatism.
- ICRS are made from PMMA
which is biocompatible, nearly
the same refractive index as
the cornea, flexible and easy to
work with.
- Each segment has
1. Arc length in degree
2. Apical diameter
3. Inner diameter
4. Outer diameter
5. Thickness
Types of ICRS
1. Kera ring, Mediphacos, Bra-
zil (Table 10) and (Fig. 45).
57 7. Treatment Modalities, Intracorneal Ring Segments

Cross Section Triangular

Arc Length 90˚, 120˚, 160˚, 210˚, 355˚
5 mm “ arc length as above ”
Diameter
6 mm “ 150˚ instead of 160˚”
Thickness 150 µm - 350 µm (50 µm increase)
Inner Diameter 6 mm
Outer Diameter 7 mm

Table 10, kera ring parameters.

- A new type of kera ring, Kera

ring AS progressive thickness
is now available (Table 11)
and (Fig. 46).

2. Ferrara ring, AJL ophthal-

mics, Spain (Table 12) and
(Fig. 47).

3. Intacs ring, Addition technol-
ogy, AJL, Spain (Table 13 and
(Fig. 48).
4. Myoring, Dioptex, Austria,
(Table 14).
Figure 45, kera ring, triangular cross
section to have a prismatic effect to de-
crease the glare and halos. The 355˚
segment 6 mm diameter only 200 µm
and 300 µm are available.

Cross Section Triangular

Arc Length 160˚
Diameter 5 mm
150 µm to 250 µm
Progressive Thickness
200 µm to 300 µm
Inner Diameter 6 mm
Outer Diameter 7 mm

Table 11, kera ring AS parameters.

7. Treatment Modalities, Intracorneal Ring Segments 58

a b

Figure 46, kera ring AS. Progres- Figure 47, a; ferrara ring, b; yellow filter to
sive thickness is with the direction absorb ultraviolet light to decrease glare and
of the arrow. halos especially at night.

Cross Section Triangular

Arc Length 90˚, 120˚, 140˚, 160˚, 210˚,340˚
Diameter 5 mm or 6 mm
Thickness 150 µm - 300 µm (50 µm increase)
Inner Diameter 4.8 mm
Outer Diameter 5.4 mm

Table 12, ferrara ring parameters.

Intacs Intacs -SK

Cross Section Hexagonal Oval
Arc Length 150˚, 210˚ 90˚,130˚, 150˚
Diameter 7 mm 6 mm
90˚( 250 - 450 µm )
150˚ ( 250 - 450 µm )
Thickness 130˚ ( 300 - 450 µm )
210˚ (250 µm )
150˚ ( 250 - 500µm )
Inner Diameter 6.7 mm 6 mm
Outer Diameter 8.1 mm 7 mm

Table 13, Intacs and Intacs - SK rings parameters.

59 7. Treatment Modalities, Intracorneal Ring Segments

- Myoring acts as a permanent

contact lens inside the cornea.
- It’s rigid to stabilize the cornea
and flexible to be entered from
a small incision and has a good
memory.
- Myoring implantation inside a
corneal pocket with or without
accelerated CXL in the same
session is still debatable. Figure 48, INTACS ring.

5. Visum ring, Mediphacos,

Brazil (Table 15) and (Fig.
49). It’s an asymmetrical ring
that is still under clinical trials.

6. Corneal allogenic intrastromal

ring segments (CAIRS), So-
san Jacob (Fig. 50).
- It is based on using corneal
stromal tissue as synthetic
ICRS.
Fig. 49, Visum ring. A new de-
sign with arc length 340˚ is tested
to avoid wound healing problems
due to proximity of ends from
main incision.

Cross Section Triangular

Arc Length 360 ˚
Diameter 5 , 6, 7, 8 mm
Thickness 200 µm - 320 µm (40 µm increase)
Inner Diameter 5 - 6 mm
Outer Diameter 7 - 8 mm

Table 14, Myoring parameters.

7. Treatment Modalities, Intracorneal Ring Segments 60

- It is prepared with a special

trephine after epithelium and
Descemet membrane are re-
moved (Fig 50 A).
- CAIRS are implanted in a
femtosecond LASER tunnel of
the recipient cornea (Fig 50 C,
D and E).
- It has an advantage of decreas-
ing complications of synthetic
ICRS, but still needs more
clinical studies to determine
the long term stability. Figure 50, CAIRS, A; ring trephine for
trephination of corneal stroma after re-
Mechanism of action of ICRS moval of epithelium and Descemet mem-
brane, C and D; implantation through
- According to Barraquer thick- femtosecond tunnels, E; final appearance
after implantation.
ness law, to flatten the central
area of the cornea, either re- - According to Blavatskaya
move tissue from the center or rule, the flattening effect of
add tissue to the periphery ICRS increases by either de-
such as ICRS that will lead to creasing the optical zone of
an arc shortening effect (Fig. implantation or increasing the
51). segment thickness.
Cross Section Quadrangular
353 ˚(2 Asymmetrical Segments) can be
Arc Length
customized from 90˚ to 160˚
Diameter 5 mm
The Thickness of each segment can be
Thickness
customized from 150 µm to 350 µm
Inner Diameter 5.5 mm
Outer Diameter 6.5 mm

Table 15, Visum ring parameters.

61 7. Treatment Modalities, Intracorneal Ring Segments

- In general, arc length of ICRS

is related to cylinder correc-
tion while its diameter and
thickness are related to my-
opic correction.
- Another proposed mechanism
of action of ICRS is new lim-
bus creation. Collagen fibers
build a frame of support
stretching from limbus to lim-
bus.
- During tunnel formation with
femtosecond LASER, the col-
lagen fibers at the tunnel are
cut leading to
Figure 51, Barraquer thickness law show-
ing arc shortening effect of ICRS.
why ICRS are implanted on
the steep axis.
For illustrative video see YouTube
Channel
- A skew action occurs at the
axis over the middle of the
body of ICRS i.e. perpendicu-
lar to the flattened axis.
For illustrative video see YouTube
Channel

1. Concentration of the periph- - Sometimes unpredictable ef-

eral damaged fibers “outside fects may be seen with ICRS
tunnel” towards the limbus. due to the abnormal biome-
2. Flattening of the central area chanical functions of kerato-
which are under the pull of the conic corneas.
central freed fibers.
- Adding ICRS acts as a new
limbus and makes an outward
pressure adding to the central
flattening (Fig. 52).
- ICRS flattens the axis con-
necting the ends of the seg-
ments. In addition, segments
ends may cause a tractional
force on the corneal surface
Figure 52, outward pressure effect of
adding to the flattening, that’s ICRS that causes central flattening
7. Treatment Modalities, Intracorneal Ring Segments 62

Indications of ICRS Types of Keratoconus

- A New Type of Kera Ring AS For illustrative video see YouTube
- Poor“Progressive
BCVA < 0.6. BCVA < is
Thickness” Channel
0.6 now
withavailable
good PVA mostly
essive
have good results after ICRS. 1. Central or Nipple kerato-
- Intolerance to contact lens. conus, (Table 16).
- Good PVA, PVA is testing
BCVA with either rigid con- 2. Peripheral or Oval kerato-
tact lens or pin hole, a good conus, most commonly seen,
PVA must be at least two lines (Table 17).
improvement.
- Difference between manifest 3. Bowtie or Snowman kerato-
astigmatism and topographic conus, (Table 18).
astigmatism ≤ 15˚, it’s not an
indication it ensures better re- 4. Pellucid like keratoconus,
sults. (Table 19).
- Low Q-value. High Q-value
signifies severe keratoconus in
which the required ICRS will Nomograms of ICRS
not be possible to be im-
planted. - Each ICRS model supplies its
- Absence of Vogt’s striae and own nomogram which is good
corneal opacity. for beginner surgeons.
- Individual modifications
Location based on personal experience
Central
may come later.
Prolate/Hyper-prolate
Q-Value
High negative value
Astigmatism Low
Posterior Elevation Map Isolated central island
210˚
Best ICRS 355˚or Myoring (in relatively high
astigmatism)

Table 16, Central or Nipple keratoconus.

63 7. Treatment Modalities, Intracorneal Ring Segments

Location Paracentral, mostly lower temporal

Prolate
Q-Value
Negative value
Astigmatism High/Low
Posterior Elevation Map Tongue extension
Best ICRS According to target Q and astigmatism

Table 17, Peripheral or Oval keratoconus.

Location Central symmetrical or asymmetrical bow tie

Prolate
Q-Value
Negative value
Astigmatism High/Low
Posterior Elevation Map Isthmus
Best ICRS According to target Q and astigmatism

Table 18, Bow tie or Snowman keratoconus.

Location Peripheral “crab claw”

Oblate
Q-Value
Zero or positive value
Astigmatism High
Posterior Elevation Map Inferior decentred isolated island
Best ICRS 1 Segment 90˚, 120˚ or 140˚

Table 19, Pellucid like keratoconus.

- Whatever nomogram you use, wavefront analysis to have an

you must do a meticulous sub- objective refraction, where
jective refraction. you can start and have the
- If it is difficult to have a re- most acceptable best corrected
fraction, you may use visual acuity.
7. Treatment Modalities, Intracorneal Ring Segments 64

Kera ring nomogram - If not sufficient choose the

- Identifies the asymmetry type
according to the distribution of
ectasia along the steep merid-
ian, (Fig. 53).
Case one
For illustrative video see YouTube
Channel
- Refraction is -5DS -4DC x
135˚ and the BCVA is 0.7.
- Check the mesopic pupil size
which must be < 5mm.
- Look at the anterior sagittal
map to identify the steep axis.
- Ectasia type 2, so, nomogram
A will be used.
- 160˚/300 µm lower temporal,
120˚/150 µm upper nasal at 5
mm.
- Before implantation, check the
thickness at implantation site,
ICRS shouldn’t exceed 60 % of
corneal thickness at the tunnel.
suitable ICRS e.g. 250 µm.
- Implantation will be at 80 %
from thickness at the tunnel.
Case two
For illustrative video see YouTube
Channel
- Refraction is -2DS -6 DC x
180˚ and the BCVA is 0.7.
- Check the mesopic pupil size
which must be < 5mm.
- Look at the anterior sagittal
map to identify the steep axis.
- Ectasia Type 4, so, nomogram
C will be used.
- 160˚/250 µm temporal,
160˚/250 µm nasal at 5 mm.
- Before implantation, check the
thickness at implantation site.
- If not sufficient choose the
suitable ICRS e.g. 200 µm.
- Implantation will be at 80 %
from thickness at tunnel.

Figure 53, types of ectasia according to the steep axis and the corresponding nomogram.
used
65 7. Treatment Modalities, Intracorneal Ring Segments
- An important issue, should we
always need to choose the
topographic steep axis ?
1. If the BCVA > 0.6, choose the
manifest axis or topographic
steep axis, mostly both will be
aligned, the difference < 15˚,
but take care that in the mani-
fest refraction the axis with
minus cylinder is the flat axis.
2. If BCVA < 0.6, you can
choose either the topographic
axis or coma axis, mostly both
aren’t aligned in > 80 % of
cases. It’s a surgical prefer-
ence with no enough clinical
data to support.
• Correcting on topographic ax-
is will decrease astigmatism
and improve BCVA but may
affect the quality of vision if
significant HOAs are present.
• Correcting on coma axis will
also improve BCVA and qual-
ity but will not treat the cylin-
der or may even increase it.
Modified kera ring nomogram
or asphericity based nomo-
gram
- One of the important parame-
ters that should be targeted in
keratoconus is the Q-value,
Q is the quality of vision.
- Sometimes the resultant flat-
tening doesn’t correlate with
the BCVA, mostly due to
missing the Q-value.
- The rule is, to achieve what
you want with the least im-
plantation even with less flat-
tening effect, this is better.
- No need to implant a segment
in a flat area except if there is
high astigmatism.
- A study done by Paulo Ferra-
ra, et al. founded a direct rela-
tion between ICRS thickness
and the change in Q-value
(Table 20), (Graph 2, 3 and 4).
- Steps of this nomogram
1. Identify the type of the cone
either central, peripheral,
bowtie or pellucid like.
2. Identify the topographic steep
axis, if two segments will be
implanted it’s better to be par-
allel to the steep axis, and if
one segment will be implant-
ed, then at least one end
should be parallel to the steep
axis.
7. Treatment Modalities, Intracorneal Ring Segments 66

K-
Ring Arc Length Astigmatism Asphericity
Readings
90˚, 120˚, 140˚ +++ + +
160 ˚ ++ ++ ++
210˚ + +++ +++
340˚ ++ ++++ ++++

Table 20, the relation between different ICRS arc lengths and their effect on astigma-
tism, asphericity and keratomeric readings.

Graph 2, mean change in Q-value with single or double 160˚ segment of different
thickness.

Graph 3, mean change in Q-value with 210˚ Graph 4, mean change in Q-value with
segment of different thickness. 340˚ segment of different thickness.
67
3. Identify the target Q-value,
preoperative Q value - change
in Q- value = -0.23 “normal Q-
value.
4. Identify the topographic astig-
matism, if high (> 5 D), choose
a short arc segment or two seg-
ments.
5. Choose the best ICRS from the
above parameters.
Case one
For illustrative video see YouTube
Channel
- The same case was discussed
before using kera ring nomo-
gram.
- The nomogram suggested im-
planting 160˚/300 µm lower
temporal and 120˚/ 150˚ upper
nasal.
- Following the steps of the as-
phericity based nomogram
1. It’s an oval cone.
2. The steep axis at 45˚.
3. -0.56 - ∆Q = -0.23, change in
Q = -0.33.
4. The topographic astigmatism
is low.
5. The best will be 160˚/250 µm,
change in Q is -0.34 and the
7. Treatment Modalities, Intracorneal Ring Segments
cone will be displaced and no
need to implant in a flat area.
Case two
For illustrative video see YouTube
Channel
- It will be discussed using the
kera ring nomogram and the
asphericity based nomogram.
Ü Kera ring nomogram
• Refraction is -1 DS -5DC x
170˚ and the BCVA is 0.8.
• Steep axis at 80˚, so, ectasia
type 4 and nomogram C will
be used.
• The nomogram suggested im-
planting 120˚/250 µm tem-
poral and 120˚/ 250 µm nasal.
• It’s not a bad option but it will
not target the Q-value, in ad-
dition, the astigmatism isn’t
high enough to use a short arc
segments, so, 140˚ or 160˚
segment will be better, but
140˚ segment isn’t available
in the kera ICRS its available
only in ferrara ICRS.
7. Treatment Modalities, Intracorneal Ring Segments
Ü Asphericity based nomogram
1. It’s a bow tie cone.
2. Steep Axis at 80˚.
3. -0.95 - ∆ Q = -0.23, the change
in Q = -0.72.
4. The topographic astigmatism
is relatively low.
5. The best will be 160˚/200 µm
temporal, 160˚/150 µm nasal,
change in Q with 200 µm and
150 µm is -0.73.
6. Another option is 210˚/200
µm, change in Q-value is -0.6
but one end must be parallel to
the steep axis.
Case three
For illustrative video see YouTube
Channel
- It will be discussed using the
asphericity based nomogram.
- Refraction is -0.5 DS -4.00 DC
x 150˚.
1. It’s an oval cone.
2. Steep Axis at 60˚.
3. -0.70 - ∆ Q = -0.23, change in
Q = -0.47.
4. The topographic astigmatism
is low.
5. The best will be 160˚/250 µm
lower temporal, change in Q-
value with 250˚ is -0.34.
68
Combined procedures
- The most common combined
procedure is cross linking.
• Results show that sequential
ICRS done first followed by
CXL within 3-6 months gives
better results than if both done
simultaneous or CXL first fol-
lowed by ICRS.
• Sometimes there may be loss
of BCVA following CXL.
- ICRS may be combined with
any other refractive procedure.
Improving vision after ICRS
- One of the main advantages of
ICRS is reversibility, you may
need to readjust or exchange an
ICRS for better results.
- Glasses or contact lens may
improve BCVA after ICRS.
- Refractive surgery e.g. phakic
IOLs, PRK + CXL may be
used to improve BCVA.
Complications of ICRS
- Surgical related complications
which are less common now
with the introduction of femto-
second LASER tunnel for-
mation are subconjunctival
69
hemorrhage, suction ring loss
and very rare corneal perfora-
tion in < 0.6 % of cases. Previ-
ously when the manual tech-
nique was used, complications
were more common as ring de-
centration, asymmetric posi-
tion and corneal perforation.
- Post-surgical complications as
• Early postoperative, foreign
body sensation and mild cor-
neal edema for 24-48 hours.
• Migration of ICRS, if early
you can re-position, but if late
it will be difficult and extru-
sion will occur with increased
incidence of infection so, bet-
ter to remove the segment.
• Extrusion which is due to in-
terfering with stromal nutrition
anterior to the segment, with
resultant stromal thinning and
extrusion. Careful slit-lamp
examination shows progres-
sive stromal thinning over the
segment. The earliest sign is
recurrent epithelial erosion
over the segment. Removal of
the segment is mandatory (Fig.
54).
7. Treatment Modalities, Refractive Surgery
• Infectious keratitis may re-
quire removal of the segments.
Pain differentiates infectious
from non-infectious causes.
• Sterile infiltrates at the tunnel.
which is asymptomatic but if
in doubt treat as infection.
Figure 54, extrusion of ICRS.
5. Refractive surgeries
Protocols
1. Selective transepithelial ab-
lation for regularization of
ectasia with simultaneous
cross linking, (STARE-XL)
- It involves single step reversed
approach topography guided
transepithelial PRK, all surface
laser ablation (ASLA) i.e. re-
moving epithelium and apply-
ing partial topography guided
7. Treatment Modalities, Refractive Surgery
ablation in one step + acceler-
ated CXL. Riboflavin for ac-
celerated protocols is used, ul-
traviolet irradiation beam is
centered on the cone apex on
the posterior elevation map.
- If RST ≥ 400 µm intensity is
15mW/cm2, pulsed “1 sec on
and 1 sec off” for 12 min with
a total dose 5.4J/cm2.
- If RST < 400 µm intensity
used is 30mW/cm2, pulsed “1
sec on, 1 sec off” for 8 min
with a total dose 7.2J/cm2.
- Prerequisite
1. Stage 1 or 2 “early and mild
keratoconus”.
2. Decreased BCVA < 0.6 “no
need to ablate progressive ker-
atoconus with good BCVA,
CXL is enough”.
3. Preoperative CCT ≥ 450 µm
and minimum RST ≥ 350 µm.
4. Preoperative epithelial map-
ping, for custom epithelium re-
moval profile and to avoid ab-
lation over the cone. A central
50 µm and peripheral 65 µm
custom profile is used aided by
reversed approach (Fig. 55).
5. Sphere, astigmatism and
HOAs correction.
70
For illustrative video see YouTube
Channel
Ü In central keratoconus, cornea
is hyperprolate with myopia
and high negative Q-value, so,
correcting myopia within 0-2
diopters decreases Q-value.
50 % of astigmatism and
HOAs are also corrected
within the limit of maximum
ablation 50 µm.
Ü In peripheral keratoconus,
cornea is less prolate with less
myopia and low negative Q-
value, so, central ablation to
correct myopia will induce
prolate cornea and induced
myopia, so, no myopic correc-
tion is done. Only 50 % of
astigmatism and HOAs are
corrected within the limit of
max ablation 50 µm.
6. Optical zone in central kerato-
conus is 6.5mm and in periph-
eral keratoconus is 6 mm.
7. Ablation zone offset to coin-
cide with cone apex (Fig 56).
Done in both central and pe-
ripheral keratoconus. With ep-
ithelium save mode to de-
crease ablation over the cone
71 7. Treatment Modalities, Refractive Surgery

a b

c d e

Figure 55, principles of the reversed approach, a; an irregular cornea, b; starting ablation
with refractive component, c; ablation with custom epithelial profile, d; smooth stromal
bed after reversed approach, e; perfect epithelial regeneration.

and to directly correct coma

aberration.
8. Don’t promise patient about
glasses independence, you are
a b
just regularizing the surface.
Figure 56, a; ablation zone centered
on corneal apex, b; ablation zone cen-
2. Athens Protocol tered on cone apex

- It involves simultaneous one of the refractive proce-

phototherapeutic keratectomy
(PTK) for epithelial removal
“50 µm” + partial topography
guided ablation approximately
“50 µm” to regularize the an-
terior corneal surface + accel-
erated CXL. Riboflavin for
accelerated protocols is used
with intensity of 9mW/cm2 for
10 min, with or without MMC
application. It’s considered as
dures in keratoconus (Table
21).
3. Cretan Protocol
- Photorefractive keratectomy
(PTK) 50 µm for epithelium
removal. It is considered as a
refractive procedure as it acts
as a partial topography guided
ablation due to epithelium
masking effect.
7. Treatment Modalities, Refractive Surgery 72

Athens protocol STARE-XL protocol

Allegretto EX-500 Linked to pen-

Laser platform Schwind Amaris linked to sirius CSO
tacam system
TE PRk + 2 Step PTK for epithelium
Single step (reversed approach)
TG - ablation followed by partial TG-ablation
Ablation offset to coincide with the
Adjusted to keep RST ≥ 400 µm cone apex
Optical zone
& ACT ≤ 50 µm 6.5 mm in central KC, 6 mm in
peripheral KC
Preoperative CCT ≥ 450 µm ≥ 450 µm

RST ≥ 400 µm ≥ 350 µm

Epithelium
50 µm Customised to avoid masking effect
removal
Included in central & peripheral KC
HOAs (Comma) Not included
(RMS ≥ 1 µm) 1st Priority
Spherical Not included (unless ACT within
In central KC
correction 50 µm)
Astigmatic
70 % If TA and MA are Aligned In central & peripheral KC (50%)
correction
Maximum
≤ 50 µm ≤ 50 µm
ablation
Centred on posterior elevation
apex,topography guided on Mosaic
Centred on corneal apex System®
Accelerated CXL 9 mW/cm2 for 10 min (Total dose RST ≥ 400µm : 15 mW/cm2, Pulsed
5.4 J/cm2) for 12 min (Total Dose 5.4 J/cm2)
RST < 400µm : 30 mW/cm2, Pulsed
for 8 min (Total Dose 7.2J/cm2)

Table 21, comparison between Athens protocol and STARE-XL protocol.

Wavefront guided ablation corneal surface.

- Ocular wavefront guided abla-
- It’s well known that HOAs are tion depends on total HOAs in-
increased in keratoconus espe- cluding anterior corneal sur-
cially coma and trefoil. face and internal astigmatism
- Corneal wavefront guided ab- that reflects mainly the poste-
lations depend on the anterior rior corneal surface and to less
extent lenticular astigmatism
73
tent lenticular astigmatism.
- Best results were seen in se-
quential CXL first followed by
wavefront guided ablation af-
ter 1 year, Shaheen et al, 2016.
- Prerequisite, Shaheen et
al,2016
1. Stage 1 or 2 “early and mild
keratoconus”.
2. Dresden protocol is applied
3mW/cm2 for 30 min + docu-
mented stability for at least 1
year following CXL.
3. Decreased BCVA < 0.6, “no
need to ablate progressive ker-
atoconus with good BCVA,
CXL is enough”.
4. Minimum corneal thickness
≥ 400 µm.
5. Maximum ablation is ≤ 15 %
of the corneal thinnest loca-
tion, “minimum ablation is 60
µm which corresponds to
corneal thickness 400 µm”.
6. Priority is HOAs followed by
cylinder and lastly physician
adjustment of sphere to keep
15 % of maximum ablation.
7. Don’t promise patient about
glasses independence, you are
just regularizing surface.
7. Treatment Modalities, Refractive Surgery
N.B.
The use of MMC in Athens
protocol, STARE-XL pro-
tocol, Cretan protocol and
WFG ablation is contro-
versy, some surgeons use it
and others don’t.
Phakic intraocular lens
- Best is Visian ICL STAAR Sur-
gical®.
- Requires stable keratoconus
with functioning BCVA, ade-
quate anterior chamber depth
and endothelial cell count.
- Commonly done after CXL or
CXL followed by ICRS “for
treating HOAs” followed by
phakic ICL “for treating
LOAs”.
- Advantages of phakic IOLs are
the wide range of correction,
doesn’t depend on corneal
thickness, reversibility and
doesn’t carry the risks of LA-
SER ablation.
- Disadvantages are endothelial
cell loss, cataract, pigment dis-
persion and difficult calcula-
tions.
- Required data for calculations
are subjective refraction, kera-
tometry, ACD and WTW.
7. Treatment Modalities, Surgery in Keratoconus
- Refraction and keratometry are
of reduced reliability and re-
peatability in keratoconus and
this is the problem that makes
calculations difficult.
Refractive lens exchange or
cataract extraction with toric
posterior chamber IOL
- Both require stable kerato-
conus with functioning BCVA
and regular astigmatism in the
central cornea. This issue
makes candidates for toric
PIOL or even toric phakic ICL
difficult.
- The main concern relies on for-
mulas required to calculate the
IOL power due to reduced reli-
ability and repeatability of ker-
atometry in keratoconus.
- The advance in IOL calcula-
tions formulas as Barrett Uni-
versal II or Radial Basis Func-
tion (RBF) gives better results.
- One problem to solve this issue
is performing the operation on
two steps, first phacoemulsifi-
cation then after few weeks
74
determine aphakic refraction
and use the vergence formula
to calculate the IOL power.
Approach to refractive surger-
ies in keratoconus
- In stable keratoconus with
good functioning BCVA, fol-
low up with glasses, contact
lens or lens-based surgeries ac-
cording to the patient age.
- In progressive keratoconus
with good functioning BCVA,
CXL is enough.
- In progressive keratoconus
with unacceptable BCVA,
CXL + LASER ablation ac-
cording to the patient and sur-
geon preference.
6. Surgery in keratoconus
- The most common surgeries
are penetrating keratoplasty
(PK) and deep anterior lamel-
lar keratoplasty (DALK).
- Bowmans membrane trans-
plantation is an evolving new
75
surgical modality for advanced
keratoconus.
- Stromal lenticule addition ker-
atoplasty has been evolved
from Bowmans membrane
transplantation.
- Any of the above surgeries are
indicated in
1. Corneal scar e.g. with RGP
contact lens or post hydrops.
2. Advanced keratoconus affect-
ing the quality of life and not
fitting any other treatment mo-
dality.
Penetrating keratoplasty
For illustrative video see YouTube
Channel
- Full thickness trephination of a
part of the recipient cornea.
- Getting a full thickness donor
cornea, better to be 0.25 mm
larger or the same size.
- Applying sutures.
Deep anterior lamellar kerato-
plasty
For illustrative video see YouTube
Channel
- It is the preferred choice in ker-
atoconus (Table 22).
7. Treatment Modalities, Surgery in Keratoconus
- Partial thickness removal of a
part of the recipient cornea till
either Dua’s layer or Descemet
membrane.
- Getting a partial thickness do-
nor cornea after removing
Descemet membrane.
- Applying Sutures.
Bowmans membrane trans-
plantation
For illustrative video see YouTube
Channel
- It is a new procedure, but long-
term outcomes are still re-
quired to proof efficacy.
- Femtosecond LASER assisted
stromal pocket is done in the
recipient cornea.
- Isolation of Bowmans mem-
brane from donor cornea is
done on an artificial anterior
chamber.
- Implanting it into the dissected
stromal pocket.
N.B.
The first trials in Bowmans
membrane transplantation
made stromal pocket by dissec-
tion through scleral tunnels
which carried risks of penetra-
tion into the anterior chamber.
7. Treatment Modalities, Surgery in Keratoconus 76

Penetrating keratoplasty Deep anterior lamellar keratoplasty

Learning curve Easy Steep
Deep scars &
Not suitable for deep scars , HSV or PPCD
pathologies Suitable
Intraoperative Descemt membrane rupture
Expulsive hemorrhage
complications (micr/macro perforation)
• Endophthalmitis
Postopeartive • Wound leak • Double anterior chamber (perforations)
complications • Shallow anterior chamber with • Interface haze
progressive PAS
Optical & visual
Comparable Comparable
outcome
Visual Late visual rehabilitation Earlier visual rehabilitation
rehabilitation (late suture removal) (Early suture removal)
• More endothelial rejections • Less endothelial rejections
Endothelium • More endothelial cell Loss • Less endothelial cell loss
(Surgical trauma) (Reduced surgical trauma)
Prolonged with increased risk of Short with reduced risk of cataract
Steroid use
cataract & glaucoma & glaucoma
Single graft Used May be used for both DALK & DMEk

Table 22, comparison between penetrating keratoplasty and deep anterior lamellar kerato-
plasty.

Stromal lenticule addition ker- in the recipient cornea.

atoplasty
For illustrative video see YouTube
Channel
- Preparation of the Bowmans
membrane on an artificial ante-
rior chamber carries the risk of
being torn.
- So, the idea of preparing a stro-
mal lenticule including Bow-
mans membrane was raised.
- First, a femtosecond LASER
assisted stromal pocket is done
- Preparation of a donor stromal
lenticule including Bowmans
membrane using femtosecond
LASER is done.
- Implanting the lenticule into
the dissected stromal pocket.
N.B.
Sometimes this lenticule is
soaked in RF for 10 min and ex-
posed to accelerated CXL for
better mechanical biocompati-
bility.
77 8. Approach to a Keratoconus Case

Approach to Keratoconus
Case

Points to remember with any visual demands.

keratoconus case
- Meticulous subjective refrac-
tion.
- Complete ophthalmological
examination, KC patients with
cataract or glaucoma which
can occur from steroids, KC
with DM, so, check the fundus.
- Family history.
- Customization of treatment ac-
cording to age, occupation and
- Never to promise the patient
for glasses independence.
- Don’t forget contact lenses as a
treatment modality in kerato-
conus patients either before or
after any chosen treatment.
- Discuss with the patient differ-
ent treatment modalities fitting
for him.
- Let the patient know the bene-
fits versus the risks for any of
the chosen treatment modality.

For illustrative video see YouTube Channel

Algorithm 2, step wise approach to a keratoconus case.

 78
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Index
Accelerated protocols · 46
Acoustic fluctuations · 26
Advanced glycation end products · 39
Age of diagnosis · 3
Age of onset · 2
Air puff deformation
ocular response analyser, corvis ST · 25
Algorithms· 30
Alio-Shabayek classification · 11
Allergic eye diseases· 3
Amsler · 10
Amsler-Krumeich classification· 11
Anterior segment OCT · 20
Approach in refractive surgeries in
keratoconus
conservative approach · 74
Approach to Keratoconus case · 77
Artificial intelligence · 11, 30
Artificial neural networks
Inputs, activation function, output · 31
All surface laser ablation · 69
Asphericity based nomogram · 65
Asymmetrical Shapes · 6
Athens protocol · 51, 71
B normal shape in pachymetry map· 9
Barraquer thickness law · 60
Beam profiles
gaussian, top hat, cosine compensated · 42
Belin
ABCD classification · 14
ABCD progression display · 17
ABCD software
oculus pentacam · 15
Belin Ambrosio display · 19
Belin Ambrosio enhanced ectasia · 19
Bell's sign
in pellucid marginal degeneration · 8
Best fit sphere
central, paracentral, peripheral cone · 7
Best fit sphere
float mode 8 mm · 7
87
Best fit toric ellipsoid
float mode 8 mm · 9
Biomechanics of cornea · 23
Blavatskaya · 60
Bowmans membrane transplantation · 75
Brillouin
spectrum, scatter · 26
Brillouin optical scanner system · 26
Bullous keratopathy · 56
Bunson roscoa law of reciprocity · 41
Butterfly pattern · 7
C
Central corneal thinning · 4
Classification of ectatic corneal diseases
keratoconus, pellucid marginal
degeneration, keratoglobus, Post LASER
refractive correction ectasia · 1
Clinical grading · 11
Coma aberration · 28, 72
Combined procedures · 68
Combined cross linking protocols · 51
Complications of ICRS · 68
Concentric
Confidence interval · 17
Confocal microscopy
in keratoconus · 29
Contact lenses · 32
Corneal allogenic intrastromal ring segments ·
59
Corneal biomechanichs
Corneal ectasia · 1
Corneal nerves · 4
Corvis biomechanical index · 25
Corvis ST · 25
Cretan protocol · 52, 71
Cross linking · 39
indications, complications · 53
Curvature based patterns · 6
Customized remodeling of vision· 49
Cycle of biomechanichal decompensation · 28
 88
Index

Deep anterior lamellar keratoplasty · 75 Generalised corneal thinning

Demarcation line in keratogolbus · 9
evidence of action after cross linking · 45
Deviation parameters
H
Df, Db, Dp, Dt, Da, final D · 20
Diagnostic tools in keratoconus · 19
Hafezi
Different contact lens
hypo-osmolar ribboflavin solution, sub400
in keratoconus · 38
protocol, transepithelial cross linking ·46 ,
Down syndrome · 2
47, 48
Dresden protocol · 40, 46
Haze
Dynamic fitting
evidence of action after cross linking · 45
with rigid gas permeable contact lens · 34
High order aberrations · 29, 72
High order aberrations
E High risk group
of progression · 18
Edge lift Holladay
documented with fluoresceine · 33 in FFKC · 10
Elasticity · 23 Hybrid contact lens · 37
Elevation based patterns · 7
Enhancers · 41
I
Epi-off cross linking · 41
Epithelium in keratoconus
Intracorneal ring segment
focal thinning, doughnut pattern · 21
structure, types · 56, 57
Epithelium thickening · 21
mechanism of action· 60
Evolution of cross linking· 39
indications · 62
Evolution of cross linking devices · 56
Improving vision after ICRS · 68
Ex-vivo flap extensiometry
Indices of irregular cornea
1D, 2D, 3D tensile loads · 24
ISV, IVA, IHA, IHD, KI, CKI · 13
Inferior thinning
F in pellucid marginal degeneration · 9
Intacs , Intacs-SK · 57
Ferrara ring · 57 Interleukin-6 · 2
Fitting of rigid gas permeable contact lens Irradiation
dynamic, static · 34 standard, accelerated · 41
Flat top beam profile · 42 Irregular shapes · 7
Fleischer ring Ishii classification · 12
brownish iron deposits · 4
Forme fruste keratoconus · 1, 10
K

G Kera ring · 56
progressive thickness · 57
General reaction mechanism kera ring nomogram · 64
in cross linking · 45 Keratoconus suspect· 10
 89
Index

Klyce P
in FFKC· 11
Pachymetry based cross linking · 48
Pachymetry Based Patterns · 9
L
Paracentral corneal thinning · 4
Patterns
Leber's congenital amaurosis · 2
of keratoconus · 5
Leon Nicolas Brillouin · 26
Pediatric
Low risk group
cross linking · 54
of progression · 18
keratoconus · 2
Pellucid like keratoconus
M crab claw or kissing birds · 7
Penetrating keratoplasty · 75
M nomogram · 48 Phakic intraocular lens · 73
Marfan syndrome · 2 Photoactivated chromophore cross linking · 55
Matrix metalloproteneases · 2 Photo-oxidative cross linking · 39
Mazzotta Photorefractive intrastromal cross linking · 55
pachymetry based accelerated cross linking, Photosensitizers · 40
iontophoresis · 47, 48 Piggyback contact lens · 35
Mechanical fluctuations · 26 Post LASER refractive correction ectasia
Mitral valve prolapse · 2 after LASIK, PRK, SMILE · 1
Morphological Patterns Potential visual acuity · 4
nipple, oval, globus · 5 Progression criteria in keratoconus · 16
Munson sign · 5 Progression index
Myoring · 57 minimum, maximum, average, ARTmax
with accelerated cross linking · 59 · 19
Prosthetic replacement of ocular surface
ecosystem · 37
N
Protocols of thin cornea · 46
Push up test
New limbus creation · 61
with rigid gas permeable contact lens· 34
Nomograms of ICRS· 62
kera ring· 64
asphericity based · 65 R

Recent trends in cross linking · 55

O
Refractive lens exchange
or cataract extraction in keratoconus · 74
Oblique displacement of thinnest location
Refractive surgeries
dome shape · 9
in keratoconus · 69
Ocular response analyser
Relative pachymetry map · 10
corneal hysteresis, corneal resistance factor
RETICS calssification · 11
· 25
Retinoscopy
Oculo-digital sign
with scissoring reflex · 4
with leber's congenital amaurosis · 2
ishii classification · 12
Oxygen boost googles· 44
 90
Index

Riboflavin Thermodynamic fluctuations · 26

homogenous diffusion, green aqueous flare Tomographic biomechanichal index · 25
· 42 Topography guided cross linking · 49
standard, accelerated, two step · 43 Topography in Keratoconus
ricrolin transepithelial, hypotonic, LASIK intra/inter test variability · 18
xtra, iontophoresis · 44 Toric posterior chamber intraocular lens · 74
Rigid gas permeable contact lens · 34 Transepithelial cross linking · 41
Risk factors in keratoconus Treatment modalities · 32
eye rubbing, atopy · 2 Trefoil aberration · 28, 72
Rizzutti sign · 4 Tumor necrosis factor alpha · 2
Types of keratoconus
central, peripheral, bow tie, pellucid like ·
S
62
Sagittal depth
vault · 33 U
Scissoring reflex · 4
Scleral Lens · 35 Ultraviolet light emitting devices · 40
Segmental tomography with epithelial
thickness · 20
V
Selective transepithelial ablation for
regularization of ectasia with simultaneous
Velocity of mechanical fluctuations · 28
cross linking · 69
Verneal keratoconjunctivitis· 3
Skew action of ICRS · 61
Very asymmetrical ectasia· 16
Skewed Shapes · 7
Virtual image phased array · 27
Soft toric contact lens · 33
Viscosity · 23
Solid state physics
Visum ring · 59
Leon Nicolas Brillouin · 26
Vogt’s Stria · 4
Spectacles · 32
Vortex pattern · 7
Spectral Microscopy · 30
Static fitting
three point touch, apical clearance, apical W
bearing · 34
Stromal lenticule addition keratoplasty · 76 Wave front guided ablation · 72
Sub400 protocol · 48 Wavefront aberrations analysis· 28
Surgery in keratoconus · 74
Symmetrical Shapes · 6
Y

T Young’s longitudinal elastic modulus · 27

Tears
of keratoconus patients · 2
Terms in contact lenses · 33
Theo Seiler
evolution of cross linking · 39