Keratoconus is a degenerative ectatic condition of the cornea that causes steepening and thinning. It typically starts in adolescence and progresses until the third or fourth decade. Cross-linking involves applying riboflavin drops to the cornea, then exposing it to UV light to induce collagen cross-links, stiffening the cornea and halting progression. The standard protocol uses UV light at 3mW/cm2 for 30 minutes, but accelerated protocols with higher intensities for shorter times are being studied. Cross-linking stabilizes vision and reduces myopia by flattening the cornea, with effects continuing for up to 4 years.

1. Dr. K. Vasantha M.S., F.R.C.S., Edin
Director RIO Chennai (Rtd)

2.  Keratoconus is an asymmetric, bilateral, progressive
ectatic condition of the cornea that can give raise to
severe visual impairment due to high, irregular myopic
astigmatism
 Since different loci are implicated even in familial
keratoconus, it is considered to be a sporadic condition
involving external factors and stimuli
 Usually starts at adolescence and progresses till third or
fourth decade. Affects both genders and all races

3.  Atopy, vernal catarrh
 Down’s
 Retinitis pigmentosa
 Turner’s
 Connective tissue disorders like Marfan’s, Ehlers-Danlos,
osteogenesis imperfecta, pseudoxanthoma elasticum
 Eye rubbing
 Contact lens wear
 Around 10% have a family history

4.  Stromal thinning caused by a combination of increased
activity of proteinase enzymes decreased proteinase
inhibitors
 There is redistribution of collagen which causes reduced
inter lamellar adhesion, lamellar inter lacing in the apex
of the cone and reduced number of lamellar insertions to
Bowman’s layer
 Gross rearrangement of vertical and horizontal fibers in
the apex of cone
 Breaks in BM are filled with collagen derived from stroma

5.  This leads on to reduced biomechanical stability and
stretching of corneal tissues
 Loss of correlation between anterior and posterior
corneal curvature
 Abnormal keratocytes and matrix proteins affects the
attachment at the limbus
 Lamellar bifurcations are opened up

6.  Decrease in decorin, lumican, biglycan and keratocan (all
proteoglycans) is seen in keratoconus. These are needed
for a strong, refractive and transparent cornea.
 Decrease in transforming growth factor beta which is
needed for contact between cells and other proteins

7.  Astigmatism >5D
 Asymmetric keratometry values.
 Dioptric powers of ring 2 and 4 are considered
 K1 or K2 more than 48 D
 Central thickness <470 micro meter

8.  Corneal asphericity > -0.50 micro meter. Human cornea
asphericity values ranges from -0.01 to -0.80 measured in
the 4.5 m optical zone
 Epithelial remodeling causes movement of the
epithelium from the surface of the cone giving raise to a
doughnut pattern – early sign

9.  A symmetrical bow tie will be horizontal in the against
the rule astigmatism and vertical in with the rule. It will
be diagonal in oblique astigmatism
 In corneal irregularities an asymmetry is noted
 It can superior steep, inferior steep, irregular, skewed
radial axis, round or oval

10.  Ectasia should be suspected if the superior K value is
more than 2.5 D greater than inferior or the inferior value
is more than 1.5 D greater than upper
 Displacement of the apex of the cornea leading on to
localized steepening
 Skewing of the radial axis
 Thinning of the cornea

11.  1: nipple cone has a diameter of 5mm or less. It is almost
circular and will be located in the central, paracentral or
more commonly inferonasal quadrant
 2: Oval cone has a diameter of >5mm. Will be paracentral
or peripheral, usually inferotemporal
 3: keratoglobus involves 75% of the cornea

12.  When retinoscopy is done scissoring reflex will be seen
 Fundoscopy will show a oil droplet sign
 If thinning is gross the lower eye lid will bulge forward –
Munson's sign
 Any other signs of atopy and vernal catarrh also must be
looked for

13.  Vogt’s striae – these are vertical stress lines seen deep
in the stroma. Will disappear when gentle pressure is
applied
 Fleischer’s iron ring- caused by deposition of
hemosiderin in the deeper parts of epithelium and
Bowman’s membrane at the base of the cone. Starts in
the lower quadrant and slowly becomes circular and
more sharp.

14.  Rizzuti’s sign: when light is shown on the temporal libus
a bright reflex will be seen on the nasal limbus in
advanced cases
 Thinning of cornea can be seen with a slit
 Increased visibility of corneal nerves

15.  This occurs when the Descemet’s membrane ruptures
due to extreme stretching
 This leads on to corneal edema and severe drop in
vision.
 After 6 to 8 weeks the edema comes down as the
endothelium covers the exposed area and secrete new
DM
 The edges of the previously ruptured DM can be seen as
rolled out scrolls

16. Before the advent of topography keratoconus was
classified by Amsler as
 Stage 1; high astigmatism, correctable with glasses
 Stage2: astigmatism present but correctable with rigid
contact lenses
 Stage 3: Cannot be corrected with glasses or contact
lenses

17.  1: Eccentric steepening, myopia, induced astigmatism or
both from 5 to 8 D with central K reading <48 D
 2: Myopia, induced astigmatism or both from 5 – 8 D with
K reading < 53 D
 3: Myopia and/or astigmatism 8 to 10 D, K > 53 D, no scar
and corneal thickness 300 to 400 micron
 4: refraction not possible, K > 55 D, corneal scar,
thickness < 200

18.  Here central keratometry value – central K
 Inferior – superior index I- S
 Astigmatism index ( measure of the regular corneal
astigmatism – simulated K1 and K2) AST
 And the skewed radial axis SRAX which occurs in
keratoconus are taken in to consideration
KISA = (central K) x (I - S)x (AST) x (SRAX) x 100/300

19.  In this classification the 3 m zone (both anterior ARC and
posterior curvature PRC)is centered on the thinnest part
instead of the center of the cornea. Scarring is also taken
in to consideration
 Stage 0 : ARC >7.25mm/ <46.5D, PRC >5.90mm/ <57.25D,
thinnest pachy >490, > 20/20 no scar
 Stage 1 : >7.05mm/<48D, >5.70mm/59.25D, >450 and
20/20 scar -,+,++

20.  Stage 2: >6.35mm/<53D, 5.15m/ <65.5D, >400, <20/20
Scar -,+,++
 Stage 3: >6.15/<55D, >4.95/<68.5D, >300 and scar -,+,++
 Stage 4: <6.15/ >55D, <4.95mm/ >68.5D, 300 or < 300
microns, <20/400, and scar -,+,++

21.  This is determined by noting changes in the thickness at
the thinnest point
 Changes in the anterior and posterior curvature taken
from the central 3 mm optical zone centered on the
thinnest point

22.  A display is made by combining the elevation and
pachymetric data.
 Early change is easily noted by comparing the elevation
data of anterior and posterior surface to an enhanced
best fit sphere. Optical zone chosen here is 8 mm
omitting the 4 mm around the cone.
 The difference map thus created is seen at the bottom of
Pentacam display

23.  Green means change of less than 5 micro meters on the
anterior surface and 12 micro meter on the posterior
surface
 Yellow denotes 5 – 7 for anterior and 12 – 16 for posterior
 Red means > 7 anterior and >16 micro meters posterior
 Posterior elevation of +15 at the thinnest point occurs in
less than 1% of normal cornea and hence should make
one suspect keratoconus

24.  All the information needed for treating and monitoring
keratoconus patients are given in one display
 If there is steepening on the tangential map,
 Along with thinning on the pachymetry map
 Elevation on the posterior float >10 micro meters,
keratoconus is suspected

25.  The overall corneal thickness, location of the apex and
the thinnest point must be looked for.
 The thickness in similar points in the superior and
inferior locations should not differ by more than 30micro
meters.
 The general pachymetry should not differ by more than
10 micro meters between the two eyes.
 In the normal cornea the central part will be uniformly
green

26.  The displacement of the thinnest part also is significant.
 When corneal thickness is measured by ultra sound
geometric center is chosen. This is not the thinnest point
in keratoconus. Measuring a single point is also useless.
 Normally nasal side is thicker.
 The average thickness on 1,2,3 ,4 and 5 mm rings are
used for noting the progression.

27.  This has been developed using 56 parameters including
the corneal volume
 This can detect forme fruste keratoconus accurately

28.  It was found that dentists use ultraviolet light for
strengthening of gums.
 It was also observed that natural cross linking occurred
in diabetics due to non enzymatic glycosylation
 Aging cornea also stops protruding
 Ultra violet light causes aging of collagen fibers
 This led to the inception of cross linking in 1990 for
keratoconus

29.  Riboflavin - A photo inducer
 UV light source

30.  All flavins are thermostable, yet photosensitive. The
molecular changes occur at a very short time
 Riboflavin is used as its alkylalloxazine structure helps it
to absorb a wide range of the light spectrum
 Riboflavin is safe even if it is absorbed systemically
 It is water insoluble. So the more soluble riboflavin – 5
phosphate is used.
 Corneal epithelium will prevent adequate absorption of
riboflavin. Hence it has to be removed.

31.  The wave length, irradiance and the exposure time
should be exact to make it safe.
 The absorption peak of riboflavin is 370 nm.
 As per Dresden protocol maximum amount of tissue
stiffening was seen to occur with 3 mW/cm2 of energy
for 30 minutes.
 This is equal to a total energy of 5.4 J/cm2

32.  To shorten the treatment time the parameters are
changed to higher intensities
 Bunsen – Roscoe law of reciprocity : photochemical
effect will be similar as long as the total fluence remains
constant
 But if the intensity is more than 45 mW/cm2 the
biomechanical stiffness drops.
 So 10 mW/cm2 for 9 minutes is used

33.  The demarcation line seen with anterior segment OCT is
at about 300 micro meters in standard protocol and at
230 micro meters in accelerated C3R
 There is less decrease in keratocyte density with
accelerated C3R
 There is also less disruption of the nerve plexus

34.  Since the availability of oxygen is less in accelerated
cross linking, an one second on and one second off
technique is tried. It is not standardized yet. But with this
technique the cross linking is seen at a slightly deeper
level

35.  For thin corneas hypotonic riboflavin can be used to
hydrate the cornea and thereby increase the thickness
 Riboflavin soaked contact lens has been tried. But the
amount of riboflavin and type of contact lens are not
standardized. There is a problem of buckling of the lens
during the procedure.
 The lenticule from SMILE procedure also is used to
increase the thickness. There is no problem of buckling
 Customized toric, arcuate and concentric circles and
small diameter cone are also being tried

36.  While there is an advantage of preserving the epithelium
and avoiding the scarring and delayed healing, the effect
is not as good as the conventional type.
 Can be tried in children and low grade keratoconus
 Problem is non availability of oxygen and poor
penetration of riboflavin
 Kanellopoulos made a femto second laser flap and
injected 0.1 ml of 0.1% riboflavin in to the stroma and
used a 7w/cm2 UV A for 15 minutes. He has reported
favourable results

37.  There is photo polymerization of the collagen fibers
 Two types of reaction occurs when C3R is done. Aerobic
type 2 and anaerobic type 1.
 The resultant reactive O2 species causes covalent bonds
between proteoglycans and collagen. This is seen as a
demarcation line at 300 – 350 microns depth.
 If the epithelium is on availability of oxygen will be less.

38.  It increases the diameter of the collagen fibrils
 There is increase in the cohesiveness between collagen
fibrils and non collagen matrix
 Increases the resistance to enzymatic digestion of the
collagenases
 Apoptosis of unhealthy keratocytes
 A decrease in the concentration of TGF beta is also seen
 Most importantly it increases the corneal rigidity by up to
330%

39.  Stabilization of progressive keratoconus
 Induced corneal flattening. So myopia is reduced
 Improvement in vision, both uncorrected and best
corrected
 Reduction in higher order aberrations
 Improvement in mean simulated keratometry

40.  The flattening continues for up to 4 years
 Eyes with advanced keratoconus show more flattening
during the first year
 Increase in corneal hysteresis

41.  In children the disease is aggressive and likely to
progress fast. Hence treatment should be started as
soon as possible.
 There is an increased risk of infection, haze, scarring and
delayed healing in children
 It must be remembered that good improvement is seen in
the age group 18- 39

42.  Oxygen is needed for the photochemical reaction to
occur.
 This may be the reason why higher intensities for a
shorter time and epi on treatments do not give
satisfactory results
 Corneal thickness of at least 400micro meters is needed
for doing C3R. Otherwise the endothelium will be
affected
 Iatrogenically hydrated and swollen cornea may not
respond similar to normal cornea. This may be because
of the increase in distance between the collagen fibers

43.  Repopulation of the keratocytes takes several weeks.
This may cause scarring
 Damage to corneal nerves
 Delayed epithelial healing due to the above factors
 Sterile infiltrates
 Infection
 Corneal haze

44.  Following C3R many patients regain good vision with
spectacles.
 Some who were intolerant to rigid lenses will be able to
wear rigid lenses with improvement in vision
 Rose K lenses and semi scleral lens help patients who
are not improving with spectacles.

45.  C3R combined with intrastromal corneal ring segments.
The rings will not reduce progression
 Topography guided Photo Refractive Keratectomy along
with C3R will have the added advantage of reducing
irregular astigmatism
 Phakic toric lens implantation can be done along with
C3R. But one must remember the fact that the
keratoconus may progress

46.  Host keratocytes which replace the donor keratocytes
may produce abnormal collagen
 The donor tissue may have been from undiagnosed
keratoconus eyes
 Mechanical trauma following surgery like rubbing,
contact lens wear etc.