Going for Gold: The new standard for cross-linking

Corneal cross-linking (CXL) has transformed the disease course of patients with corneal ectasias since its introduction to clinical practice in 2002. But what CXL had not been designed to achieve was improvements in visual outcomes.

The original (and until recently, the undisputed gold standard) CXL protocol for ectasia has, for most of this time, been the Dresden protocol.1 It involves epithelium removal and 20 minutes of riboflavin application, followed by 30 minutes of UV light irradiation at 3 mW/cm² to deliver a total fluence of 5.4 J/cm². Dresden protocol cross-linking might flatten the cornea by a small amount—often in the range of 1.5 D—but this flattening is too small to make a meaningful difference to the vision of patients with corneal ectasias who undergo the procedure.

But CXL has moved on. We know that oxygen diffusion into the stroma is an essential – and rate-limiting – step in the UV-riboflavin photochemical reaction, and that accelerating the delivery of the 5.4 J/cm² fluence results in a reduction in the stiffening effect.2-5 The essential role of oxygen also explains why many of the older epithelium-on (epi-on) CXL protocols delivered a poorer corneal stiffening effect than epi-off protocols3: the epithelium consumes oxygen and absorbs UV energy.5-8 Today, modern, higher-fluence (up to 10 J/cm²) protocols are set to close this efficacy gap.9 Learnings made during these developments prompted a re-thinking of how corneal flattening might be achieved.

The evolution of customised cross-linking

The first generation of customised cross-linking employed the following approach: delivering gradients of UV energy fluences over an epi-off cornea with the highest fluence over the tomographically largest bulging of the posterior cornea. This tomography-guided pattern generates more cross-links over the tip of the keratoconus and thus a greater flattening.10 To achieve the effect, surgeons have to use a UV-A delivery device with an integrated eye tracker that can deliver the different UV fluences to different parts of the cornea, rather than using a regular cross-linking device that delivers a uniform fluence across the cornea.11 Even so, the flattening effects were only moderately predictable: approximately 2 D to 4 D in total,12-14 even when using adjuncts like supplemental oxygen to improve the cross-linking effect.¹⁵

ELZA-PACE customised CXL: The next generation

The ELZA Institute has developed a second-generation customised cross-linking method, called ELZA phototherapeutic keratectomy (PTK)-assisted customised epi-on cross-linking (PACE). ELZA-PACE is a mixture of ELZA’s new epi-on CXL (which needs neither iontophoresis nor additional oxygen) and an epi-off area over the centre of the keratoconus. The epi-off area is created using an excimer laser PTK.

Figure. ELZA-PACE Procedure. Before (A) and at 1 month after (B) the procedure. The difference image (C) shows the overall reduction in asymmetry (flattening in blue, additional coupling effect in red). (Courtesy of Farhad Hafezi, MD, PhD, FARVO)

PACE, phototherapeutic keratectomy-assisted customised epi-on corneal cross-linking

The PTK is tailored to the center of the keratoconus cone, respecting the individual epithelial thickness profile of that area, thus entirely preserving the stromal tissue – and this brings with it a corresponding impact on oxygen and UV energy penetration into the stroma.

Following the epithelial map-driven PTK, a penetration-enhancer is applied, followed by the riboflavin we developed, which establishes a riboflavin concentration gradient that peaks at the cone. In addition, a greater amount of UV irradiation is applied over the cone area and less over the peripheral regions of the cornea during cross-linking (Figure).

Taken together, this generates three gradients: UV fluence, riboflavin and oxygen, as opposed to the one gradient (UV fluence) generated by the earlier, first-generation approach.

Clinical outcomes and patient benefits

Initial findings show a flattening effect significantly stronger than that achieved by earlier generations of customised CXL. Most interestingly, we not only observed maximum keratometry (Kmax) reductions of 4 D to 5 D within the first post-procedure month, but we also saw a steepening of the opposing superior area of several diopters, due to a coupling effect. Taking these two effects together, we often see a marked improvement in the symmetry of the astigmatism.

These changes lead to improvements in the wavefront errors and thus an increase in corrected distance visual acuity with glasses. Over six months to a year, PACE often achieves 8 D to 12 D of total asymmetry reduction and, in some cases, a gain of corrected distance visual acuity with glasses of up to 6 lines. This regularisation of the corneal surface is achieved by remodeling only, all without removing stromal tissue.

Can PACE be performed with a manual abrasion?

We tried and we failed to see a similar effect when performing PACE with a manual abrasion. The reason is that the abrasion has to be tailored around the tip of the keratoconus using a specific topographic map. Doing this manually would mean transferring a specific abrasion offset in the range of 20 µm onto the cornea, and performing an abrasion that includes the area of interest within a few micrometerss.

Ideal candidates for ELZA-PACE

Patients with corneal ectasias with Kmax values in the range of 50 D to 60 D are excellent candidates for ELZA-PACE. The marked flattening over the cone shifts the patient’s refraction towards hypermetropia. The patients should therefore be at least mildly myopic to begin with. Also, the classic bow-tie keratoconus pattern responds better to ELZA-PACE than other topographical forms.

ELZA-PACE can be used not only in progressive keratoconus but also in stable keratoconus: a typical example would be a 35-year-old patient with stable keratoconus who had been using contact lenses for almost 20 years and who started developing contact lens intolerance.

We avoid performing ELZA-PACE in K readings below 50 D, because we might theoretically encounter slow and long-term flattening. So having a starting point that is beyond 50 D will prevent the cornea from flattening intonon-physiological values.

ELZA-PACE can be combined with other treatments such as the use of intracorneal ring segments (such as the all-Femto-CAIRS [corneal allogenic intrastromal ring segments] procedure by Soosan Jacob, DNB, MS, FRCS, and Shady Awwad, MD, that uses allogenic corneal tissue) and corneal wavefront-guided photorefractive keratectomy.

When will ELZA-PACE be available?

Our method is based on our new epi-on CXL protocol. During epi-on CXL, we pre-treat the cornea with special drops that enhance the penetration of riboflavin. These penetration enhancers are the result of several years of research and are currently awaiting the CE mark. Once the CE mark is given, ELZA-PACE can be performed by any colleague equipped with an MS-39 device for the epithelial maps and generation of the ablation file (CSO Italy), a SCHWIND AMARIS excimer laser for the custom PTK driven by epithelial maps (SCHWIND-eye-tech-solutions GmbH) and the C-eye cross-linking technology for customised CXL (EMAGine Switzerland).

Conclusion

ELZA-PACE represents a significant advancement in keratoconus treatment without the need for corneal tissue removal. By leveraging the combined gradients of riboflavin, oxygen, and UV irradiation, ELZA-PACE achieves outcomes that surpass those of first-generation customised cross-linking. As ophthalmologists, we must consider ELZA-PACE as a first-line visual rehabilitation option for patients with keratoconus, ensuring they receive the most effective and advanced care available.

References

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Farhad Hafezi, MD, PhD, FARVO |E: farhad@hafezi.ch

Hafezi is a refractive and cataract surgeon based at the ELZA Institute in Zurich, Switzerland. Prof Hafezi is a council member of the European Society of Cataract & Refractive Surgeons and holds academic positions at the University of Geneva, the Keck School of Medicine of USC, the NYU Grossman School of Medicine, and Wenzhou Medical University. Financial disclosures: EMAGine AG (shareholder); PCT patent/application holder (corneal apparatus for CXL)