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Trans-epithelial Versus Epithelium-off Corneal
Cross-linking for the Treatment of Progressive
Keratoconus: A Randomized Controlled Trial
NIENKE SOETERS, ROBERT P.L. WISSE, DANIEL A. GODEFROOIJ
AMERICAN JOURNAL OF OPHTHALMOLOGY, MAY 2015
PURPOSE
To compare the clinical effects and safety of trans-epithelial corneal cross-
linking (CXL) to epithelium-off (epi-off) CXL in progressive keratoconus.
 DESIGN: Randomized clinical trial (noninferiority).
 METHODS: Patients received either trans-epithelial CXL with
Ricrolin TE (n [ 35) or epi-off CXL with isotonic riboflavin (n [ 26)
in 1 academic treatment center, using a simple unrestricted
randomization procedure. The main outcome measure was
clinical stabilization of keratoconus after 1 year, defined as a
maximal keratometry (Kmax) increase <1 diopter (D).
SURGICAL TECHNIQUE:
 In the trans-epithelial CXL group
 Local anesthetic eye drops (oxybuprocaine 0.4% and tetracaine 1%)
were applied 3 times during 5 minutes, and Ricrolin TE solution (consisting
of riboflavin 0.1% eye drops with Dextran T500 15 mg and EDTA; SOOFT
Italia) were instilled every 2 minutes for 15 minutes. Next, an eyelid
speculum was placed and a silicone ring was positioned between the
eyelids; the ring was filled with Ricrolin TE and used to retain a Ricrolin
‘‘pool’’ on the cornea. After 15 minutes, the silicone ring was removed,
the cornea was rinsed with balanced salt solution, and pachymetry was
performed. UVA irradiation was performed during 30 minutes, while
Ricrolin TE solution was reapplied to the cornea every 5 minutes.
Epi-off CXL technique
was performed following the Dresden protocol, adjusted with the
avoidance of the eyelid speculum during riboflavin instillation. Epithelial
removal (9-mm) was performed using a blunt knife. After pachymetry
measurements, isotonic riboflavin 0.1% solution with 20% Dextran (Medio
Cross) was applied every 3 minutes for 30 minutes, with no eye lid
speculum in place
RESULTS
 Average Kmax was stable at all visits in the transepithelial group, while after epi-
off CXL a significant flattening of 1.2–1.5 D was demonstrated from the 3-month
follow-up onwards. The trend over time in Kmax flattening was significantly
different between the groups.
 There was significant different trend in corrected distance visual acuity (CDVA),
with a more favorable outcome in thetransepithelial group.
 In the transepithelial group no complications were observed while in epi-off
group, 4 eyes (15%) developed complications owing to healing problems (sterile
infiltrate, herpes keratitis, central haze, and stromal scar).
DISCUSSION
 This trial showed that transepithelial cross-linking with EDTA riboflavin* was
less effective to halt keratoconus progression after 1 year compared to
epithelium-off cross-linking.
indicators for a CXL effect
 General indicators (with stabilization being the main purpose) are a
1. visible demarcation line,
2. a flattened keratometry, and
3. reduced pachymetry.
 No demarcation line was found in the transepithelial CXL group and the
average central keratometry, maximal keratometry, and pachymetry were
unchanged after treatment.
 The average Kmax flattening after 1 year in the epi-off group in this study
was more pronounced (-1.5 D).
CONCLUSION
 This study showed that although transepithelial CXL was a safe procedure
without epithelial healing problems, 23% of cases showed a continued
keratoconus progression after 1 year
Trans epithelial versus epithelium-off corneal cross-linking for the treatment

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Trans epithelial versus epithelium-off corneal cross-linking for the treatment

  • 1. Trans-epithelial Versus Epithelium-off Corneal Cross-linking for the Treatment of Progressive Keratoconus: A Randomized Controlled Trial NIENKE SOETERS, ROBERT P.L. WISSE, DANIEL A. GODEFROOIJ AMERICAN JOURNAL OF OPHTHALMOLOGY, MAY 2015
  • 2. PURPOSE To compare the clinical effects and safety of trans-epithelial corneal cross- linking (CXL) to epithelium-off (epi-off) CXL in progressive keratoconus.
  • 3.  DESIGN: Randomized clinical trial (noninferiority).  METHODS: Patients received either trans-epithelial CXL with Ricrolin TE (n [ 35) or epi-off CXL with isotonic riboflavin (n [ 26) in 1 academic treatment center, using a simple unrestricted randomization procedure. The main outcome measure was clinical stabilization of keratoconus after 1 year, defined as a maximal keratometry (Kmax) increase <1 diopter (D).
  • 4. SURGICAL TECHNIQUE:  In the trans-epithelial CXL group  Local anesthetic eye drops (oxybuprocaine 0.4% and tetracaine 1%) were applied 3 times during 5 minutes, and Ricrolin TE solution (consisting of riboflavin 0.1% eye drops with Dextran T500 15 mg and EDTA; SOOFT Italia) were instilled every 2 minutes for 15 minutes. Next, an eyelid speculum was placed and a silicone ring was positioned between the eyelids; the ring was filled with Ricrolin TE and used to retain a Ricrolin ‘‘pool’’ on the cornea. After 15 minutes, the silicone ring was removed, the cornea was rinsed with balanced salt solution, and pachymetry was performed. UVA irradiation was performed during 30 minutes, while Ricrolin TE solution was reapplied to the cornea every 5 minutes.
  • 5. Epi-off CXL technique was performed following the Dresden protocol, adjusted with the avoidance of the eyelid speculum during riboflavin instillation. Epithelial removal (9-mm) was performed using a blunt knife. After pachymetry measurements, isotonic riboflavin 0.1% solution with 20% Dextran (Medio Cross) was applied every 3 minutes for 30 minutes, with no eye lid speculum in place
  • 6. RESULTS  Average Kmax was stable at all visits in the transepithelial group, while after epi- off CXL a significant flattening of 1.2–1.5 D was demonstrated from the 3-month follow-up onwards. The trend over time in Kmax flattening was significantly different between the groups.  There was significant different trend in corrected distance visual acuity (CDVA), with a more favorable outcome in thetransepithelial group.  In the transepithelial group no complications were observed while in epi-off group, 4 eyes (15%) developed complications owing to healing problems (sterile infiltrate, herpes keratitis, central haze, and stromal scar).
  • 7.
  • 8.
  • 9.
  • 10. DISCUSSION  This trial showed that transepithelial cross-linking with EDTA riboflavin* was less effective to halt keratoconus progression after 1 year compared to epithelium-off cross-linking.
  • 11. indicators for a CXL effect  General indicators (with stabilization being the main purpose) are a 1. visible demarcation line, 2. a flattened keratometry, and 3. reduced pachymetry.
  • 12.  No demarcation line was found in the transepithelial CXL group and the average central keratometry, maximal keratometry, and pachymetry were unchanged after treatment.  The average Kmax flattening after 1 year in the epi-off group in this study was more pronounced (-1.5 D).
  • 13.
  • 14. CONCLUSION  This study showed that although transepithelial CXL was a safe procedure without epithelial healing problems, 23% of cases showed a continued keratoconus progression after 1 year

Notas do Editor

  1. Department of Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  2. The standard technique of CXL was first applied in 1998 and consists of an epithelial removal, after which riboflavin eye drops and ultraviolet- A (UVA) light are applied. .The rationale for the removal of the epithelium was described as allowing adequate penetration of riboflavin into the stromal tissue,where it absorbs the UVA light and produces the actual cross-linking between collagen fibrils in the corneal stroma
  3. When pachymetry was <400 mm, hypo-osmolar riboflavin was additionally applied every 20 seconds for 5 minutes and repeated up to 2 times until the required pachymetry value of >400 mm was achieved. With an eyelid speculum in place, UVA irradiation was performed during 30 minutes, during which isotonic riboflavin drops were given every 5 minute
  4. In both groups, the post-CXL medication consisted of antibiotic eye drops (Vigamox, 5 mg/mL, and preservative-free artificial tears (Duratears Free, 2%; Alcon Nederland BV) and were used for 4 weeks, while nonsteroidal anti-inflammatory drops (Nevanac 0.1%; Alcon Nederland BV) were used during the first week. Starting 1 week after CXL, topical steroids (fluorometholone 0.1% drops; Allergan Nederland BV) were applied twice a day for 2 weeks. Bcl in epi off
  5. can be explained by the haze formation at the 1-month follow-up in the epi-off group, which was noted after epithelium removal.31 Another explanation for CDVA and keratometry changes at the 1-month follow-up could be the remodeling of epithelium (in keratoconus, the epithelium layer is thinnest at the cone, and the epithelium thickness profile can reestablish a smoother surface).
  6. (Ricrolin TE), although showing no adverse events,
  7. Recent developments of transepithelial CXL in another manner, for instance by iontophoresis, showed increased uptake of riboflavin into the stroma, and resulted in stable and decreased keratometry and improved UDVA or CDVA after 1 year in small groups of patients (20–22 eyes)
  8. The fact that these indicators were absent in the transepithelial CXL group suggests that this treatment was not sufficiently effective in halting progressive keratoconus. However, if we compare the mean Kmax value after 1 year in our transepithelial CXL group (þ0.3 D) to those of the untreated control groups of 3 randomized controlled trials (þ1.2 D,16 0.1 D (18 months),30 and þ0.3 D18), the effect is debatable. Another notable finding in our transepithelial CXL group was a significant CDVA increase, in addition to a significantly increased cylinder. This indicates that there might be something going on in transepithelial CXL with Ricrolin TE after all.