types of CXL,complications and future aspects

1. Collagen Cross Linking
(C3R)
Dr L.Venkatesh Reddy
Cornea Fellow
Sri Kiran eye hospital

2. INTRODUCTION
• CXL aims to improve the intrinsic biomechanical
characteristics of corneal stroma in order to stabilise
progressive KC.
• The current technique involves the use of riboflavin
(vitamin B2), which is exposed to a measured dose of
longer wavelength UV-A radiation (370nm) at 3 mW/cm2
(5.4 J/cm2).
• Riboflavin acts as a photosensitiser as well as absorbs UV
radiation to limit the depth of the treatment effect

3. • Free radicals produced by photosensitising process catalyse a
reaction resulting in formation of covalent bonds between the
collagen molecules and microfibrils.
• The induction of molecular crosslinks appears to increase
corneal stability and thus slows the progression of the disease.
• The accepted criteria to perform a corneal crosslinking include
patients with topographic evidence of KC progression, corneal
thickness > 400µm and KC without deep stromal scarring or
history of corneal hydrops.

5. Newer CXL Protocols
• The originally developed Dresden Protocol is still most widely
used, however, a number of variations to reduce the duration
of treatment and to apply CXL in corneas thinner than 400µm
have been tried.

6. CXL with Hypo-osmolar Riboflavin
• Hypo-osmolar riboflavin formulated with Dextran or
Hydroxypropyl Methyl Cellulose has a low colloidal osmotic
pressure (310mOsmol/L as compared to 402.7 mOsmol/L in
isotonic riboflavin) and has been used to cause stromal
swelling where stromal bed is <400µm thick.
• A variable degree of stromal swelling ranging from 36-105µm
over periods ranging from 3 to 20 min is noted. The response
of CXL may be less because of the decreased concentration of
collagen fibrils in a hydrated cornea.

7. Accelerated CXL
• According to the Bunsen–Roscoe law of reciprocity, the
effect of a photochemical reaction is directly
proportional to the total irradiation dose, regardless of
how the combination of time and intensity are
distributed.
• When the duration of UV light exposure is reduced,
intensity of treatment has to be increased in order to
maintain the appropriate fluence.

8. • Various accelerated CXL protocols available use an irradiation
time of 10 min,5 min or 3 min with UV-A fluence of 9,18 or 30
mw/cm2, respectively.
• A study comparing accelerated and conventional CXL showed
no difference at 1 year in:
visual acuity
maximum keratometry
anterior stromal keratocyte density
sub-basal nerve density or endothelial cell count.

9. Trans-epithelial CXL
• Due to post-operative pain and risk of complications that
result from epithelial debridement, as well as the limitations
of use of CXL in corneas thinner than 400 µm the concept of
cross-linking with the epithelium remaining largely intact has
been introduced.
• Methods using drops containing preservatives, such as
benzalkonium chloride (BAC) pre-operatively to break the
epithelial tight junctions, or use of riboflavin combined with
EDTA, BAC and tris hydroxymethyl aminomethane to
facilitate the penetration of riboflavin have been tried.

10. • Examination using anterior segment optical
coherence tomography (AS-OCT) has demonstrated a
dense line at 100 µm, which compares with the
demarcation line seen at a depth of 320 to 340 µm in
conventional collagen cross-linking.
• This suggests that the effect of transepithelial CXL
may be more superficial. Various studies suggest a
significantly lesser effect of transepithelial CXL
compared to standard CXL with epithelial
debridement.

11. CXL Plus
• The term CXL Plus pertains to treatment with CXL
combined with an additional refractive treatment.
• Patients who are intolerant to contact lenses showing
progression of the disease can be considered for
Topography guided photorefractive keratectomy (T-
PRK) with adjunctive CXL rather than CXL alone.
• T-PRK allows shaping of the irregular cornea without
addressing the progressive nature of the disease in KC.

12. • Patients with early to moderate KC and a preoperative
thinnest pachymetry of at least 450µm (after epithelial
debridement) can be considered for T-PRK.
• However, it is not recommended for ablations larger than
50µm.
• Various studies have shown improvement in visual acuity and
stabilisation of keratometry with T-PRK combined with CXL.
• Other refractive options with CXL include Phototherapeutic
Keratectomy (PTK), ICRS, Phakic IOLs and combinations of all
of the above-mentioned procedures.

13. Complications
• Postoperative Infection/Ulcer
• Corneal Haze
• Endothelial Damage
• Peripheral Sterile Infiltrates
• Herpes Reactivation
• Treatment Failure

14. Keraflex
• Keraflex (KXS) is a new procedure that aims to cause
significant flattening using thermal heat below the
corneal surface.
• A single low-energy microwave pulse lasting < 1 sec
is applied to the cornea using a dielectrically
shielded microwave emitter, which noninvasively
contacts the epithelial surface.

15. • Through capacitive coupling, the single pulse raises the
temperature of the selected region of corneal stroma to
approximately 65°C, shrinking the collagen, and forming
a toroidal lesion in the upper 150 μm of the stroma
below Bowman’s membrane.
• The treatment is then followed by CXL to “lock in” the
flattening effect.Clinical trials to study its efficacy are
under way.

16. Future Prospects in CXL
• Rocha and colleagues introduced the concept of
‘flashlinking’, whereby a new cross linking agent (polyvinyl
pyrrolidone) is used instead of riboflavin and the UVA
irradiation stage only takes 30 seconds at 4.2 mW/cm2, rather
than the conventional 30 minutes at 3 mW/cm2.
• Measurements of corneal stiffness using surface wave
elastometry in ex vivo porcine eyes suggested that
‘flashlinking’ and conventional CXL may have a comparable
effect.

17. • Iontophoresis: Recent reports suggest that iontophoresis
may increase the efficiency of riboflavin penetration into the
corneal stroma.
• Iontophoresis involves the use of a small electrical current to
enhance the penetration of a drug across a tissue (including
an intact corneal epithelium).

18. • Pre-clinical testing has demonstrated the efficacy of this
method in increasing the mechanical rigidity of the
cornea.
• Demarcation line using iontophoresis appears less
pronounced than traditional epi-off CXL but still better
than standard transepithelial procedures. Research into
this promising new technique is continuing

19. Thank You