Ionto sferov 2014

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Présentation proposée aux journées d'actualités thérapeutique de la SFEROV en octobre 2014. Intérêt de la Iontophorèse pour l'imprégnation de la cornée par la riboflavine avant cross-linking du collagène cornéen.

Publié dans : Santé & Médecine
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  • Good afternood Ladies and Gentlemen, before talking about iontophoresis and its application to corneal cross-linking, I’d like to thank the ECVO comitee for allowing me to present these results.
  • As you know, melting keratitis is a serious condition which is considered as an ocular emergency due to the high risk or corneal perforation. The melting of the cornea is due to metalloproteinase imbalance in relation with infectious or not infectious conditions. When the medical treatment, based on antibiotics and anticollagenases doesn’t succeed, surgery is indicated for tectonic purposes. Corneal collagen cross-linking is used for the treatment of infectious or melting keratitis in humans for some years and more recently for dogs, cats and horses.
  • To remind you with the technical aspects of collagen cross-linking, this process is a photochemical reaction between free radicals generated by the activation of riboflavin by UVA light and the fibrils of corneal collagen. This photoactivation leads to collagen reticulation responsible for the improvement of the mechanical strength and resistance to enzymatic digestion of the stroma, direct antiinfectious effects and a modulation of inflammatory corneal response via keratocyte apoptosis.
    The process is divided in two parts :
    -impregnation of the stroma by riboflavin
    - Irradiation by UVA.
  • Collagen cross-linking has been primarily developed for the treatment of human progressive keratoconus and all the protocols used are adapted from the conventional protocol. This consists in instillation of riboflavin during 30 minutes after removal of the epithelium and UV exposition for 30 minutes à 3 mW/cm². Modifications of this protocol have been proposed for 3 aims : preserving the epithelium, enhancing the riboflavin impregnation or shortening the exposition time by increasing the UV light intensity. Iontophoresis is a way of enhancing riboflavin impregnation.
  • The principle of iontophoresis is to increase the penetration of a ionized substance through a tissue by the application of a constant electric current. It has been used for first time in ophthalmology in the beginning of the 20th century. Many studies have been conducted since 1990 for the delivery of many drugs in the eye (like steroids and so on). The first use of iontophoresis for riboflavin delivery was published recently for the treatment of keratoconus. For the moment, no veterinary clinical use of ionto has been described and no data for keratitis treatment is available.
  • The aim of this study is to evaluate the clinical outcome after treatment of melting keratitis after iontophoresis of riboflavin and cross-linking in feline patients.
  • Inclusion criteria were represented by feline patients presenting with corneal melting with poor response to previous medical treatment
  • … and were selected on the presence of epithelial loss, cellular infiltration and stromal dissolution and a minimal corneal thickness of 300 µm.
  • On day one, cats under general anesthesia have their cornea cleaned and sampled. Riboflavin impregnation by iontophoresis and an accelerated cross-linking.
  • The iontophoresis device we have used has three parts :
    The corneal electrode is maintained on the corneal surface by suction and is filled with riboflavin till the grid is covered.
    The generator applies a constant current between the electrodes
    The return electrode which is connected to a needle inserted under the frontal skin.
  • Follow-up was conducted for one month with evaluation of pain and clinical score and measurement of ulceration and infiltration surface.
  • Clinical score was established by the evaluation on a scale ranging from 0 to 3 of six ocular signs, and pain score was established in the same way by presence or absence of pain symptoms.
  • 6 cats were included in this study and presented with melting keratitis with an average duration time befor cross-linking treatment of 40 days. Two of them were Persians, One from 6 had a positive bacterial culture and 1/6 was positive for herpes virus.
  • After treatment, we see a rapid reduction in pain and clinical score and disappearance of the ulcer and of the zone of infiltration.
    You see that there is a positive clinical score à one month, this is due to
  • … the persistance of corneal vascularization which was mild in some cases, and moderate in others.
  • The aim of this study was to evaluate the efficacy of cross-linking after iontophoresis of riboflavin. We have observed the resolution of corneal melting with complete epithelial healing and reduction of clinical and pain scores in all cases.
  • If we compare to the results observed with conventional impregnation of riboflavin,
  • … we see that all the criteria have a similar progression in both groups during the follow-up period.
  • One of the question we can draw for this study is : what is the exact impregnation of riboflavin ? It is known in clear corneas that the diffusion of riboflavin is not the same with two different protocols.
    In the cases of keratitis, we don’t know what are the depth and concentration of riboflavin. We can just assume that it is enough to get a good clinical outcome.
  • Adverse effects of iontophoresis have been described during the experimental phase with conditions which are very far from those we have used in this study. No adverse effect was observed.
  • If we consider the duration of treatment, we see that conventional protocol takes more than an hour to be completed. With iontophoresis and accelerated cross-linking the duration of treatment can fall under 20 minutes according to the intensity of UVA you’re using. This has the advantage to shorten the duration of anesthesia.
  • In a first step, we can conclude that iontophoresis of riboflavin followed by accelerated cross-linking was associated with a good outcome in the resolution of corneal melting in cats. That these results are similar to conventional instillation with a shorter treatment duration and no adverse reaction.
  • But in second step, we can imagine that if iontophoresis could enhance penetration of riboflavin, this process could work for other therapeutic agents like antibiotics. There’s a big work to do in this field and this is another story…
  • Thank you for your attention. I’ll be happy to answer to any question.
  • Ionto sferov 2014

    2. 2. Kératomalacie Déséquilibre des MMP Risque de perforation Traitement : ATb & anticollagenases Chirurgie tectonique PACK-CXL
    3. 3. PACK-CXL Processus photochimique Réticulation du Collagène Effets bactéricides Directs Apoptose des Keratocytes
    4. 4. CXL: les protocoles Epithelium Distribution RF Irradiation UVA
    5. 5. Iontophorèse Application d’un courant électrique continu pour augmenter la pénétration d’une substance ionisée à travers un tissu
    6. 6. But des études réalisées Evaluer le résultat clinique de kératomalacies traitées par PACK-CXL après imprégnation de riboflavine par iontophorèse chez le chien et le chat
    7. 7. Critères d’inclusion Chiens et chats Kératomalacie Echec des traitements préalables
    8. 8. Critères d’inclusion Déficit épithélial Infiltration cellulaire et fonte stromale Epaisseur cornéenne Minimale > 300 μm (OCT)
    9. 9. Protocole Anesthésie générale Nettoyage cornéen Imprégnation de riboflavine Exposition UVA 365 nm Traitement Post-CXL OCT Medetomidine Ketamine Prélèvements bactériologie PCR (FHV1) RF 0,1% (Ricrolin TM) Iontophorèse 5 min 1mA/min 30 mW/cm² 3 min 5,4J/cm² TobrexTM BID 7 jours Protocole accéléré (KXLTM – Avedro)
    10. 10. Le système de iontophorèse
    11. 11. Suivi Inclusion J1 J4 J8 J15 J31 Signes cliniques + douleur Surfaces d’infiltration et d’ulcération
    12. 12. Suivi 0 : absent 1 : faible 2 : modéré 3 : sévère 0 : absent 1 : présent Score clinique (0-18) Score douloureux (0-7) Ecoulement mucopurulent OEdème cornéen Vascularisation cornéenne Conjonctivite Blepharitis Uveitis Prostration Comportement agressif Blépharospasme Enophtalmie Photophobie Démangeaison oculaire Réaction de défense
    13. 13. Résultats Durée évolution moyene : 40 jours Profondeur 21-60% 4/12 Brachycephales 3/12 culture bactérienne positive 1/10 FHV1 positive 10 chats 2 chiens
    14. 14. 12 10 8 6 4 2 0 Evolution des scores moyens D1 D4 D8 D15 D31 Clinical score Pain score 35 30 25 20 15 10 5 0 Evolution des Surfaces moyennes (mm²) D1 D4 D8 D15 D31 Ulcer surface Infiltration surface
    15. 15. Vascularisation cornéenne
    16. 16. Discussion : efficacité Reduction des scores cliniques Cicatrisation épithéliale complète Resolution de la kératomalacie
    17. 17. Comparaison à l’imprégnation conventionnelle de riboflavine
    18. 18. Distribution de la riboflavine ? Cornée claire Kératite Etude humaines et exp. (fluorometrie, histologie, HPLC, OCT…) Stroma antérieur (150 μm) : Cinstillation= 2x Ciontophoresis Diffusion moins uniforme ?
    19. 19. Effets secondaires de l’iontophorèse Brûlure electrique Intensité du courant Brûlure chimique pH des solutions Non observée chez l’homme avec I < 4mA/min Douleur
    20. 20. Durée du traitement ? Instillation 30 min Iontophorèse 5 min Irradiation 30 min CXL accéléré 3-10 min Protocole classique durée > 1 heure Ionto + acc. CXL protocol Durée < 20 min.
    21. 21. Conclusion: IONTOPHORESE Résolution de la kératomalacie Résultats similaires à l’instillation conventionnelle Reduction de la durée du processus Pas de douleur ou d’effet indésirable
    22. 22. Perspectives: IONTOPHORESE Augmentation de la pénetration de la riboflavine ? …ou d’autres agents thérapeutiques
    23. 23. Iontophorèse de Solu-Medrol (ND) J1 J1 J8
    24. 24. Merci