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Klin Monbl Augenheilkd 2018; 235(07): 809-819
DOI: 10.1055/s-0043-102577
Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Morphologische Hornhautveränderungen nach Crosslinking bei Keratokonus

Morphologic Corneal Changes after Crosslinking for Keratoconus
P. L. Müller
1   Universitäts-Augenklinik Bonn, Bonn, Deutschland
2   Sektion Ophthalmopathologie, Universitäts-Augenklinik Bonn, Bonn, Deutschland
,
K. U. Löffler
1   Universitäts-Augenklinik Bonn, Bonn, Deutschland
2   Sektion Ophthalmopathologie, Universitäts-Augenklinik Bonn, Bonn, Deutschland
,
M. Kohlhaas
3   Augenklinik des St. Johannes Hospital, Dortmund, Deutschland
,
F. G. Holz
1   Universitäts-Augenklinik Bonn, Bonn, Deutschland
,
M. C. Herwig-Carl
1   Universitäts-Augenklinik Bonn, Bonn, Deutschland
2   Sektion Ophthalmopathologie, Universitäts-Augenklinik Bonn, Bonn, Deutschland
› Author Affiliations
Further Information

Publication History

eingereicht 21 December 2016

akzeptiert 24 January 2017

Publication Date:
03 May 2017 (online)

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Zusammenfassung

Der Keratokonus ist eine relativ häufige (1 : 2000), meist bilateral auftretende Erkrankung, die zu einer Verdünnung, Veränderung der biochemischen und biomechanischen Struktur sowie Vorwölbung der Hornhaut führt. Seit mehr als 10 Jahren steht das Crosslinking als therapeutisches Verfahren für den progredienten Keratokonus zur Verfügung. Dabei wird mittels Riboflavin und UVA-Bestrahlung eine Verfestigung der Quervernetzung der Kollagenfasern in den vorderen 300 µm des Hornhautstromas erreicht. Es ist als wirksam und komplikationsarm beschrieben worden, sofern entsprechende Protokolle und Indikationen eingehalten werden. Diese Übersicht beinhaltet die physiologischen und pathologischen morphologischen Veränderungen der Hornhaut vor und nach Crosslinking bei Keratokonus. Die verfügbare Literatur wird aufgearbeitet und um eigene Beobachtungen und Erfahrungen, basierend auf histopathologischen Untersuchungen, ergänzt.

Abstract

Keratoconus is a relatively common (1 : 2000) bilateral disease leading to a change in biochemical and biomechanical corneal structure as well as thinning and ectasia. For more than 10 years, crosslinking has been a therapeutic option in cases of progression. Using riboflavin and UVA-radiation, the anterior corneal stroma (300 µm) gets stiffened by crosslinking of collagen fibers. When protocols and limitations are adhered, the procedure is described to be effective and of low-risk. This review gives an overview about physiologic and pathologic changes in keratoconic corneas before and after crosslinking. Based on histopathologic examination, the current knowledge in published literature is reviewed and is complemented by our own investigations.

Schlüsselwörter

Crosslinking - Ophthalmopathologie - Keratokonus

Key words

crosslinking - ophthalmic pathology - keratoconus
 

  • Literatur

  • 1 Nottingham J. Practical observations on conical cornea: and on the short sight, and other defects of vision connected with it. London, Liverpool: John Churchill, Deighton & Laughton; 1854
    Google Scholar
  • 2 Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980; 31: 435-441
    CrossrefPubMedGoogle Scholar
  • 3 Wollensak J, Buddecke E. Biochemical studies on human corneal proteoglycans – a comparison of normal and keratoconic eyes. Graefes Arch Clin Exp Ophthalmol 1990; 228: 517-523
    CrossrefPubMedGoogle Scholar
  • 4 Meek KM, Tuft SJ, Huang Y. et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci 2005; 46: 1948-1956
    CrossrefPubMedGoogle Scholar
  • 5 Rehany U, Lahav M, Shoshan S. Collagenolytic activity in keratoconus. Ann Ophthalmol 1982; 14: 751-754
    PubMedGoogle Scholar
  • 6 Sawaguchi S, Twining SS, Yue BY. et al. Alpha-1 proteinase inhibitor levels in keratoconus. Exp Eye Res 1990; 50: 549-554
    CrossrefPubMedGoogle Scholar
  • 7 Sawaguchi S, Yue BY, Sugar J. et al. Lysosomal enzyme abnormalities in keratoconus. Arch Ophthalmol 1989; 107: 1507-1510
    CrossrefPubMedGoogle Scholar
  • 8 Sawaguchi S, Yue BY, Chang I. et al. Proteoglycan molecules in keratoconus corneas. Invest Ophthalmol Vis Sci 1991; 32: 1846-1853
    PubMedGoogle Scholar
  • 9 Sawaguchi S, Fukuchi T, Abe H. et al. Three-dimensional scanning electron microscopic study of keratoconus corneas. Arch Ophthalmol 1998; 116: 62-68
    CrossrefPubMedGoogle Scholar
  • 10 Sawaguchi S, Twining SS, Yue BY. et al. Alpha 2-macroglobulin levels in normal human and keratoconus corneas. Invest Ophthalmol Vis Sci 1994; 35: 4008-4014
    PubMedGoogle Scholar
  • 11 Zhou L, Sawaguchi S, Twining SS. et al. Expression of degradative enzymes and protease inhibitors in corneas with keratoconus. Invest Ophthalmol Vis Sci 1998; 39: 1117-1124
    PubMedGoogle Scholar
  • 12 Kao WW, Vergnes JP, Ebert J. et al. Increased collagenase and gelatinase activities in keratoconus. Biochem Biophys Res Commun 1982; 107: 929-936
    CrossrefPubMedGoogle Scholar
  • 13 Daxer A, Fratzl P. Collagen fibril orientation in the human corneal stroma and its implication in keratoconus. Invest Ophthalmol Vis Sci 1997; 38: 121-129
    PubMedGoogle Scholar
  • 14 Radner W, Zehetmayer M, Skorpik C. et al. Altered organization of collagen in the apex of keratoconus corneas. Ophthalmic Res 1998; 30: 327-332
    CrossrefPubMedGoogle Scholar
  • 15 Wisse RPL, Kuiper JJW, Gans R. et al. Cytokine expression in keratoconus and its corneal microenvironment: a systematic review. Ocul Surf 2015; 13: 272-283
    CrossrefPubMedGoogle Scholar
  • 16 Davidson AE, Hayes S, Hardcastle AJ. et al. The pathogenesis of keratoconus. Eye (Lond) 2014; 28: 189-195
    CrossrefPubMedGoogle Scholar
  • 17 Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol 1986; 101: 267-273
    CrossrefPubMedGoogle Scholar
  • 18 Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42: 297-319
    CrossrefPubMedGoogle Scholar
  • 19 Gomes JAP, Tan D, Rapuano CJ. et al. Global consensus on keratoconus and ectatic diseases. Cornea 2015; 34: 359-369
    CrossrefPubMedGoogle Scholar
  • 20 Bykhovskaya Y, Margines B, Rabinowitz YS. Genetics in keratoconus: where are we?. Eye Vis (Lond) 2016; 3: 16
    PubMedGoogle Scholar
  • 21 Hallerman W, Wilson E. Genetische Betrachtungen über den Keratokonus. Klin Monatsbl Augenheilkd 1977; 170: 906-908
    PubMedGoogle Scholar
  • 22 Gordon-Shaag A, Millodot M, Shneor E. et al. The genetic and environmental factors for keratoconus. Biomed Res Int 2015; 2015: 795738
    PubMedGoogle Scholar
  • 23 Cullen JF, Butler HG. Mongolism (Downʼs syndrome) and keratokonus. Br J Ophthalmol 1963; 47: 321-330
    CrossrefPubMedGoogle Scholar
  • 24 Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984; 28: 293-322
    CrossrefPubMedGoogle Scholar
  • 25 Zadnik K, Barr JT, Edrington TB. et al. Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study. Invest Ophthalmol Vis Sci 1998; 39: 2537-2546
    PubMedGoogle Scholar
  • 26 Seiler T, Huhle S, Spoerl E. et al. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol 2000; 238: 822-825
    CrossrefPubMedGoogle Scholar
  • 27 Sady C, Khosrof S, Nagaraj R. Advanced Maillard reaction and crosslinking of corneal collagen in diabetes. Biochem Biophys Res Commun 1995; 214: 793-797
    CrossrefPubMedGoogle Scholar
  • 28 Spoerl E, Raiskup-Wolf F, Kuhlisch E. et al. Cigarette smoking is negatively associated with keratoconus. J Refract Surg 2008; 24: S737-S740
    CrossrefPubMedGoogle Scholar
  • 29 Parker JS, van Dijk K, Melles GRJ. Treatment options for advanced keratoconus: a review. Surv Ophthalmol 2015; 60: 459-480
    CrossrefPubMedGoogle Scholar
  • 30 Gore DM, Shortt AJ, Allan BD. New clinical pathways for keratoconus. Eye (Lond) 2013; 27: 329-339
    CrossrefPubMedGoogle Scholar
  • 31 Downie LE, Lindsay RG. Contact lens management of keratoconus. Clin Exp Optom 2015; 98: 299-311
    CrossrefPubMedGoogle Scholar
  • 32 Godefrooij DA, Boom K, Soeters N. et al. Predictors for treatment outcomes after corneal crosslinking for keratoconus: a validation study. Int Ophthalmol 2016; DOI: 10.1007/s10792-016-0262-z.
    CrossrefPubMedGoogle Scholar
  • 33 Mastropasqua L. Collagen cross-linking: when and how? A review of the state of the art of the technique and new perspectives. Eye Vis (Lond) 2015; 2: 19
    PubMedGoogle Scholar
  • 34 Lang S, Reinhard T. Crosslinking bei Keratokonus. Klin Monatsbl Augenheilkd 2016; 233: 713-716
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Sorkin N, Varssano D. Corneal collagen crosslinking: a systematic review. Ophthalmologica 2014; 232: 10-27
    CrossrefPubMedGoogle Scholar
  • 36 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135: 620-627
    CrossrefPubMedGoogle Scholar
  • 37 Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006; 17: 356-360
    CrossrefPubMedGoogle Scholar
  • 38 Spoerl E, Mrochen M, Sliney D. et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26: 385-389
    CrossrefPubMedGoogle Scholar
  • 39 Wollensak G, Spörl E, Reber F. et al. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003; 35: 324-328
    CrossrefPubMedGoogle Scholar
  • 40 Wollensak G, Spoerl E, Reber F. et al. Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye (Lond) 2004; 18: 718-722
    CrossrefPubMedGoogle Scholar
  • 41 Wollensak G, Aurich H, Pham D-T. et al. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg 2007; 33: 516-521
    CrossrefPubMedGoogle Scholar
  • 42 Mencucci R, Mazzotta C, Rossi F. et al. Riboflavin and ultraviolet A collagen crosslinking: in vivo thermographic analysis of the corneal surface. J Cataract Refract Surg 2007; 33: 1005-1008
    CrossrefPubMedGoogle Scholar
  • 43 Tabibian D, Mazzotta C, Hafezi F. PACK-CXL: Corneal cross-linking in infectious keratitis. Eye Vis (Lond) 2016; 3: 11
    PubMedGoogle Scholar
  • 44 Seiler TG, Schmidinger G, Fischinger I. et al. Komplikationen der Vernetzung der Hornhaut. Ophthalmologe 2013; 110: 639-644
    CrossrefPubMedGoogle Scholar
  • 45 Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009; 35: 1358-1362
    CrossrefPubMedGoogle Scholar
  • 46 Kymes SM, Walline JJ, Zadnik K. et al. Changes in the quality-of-life of people with keratoconus. Am J Ophthalmol 2008; 145: 611-617
    CrossrefPubMedGoogle Scholar
  • 47 Maeno A, Naor J, Lee HM. et al. Three decades of corneal transplantation: indications and patient characteristics. Cornea 2000; 19: 7-11
    CrossrefPubMedGoogle Scholar
  • 48 Wahrendorf I. Leben mit Keratokonus. Klin Monatsbl Augenheilkd 2006; 223: 877-888
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Duncan JK, Belin MW, Borgstrom M. Assessing progression of keratoconus: novel tomographic determinants. Eye Vis (Lond) 2016; 3: 6
    CrossrefPubMedGoogle Scholar
  • 50 Maguire LI, Meyer RF. Ectatic corneal Degenerations. In: Kaufman HE, Barron BA, McDonald MB, Waltman SR. eds. The Cornea. New York: Churchill Livingstone; 1988: 485-510
    Google Scholar
  • 51 Pouliquen Y. Doyne lecture keratoconus. Eye (Lond) 1987; 1: 1-14
    CrossrefPubMedGoogle Scholar
  • 52 Pouliquen Y, DʼHermies F, Puech M. et al. Acute corneal edema in pellucid marginal degeneration or acute marginal keratoconus. Cornea 1987; 6: 169-174
    CrossrefPubMedGoogle Scholar
  • 53 Sung H-W, Chang W-H, Ma C-Y. et al. Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A 2003; 64: 427-438
    PubMedGoogle Scholar
  • 54 Chan BP, So K-F. Photochemical crosslinking improves the physicochemical properties of collagen scaffolds. J Biomed Mater Res A 2005; 75: 689-701
    PubMedGoogle Scholar
  • 55 Cannon DJ, Davison PF. Aging, and crosslinking in mammlian collagen. Exp Aging Res 1977; 3: 87-105
    CrossrefPubMedGoogle Scholar
  • 56 Cannon DJ, Foster CS. Collagen crosslinking in keratoconus. Invest Ophthalmol Vis Sci 1978; 17: 63-65
    PubMedGoogle Scholar
  • 57 Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf 2013; 11: 65-74
    CrossrefPubMedGoogle Scholar
  • 58 Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998; 66: 97-103
    CrossrefPubMedGoogle Scholar
  • 59 Spoerl E, Seiler T. Techniques for stiffening the cornea. J Refract Surg 1999; 15: 711-713
    PubMedGoogle Scholar
  • 60 Spörl E, Huhle M, Kasper M. et al. Erhöhung der Festigkeit der Hornhaut durch Vernetzung. Ophthalmologe 1997; 94: 902-906
    CrossrefPubMedGoogle Scholar
  • 61 Spörl E, Schreiber J, Hellmund K. et al. Studies on the stabilization of the cornea in rabbits. Ophthalmologe 2000; 97: 203-206
    CrossrefPubMedGoogle Scholar
  • 62 Spoerl E, Wollensak G, Dittert D-D. et al. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica 2004; 218: 136-140
    CrossrefPubMedGoogle Scholar
  • 63 Spörl E, Raiskup-Wolf F, Pillunat LE. Biophysikalische Grundlagen der Kollagenvernetzung. Klin Monatsbl Augenheilkd 2008; 225: 131-137
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004; 29: 35-40
    CrossrefPubMedGoogle Scholar
  • 65 Kolli S, Aslanides IM. Safety and efficacy of collagen crosslinking for the treatment of keratoconus. Expert Opin Drug Saf 2010; 9: 949-957
    CrossrefPubMedGoogle Scholar
  • 66 Beshtawi IM, OʼDonnell C, Radhakrishnan H. Biomechanical properties of corneal tissue after ultraviolet-A-riboflavin crosslinking. J Cataract Refract Surg 2013; 39: 451-462
    CrossrefPubMedGoogle Scholar
  • 67 Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. Part II. Clinical indications and results. Ocul Surf 2013; 11: 93-108
    CrossrefPubMedGoogle Scholar
  • 68 Xie J, Xu G, Wang J. et al. Steady-state motion visual evoked potentials produced by oscillating Newtonʼs rings: implications for brain-computer interfaces. PLoS One 2012; 7: e39707
    CrossrefPubMedGoogle Scholar
  • 69 Farjadnia M, Naderan M. Corneal cross-linking treatment of keratoconus. Oman J Ophthalmol 2015; 8: 86-91
    PubMedGoogle Scholar
  • 70 Li Z, Jhanji V, Tao X. et al. Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol 2013; 97: 669-671
    CrossrefPubMedGoogle Scholar
  • 71 Anwar HM, El-Danasoury AM, Hashem AN. Corneal collagen crosslinking in the treatment of infectious keratitis. Clin Ophthalmol 2011; 5: 1277-1280
    PubMedGoogle Scholar
  • 72 Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea 2010; 29: 1353-1358
    CrossrefPubMedGoogle Scholar
  • 73 Morén H, Malmsjö M, Mortensen J. et al. Riboflavin and ultraviolet a collagen crosslinking of the cornea for the treatment of keratitis. Cornea 2010; 29: 102-104
    CrossrefPubMedGoogle Scholar
  • 74 Micelli Ferrari T, Leozappa M, Lorusso M. et al. Escherichia coli keratitis treated with ultraviolet A/riboflavin corneal cross-linking: a case report. Eur J Ophthalmol 2009; 19: 295-297
    CrossrefPubMedGoogle Scholar
  • 75 Kymionis G, Portaliou D. Corneal crosslinking with riboflavin and UVA for the treatment of keratoconus. J Cataract Refract Surg 2007; 33: 1143-1144
    PubMedGoogle Scholar
  • 76 Kohlhaas M. Kollagen-Crosslinking mit Riboflavin und UVA-Licht beim Keratokonus. Ophthalmologe 2008; 105: 785-796
    CrossrefPubMedGoogle Scholar
  • 77 Daxer A, Mahmoud HA, Venkateswaran RS. Corneal crosslinking and visual rehabilitation in keratoconus in one session without epithelial debridement: new technique. Cornea 2010; 29: 1176-1179
    CrossrefPubMedGoogle Scholar
  • 78 Rechichi M, Mazzotta C, Daya S. et al. Intraoperative OCT pachymetry in patients undergoing dextran-free riboflavin UVA accelerated corneal collagen crosslinking. Curr Eye Res 2016; 41: 1310-1315
    CrossrefPubMedGoogle Scholar
  • 79 Aldahlawi NH, Hayes S, OʼBrart DPS. et al. Enzymatic resistance of corneas crosslinked using riboflavin in conjunction with low energy, high energy, and pulsed UVA irradiation modes. Invest Ophthalmol Vis Sci 2016; 57: 1547-1552
    CrossrefPubMedGoogle Scholar
  • 80 Mazzotta C, Traversi C, Caragiuli S. et al. Pulsed vs. continuous light accelerated corneal collagen crosslinking: in vivo qualitative investigation by confocal microscopy and corneal OCT. Eye (Lond) 2014; 28: 1179-1183
    CrossrefPubMedGoogle Scholar
  • 81 Mazzotta C, Traversi C, Paradiso AL. et al. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: one-year results. J Ophthalmol 2014; 2014: 604731
    PubMedGoogle Scholar
  • 82 Moramarco A, Iovieno A, Sartori A. et al. Corneal stromal demarcation line after accelerated crosslinking using continuous and pulsed light. J Cataract Refract Surg 2015; 41: 2546-2551
    CrossrefPubMedGoogle Scholar
  • 83 Mastropasqua L, Lanzini M, Curcio C. et al. Structural modifications and tissue response after standard epi-off and iontophoretic corneal crosslinking with different irradiation procedures. Invest Ophthalmol Vis Sci 2014; 55: 2526-2533
    CrossrefPubMedGoogle Scholar
  • 84 Torricelli AAM, Ford MR, Singh V. et al. BAC-EDTA transepithelial riboflavin-UVA crosslinking has greater biomechanical stiffening effect than standard epithelium-off in rabbit corneas. Exp Eye Res 2014; 125: 114-117
    CrossrefPubMedGoogle Scholar
  • 85 Rush SW, Rush RB. Epithelium-off versus transepithelial corneal collagen crosslinking for progressive corneal ectasia: a randomised and controlled trial. Br J Ophthalmol 2016; DOI: 10.1136/bjophthalmol-2016-308914.
    CrossrefPubMedGoogle Scholar
  • 86 Lombardo M, Serrao S, Carbone G. et al. Corneal light backscattering after transepithelial corneal crosslinking using iontophoresis in donor human corneal tissue. J Cataract Refract Surg 2015; 41: 635-643
    CrossrefPubMedGoogle Scholar
  • 87 Shalchi Z, Wang X, Nanavaty MA. Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus. Eye (Lond) 2015; 29: 15-29
    CrossrefPubMedGoogle Scholar
  • 88 Cassagne M, Laurent C, Rodrigues M. et al. Iontophoresis transcorneal delivery technique for transepithelial corneal collagen crosslinking with riboflavin in a rabbit model. Invest Ophthalmol Vis Sci 2016; 57: 594-603
    CrossrefPubMedGoogle Scholar
  • 89 Bouheraoua N, Jouve L, El Sanharawi M. et al. Optical coherence tomography and confocal microscopy following three different protocols of corneal collagen-crosslinking in keratoconus. Invest Ophthalmol Vis Sci 2014; 55: 7601-7609
    CrossrefPubMedGoogle Scholar
  • 90 Filippello M, Stagni E, OʼBrart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012; 38: 283-291
    CrossrefPubMedGoogle Scholar
  • 91 Chan CC, Squissato V. Keratoconus and crosslinking: pharmacokinetic considerations. Expert Opin Drug Metab Toxicol 2013; 9: 1613-1624
    CrossrefPubMedGoogle Scholar
  • 92 Çerman E, Toker E, Ozarslan Ozcan D. Transepithelial versus epithelium-off crosslinking in adults with progressive keratoconus. J Cataract Refract Surg 2015; 41: 1416-1425
    CrossrefPubMedGoogle Scholar
  • 93 Bouheraoua N, Jouve L, Borderie V. et al. Three different protocols of corneal collagen crosslinking in keratoconus: conventional, accelerated and iontophoresis. J Vis Exp 2015; DOI: 10.3791/53119.
    CrossrefPubMedGoogle Scholar
  • 94 Baiocchi S, Mazzotta C, Cerretani D. et al. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009; 35: 893-899
    CrossrefPubMedGoogle Scholar
  • 95 Spadea L, Mencucci R. Transepithelial corneal collagen cross-linking in ultrathin keratoconic corneas. Clin Ophthalmol 2012; 6: 1785-1792
    CrossrefPubMedGoogle Scholar
  • 96 Bikbova G, Bikbov M. Standard corneal collagen crosslinking versus transepithelial iontophoresis-assisted corneal crosslinking, 24 months follow-up: randomized control trial. Acta Ophthalmol 2016; 94: e600-e606
    CrossrefPubMedGoogle Scholar
  • 97 Lombardo M, Serrao S, Rosati M. et al. Biomechanical changes in the human cornea after transepithelial corneal crosslinking using iontophoresis. J Cataract Refract Surg 2014; 40: 1706-1715
    CrossrefPubMedGoogle Scholar
  • 98 Caporossi A, Mazzotta C, Paradiso AL. et al. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg 2013; 39: 1157-1163
    CrossrefPubMedGoogle Scholar
  • 99 Ozmen MC, Hondur A, Yilmaz G. et al. A histological study of rabbit corneas after transepithelial corneal crosslinking using partial epithelial photoablation or ethanol treatment. Int J Ophthalmol 2014; 7: 959-963
    PubMedGoogle Scholar
  • 100 De Bernardo M, Capasso L, Tortori A. et al. Trans epithelial corneal collagen crosslinking for progressive keratoconus: 6 months follow up. Cont Lens Anterior Eye 2014; 37: 438-441
    CrossrefPubMedGoogle Scholar
  • 101 Nawaz S, Gupta S, Gogia V. et al. Trans-epithelial versus conventional corneal collagen crosslinking: A randomized trial in keratoconus. Oman J Ophthalmol 2015; 8: 9-13
    CrossrefPubMedGoogle Scholar
  • 102 Wollensak G, Wilsch M, Spoerl E. et al. Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/UVA. Cornea 2004; 23: 503-507
    CrossrefPubMedGoogle Scholar
  • 103 Hayes S, OʼBrart DP, Lamdin LS. et al. Effect of complete epithelial debridement before riboflavin-ultraviolet-A corneal collagen crosslinking therapy. J Cataract Refract Surg 2008; 34: 657-661
    CrossrefPubMedGoogle Scholar
  • 104 Schmidinger G, Pachala M, Prager F. Pachymetry changes during corneal crosslinking: effect of closed eyelids and hypotonic riboflavin solution. J Cataract Refract Surg 2013; 39: 1179-1183
    CrossrefPubMedGoogle Scholar
  • 105 Wand K, Neuhann R, Ullmann A. et al. Riboflavin-UV – a crosslinking for fixation of biosynthetic corneal collagen implants. Cornea 2015; 34: 544-549
    CrossrefPubMedGoogle Scholar
  • 106 Rosenblat E, Hersh PS. Intraoperative corneal thickness change and clinical outcomes after corneal collagen crosslinking: Standard crosslinking versus hypotonic riboflavin. J Cataract Refract Surg 2016; 42: 596-605
    CrossrefPubMedGoogle Scholar
  • 107 Hirji N, Sykakis E, Lam FC. et al. Corneal collagen crosslinking for keratoconus or corneal ectasia without epithelial debridement. Eye (Lond) 2015; 29: 764-768
    CrossrefPubMedGoogle Scholar
  • 108 Hafezi F, Mrochen M, Iseli HP. et al. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 2009; 35: 621-624
    CrossrefPubMedGoogle Scholar
  • 109 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). IQWiG-Berichte Nr. 436: UV-Vernetzung mit Riboflavin bei Keratokonus Köln (2016). Im Internet: https://www.iqwig.de/download/N15-05_Abschlussbericht_1-1_Hornhautvernetzung-bei-Keratokonus.pdf Stand: 09.02.2017
    PubMedGoogle Scholar
  • 110 Lang SJ, Messmer EM, Geerling G. et al. Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus. BMC Ophthalmol 2015; 15: 78
    CrossrefPubMedGoogle Scholar
  • 111 Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg 2011; 37: 149-160
    CrossrefPubMedGoogle Scholar
  • 112 Reidy J. Treatment of keratoconus using collagen cross-linking (2012). Im Internet: https://clinicaltrials.gov/ct2/show/NCT00841386 Stand: 07.02.2017
    PubMedGoogle Scholar
  • 113 OʼBrart DPS, Chan E, Samaras K. et al. A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus. Br J Ophthalmol 2011; 95: 1519-1524
    CrossrefPubMedGoogle Scholar
  • 114 Wittig-Silva C, Chan E, Islam FMA. et al. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology 2014; 121: 812-821
    CrossrefPubMedGoogle Scholar
  • 115 Seyedian MA, Aliakbari S, Miraftab M. et al. Corneal collagen cross-linking in the treatment of progressive keratoconus: a randomized controlled contralateral eye study. Middle East Afr J Ophthalmol 2015; 22: 340-345
    CrossrefPubMedGoogle Scholar
  • 116 Sharma N, Suri K, Sehra SV. et al. Collagen cross-linking in keratoconus in Asian eyes: visual, refractive and confocal microscopy outcomes in a prospective randomized controlled trial. Int Ophthalmol 2015; 35: 827-832
    CrossrefPubMedGoogle Scholar
  • 117 Hashemi H, Fotouhi A, Miraftab M. et al. Short-term comparison of accelerated and standard methods of corneal collagen crosslinking. J Cataract Refract Surg 2015; 41: 533-540
    CrossrefPubMedGoogle Scholar
  • 118 Beckman Rehnman J, Behndig A, Hallberg P. et al. Initial results from mechanical compression of the cornea during crosslinking for keratoconus. Acta Ophthalmol 2014; 92: 644-649
    CrossrefPubMedGoogle Scholar
  • 119 Razmjoo H, Rahimi B, Kharraji M. et al. Corneal haze and visual outcome after collagen crosslinking for keratoconus: A comparison between total epithelium off and partial epithelial removal methods. Adv Biomed Res 2014; 3: 221
    CrossrefPubMedGoogle Scholar
  • 120 Sherif AM. Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clin Ophthalmol 2014; 8: 1435-1440
    CrossrefPubMedGoogle Scholar
  • 121 Kanellopoulos J. Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus. Clin Ophthalmol 2012; 6: 97
    PubMedGoogle Scholar
  • 122 Ozgurhan EB, Sezgin Akcay BI, Yildirim Y. et al. Evaluation of corneal stromal demarcation line after two different protocols of accelerated corneal collagen cross-linking procedures using anterior segment optical coherence tomography and confocal microscopy. J Ophthalmol 2014; 2014: 981893 DOI: 10.1155/2014/981893
    PubMedGoogle Scholar
  • 123 Hashemian H, Jabbarvand M, Khodaparast M. et al. Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: a randomized controlled trial. J Refract Surg 2014; 30: 837-842
    CrossrefPubMedGoogle Scholar
  • 124 Stojanovic A, Zhou W, Utheim TP. Corneal collagen cross-linking with and without epithelial removal: a contralateral study with 0.5 % hypotonic riboflavin solution. Biomed Res Int 2014; 2014: 619398 DOI: 10.1155/2014/619398
    PubMedGoogle Scholar
  • 125 Soeters N, Wisse RPL, Godefrooij DA. et al. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol 2015; 159: 821-828.e3
    CrossrefPubMedGoogle Scholar
  • 126 Rossi S, Orrico A, Santamaria C. et al. Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking. Clin Ophthalmol 2015; 9: 503-509
    PubMedGoogle Scholar
  • 127 Al Fayez MF, Alfayez S, Alfayez Y. Transepithelial versus epithelium-off corneal collagen cross-linking for progressive keratoconus: a prospective randomized controlled trial. Cornea 2015; 34 (Suppl. 10) S53-S56
    CrossrefPubMedGoogle Scholar
  • 128 Acar BT, Utine CA, Ozturk V. et al. Can the effect of transepithelial corneal collagen cross-linking be improved by increasing the duration of topical riboflavin application? An in vivo confocal microscopy study. Eye Contact Lens 2014; 40: 207-212
    CrossrefPubMedGoogle Scholar
  • 129 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Dokumentation und Würdigung der Anhörung zum Vorbericht N15-05, Köln (2016). Im Internet: https://www.iqwig.de/download/N15-05_DWA-VB_Hornhautvernetzung-bei-Keratokonus.pdf Stand: 09.02.2017
    PubMedGoogle Scholar
  • 130 Mazzotta C, Hafezi F, Kymionis G. et al. In vivo confocal microscopy after corneal collagen crosslinking. Ocul Surf 2015; 13: 298-314
    CrossrefPubMedGoogle Scholar
  • 131 Xia Y, Liu B, Fan Z. et al. Corneal collagen fibril changes after ultraviolet a/riboflavin corneal crosslinking. Cornea 2014; 33: 56-59
    CrossrefPubMedGoogle Scholar
  • 132 El-Raggal TM. Riboflavin-ultraviolet A corneal cross-linking for keratoconus. Middle East Afr J Ophthalmol 2009; 16: 256-259
    PubMedGoogle Scholar
  • 133 Greenstein SA, Fry KL, Bhatt J. et al. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36: 2105-2114
    CrossrefPubMedGoogle Scholar
  • 134 Knappe S, Stachs O, Zhivov A. et al. Results of confocal microscopy examinations after collagen cross-linking with riboflavin and UVA light in patients with progressive keratoconus. Ophthalmologica 2011; 225: 95-104
    CrossrefPubMedGoogle Scholar
  • 135 Salomão MQ, Chaurasia SS, Sinha-Roy A. et al. Corneal wound healing after ultraviolet-A/riboflavin collagen cross-linking: a rabbit study. J Refract Surg 2011; 27: 401-407
    CrossrefPubMedGoogle Scholar
  • 136 Kymionis GD, Tsoulnaras KI, Grentzelos MA. et al. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg 2014; 40: 736-740
    CrossrefPubMedGoogle Scholar
  • 137 Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg 2014; 40: 1013-1020
    CrossrefPubMedGoogle Scholar
  • 138 Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea 2006; 25: 1057-1059
    CrossrefPubMedGoogle Scholar
  • 139 Doors M, Tahzib NG, Eggink FA. et al. Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol 2009; 148: 844-851.e2
    CrossrefPubMedGoogle Scholar
  • 140 Asri D, Touboul D, Fournié P. et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011; 37: 2137-2143
    CrossrefPubMedGoogle Scholar
  • 141 Kampik D, Koch M, Kampik K. et al. Kollagenvernetzung mittels Riboflavin und UV-A-Strahlung (CXL) bei Keratokonus: Zwei-Jahres-Ergebnisse. Klin Monatsbl Augenheilkd 2011; 228: 525-530
    Article in Thieme ConnectPubMedGoogle Scholar
  • 142 Ivarsen A, Hjortdal J. Collagen cross-linking for advanced progressive keratoconus. Cornea 2013; 32: 903-906
    CrossrefPubMedGoogle Scholar
  • 143 Pecorella I, Appolloni R, Tiezzi A. et al. Histological findings in a failed corneal riboflavin-UVA collagen cross-linking performed for progressive keratoconus. Cornea 2013; 32: 191-195
    CrossrefPubMedGoogle Scholar
  • 144 Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25: S824-S828
    CrossrefPubMedGoogle Scholar
  • 145 Kato N, Konomi K, Saiki M. et al. Deep stromal opacity after corneal cross-linking. Cornea 2013; 32: 895-898
    CrossrefPubMedGoogle Scholar
  • 146 Messmer EM, Meyer P, Herwig MC. et al. Morphological and immunohistochemical changes after corneal cross-linking. Cornea 2013; 32: 111-117
    CrossrefPubMedGoogle Scholar
  • 147 Javadi M-A, Feizi S. Sterile keratitis following collagen crosslinking. J Ophthalmic Vis Res 2014; 9: 510
    CrossrefPubMedGoogle Scholar
  • 148 Koppen C, Vryghem JC, Gobin L. et al. Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus. J Refract Surg 2009; 25: S819-S823
    CrossrefPubMedGoogle Scholar
  • 149 Mangioris GF, Papadopoulou DN, Balidis MO. et al. Corneal infiltrates after corneal collagen cross-linking. J Refract Surg 2010; 26: 609-611
    CrossrefPubMedGoogle Scholar
  • 150 Arora R, Jain P, Gupta D. et al. Sterile keratitis after corneal collagen crosslinking in a child. Cont Lens Anterior Eye 2012; 35: 233-235
    CrossrefPubMedGoogle Scholar
  • 151 Rodríguez-Ausín P, Gutiérrez-Ortega R, Arance-Gil A. et al. Keratopathy after cross-linking for keratoconus. Cornea 2011; 30: 1051-1053
    CrossrefPubMedGoogle Scholar
  • 152 Ghanem RC, Netto MV, Ghanem VC. et al. Peripheral sterile corneal ring infiltrate after riboflavin-UVA collagen cross-linking in keratoconus. Cornea 2012; 31: 702-705
    CrossrefPubMedGoogle Scholar
  • 153 Camesasca FI, Vinciguerra P, Seiler T. Bilateral ring-shaped intrastromal opacities after corneal cross-linking for keratoconus. J Refract Surg 2011; 27: 913-915
    CrossrefPubMedGoogle Scholar
  • 154 Thorsrud A, Nicolaissen B, Drolsum L. Corneal collagen crosslinking in vitro: inhibited regeneration of human limbal epithelial cells after riboflavin-ultraviolet-A exposure. J Cataract Refract Surg 2012; 38: 1072-1076
    CrossrefPubMedGoogle Scholar
  • 155 Vimalin J, Gupta N, Jambulingam M. et al. The effect of riboflavin-UV-A treatment on corneal limbal epithelial cells – a study on human cadaver eyes. Cornea 2012; 31: 1052-1059
    CrossrefPubMedGoogle Scholar
  • 156 Labiris G, Sideroudi H, Angelonias D. et al. Impact of corneal cross-linking combined with photorefractive keratectomy on blurring strength. Clin Ophthalmol 2016; 10: 571-576
    PubMedGoogle Scholar
  • 157 Kozobolis V, Gkika M, Sideroudi H. et al. Effect of riboflavin/UVA collagen cross-linking on central cornea, limbus and intraocular pressure. experimental study in rabbit eyes. Acta Medica (Hradec Kralove) 2016; 59: 91-96
    PubMedGoogle Scholar
  • 158 Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009; 35: 588-589
    CrossrefPubMedGoogle Scholar
  • 159 Garcia-Delpech S, Díaz-Llopis M, Udaondo P. et al. Fusarium keratitis 3 weeks after healed corneal cross-linking. J Refract Surg 2010; 26: 994-995
    CrossrefPubMedGoogle Scholar
  • 160 Zamora KV, Males JJ. Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report. Cornea 2009; 28: 474-476
    CrossrefPubMedGoogle Scholar
  • 161 Kymionis GD, Portaliou DM, Bouzoukis DI. et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007; 33: 1982-1984
    CrossrefPubMedGoogle Scholar
  • 162 Eberwein P, Auw-Hädrich C, Birnbaum F. et al. Hornhauteinschmelzung nach Cross-Linking und tiefer lamellärer Keratoplastik („DALK“) bei Keratokonus. Klin Monatsbl Augenheilkd 2008; 225: 96-98
    Article in Thieme ConnectPubMedGoogle Scholar
  • 163 Wollensak G, Spoerl E, Wilsch M. et al. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg 2003; 29: 1786-1790
    CrossrefPubMedGoogle Scholar
  • 164 Kymionis GD, Portaliou DM, Diakonis VF. et al. Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. Am J Ophthalmol 2012; 153: 24-28
    CrossrefPubMedGoogle Scholar
  • 165 Bagga B, Pahuja S, Murthy S. et al. Endothelial failure after collagen cross-linking with riboflavin and UV-A: case report with literature review. Cornea 2012; 31: 1197-1200
    CrossrefPubMedGoogle Scholar
  • 166 Sharma A, Nottage JM, Mirchia K. et al. Persistent corneal edema after collagen cross-linking for keratoconus. Am J Ophthalmol 2012; 154: 922-926.e1
    CrossrefPubMedGoogle Scholar
  • 167 Cagil N, Sarac O, Can GD. et al. Outcomes of corneal collagen crosslinking using a customized epithelial debridement technique in keratoconic eyes with thin corneas. Int Ophthalmol 2016; 37: 103-109
    PubMedGoogle Scholar
  • 168 Lange C, Böhringer D, Reinhard T. Corneal endothelial loss after crosslinking with riboflavin and ultraviolet-A. Graefes Arch Clin Exp Ophthalmol 2012; 250: 1689-1691
    CrossrefPubMedGoogle Scholar
  • 169 Vinciguerra P, Camesasca FI, Romano MR. Corneal crosslinking and lens opacity. Ophthalmology 2011; 118: 2519.e1-e2
    PubMedGoogle Scholar
  • 170 Goldich Y, Marcovich AL, Barkana Y. et al. Safety of corneal collagen cross-linking with UV-A and riboflavin in progressive keratoconus. Cornea 2010; 29: 409-411
    CrossrefPubMedGoogle Scholar
  • 171 Poli M, Cornut P-L, Balmitgere T. et al. Prospective study of corneal collagen cross-linking efficacy and tolerance in the treatment of keratoconus and corneal ectasia: 3-year results. Cornea 2013; 32: 583-590
    CrossrefPubMedGoogle Scholar
  • 172 Marino GK, Torricelli AAM, Giacomin N. et al. Accelerated corneal collagen cross-linking for postoperative LASIK ectasia: two-year outcomes. J Refract Surg 2015; 31: 380-384
    CrossrefPubMedGoogle Scholar
  • 173 Bamdad S, Sedaghat M, Bagheri M. et al. Changes in corneal topography and biomechanical properties after collagen cross linking for keratoconus: 1-year results. Middle East Afr J Ophthalmol 2015; 22: 212-219
    CrossrefPubMedGoogle Scholar
  • 174 Hayes S, Kamma-Lorger CS, Boote C. et al. The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. PLoS One 2013; 8: e52860
    CrossrefPubMedGoogle Scholar
  • 175 Vetter JM, Brueckner S, Tubic-Grozdanis M. et al. Modulation of central corneal thickness by various riboflavin eyedrop compositions in porcine corneas. J Cataract Refract Surg 2012; 38: 525-532
    CrossrefPubMedGoogle Scholar
  • 176 Gokhale NS. Corneal endothelial damage after collagen cross-linking treatment. Cornea 2011; 30: 1495-1498
    CrossrefPubMedGoogle Scholar
  • 177 Richoz O, Schutz JS, Pajic B. et al. Crosslinking for recurrent keratoconus. Ophthalmology 2012; 119: 878-878.e2
    PubMedGoogle Scholar
  • 178 Jordan C, Patel DV, Abeysekera N. et al. In vivo confocal microscopy analyses of corneal microstructural changes in a prospective study of collagen cross-linking in keratoconus. Ophthalmology 2014; 121: 469-474
    CrossrefPubMedGoogle Scholar