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Minerva Oftalmologica 2012 March;54(1):9-20


language: English, Italian

A combined therapeutic approach in the treatment of keratoconus: timolol and transepithelial corneal collagen crosslinking (TE-CXL)

Camardi A. D. V.

Private Pratictioner Catania, Italia


Aim. This article proposes a combined approach with timolol and transepithelial corneal collagen crosslinking (TE-CXL) in the treatment of early keratoconus (Amsler-Krumeich classification stages I and II) assessed with refractive diagnostics (uncorrected and best spectacle-corrected visual acuity [UCVA-BSCVA]). The therapeutic goal is to halt disease progression at stage I so as to obviate the need for corneal transplant. In this combined approach, timolol therapy is followed by TE-CXL surgery, a minimally invasive procedure which can be repeated as needed to resolve early stage keratoconus. Finally, the article delineates an experimental clinical protocol under which such a combined approach could be tested.
Methods. A hypothesis for the etiopathogenesis of corneal edema (Amsler-Krumeich classification stages I and II) is presented together with a proposal for its treatment with beta-blocker therapy (topical timolol) followed by TE-CXL surgery. The rationale underpinning this combined approach would be validated by simple clinical reasoning (observatio et ratio) applied to an experimental model tested under a feasible, effective and demonstrative protocol. A clinical trial designed to validate the proposed therapeutic hypothesis would involve a sample of patients with early stage keratoconus (Amsler-Krumeich stages I and II), alterations in corneal aberrometric parameters and in corrected distance visual acuity (CDVA), uncorrected visual acuity (UCVA), and best spectacle-corrected visual acuity (BSCVA). Timolol is a beta-blocker that decreases the pressure inside the anterior eye chamber and facilitates the outflow of aqueous humor from the corneal stroma to the anterior eye chamber through the pumping action of endothelial cells, supported in this mechanism by timolol which has a hypotonic action on the fluid of the anterior eye chamber. At this stage, decreased hyperhydration of the interstitial fluid of the corneal stroma, as verified clinically by improvement of refractive indices, the patient is advised to undergo TE-CXL surgery, avoiding the need for uncomfortable contact lens wear. Moreover, this could extend the indications for TE-CXL surgery.
Results. After patient enrolment, one group is assigned to placebo and the other to timolol treatment. Timolol, a beta-adrenergic receptor antagonist, is administered with eye drops and is indicated as drug of first choice because of its good effectiveness-safety profile and lack of adverse or systemic reactions. Timolol is a hypotonic agent used to reduce eye pressure from high to normal. Peak reduction is defined as a 15% reduction in pressure (at two hours after instillation); trough reduction is defined as a reduction of 18% compared to baseline value before the next drug instillation (12 hours for beta-blockers). The drug is administered in a single low-dose application for one week. Monotherapy is suggested by the European Glaucoma Society. In patients with stage I and II keratoconus and treated with timolol, the drug decreases the pressure of the anterior eye chamber, facilitates the flow of aqueous humor from the corneal stroma, enhancing the pumping function of the endothelial cells due to timolol-induced hypotonic fluid of the anterior eye chamber,. A zero pressure is obtained at the intrastromal level of the cornea and a normal pressure at the level of the anterior eye chamber, as in the normal eye. At this stage, hyperhydration of the interstitial fluid of the corneal stroma is decreased and refractive indices are improved; the patient can then be referred for TE-CXL surgery. The apparent healing after timolol or acetazolamide treatment has been reported in two study groups: one group of patients normalized with timolol or acetazolamide and the other composed of untreated patients; both groups were evaluated with refractometric indices. In this proposed combined approach, patients stabilized with the drug are then enrolled for TE-CXL surgery, assessed with pre-and postsurgical follow-up evaluation, and the outcomes are compared with refractometric analysis, UCVA and BSCVA, at 1, 3, 6, and 12 months.
Conclusions.To implement this strategy we should not wait for a reduction in visual acuity or an increase in symmetry and keratorefractive indices, or worsening of the thinnest point and the average central thickness or worsening of comatic aberrations and high order components. When the cornea stabilizes after edema, we see an improvement in refractive indices, which is the opportune time for TE-CXL surgery.
TE-CXL surgery, after timolol pretreatment, can prevent the need for special corneal contact lenses. Finding a tolerable contact lens can be a difficult and frustrating experience for the patient. To strengthen the cornea with a minimally invasive operation like TE-CXL,14 I believe represents a conquest, especially in pediatric patients.
From an economic perspective, in terms of quality-adjusted life years (QUALY), the healthcare cost of this operation is low and TE-CXL may prevent the need for corneal transplant and enhance the patient’s quality of life.
QUALY 15 implies savings for the national health system, optimizing resources, offering better health as promulgated in our national constitution. The oculist will need to select those patients who could benefit from this alternative therapeutic option: a non-invasive, painless procedure that could prevent the need for corneal transplant.

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