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Security Analysis and ultraviolet irradiation efficiency using the riboflavin like photosensitive (Cross-link) on the corneal collagen

in patients with keratoconus level I and II.


INTRODUCTION

About the Keratoconus: Generally it can be defined as cone shaped


cornea; it causes a distorted image perception. In this condition the corneal stroma becomes thin and loses the rigidity. This rigidity loss allows the formation of a conical area provoking a corneal bending irregularity. The image perception difficult is similar as astigmatism and in the most advanced cases the vision is very low or quite distorted. There is not scientific consensus about the illness origin, but it is more frequently in allergic patients, patients with retinitis pigmentosa, Lebers congenital amaurosis, Ehlers-Danlos syndrome, Marfan syndrome, mitral valve prolapse, atopic dermatitis and Down syndrome. Also, it presents hereditary or genetic linking, it is not quite clarified yet. The Keratoconnus is painless, not inflammatory and it can be unilateral or bilateral, sometimes one of the eyes has bigger severity. Generally it begins in the puberty and grow up in 20% of the cases, the evolution continues until approximately the 35 to 40 years old when, in the majority of the cases, occurs a alteration spontaneous stabilization. The Collaborative Longitudinal Evaluation Keratoconus Study(CLEK) showed that 12% of the patients will need a cornea transplant, totaling 1065 patients followed up for eight years. The Keratoconus can be classified by [1] the bending in the two meridians in: Degree I - incipient (bigger that 45:00 Di), Degree II - moderate (of 45:00 the 52:00 Di), Degree III - advanced (bigger that 52:00 Di) and Degree IV - severe (bigger that 62:00Di) and [2] by the shape : in peak (small diameter - until 5mm), oval (its diameter bigger than 5mm and less than 6mm) or round (diameter bigger than 6mm). The Keratoconus diagnosis is made through the history and refractive examinations with retinoscopy, visual accuracy, biomicroscope, keratometry, keratoscopy, topography, based in slit lamp (Orbscan and Pentacan), optical coherence tomography (Visante), among others.

Keratoconus Level I reaches good visual accuracy with eyeglasses and rarely they need use contact lens; the Level II are generally more dislocated inferiorly, the visual accuracy with eyeglasses can be harmed having necessity of contact lenses adaptation; for the Level III the satisfactory visual accuracy is only gotten with the contact lenses use, as well as for the Level IV, for this even with the lenses use the a vision is low and without quality, intolerance, discomfort and difficulty in the use, to this cases is frequently cogitated the surgical treatments (fe, cornea transplant). The cornea transplant is the only healing procedure for Keratoconus, however it is known the risk of complications as high astigmatism, anisometropia, rejection, infection, glaucoma, cataract and illnesses related with the ocular surface. New surgical procedures have been developed to simplify or to supply more security in the Keratoconus treatment, such as the intracorneal ring implantations and the profound anterior lamellar Keratoplasty.

About the Cross Link of Corneal Collagen:is the first real possibility
of clinical treatment of Keratoconus. The Cross-linking of the corneal collagen with the riboflavin (B2 vitamin) is one innovative technique in the treatment of patients with Keratoconus with the objective to harden the corneal layer. The light UV-A (370 nm) associated to the riboflavin creates new linking between molecules of adjacent collagens; it produces a corneal thickness as well as diminishing its malleability. The riboflavin molecules irradiation through UV-A loses the corneal internal balance, which will only be recouped when to occur a new linking between two collagen fibril. One crossed bridged is created between collagen fibrils (therefore the term: cross-linking), it produces a rigidity increase of corneal layer. Articles in literature are pointing a corneal rigidity increase up to 329%. Wollensack et al. they had treated 22 patients with keratoconus , which were followed up for four years and the illness progression was interrupted in all the treated patients with Riboflavin UV-A. Moreover, a reduction of 2 dioptres in the maximum keratometric value in 70% of the patients was occurred. The corneal transparency and the crystalline lens as well as the endothelia cells density had remained unchanged. Another European study had showed an average reduction of 2,5 dioptres in the spherical equivalent,

it was confirmed by topography for the reduction of the average keratometry. Recent findings of the results gotten with follow-up from 3 to 5 years (Dresden Clinical Study) had shown that all the 60 eyes with Keratoconus treated with cross-linking of induced collagen by riboflavinUV-A had at least parked its evolutions. In 31 eyes happened a discrete leveling of the cone with equal value the 2,87 dioptres. The best visual accuracy corrected increased in 1,4 lines. More than 150 patients with Keratoconus had been submitted to the treatment with cross-linking in Dresda, the studies had disclosed a treatment maximum effect in the 300 m corneal anterior . Kholhaas et al. they had shown that after the treatment of cross-linking induced by riboflavin UV-A , 65% to 70% of the radiation UV-A are absorbed in the 200 m corneal anterior and only 20% in the 200 m corneal posterior, therefore the deep structures and the endothelium are not affected. The literature tells that corneal collagen cross-link has none or few collateral effect and amongst these we can designate: [1] Allergies and or collateral effect (fe., toxicity) of the collyrium used in the study; [2] pain and vision low in the first days after the treatment due to corneal epithelium withdrawal; [3] damages for the ultraviolet rays exposition (fe., alteration of the ocular surface cells, cataract, macular degeneration ); [4] difficulty in the corneal epithelium cicatrization; [5] infection that can eventually cause the cornea opacity, a transplant will be need for the visual rehabilitation; [6] change in the eyeglasses degree and the degree and bending of the contact lenses, [7] loss of the treatment effectiveness with the time and [8] unknown collateral effect due to a new procedure. Laboratory studies disclose that the maximum effect of the irradiation occurs in the 300 micra of the anterior cornea. The endothelial cytotoxicity would only be reached in cornea with a stromal thickness less those 400 micra. OBJECTIVE To evaluate the ocular repercussions and especially corneal of the CrossLink of the Corneal Collagen through the use of the riboflavin as photosensitive associate to the ultraviolet irradiation in carrying patients of keratoconus Level I and II. The Cross-Link of the corneal collagen can become an election therapy in cases of Keratoconus gradual, diminishing significantly the necessity of cornea transplant.

MATERIAL AND METHODS Criteria of Inclusion: [1] keratoconus disgnostic based in the examinations that are cited bellow and [2] progression signals in the last six months confirmed by changes in the cited examinations below. It is indicated for cases where good vision can still be gotten with the eyeglasses use and or lenses of contact, whereas the treatment has the objective to stop the condition progress and not to revert it. Therefore, advanced cases and candidates to a surgical procedure do not have to be submitted to this treatment;

Criteria of Exclusion: [1] age less than 15 years and greater than 40; [2] pregnancy or breast-feeding; [3] antecedent of herpes ocular or around the eyes; [4] antecedent of corneal surgery; [5] corneal thickness less than 350 micra; [6] carrier of other illnesses or corneal scars; [7] antecedent of corneal dysplasia or conjunctivas tumoral lesion; [8] antecedent of bad corneal cicatrization ; [9] antecedent of ocular burning; [10] carrier of Retinal Degenerations; [10] carrier of cataract; [11] allergy to the riboflavin.
Patients with cornea transplant in an eye can be submitted to the treatment in the contra lateral eye; patients with transplant and possible return of the illness cannot be enclosed in the study. The patients who obey the criteria of inclusion and exclusion of the study must have full condition to understand and to sign by yourselves or by main responsible the Term of Informed Assent and also to have condition to fulfill with all the listed returns below.

About the study drawing: the enclosed patients in the study will be
divided in two groups: treatment and control. All the patients will be submitted to the examinations below in the cited frequency. The treatment is single; it uses riboflavin collyrium and eye exposition to the ultraviolet irradiation.

About Group Treatment: it is initiated first with the partial removal of the
corneal epithelium (linear abrasion of 50% of the cornea with disposable blade of bistoury number 15), followed of the application of a drop of collyrium of riboflavin B2 0,1% dissolved in solution of Dextran 20% to each 5 minutes, per 30 minutes. That is, 6 times during the 30 minutes. Then the eye is displayed to the ultraviolet light per 30 minutes with an Irradiance

of 3.0 mW/cm2. While these 30 minutes, a drop of riboflavin collyrium B2 0,1% dissolved in solution of Dextran 20% is applied to each 5 minutes, per 30 minutes. That is, 6 times while the 30 minutes of exposition to light UV. When this period is completed a therapeutical contact lens is put on, until the corneal epithelium heals and the doctor does antimicrobial prophylaxis with collyrium of quinolone of fourth generation (Vigamox, Alcon or Zymar, Allergan) 4x/day per five days and control of the inflammation with 4x/day collyrium of acetate of prednisolone, for 7 to 10 days, on average, depending on the inflammatory process. Obs.: Not to treat corneas with thickness less than 400 micra in the thinnest region.

About the Group Control: the patients will not be submitted to none
specific treatment. They will be submitted the complete optometrist examinations to analyze the natural Keratoconus evolution, following the same behaviors used currently by the optometrist centers in cases of initial keratoconus. If will be necessary test of visual accuracy and prescription of eyeglasses or contact lenses will be done, to offer the patient the best possible visual accuracy. If, in study elapsing, the benefits of the treatment with crosslink become evident, these patients will be able to opt to this treatment.

About the exams: the enclosed patients in this study will be submitted to
the following examinations below listed in the frequency of 1, 3, 6 and 9 months and of 1, 2, 3, 4 and 5 years of follow-up. 1. Complete optometrist examination through history, refraction with retinoscopy, measured of the best visual accuracy, biomicroscopy and measure of the keratometry; 2. Accomplishment of Topography (computerized video-cornea keratography); 3. Corneal analysis with Slit lamp (OrbscanTM, Bausch & Lomb and PentacanTM, Oculus, Incorporation); 4. Optcial coherence tomography Inc.); (VisanteTM, Carl Zeiss Meditec,

5. Confocal microscopy (HRT2 CorneaTM, Heidelberg Engineering);

6. Specular microscopy; 7. OCT (Optcial coherence tomography ); 8. Test of sensitivity to the contrast; 9. ORA (Ocular Response Analyzer). POSSIBLE DISCOMFORTS AND RISKS There are potential risks exist, but few complications have been told in literature. [1] Allergies and or collateral effect (fe., toxicity) of the collyrium used in the study; [2] pain and vision low in the first days after the treatment due to withdrawal of the corneal epithelium ; [3] damages for the ultraviolet rays exposition (fe., alteration of the ocular surface cells, cataract, macular degeneration ); [4] difficulty in the corneal epithelium cicatrization; [5] infection that can eventually cause the cornea opacity, a transplant will be need for the visual rehabilitation; [6] change in the eyeglasses degree and the degree and bending of the contact lenses, [7] loss of the treatment effectiveness with the time and [8] endotelial injury (deeper cells of the crnea) and [9] unknown collateral effect due to a new procedure.

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