*5.2.1 Corneal collagen cross-linking (CXL)*

Keratoconus typically progresses until the fourth decade, when most but not all, slows or stabilizes [36]. Corneal crosslinking (CXL) has been proposed as a new treatment modality to stop progression of keratoconus since the late 1990s [27]. Currently, CXL is the gold standard and only minimally invasive surgical procedure that halt the progression of keratoconus [27]. The indications for CXL are progressive keratoconus in adults and postoperative ectasia, central corneal thickness more than 400 μm, Kmax 58 D or less [36, 38]. However, the procedure is not approved for stable keratoconus currently. CXL is the promising treatment that can prevent progressive visual loss due to disease evolution and delay invasive surgical procedures such as corneal transplantation. The mechanism of cornea strengthening is a photochemical reaction of corneal collagen by the Riboflavin as a photosensitizer in the photopolymerization process and ultraviolet A irradiation (UVA). The interaction between Riboflavin and UVA can increases the formation of intrafibrillar and interfibrillar carbonyl-based collagen covalent bonds [37].

The standard Dresden protocol was proposed as a treatment option for keratoconus by Wollensak et al. in 2003 [38]. This standard technique is conducted under topical anesthesia. The central corneal epithelium is removed followed by application of 0.1% riboflavin solution (0.1% riboflavin in 2o% dextran solution) as a photosensitizer every 5 minutes for 30 minutes. Then the cornea is exposed to 370 nm UVA with an irradiance of 3 mW/cm2 or 5.4 J/cm2 , during which time riboflavin solution is re-applied every 5 minutes. After the treatment, topical antibiotics eye drops are applied and bandage contact lens placed upon the eye [38]. Although this standard protocol has been proven to be an effective procedure to halt keratoconus progression [39], it is a time-consuming procedure, may create patient discomfort and has post-operative complications related to corneal abrasion. The reported complications in association with CXL include corneal haze, corneal infection, corneal edema, and corneal melting. Adverse effects are common but mostly transient and of low clinical significance [40]. However, anterior corneal stromal haze is a typical postoperative finding that often occurs in the first month after treatment and typically resolves after 12 to 20 weeks [41]. The posterior aspect of this haze is an indistinct hyperreflective demarcation line seen in the mid stroma that represents the depth of CXL [37]. Two trends have emerged to modify the standard Dresden protocol. The first is a tendency to shorten treatment times [42]. Alternative treatment protocols with different formulations of riboflavin solution


**45**

5.4 J/cm<sup>2</sup>

in evolution.

following sections.

**Table 3.**

*5.2.1.1 Accelerated CXL (ACXL)*

ultrafast settings such as 43 mW/cm<sup>2</sup>

*Keratoconus Treatment Toolbox: An Update DOI: http://dx.doi.org/10.5772/intechopen.94854*

**Considerations Details**

**Ability to cooperate (Mental disability)**

**Pre-existing corneal scarring (previous hydrops)**

and delivery methods by altered UV exposures have been proposed. These newer techniques can shorten duration times, reduce patient discomfort, and minimize postoperative complications. The second trend is "epi-on" approach, such that the epithelium remains intact during CXL. These modifications were described in the

*ICRS = Intrastromal corneal ring segments, DALK = Deep Anterior Lamellar Keratoplasty, PK = Penetrating keratoplasty, D = diopter, KC = keratoconus, Kmax = Maximal corneal steepness, BCVA = best corrected visual acuity. Adapted from Surv Ophthalmol. 2015 Sep;60(5):459–80. [18] J Cataract Refract Surg. 2015 Apr;41(4):842–72* 

• **CXL**: risk of postoperative complications, only patients capable of

• **Bowman layer transplantation**: less risky and fewer postoperative

• **CXL**: may be less successful, cannot replace corneal scar then central

• **ICRS, Bowman layer transplantation**: central corneal scar is a contraindication, may arrest disease progression and permit continued

• **DALK**: may be preferred over PK, prefer Melles manual dissection,

• **PK**: outcomes tend to be worse (not be considered mandatory to replace

• **PK**: worse outcomes from higher incidence of postoperative

• **ICRS**: less risky and fewer postoperative requirements than CXL, DALK, PK but aware of ICRS stem from migration/ superficialization from eye

reliable cooperation, with good family support

requirements than CXL, DALK, PK • **DALK**: may be preferred over PK

corneal scar is a relative contraindication

CL wear in non- visually disabling scarring

Anwar "big-bubble" technique is contraindicated

rubbing

complications

endothelium) *CCT = central corneal thicknesses, Epi-on CXL = Epithelium-0n Corneal collagen cross-linking,* 

*[37].\*currently little to recommend UV-CXL in corneas thinner than 400 μm [18] .*

*Special considerations in surgical management of keratoconus.*

According to Bunsen- Roscoe law of photochemical reciprocity, which states that "the same photochemical effect can be achieved with a reduced irradiation interval provided the total energy level is kept constant through a corresponding increase in irradiation intensity" [37]. ACXL is a modified CXL technique that increase the intensity of ultraviolet A (UV-A) irradiation and shortening the exposure time without altering the total energy delivered. Currently commercial devices now offer

achieve the standard Dresden protocol energy dose of 3.4 J or a radiant exposure of

the CXL reaction, the time needed for oxygen replenishment, and potential physical damage due to higher irradiance [36]. The reduced efficacy of ACXL is believed to be due to depletion of oxygen in these high-fluence treatments [43]. The efficacy, safety, and treatment protocols of accelerated CXL are still being investigated and

within 2 minutes [42]. However, it ignores the requirement of oxygen in

for 2 minutes [42]. Using this setting, would

*Keratoconus Treatment Toolbox: An Update DOI: http://dx.doi.org/10.5772/intechopen.94854*


*ICRS = Intrastromal corneal ring segments, DALK = Deep Anterior Lamellar Keratoplasty, PK = Penetrating keratoplasty, D = diopter, KC = keratoconus, Kmax = Maximal corneal steepness, BCVA = best corrected visual acuity. Adapted from Surv Ophthalmol. 2015 Sep;60(5):459–80. [18] J Cataract Refract Surg. 2015 Apr;41(4):842–72 [37].\*currently little to recommend UV-CXL in corneas thinner than 400 μm [18] .*

#### **Table 3.**

*Eyesight and Imaging - Advances and New Perspectives*

• **CXL**:

CCT < 400 μm

Epi-on CXL\*

technique

preferable

in Kmax > 58 D

outcomes • **PK**: do not affect

exceed 1 0r 2 lines

**Endothelial health** • **CXL**: risks of endothelial damage if CCT < 400 μm

different age groups

of graft rejection, failure

safest options

dystrophy

• Hypotonic riboflavin solution

the length of their path >400 μm

CCT > 400 μm can use standard Dresden protocol

• **ICRS**: minimum corneal thickness at the site of their insertion and along

• **DALK**: Prefer Melles manual dissection than Anwar "big-bubble"

DALK or modified procedure "tuck-in lamellar keratoplasty" may be

• **ICRS**: associated with poorer visual outcomes and more complications

• **DALK**: central curvatures >60 diopters (D) may experience worse

• **ICRS, Bowman layer transplantation, DALK**: No or mild endothelial

• **PK**: cataractogenesis, may be the least desirable option for phakic eyes

additional complications, smaller gain and less durable than adults • **ICRS**: approved for age > 18 years (worldwide), 21 years in US, no difference between visual outcome or corneal topography between

• **Bowman layer transplantation**: extraocular procedure, one of the

• **PK**: outcomes are slightly worse, principally attributable to higher rates

• Pachymetry-guided epithelial debridement Decreasing the UVA irradiance dose • Reducing the duration of riboflavin soaking Increasing the riboflavin concentration or a combination of the above

• **Bowman layer transplantation**: do not affect

**Kmax** • **CXL**: risk of failure, continue progression in Kmax > 58 D, increase risk of

• **Bowman layer transplantation**: do not affect

**Preoperative BCVA** • **CXL, ICRS, Bowman layer transplantation**: rarely do the visual gain

• **DALK or PK**: extremely poor vision

• **PK**: advanced KC and a failed endothelium **Lens status** • **CXL, ICRS, Bowman layer transplantation**: not promote cataractogenesis, preferable options for phakic eyes • **DALK**: No/less cataractogenesis than PK

**Patient age (Pediatric)** • **CXL**: modest corneal flattening effect, mild visual benefit without any

• **DALK**: similar outcomes with adults

losing vision in Kmax > 55 D

• **PK**: not suitable for significant peripheral thinning

**Considerations Details**

**Corneal thickness (Corneal thinness)**

**44**

*Special considerations in surgical management of keratoconus.*

and delivery methods by altered UV exposures have been proposed. These newer techniques can shorten duration times, reduce patient discomfort, and minimize postoperative complications. The second trend is "epi-on" approach, such that the epithelium remains intact during CXL. These modifications were described in the following sections.

#### *5.2.1.1 Accelerated CXL (ACXL)*

According to Bunsen- Roscoe law of photochemical reciprocity, which states that "the same photochemical effect can be achieved with a reduced irradiation interval provided the total energy level is kept constant through a corresponding increase in irradiation intensity" [37]. ACXL is a modified CXL technique that increase the intensity of ultraviolet A (UV-A) irradiation and shortening the exposure time without altering the total energy delivered. Currently commercial devices now offer ultrafast settings such as 43 mW/cm<sup>2</sup> for 2 minutes [42]. Using this setting, would achieve the standard Dresden protocol energy dose of 3.4 J or a radiant exposure of 5.4 J/cm<sup>2</sup> within 2 minutes [42]. However, it ignores the requirement of oxygen in the CXL reaction, the time needed for oxygen replenishment, and potential physical damage due to higher irradiance [36]. The reduced efficacy of ACXL is believed to be due to depletion of oxygen in these high-fluence treatments [43]. The efficacy, safety, and treatment protocols of accelerated CXL are still being investigated and in evolution.

#### *5.2.1.2 Epi-on CXL/transepithelial CXL*

Due to the epithelial debridement is a major contributor to the postoperative complications of CXL, such as infective keratitis and an abnormal wound-healing response [37]. This issue has perpetuated interest in epithelium-on technique. Epi-on CXL has less discomfort to the patient and reduces postoperative complications [43]. This CXL technique has low complication rate, 0% to 3.9% of the patients has only transient haze [37]. According to the hydrophilic property of riboflavin solution, the penetration through the intact hydrophobic corneal epithelium is difficult. The standard formulations show minimal penetration through intact epithelium. The modifications by adding various additives, such as benzalkonium chloride, topical anesthetic, tris(hydroxymethyl) aminomethane (trometamol), sodium ethylenediaminetetraacetic acid, have been proposed to improve epithelial permeability to riboflavin [36]. Riboflavin penetration can be improved by increased riboflavin concentration and iontophoresis [36]. Since even the low amount of riboflavin surface films will markedly block UV-A transmission, transepithelial formulations are often rinsed from epithelial surface before irradiation [36]. The iontophoretic delivery system uses of mild electrical current for delivering riboflavin through the epithelium [36]. It allows greater and deeper riboflavin penetration in the corneal stroma than the conventional epithelium-on technique. Overall, the effectiveness of transepithelial techniques has been disappointing [27]. Epi-on CXL has limited keratocyte apoptosis, shallower demarcation line and less biomechanical rigidity than standard epi-off CXL [37]. In general, better outcomes can be achieved by standard epithelium off technique and epi-on CXL have resulted in progression of the disease after treatment [36, 44]. However, recent research with innovative transepithelial CXL system achieved 4-fold higher corneal stromal concentrations of riboflavin than commercially available epi-on CXL system, and this level is theoretically adequate for effective CXL [44].

#### *5.2.1.3 Pulsed-light accelerated CXL (PLA-CXL)*

Due to the presence of oxygen is required for CXL, but high-exposure doses of UVA light cause a decrease in the oxygen concentration rapidly [45]. The recent technique has focused on pulsing the UVA light with "on" and "off" periods to increase the efficacy of CXL treatment by replenishing the consumed oxygen [46]. This technique is an effective treatment modality to stop progression in progressive keratoconus but regresses some of the cases [46].

#### *5.2.1.4 CXL plus*

Despite the fact that CXL can halt the progression of keratoconus and provide corneal stability, functional visual acuity remains a problem [47]. Recent data from the systematic review disclosed that conventional epi-off CXL can flattening cornea 2 D approximately and improving visual acuity 2 lines or 10 letters on average [48]. CXL normalizes the corneal shape by changing the physical properties of the cornea, resulting in reduction of all corneal aberrations, high order and low order. The improvement in uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) are related to improvement in the total corneal aberrations and only high-order aberrations respectively [49].

In order to address this issue, CXL can be performed alone or in combination with topo guided photorefractive keratectomy (PRK), ICRS, phakic IOLS or Topo guided PRK plus ICRS for better improvement of visual acuity [15].

**47**

*Keratoconus Treatment Toolbox: An Update DOI: http://dx.doi.org/10.5772/intechopen.94854*

Kanellopoulos et al. reported the first case of topography-guided PRK performed 1 year after CXL for treatment of keratoconus and showed visual acuity improvement [50]. On the contrary, the Athens protocol which combines accelerated UV-CXL with same-day photorefractive keratectomy (PRK) was more effective with improvement in UDVA and CDVA of 20/45 or better (2.25 logMAR) was founded in 83% of patients at last follow up [51]. However, this study was conducted in post-LASIK ectasia [51]. Same-day simultaneous topography guided PRK CXL in progressive keratoconus appears to be superior to sequential CXL with later PRK (6 months later) in the aspect of UCVA, BSCVA, spherical equivalent (SE) and mean reduction in K [52]. This combined technique also prevents regression of keratoconus and reduce the risk of keratectasia and might be suitable for eyes requiring improvements in irregular astigmatisms but still have good

The CXL can be performed before, simultaneously or after the ICRS. The advantage of performing the CXL first is slowing the progression of the keratoconus and selects the best alternative way to treat the residual refractive error [54]. The recent systematic review and meta-analysis demonstrated that simultaneous ICRS implantation and CXL may provide better outcomes in term of refraction and keratometry. However, UDVA, BCVA and cylindrical refractive error were similar between combined technique and staged procedure [55]. The combined procedure of CXL plus ICRS implantation appears safe and efficacious for the treatment of progressive keratoconus with significant improvements in visual acuity, keratometry values, and refractive error [54]. This technique might be effective for eyes with more

The simultaneous topography-guided photorefractive keratectomy (PRK) and crosslinking (Athens protocol) followed by phakic intraocular lens (IOL) implantation 2–4 months later for managing keratoconus improved and stabilized visual performance in patients with keratoconus. The Kmean, SE, UDVA, CDVA improved significantly. At last follow-up, all eyes could achieve CDVA of 0.3 or better [56].

Three steps treatment of keratoconus by ICRS implantation, CXL and phakic IOLS significantly improve UDVA, CDVA, higher order aberrations and corneal shape in moderate to severe keratoconus [57]. Moreover, keratometry (Ksteep, Kflat, Kmax) and refraction (sphere, SE, but not cylinder) were also improved [58]. The time interval between ICRS implantation and CXL was 4–6 weeks and ICL implan-

The 0.1% riboflavin in 20% dextran solution is used in original Dresden protocol. Only the anterior 300 μm of stroma can be treated [38, 59]. This standard technique requires corneal pachymetry more than 400 μm after deepithelization to decrease complications such as corneal stromal scar and corneal

• CXL + Topo guided PRK

CDVA [47, 53].

• CXL + ICRS

irregular astigmatism and worse CDVA [53].

• CXL + ICRS+ + phakic IOLS

*5.2.1.5 CXL in thin cornea*

• CXL + Topo guided PRK + phakic IOLS

tation was performed 6–8 months after CXL [57, 58].

*Keratoconus Treatment Toolbox: An Update DOI: http://dx.doi.org/10.5772/intechopen.94854*
