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Keywords:

  • cornea;
  • cross-linking;
  • endothelium;
  • riboflavin;
  • thickness;
  • UV light

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

Purpose:  To evaluate the potential of collagen cross-linking in the treatment of corneal oedema caused by endothelial decompensation.

Methods:  Riboflavin-ultraviolet (UV) treatment induces cross-linking and reduces stromal swelling. Eleven patients with corneal oedema were treated. The technique comprised: epithelial abrasion; instillation of 0.1% riboflavin in saline, and 5.4 J/cm2 illumination with 365 nm UV-A light over approximately 30 mins (3 mW/cm2).

Results:  A reduction in corneal thickness was observed in 10 patients. The majority also experienced improvement in vision. The effect occurred over weeks and lasted for months.

Conclusions:  The study shows a potential application of collagen cross-linking in the management of patients with corneal oedema. Experimental and additional clinical studies are necessary in order to define the precise indications for this type of treatment.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

A positive linear correlation exists between stromal water content and the thickness of the cornea (Ytteborg & Dohlman 1965). Thickness regulation therefore implies regulation of stromal hydration, determined by the barrier functions of the epithelium and endothelium. Interference with either of these boundary layers is followed by oedema and an increase in thickness. Because of the mechanical structure of the corneal fibres, a breakdown of the epithelial barrier results in only a modest thickness increase: values > 0.6 mm are rare. By contrast, endothelial decompensation is followed by considerable stromal swelling, with thickness values of 0.8–1.0 mm, which, because of the interwoven fibril texture of the human corneal stroma, is the maximum swelling possible.

With increasing thickness, the tendency to absorb fluid, the imbibition pressure, is reduced from 60 mmHg at normal hydration (Hedbys & Dohlman 1963; Olsen & Sperling 1987) to virtually zero at 1 mm thickness. When the epithelium is healthy and intact, and almost water-impermeable, fluid to increase the stromal volume comes from the aqueous humour. The net inflow represents the difference between passive pressure-driven inflow and active metabolic pumping out:

  • image
  • image

where P = pressure, R = resistance, and IOP = intraocular pressure. Inflow stops, which means that thickness stabilizes over time, when inflow equals outflow.

Passive inflow over the endothelium can be reduced by diminishing stromal imbibition pressure. By cross-linking, the stromal swelling capacity and swelling pressure may be reduced. The cross-linking can be accomplished by free oxygen radicals produced by ultraviolet (UV) radiation of riboflavin (vitamin B2). This treatment modality was introduced by Wollensak et al. (2003a), mainly with the purpose of strengthening the stromal fibril texture in the longitudinal direction, and has been used in the treatment of keratoconus.

During some preliminary animal experiments (Ehlers et al. 2003), the idea of cross-linking stromal fibres in an attempt to reduce corneal oedema by reducing swelling tendency and thickness, and to increase optical clarity by reducing fibril scattering, emerged. This paper presents the preliminary clinical results of stromal cross-linking, and suggests that this treatment principle does in fact work.

Materials and Methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

The treatment with riboflavin and subsequent UV radiation essentially followed the technique described by Wollensak et al. (2003b).

The treatment was administered under topical anaesthesia with drops of 0.4% oxybuprocaine and 1% lidocaine gel with the patient in the supine position. The patient was asked to look at a red fixation light in the operating microscope. The epithelium was mechanically abraded (which was very easy in cases of incipient or manifest oedema). The cornea was then exposed to 0.1% riboflavin solution in 0.9% saline for 15–30 mins. The cornea was treated by establishing a small, open reservoir with an 8-mm corneal marker lightly pressed against the cornea. Some patients required another drop of anaesthetic during the treatment. When the staining period ended, the eye was flushed with saline to remove any riboflavin on the conjunctiva and limbal cornea.

Radiation was performed with commercially available equipment (IROC UV-X; IROC A6, Zürich, Switzerland), according to the manufacturer’s instructions. The radiation intensity was checked before each treatment and the lamp placed above the cornea at the optical focal distance. The wavelength was 365 nm (UV-A), with an effect of 3 mW/cm2. The treatment time was intended to be 30 mins (5.4 J/cm2), but this was shortened in some cases when the patient felt uncomfortable. The immediate aftercare comprised voltaren drops administered a maximum of four times per day and chloramphenicol ointment to prevent infection until the epithelium had healed.

Postoperative follow-up in all cases exceeded 3 months and included slit-lamp biomicroscopy, optical non-contact pachymetry (Haag-Streit, Bern, Switzerland) and determination of visual acuity (VA).

Patients

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

This preliminary clinical study comprised 11 patients. Diagnoses included Fuchs’ dystrophy (n = 4), secondary bullous keratopathy (n = 2), oedematous rejected grafts (n = 3), corneal oedema resulting from longstanding secondary glaucoma (n = 1) and endothelial damage possibly caused by mechanical damage after a complicated forceps delivery (n = 1). Four of the patients were treated twice (patients 4–7). Table 1 shows patient details.

Table 1.   Patients treated by ultraviolet cross-linking for stromal oedema.
 DiagnosisPreoperative CCTVisual acuityPostoperative CCTVisual acuity
  1. * Cases 4 to 7 were treated twice.

  2. CCT = central corneal thickness.

1. 68-year-old womanFuchs’ dystrophy0.680.30.600.5
2. 54-year-old womanFuchs’ dystrophy0.580.60.510.8
3. 79-year-old womanFuchs’ dystrophy0.660.20.530.2
4. 69-year-old woman*Fuchs’ dystrophy0.650.70.61 
0.61 0.58 
5. 80-year-old woman*Bullous keratopathy0.73 0.75 
0.75 0.510.05
6. 76-year-old man*Bullous keratopathy0.90.050.780.05
0.78 0.90 
7. 52-year-old man*Graft0.800.010.66 
0.66 0.570.05
8. 86-year-old womanGraft0.760.020.670.05
9. 55-year-old womanGraft0.690.050.580.05
10. 60-year-old manGlaucoma0.5950.10.500.32
11. 58-year-old womanTrauma0.6590.10.5600.25

In all cases the alternative to UV cross-linking would have been grafting. The patients accepted the treatment in the hope of avoiding or postponing transplantation and the time-consuming aftercare it involves.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

All patients indicated some pain in the first few postoperative days until epithelial healing was complete.

Effect of cross-linking on central corneal thickness

As Table 1 shows, 10 of 11 cases showed a redction in central corneal thickness (CCT), the exception being case 6, which showed very advanced secondary bullous keratopathy after cataract operation. Examination of the central corneal button after a penetrating graft revealed almost complete loss of endothelium. Four patients (4, 5, 6 and 7) were treated twice and showed a further decrease in thickness after retreatment. Several patients demonstrated increased thickness in the first postoperative days before the epithelium had healed and then a decrease in thickness that occurred over several weeks. This same pattern of events was observed after the retreatments. Fig. 1 illustrates the clinical response.

image

Figure 1.  Corneal thickness decrease after cross-linking induced by riboflavin-ultraviolet in a 52-year-old man (case 7) grafted 3 years previously for a perforated corneal ulcer. A rejection was treated by steroids, with only temporary effect. The graft had been oedematous for almost a year before treatment. The patient was treated twice, as indicated by the arrows.

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Effect on visual acuity

In some patients (1, 2 and 10), VA improved (Table 1). In other cases this effect was limited as the dystrophic-degenerative changes in the very posterior aspect of the cornea remained opaque and reduced the total corneal transparency, despite an evident increase in the clarity of the stroma.

The effect over time

Usually the reduced stromal thickness was observed after weeks, but in some cases a result was seen only after a longer period. Other patients showed a longer term increase in thickness, suggesting that the obtained effect may not be permanent.

Complications of treatment

No corneal side-effects were noticed, in particular no corneal infections, no retarded epithelial healing, no intraocular inflammation, and no progression in lenticular opacification. However, the observation period was too short to allow any conclusions about possible complications.

Corneal thickness

In all cases but one, corneal oedema decreased. The graphs show an immediate increase in CCT, no doubt related to the epithelial abrasion. Over longer periods (weeks to months) the CCT was reduced.

Visual acuity

Only one patient (patient 9) experienced visual deterioration. The other patients all experienced some improvement in vision, in particular when the posterior boundary (Descemet’s membrane and endothelium) showed little alteration.

In case 10 the treatment was given prior to a planned phacoemulsification in an attempt not to elicit a decompensation. Three months after cataract surgery, CCT thickness was 0.53 mm, VA 0.32 and IOP 12 mmHg.

Conclusions

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References

The cross-linking induced by riboflavin-UV irradiation seems to lead to stromal deswelling and increased transparency. This effect can be attributed to decreased stromal imbibition pressure and hence reduced transendothelial inflow.

The small series presented here would seem sufficient to suggest a way of treating corneal oedema that attempts to avoid or postpone corneal grafting, and possibly offers some protection to the cornea during and after cataract surgery. Endothelial damage by the irradiation is a potential complication of this treatment. Ultraviolet-B radiation, with wavelengths of around 280 nm, is absorbed in aromatic aminoacids of the cell nuclei (Olsen & Ringvold 1982; Ringvold et al. 1982; Riley et al. 1987; Hamil 2005). The effect of UV-A, with a wavelength of 365 nm, has been less studied. If the photochemical damage to cells caused by UV-A is dose-related, a fractionation may be preferable.

Detailed experimental studies will be needed before this treatment can find a place in the management of corneal oedema.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Patients
  6. Results
  7. Conclusions
  8. References