Ординатура / Офтальмология / Английские материалы / Mastering Corneal Collagen Cross Linking Techniques (C3-R, CCL, CxL)_Garg_2009

INTRODUCTION

Keratoconus is a non inflammatory, degenerative disease that compromises the structural integrity of the collagen matrix within the corneal stroma. The development of a localized, cone shaped ectasia that is accompanied by thinning of the stroma in the area of the cone is the hallmark of this condition. The stromal thinning and loss of Bowman’s layer are associated with increased degradative enzyme activities and a decline in the enzyme inhibitors. Keratoconic corneas have decreased total protein and sulphated proteoglycan levels, decreased collagen cross-linking and a variable total collagen content (Fig. 12.1). 60% of the keratoconic corneas have apoptotic stromal keratocytes compared to normals and signs of increased oxidative damage that further lead to decreased cell function and cell death. The keratoconic corneas have unevenly distributed stromal lamellae that insert transversely into the Bowman’s layer. This can lead to corneal lamellar slippage and stretching, another possible hypothesis.

radical byproducts of metabolism in a young cornea and the lower cross-linking explains the increased incidence of keratoconus in the young population. However, the young diabetics escape this hypothesis because of the glucose related glycation that accelerates cross-linking in diabetic corneas.

Collagen cross-linking is a new non invasive procedure for keratoconus described by Woolensak et al which strengthens the weak cornea. With the help of ultraviolet light (UV-A) and photosensitizer riboflavin (0.1%), the collagen cross-linking is increased. Thus the basic pathology of keratoconus is addressed with changes in the intrinsic biochemical properties of the corneal collagen.

MECHANISM OF C3-R TREATMENT

Application of 0.1% of riboflavin on the cornea along with penetration for approximately 250µ and irradiation of riboflavin molecules through UV-A (at 370 nm) leads to loss of internal chemical balance of riboflavin molecules producing oxygen free radicals. This makes the riboflavin molecule unstable and it regains stability by cross-linking with collagen fibrils. Cross-linking is brought about by bridging amino groups of collagen fibrils (Fig. 12.2).

Collagen cross-linking results in an increased intra and inter fibrillar covalent bonds by photo sensitized oxidation and cause biomechanical stabilization of the cornea. A significant increase of 328.9% in the biomechanical rigidity of human corneas has been documented.

APPLICATIONS

C3-R treatment by enhancing the collagen crosslinking has gained enormous appeal in the treatment of early and moderately advanced progressive keratoconus (Figs 12.3 and 12.4).

However patients with advanced cone/ectasia, those with significant stromal scarring, corneal thickness of less than 400µ at the thinnest point and a poor BCVA with contact lenses are poor candidates for a C3-R treatment as a rehabilitation option.

C3R AND POSTLASIK ECTASIA

C3-R treatment is again a viable option in post lasik 6 6 ectasia which hitherto had the only option of a custom

designed contact lenses or a corneal transplant in advanced stages. The dictum of 400µ in the thinnest point of the cornea could be a limiting feature in post lasik ectasia. The process of swelling the cornea to 400µ and then harnessing C3-R treatment is the way to proceed. 0.1% riboflavin (in 20% dextran) is applied for the first ½ hour. Pachymetry is measured and in situations where the corneal thickness falls short of 400µ, 0.5% riboflavin drops (diluted in BSS in 1:4 proportion) is used every 5 seconds, thus swelling the cornea to the optimal 400µ limit. The hypo-osmolar solution should be applied deligently every 5 seconds as the cornea deswells if the drop application is done in a slower fashion. Again one should not swell a keratoconic cornea greater than 80µ as these eyes have a different swelling behavior.

C3-R WITH INTACS

Intacs enable targeted flattening of the cornea. However it does not address the underlying structural problem which is weakened collagen. It appears intuitive to combine C3-R with intacs in patients with keratoconus

to derive the maximal advantage. There are several possible explanations for the increased effect of intacs with the addition of cross-linking. It could be a simple additive measure to flatten the cornea. It is also reasonable to postulate that C3-R treatment following intacs causes pooling of riboflavin in the area of intac segment with resultant increased cross linkage. The increased biomechanical effect of C3-R clubbed with Intacs enhances the pattern and distribution of collagen changes. Further on, the increased collagen diameter of the newly synthesized collagen has a further pulling effect on the cone, a consequent potentiated flattening.

C3-R ENHANCED PRK IN KERATOCONIC EYES

This is another area of increased interest. Surface ablation is definitely accepted to result in lesser biomechanical stress than Lasik. Hence the pretreatment option of C3-R followed by PRK a couple of months later is a possible detour in these eyes, may be a window period of better visual acuity till the eventual corneal transplant.

C3-R FOR PROGRESSIVE HYPEROPIC FOLLOWING RK

Continued uncontrolled flattening with increasing hyperopia is noticed occasionally in post RK eyes. C3- R treatment improves cross-linking and tightens the RK incisions and leads to a more stable cornea, halting progressive flattening and hyperopia.

C3-R TREATMENT IN PELLUCID MARGINAL DEGENERATION

Collagen cross-linking has shown favorable outcomes in eyes with pellucid marginal degeneration. However a larger 11 mm should be exposed as of against the usual 9 mm advocated. A merocoel protection ring is adviced to protect the limbal stem cells and an eccentric corneal light exposure is advised.

PREGNANCY AND ESTROGEN

Estrogen receptors are present in human corneas. Increased estrogen levels during pregnancy has been

found to reduce the biomechanical stability of the cornea with increasing K values to ectasia. Collagen cross-linking, if performed, is noticed to bring about a regression of K values.

C3-R AND PSEUDOPHAKIC BULLOUS KERATOPATHY

These eyes need to be initially treated with glycerol to deswell the cornea. Once the thickness of cornea drops to 400µ, C3-R treatment could be performed optimally.

C3-R AND IOP VALUES

False high IOP values are noted in cross linked eyes as the cornea tends to become stiffer and harder.

CORNEAL MELTS AND C3-R

Successful use of cross-linking is reported in literature for corneal melts. A lower surface irradiation (2.5 mw/ cm²) is suggested to compensate for a thinner cornea.

The proposed mechanism is that cross-linking increases the cornea’s resistance to digestive enzymes such as collagenases which are a part of the inflammatory melting process.

INFECTIOUS CORNEAL ULCERS AND C3-R

Small study groups have treated recalcitrant infectious corneal ulcers with slowly improved resolution and epithelial healing.

CONCLUSIONS

C3-R treatment has gained universal acceptance and brings in hope and better realization of vision in this section of the population, the keratoconic eyes.

REFERENCES

1.Textbook on “Modern Management of Keratoconus” Brian S Boxer Wachler MD, Shawn Jalali MD, Colin CK Chan MD (Eds): 1st Edition 2008;7(3):76-91.

INTRODUCTION

LASIK SURGERY has become a medical phenomenon throughout the world over the last 20 years.

It all started in the laboratories of the University of Krete in Greece and under the direction of Ioannis Pallikaris, MD in 1988. It was the natural evolution of the boom in automated lamellar surgery that was popularized in South America that same decade and the introduction of cornea shaping by the excimer laser. It has become one of the most common procedures humans undergo worldwide, and for sure, the most common elective procedure that medicine offers today.

Throughout the years there have been several lessons in LASIK that have been learned by refractive surgeons. One of those has been the limitation to the amount of laser ablation that the human cornea can withhold, before changing its biomechanical properties. Post-LASIK ectasia has been recognized as a serious complication from the early years of LASIK development.1 Throughout this time several safety “paradigms” have been arbitrarily communicated through meetings and publications establishing the safety margin for residual stroma bed.

Even today procedures performed years ago may complicate and develop ectasia. In most cases a very small residual stromal bed is usually the isolated contributing factor along with irregular cornea topography pre-operatively suggesting forme fruste keratoconus.2 It remains though quite a challenge to explain why some “uneventful” procedures that had perfect pre-op topography and well documented “enough” residual stromal bed thickness may develop keratectasia.

As a cornea surgeon I have had the opportunity to treat several patients with this dreaded complication in the past. The initial treatment in the 90’s was penetrating keratoplasty when the ectasia could not be rehabilitated with RGP contact lenses.3 In the early 2000’s INTACS became a potential option. I have personally have not had a good clinical results with INTACS in regard to their stability in ecstatic corneas.4 In 2002 I became involved with collagen cross-linking with the use of UVA irradiation and topical riboflavin after I became familiar with the work of Seiler Wollensak and Spoel in Dresden and Zurich with this application.5-8 This is the case report of the first patient

7 0 I encountered:9

A 29-year old patient that had underwent uniocular LASIK for the correction of myopic astigmatism 3 years ago. His initial UCVA was 20/80 and his BSCVA was 20/20 with a refraction of –2.00 –175 ’ 85. Three months post-LASIK he began experiencing regression with myopia and astigmatism to the point of UCVA 20/200 and BSCVA 20/80 with –3.50 –2.00 ’ 120. Based on irregular topography and the loss in BSCVA, the treating physician soon recognized that a mechanism of ectasia had begun. Because this was not functionally correctable with spectacles or contact lenses, the decision was made to implant intracorneal ring segments for the management of this complication. Unfortunately, the patient’s UCVA remained 20/200 and BSCVA 20/100. The treating surgeon recommended cornea transplantation as the next step. My initial evaluation of the patient was made 11 months post-LASIK and 3 months after intracorneal ring implantation. Corneal thickness by Orbscan (Bausch and Lomb, Rochester, NY) and ultrasound pachymetry was 410 μm at the thinnest point, and the endothelial cell count was 2,750 cells per μm2 (Noncon Robo; Konan Medical, Hyogo, Japan).

OPTIONS FOR TREATMENT

We have had poor long-term outcomes with intracorneal ring segments in post-LASIK ectasia4, a fact which we discussed with the patient. We discussed the benefits and risks of corneal transplant, as well as combined ultraviolet radiation and riboflavin treatment in order to achieve collagen cross-linking and biomechanical stabilization of the corneal ectasia. We then obtained patient consent to remove the failed intracorneal ring segments. Itreated his cornea with a single application of UV-A radiation at 3 mW/cm2 for 30 minutes (KeraCure; Priavision, Menlo Parl, Ca) combined with 0.1% riboflavin ophthalmic solution. This treatment was performed after removing the corneal epithelium with 20% ETOH placed on the surface for 30 seconds. The riboflavin solution was applied for about 2 minutes in order to soak the stromal bed and protect the iris, crystalline lens and retina from UV irradiation. One drop every 2 minutes was applied during the 30 minutes of irradiation. A bandage contact lens was placed on the cornea for 5 days, and the patients was treated with topical ofloxacin 1% (Ocuflox; Allergan, Irvine, Ca) and prednisolone acetate 1% (Predforte, Allergan) four times a day for

10 days. The bandage contact lens was removed at day 4, following complete reepithelialization.

IMPROVEMENT IN VISUAL ACUITY

At 3 months, the patient’s UCVA improved from 20/ 400 to 20/70 and his BSCVA improved from 20/200 to 20/40. The refraction changed from –4.50 –4.50 ’ 120 to –4.50 –4.00 ’ 115, and corneal topography changed as seen in (Figure 13.1B). The stability of these parameters and the corneal topography between months 1 and 3 of this treatment, encouraged us to proceed with topography-guided PRK. We sought to reduce the irregular astigmatism and attempt to provide the patient with visual acuity not requiring spectacle or soft contact lens correction. Because the patient’s corneal thickness was 410 μm, we were able to treat his full spectacle correction using the Allegretto Wave excimer laser (Wavelight, Erlangen Germany) topography-guided customized ablation treatment (T- CAT) software. After placing 20% dilution of ETOH on the corneal surface for 30 seconds and subsequent epithelium removal, I performed laser treatment. A bandage contact lens was placed for 5 days and the patient was treated again with ofloxacin and prednisolone four times a day for 10 days. The bandage contact lens was removed at day 4, following complete re-epithelialization. One month after topographyguided treatment, the patient’s UCVA was 20/20and BSCVA was 20/20 with a refraction of +0.50 –5.0 ’ 160. The corneal endothelium count has remained stable at 2,700 cells per μm2. The patient complained of night vision symptoms of halos and ghosting. The patient is now at 34 months postoperative and enjoys UCVA of 20/20 with some mild night vision problems and corneal topography as shown in (Figure 13.1). One can also appreciate the difference map between pre and post topography-guided treatment in Figure 13.1D, as well as the actual ablation profile that was used for the treatment.

TREATMENT OF IATROGENIC

KERATECTASIA

Different techniques have been suggested for the treatment of iatrogenic keratectasia without satisfactory outcomes either biomechanically or visually, with the patient’s journey most frequently ending with pentrating conreal graft. Reports of the use of riboflavin/

UV-A corneal cross-linking have been shown to slow down keratoconus and progressive iatrogenic ectasia. During the past 3years, we have had extensive experience with customized topography-guided excimer ablations which we have presented and reported.10,11 This customized approach can, in our opinion, address the extreme cornea irregularity that these cases may have and enhance visual rehabilitation. This was the first report of post-LASIK ectasia treatment using a combination of UVA collagen cross-linking to stabilize the corneal biomechanics, followed by surface excimer laser ablation for visual rehabilitation. Remarkable corneal stabilization, together with full visual rehabilitation, leads us to believe that this approach may have a wider application in the near future. Considering the tremendous burden on the patient in everyday life, as well as the medical-legal issues involved in such a complication of elective excimer laser refractive surgery as iatrogenic keratectasia, we feel that the combined procedure discussed here is now a valuable alternative to therapeutic cornea transplantation and should be considered in any case that enables the application of this treatment.

It is though in my opinion necessary for the clinician to take special consideration in treating these cases. By no means can the excimer laser be considered an instrument for emmetropia in these patients in a fashion similar to routine LASIK and/or PRK refractive cases. The treatment should be directed towards “ normalizing” the cornea surface and allowing for improvement of BSCVA. There is an obvious danger in thinning these corneas to much by giving in to the “temptation” to correct the refractive error. This was the initial desire of these patients anyway. Having no previous work to relay on, I arbitrarily took a conservative approach to the matter and limited the refractive laser treatment to the minimum and never to allow removal of over 50 microns the thinnest cornea.

Several cases followed this success story over the last 5 years. We have presented a case series at the

in both eyes. The manifest refraction was +0.25 -1.25 ’ 090 (20/20) OD and was +0.25 -0.25 ’ 110 (20/15) OS but the topography suggested the early development of ectasia . At this time, the keratometry readings were 38.75/39.25 ’ 22 (OD) and 38.50/ 39.00x162 (OS) and the pachymetry readings were

375 microns (OD) and 407 microns (OS).

7 2

The patient returned on February 21, 2005, with an uncorrected vision of 20/40 in the right eye and 20/20 in the left eye. A manifest refraction in the affected right eye of -0.75 -3.50 ’ 091 (20/30), and +0.75 -0.50 X0128 (20/20) OS. The topography at this point suggested the presence of ectasia only in the right eye 2a and Orbscan 2c.