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    Bettis. Corneal Collagen Cross-Linking For Nonectatic Disorders. A Systematic Review

    Uploaded by

    Javier Infantes Molina

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    © All Rights Reserved
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    Corneal Collagen Cross- inking for Nonectatic Disorders: A Systematic Review Daniel |. Bettis, MD; Maylon Hsu, MD; Majid Moshirfar, MD ABSTRACT PURPOSE: To provide a background regarding the bio Chemical rationale for corneal collagen cross-linking (CX) and autine ts curent use, ertically evaluate the current Iterature forthe use of CXL in noneetatie disor ders, highlight imitations and areas for further research, ‘and address adaitional novel applications of CXL. METHODS: A literature search was performed using the EMBASE and MEDLINE database from 1970 to November 2011. Keywords included “comeal collagen 105s linking,” “crosslinking,” “cross-inking,”_ “ultra Violet,” “ibofiavin,” “corneal edema,” and “keratitis” in Varios combinations. A search through the references. of retneved articles was also performed. RESULTS: Cross-linking for comeal edema showed 3 temporary improvement in objective measures of cen- tral comeal thickness, corrected distance visual acuity, ‘and corneal clarity along with subjective measures such {8 pain and imitation. Cross-linking was also tolerated {8 an adjunctive therapy for infectious keratitis without ‘complications. In all studies, the progression of comeal ‘melting was halted ater treatment, avoiding the need. Tor emergency keratoplasty CONCLUSIONS: Cross-inking with riboflavin and uitra- Violet A light is @ promising, minimally invasive treat. ‘ment for comeal ectasia. A growing number of studies. suggest additional application in comeal edema and Infectious keratts may be beneficial. However, further Studies are needed to adress long-term outcomes and. Safety concems. J Refract Surg. 2012;28(11):798-807,] i:10.3028/1081507%-20121011.00 orneal collagen cross-linking (CXL) is a novel tech: nique using the photosensitizer riboflavin (vitamin B2) and ultraviolet A (UVA) irradiation at 370 nm lent bonds between amino groups ity up to Although CXL is increasingly recognized as a viable treatment for corneal ectatic. disor ders, less known are its applications in nonectatic dis- orders such as corneal edema and infectious keratitis. The purpose of this review is to provide a background regarding the biochemical rationale for CXL. and outline its current use, critically evaluate the current literature for the use of CXL in nonectatic disorders, highlight limitations and areas for further research, and briefly address additional novel applications of CXL. METHODS A literature search was performed using the EMBASE and MEDLINE database from 1970 to November 2011. Keywords included “corneal collagen cross linking,” “crosslinking,” “cross-linking,” “ultraviolet.” “riboflavin,” “comeal edema,” and “keratitis” in various combinations. A search through the roferonces of retrieved articles was also performed BACKGROUND Collagen functions as an important support. structure throughout the human body and nature at large. Collagen fibrils are further strengthened by the formation of intrahe- lical or interhelical cross-links within or between tropocol- lagen units. This may occur as part of normal development, From the University of Utah, John A. Moran Eye Genter, Department of (Ophthalmology and Visual Sciences, Sat Lake (ity. Utah. Funding obtained from the Research fo Prevont Blindn York, New York) Foundation (New Tho authors have no financial or proprietary intrest in tented heron, materials pro- Correspondence: Majd Moshifar, MD. John A. Moran Bye Conte, 65 Mario Gapecehi Dr, Salt Lake City, UT a132. Tel: 801.587 3020; Fax: 801. Esme: mod. moshinforahsc utah ed eceived: May 2,2012; Accepted: September 11, 2012 798 ‘Copyright © SLACK Incorporated Comeal Collagen CXL for Nonectatic Disorders/Bettis et al the aging process,7" disease states such as diabetes," or secondary to oxidation mediated by reactive oxygen species or photooxidation (UV-light mediated). In- duction of collagen cross-links has wide applications, in other industries, from tanning leather to synthetic, polymer chemistry. In fact, it was a dentist who used, UY irradiation to harden a synthetic filling material that led to the serendipitous inspiration to apply a similar process to stiffen the human cornea."* The phonomenon of collagen cross-linking after UVA light exposure was reported by Klingman and Gobre"? in 1991, when they observed biochomical changos in the skin of hairless mice after chronic UVA radiation exposure. Those changes rendered collagen highly re- sistant to pepsin digestion, indicating increased col- lagen cross-linking." Spoor! ot al first induced CXL in porcine eyes in 1907. Aftor epithelial removal, corneas treated with riboflavin and UVA light, glutaraldehyde, and Karnovsky solutions (0.1% glutaraldehyde, 0.1% paraformaldehyde, 0.1 m sodium phosphate buffer pH 7.4) all showed a significant increase in corneal stiffness. Using in vivo studies of rabbit eyes, only riboflavin/UVA showed sufficient promise for explora- tion in pilot human studies."* Human studies for use in Keratoconus began in Dresden, Germany in 1998, with the results published in 2003.2" In follow-up laboratory riboflavin/UVA cross-linkage was shown to increase stress-strain measurements, reduce swelling rates, raise hydrothermal shrinkage temperature, and increase resistance against enzymatic degeneration (pepsin) of corneal stromal *” Furthermore, animal and human longitudinal studies indicate that, this increase in biomechanical stability may be stable over time.**™" In 2009, the United States Food and Drug, Administration approved clinical trials evaluating the use of CXL, and phase Il trials are ongoing. Biochemically speaking, when the riboflavin- saturated cornea is exposed to UV irradiation, the ribo- flavin molecule fuoresces and becomes excited into a triplet state with subsequent generation of singlet oxygen and superoxide anion radicals.*" Although the precise mechanism of corneal CXL is still under in vestigation, many researchers believe these reactive oxygen species may act in conjunction with activated riboflavin or the UVA itself to induce intra- and/or interhelical cross-links. Additional linkages and/or modifications to glycosaminoglycans may also be in- volved. The use of riboflavin as a photosensitizer fur- ther ensures the cornea absorbs up to 95% of the UVA irradiation, as opposed to 32% without riboflavin." In addition to maximizing the in situ therapeutic benefit, of CXL, this also helps prevent damage to deeper ocu- lar structures such as the corneal endothelium, lens, and retina,*### CURRENT USE Corneal CXL with riboflavin and UVA has been pre- dominately used to treat comeal ectasia, including that present in keratocomus,*"* pellucid-marginal degener- ation,#*#" and keratectasia induced by laser refractive surgery.*7® Corneal CXL. has further been combined with other modalities, including intrastromal corneal ring segments.""* conductive keratoplasty," and pho- torofractive keratectomy."*** For a growing number of pationts, those treatments have delayed or obviated the noed for keratoplasty. ‘The technique, efficacy, safety, and contraindications of CXL for these diseases have boon described elsowhere.**"25 ‘Table 1 presents a of reported postoperative complications of GXL#°2" Intorestingly, Koller ot al noted that restricting pationt ago to <35 years reduced the complication rate to 1% when treating keratoconus with CXL. Although CXL is increasingly accepted for use in comeal ectasia, the potential use for noneotatic disorders, in particular corneal edema and refractory infectious keratitis, are currently being explored. CXL IN CORNEAL EDEMA STATES Without sufficient endothelial pump function, as can occur with aphakic or pseudophakic bullous kero- topathy or Fuchs endothelial dystrophy, the cornea swells as fluid accumulates in the extracellular spaces between collagen fibers and lamellae. ‘This disrupted architecture affects corneal transparency and leads to light scatter and reduced visual function, Over time, this fuid may percolate to the epithelium, a formation of painful bullae and profound vision loss due to disruption of the optically critical airtear film interlace.*® Current treatment options include topical hypertonic solutions,» therapeutic soft contact lenses,* anterior stromal cauterization, anterior stro- ‘mal puncture with or without yttrium-aluminum-gar- net laser,”*" phototherapeutic keratectomy,” conjunc tival flaps, and amniotic membrane transplantation.°" Ultimately, endothelial dysfunction with significant, ‘morbidity is a leading indication for corneal transplant worldwide.*™® Theoretically, the stromal compaction observed with CXL™ could lead to improved optical function in edematous corneas. ‘After initially noting the dehydrating effect of inking on porcine corneal tissue, Wollensak et al examined whether this could be applied to three patients with bullous keratopathy. To combat the dif- ficulty of penetrating thickened corneas, the authors implemented a two-step approach, applying topical glycerin for 1 day to dehydrate the cornea followed. by CXL to stabilize the stroma. It was hoped that the additional intra- and interfibrillar chemical bonds would increase resistance to further osmotic and Journal of Refractive Surgery + Vol 28, No, £4, 2042 i) Corneal Collagen CXL for Nonectatic Disorders/Bettis et al TABLE 1 Reported Postoperative Complications of Cross-linking ‘comes hae De lariat? Comes caning! Stee initratest Reactvation of hemes Herat! Infectous Keratus atrbuted to bacteria" Acanthamoeba, ** ‘and herpes simplex virus hydrostatic fluid accumulation, particularly in the anterior 350 ym of the cornea." The study showed decreased pain, improved visual acuity in the patient, without stromal scarring, and a mean decrease in cen- tral corneal thickness (CCT) by 90.33 ym at 3 days and. 93.67 ym at 8 months.* Sinco this initial study, eight similar studies have reported their results (Table 2). Overall, the study mothodologies, in terms of inclusion and exclusion criteria, treatment parameters, outcome measures, and analysis are highly variable. Howovor, nearly all, of tho studies show at least a temporary improvement in objective measures such as CCT, corrected distance ial acuity (CDVA), and corneal clarity along with subjective measures such as pain and irritation.**?* The corneal thickness that accompanies these edema states impedes delivery into deoper corneal tissue, 80, corneal thinning prior to CXL may improve results in these patients. Various strategies have been employed, the most common being empiric treatment with top’ cal glycerin or dextran." In the treatment of three patients with early Fuchs dystrophy, Hafezi et al” took @ more controlled approach, applying glycerol 70% to comeas thicker than 450 jum until a target corneal thickness of 370 to 430 ym was reached prior to ira- diation, This strategy not only decreased CCT, but also reduced the diurnal fluctuation in visual acuity that of- ten accompanies this disease. Krueger etal" developed an alternative method of CXL following staged intra- stromal riboflavin administration using laser and eye bank corneas. Two consecutive comeal pockets (350- and 150-um depth) were created using a femtosecond laser. Sequential intrastromal injections of 0.1% ribo- flavin followed by UVA irradiation (15 mW/cm*) for 7 minutes were performed for each pocket. In vitro, this method demonstrated improvement based on a subjective Corneal Clarity Score (range: 1) very opaque comea/difficult to visualize underlying structures, 2) relatively opaque cornea/some visualization of un- derlying structures, 3) diffuse corneal edema with rela- tive clarity to visualize underlying structures, and 4) clear cornea). It also showed an average decrease in CCT of 273 pm (P=.0004) in five eye bank comeas com- pared to controls. Applied to one patient with pseudo- phakic bullous keratopathy, pain symptoms improved, CCT decreased from 675 to 550 jam, CDVA improved from counting fingors to 20/80, and corneal transplan- tation was postponed for >6 months." Unfortunately, CXL cannot address the root cau of edema, which in most cases is endotholial dysfui tion, Recurrence of swelling is commonly observed, manifesting anywhere from 3 to 8 months postop- ratively. Bottés ot al” used immunofluorescence to examine the effect of CXL on stromal fibril organiza- tion in corneal buttons from 7 patients who under- wont penotrating keratoplasy for corneal edema 7 to 90 days aftor CXL treatment. ‘They showed histologic evidence of collagen fiber organization even in cases with advanced bullous keratopathy and stromal fibro- sis, although to a lesser degree than cases treated in initial stages of disease. They demonstrated that the CXL effect began 1 week after treatment but had de- creased by 3-month follow-up. In c Ehlers and Hjortdal® reported 10 of 11 patients with varying, levels of endothelial decompensation showed a reduc- tion in CCT over several weeks following CXL. How- ever, 4 patients required retreatment, and several oth- ers showed a longer term increase in thickness over the follow-up period. Ghanem et al studied 14 eyes with painful pseudophakic bullous keratopathy, again finding limited duration of efficacy, Corneal transpar- ency was improved in all patients at 1 month, but by 6 ‘months this effect had regressed to pretreatment levels, in 9 eyes, Mean CCT decreased from 747 um to 623 am. at 1 month (P<,001) and 710 ym at 6 months (P=.006). All patients had a recurrence of microbullae, and 11 had macrobullae. All but 1 patient required therapeutic contact lenses for adequate pain control. Cordeiro Bar- bosa et al” further studied pachymetric changes in 25 eyes for 6 months following CXL for corneal edema. Central comeal thickness at 6-month follow-up had. increased >50 wm over preoperative CCT. Fourteen, (66%) patients developed new epithelial bullae after 3 months. Currently, CXL appears unlikely to supplant pen- etrating keratoplasty or Descemet stripping endothe- lial keratoplasty as the treatment of choice for corneal edema, the latter of which can definitively provide both sual rehabilitation and relief of symptoms. However, CXL. appears to be a minimally invasive treatment capable of transient improvement in CCT and pain symptoms. Apart from occasional delays in reepithe- lialization,”* there appear to be limited complications. Only one case of crystalline keratopathy was observed ‘Copyright © SLACK Incorporated Comeal Collagen CXL for Nonectatic Disorders/Bettis et al TABLE 2 ‘Studies Evaluating CXL for Corneal Edema No, of Type of —Pationts Follow-up Study 6) Study (Eyes). ‘Treatment Regimen (mo) Findings Woilensak et a® Case series 3(3) __Dehycrated wth topical goer 40% for 8 Decreased CCT, improvement of (2008) ‘one day, flamed by conventional CXL butous changes, ess parviscorfr, increased VA n case Without searing ruoger et lS Case report’ 1.(2) Two consecutive CXL weatrnents ater 6 Improved pai, reduced Cor, (2008) staged inastromalriboavin administration increased Comeal Clary Sore, sing femtosecond laser improved CDVA, postponement of twansplant Ehlers & Horta” Case senes 11 (14) Conventional CXL witout prior >3_ Redo OOF, improved VA 3 patents, (2008) ‘erycraton ossble nga reduced eect Gada et aI Case series 12 (12) CConwentonal CXL without prior 2 No signifcan improvement in VA or (2000), 450 ym 3_—Modiied CXL reduced comes! edema (2010) unt thickness of 370 t 430 gm prior 0 CXL. ‘and dumal visual fuctuation in eaty Fuchs dystopty Boss otal Caso contol 13 (14) _ Rboftvn 0.1% with dextran 20% for NA CX promoted increased coliagon (2010) 30 minutes followed by convertonal CXL ‘ber organzaton, even in vanced Dullous keratopathy; decreased effect ‘observed at 3 months Gharace otal Case sores 20 (20) Comentional CXL without pror detydrton 6 _~——CXL was not effective wit respect to aot) VA and CCT, although it may improve irtation and discomfort ‘GL = cameo! eoseinking CCT = cena eomeal Oise, VA visa acu, CDNA = coneced ata veal SoaKy by Cordiero Barbosa et al,” but this may have been attributable to chronic steroid use from prior pen- ctrating keratoplasty. Although a number of strategies may be employed to help increase penetration of CXL therapy in swollen corneas, CXL may ultimately prove better suited for less advanced edema”? CXL FOR REFRACTORY INFECTIOUS/ ULCERATIVE KERATITIS Bacterial keratitis is a cause of significant morbidity worldwide and can cause rapid and devastating vision loss. Although treatment of keratitis with topical anti- ‘microbial agents has been mostly successful, patterns of emerging resistance’*”? have prompted an ongoing, search for new agents capable of rapid and complete microbe eradication with minimal side effects. Studies, as early as the 1960s and 1970s demonstrated that, riboflavin exposed to UV light could inactivate viruses, and bacteria.’” In fact, this technology has been widely used to disinfect water and sterilize blood products prior to transfusion.”””* Riboflavin/UVA therapy is now reemerging as a possible modality to help address the growing problem of resistance through a variety of proposed mechanisms (Fig)."*77"8 Many studies have demonstrated a wide spectrum of CXL in vitro antimi- crobial activity (Table 3).”"** ‘Table 4 outlines the clinical studies evaluating CXL for refractory infectious/ulcerative keratitis. ‘These be- gan in 2000, when Schnitzler et al® reported 4 cases of noninfectious corneal melt, finding that a single ses- sion of CXL resulted in complete healing in 2 cases and delayed the need for emergency surgery in the other 2 cases. Iseli et al" later reported 5 patients with refrac- tory infectious keratitis who underwent therapeutic, CXL as an adjunct to standard antimicrobial therapy. ‘The areas of epithelial debridement were tailored to include removal of all microbial infiltrates. In 4 of 5 cases, the infiltrate size and melting process imme- diately regressed after CXL, although 4 of 5 patients ultimately required lamellar or full-thickness comeal, Journal of Refractive Surgery + Vol 28, No, £4, 2042 Corneal Collagen CXL for Nonectatic Disorders/Bettis et al Figure. Pepsed mechanisms of cross-linking antimicrobial eect, grafts for residual scarring. Micolli Ferrari ot al" do- soribed a patient with treatmont-rosistant Escherichia coli keratitis who underwont CXL in addition to topi- cal and systemic antimicrobial therapy. One day post operatively, the ulceration was covered by cicatricial tissue, and the patient reported significant improve- ment in symptoms. One month later, corneal edema was almost resolved, corneal ulceration was healed, and painful symptoms had disappeared, Makdoumi et al” reported 7 eyes with severe infectious kerati- tis treated with CXL, Corneal melting was present in all cases. All but 1 patient received topical antibioti treatment in addition to CXL, In all but 1 eve, patient experienced improvement in symptoms such as epiph- ora, photophobia, and pain within 24 hours. Comeal melting was arrested and complete epithelialization was achieved in all cases. In contrast, Ehlers et al" re- ported 14 eyes with non-healing infectious and non- infectious ulcers, all treated with CXL and followed for at least 3 months. Six eyes demonstrated epithelial healing, whereas 8 showed no clear effect. Despite the lack of in vitro data supporting CXL against Acanthamoeba, Khan et al” described three cases, unresponsive to multidrug conventional therapy, that were successfully treated with two 30-minute ses- sions of adjunctive CXL. Patients showed a rapid re- duction of pain, photophobia, and ulcer size aftor the first treatment session, Ancillary signs of inflammation mostly resolved after the 2 wooks later. Uleers were closed within 3 to 7 weeks of the first application. wo patients still required pen- etrating keratoplasty for dense central corneal seat Histopathology showed excised tissues free of Acan- thamoeba organisms, and neither patient demonstrated recurrence. Morén et al reported another patient with presumptive Acanthomoeba keratitis, progressing de- spite broad-spectrum antibtiotics, who was treated with CXL, Reepithelialization started within a few days, and after 2 months the wound had healed completely. Nine ‘months later, CDVA was 20/30. One study highlights the potential for CXL in patients who have both corneal edema and infectious keratitis. Kozobolis et al” reported two cases of bul- lous keratopathy with gradually deteriorating, cen- tral corneal ulcers despite intense antibiotic therapy. Within 24 hours of a single 30-minute treatment of CXL, both patients reported significant subjective improvement in visual acuity and ocular discomfort. Reepithelialization was complete within 1 week for both cases. Two months later, both haze and corneal, thickness had decreased (from 641 and 714 um to 595 and 635 um, respectively)."! ‘Although the clinical evidence for using CXL to treat infectious keratitis is not as robust as that for ectasia or edema, it is encouraging. Cross-linking was tolerated as an adjunctive therapy without complication, and in all cases, the progression of corneal melting was halted after treatment, avoidling the need for emergency kera- toplasty. This benefit should not be underestimated, as emergent penetrating keratoplasty tion rates as high as 15% and rejection rates 38%." With standard keratoplasty these rates are less ‘Copyright © SLACK Incorporated Comeal Collagen CXL for Nonectatic Disorders/Bettis et al ‘a ey sos pi08009 = wc Buns eouo> = 1) Suunaos wy wercaue e9UIco ands: suaned z sovaunes ‘saan J ob € UM posop S10 pede sj90H 21 T !eungan puooes 12ye paNosay fasow worse eas 129 ue ‘ue2 Laur "u9wepigep Ou pooeds suoss2s wowi09n avNUR-Ce om (pawnsoud r ‘pauuyue9 2) ‘r@pyseUd ‘ued Ui Uonanea! PRY ZT Oy ‘hveuaeen sxnounipy egooueynu0%y (©) SVE" 2600 (F102) 229 UD » wounean anwurce ous (orca) Pe UMA AUEODU mews —_Z ‘vauae=n @Anounipy angeou ‘suipun snovdsordans — @) zz seues se] go 10 ION, siquow 6 18 oe/0z waa wouaeen amnuRroe BUR ‘auDe Ug eo "papnuop fee unyoxgice (oro2) uoqezereunisoy = g "uaugean axnounioy eqeoweyiueny pownsaig ——() Todas ase cele 19 UBIO uo 1a sofa z (@) axmyno ou ‘rnesou ;poplone AgBin 1u980w9 S256 Ul wounean aywurce oBuE “eavanyu) sniydowoeH Posotuce voueajerende aiaehuoo pul "ueulapidep (200) ‘eun2e efaeOW alsaue Yeu ound waned 2 40 9 saseo 1409 sipuuepde snoannoitydes ‘oror) Usinoy fz UMA SuCLTLNS paroxdL QOL T Uy uountean atnounfoy "snaune snooceoyides (D9 seuss 2689.18 TOE pateajonua z payestoz ‘evenuew opoRwe Gm psI29a (6) poypodsun ‘woyosns zp Mejeunp oaya zap ou panous @ waunean enuurge Bus %@) eqsowequeay “Ruppoy Plouide poyensuowlsp se 9 =e mot sous o8e9 ‘@yusta eau 01 anp paonpa1) uo + fa pojeay wouean eywin's opus “euopo feau0d Jo waWse%odwy pue "uaulopixop (200) uaumrosdus onewoKIUS UEONBS suauaeon saneunipy yo euso4o%3 (Todor 9809 suo) ytuo> a8epueq unas oe sxBury sneueens ‘2evojeup wnyoaeqaotW ‘unpesny (2) wnustzoqoahn, pepo payey Bunjau e809 6 OT snoynausqrsUon (2s seven ase ofoap Aare soto y yo ew (oooe) Buyout jeauoo 10 voweaideis (sn0392]uU0NI VIN fr) _seuas 2629 te Y9 EIS supa wouiiay wouneen Tehusetio 0.003 (eats) Aoi Wins ‘swonea 0 0441 1-0N SHAEIOY OAHeIOD/N/SNORIaIu K10;Dej9Y 405 1X9 SUNEN|EAT SOIPMS [EOIUTD pmavi Journal of Refractive Surgery + Vol 28, No, £4, 2042 Corneal Collagen CXL for Nonectatic Disorders/Bettis et al than 10%."* Cross-linking also carries the theoretical benefit of not furthering and perhaps bypassing antibi: otic resistance, making it especially beneficial in cases, refractory to standard treatment or in cases where re- sistance is strongly suspected. Additionally, CXL may potentially bypass compliance concerns with compli- cated antimicrobial regimens. Nonotholess, CXL for keratitis is not without un- cortainty. Although most of the provious «i doomed refractory to standard treatment, the ol clinical improvement is difficult to attribute to CXL, alone given ongoing or recent intensive antimicrobial, therapy. Furthermore, as the effect of CXL appears concentrated within the anterior 300 to 350 yun of the comea, use with deoper penetrating infections may have limited efficacy. Conversely, pationts with significant stromal thinning may have pachymotry =400 jum, which is often considered the minimum CCP n lo endothelial damage. Additionally, any infectious opacity or fibrosis may also theoretically block UVA penetration and limit effectiveness. Although CXL for bacterial keratitis ap- pears effective with a single treatment in the above studies, there are currently no clear criteria for retreat- ment, Moreover, additional risks associated with re- peat CXL are unknown, Cross-linking itself has been associated with infectious keratitis attributed to bacte- ria,4” Acanthamoeba," and herpes simplex virus.*® However, this risk is likely increased by corneal epi thelial defects from debridement and/or the use of bandage soft contact lenses for control of postopera- tive discomfort.”” Nevertheless, it may be prudent to document herpes simplex virus polymerase chain re- action negativity prior to initiating treatment. Cross- linking has been shown to induce a transient dropout, of Keratocytes in the treated anterior corneal stroma, lasting 4 to 6 weeks." The effect on wound healing is unknown, Further study is needed to help address, these concerns. Until more data are available, CXL for the treatment of keratitis should only be considered in therapy-resistant keratitis or ulceration. OTHER NOVEL APPLICATIONS OF CXL Application of CXL is currently being explored in a number of other settings, including ocular tissues, apart from the cornea. For instance, Wollensak et al" showed cross-linking scleral collagen in rabbits was, effective in increasing scleral mechanical strength, postulating this may represent an option in the treat- ment of progressive axial myopia. However, over- all dosage would need to be reduced to avoid retinal cytotoxic effects. Thornton et al later demonstrated that stiffening peripapillary sclera in pigs reduces the biomechanical sensitivity of the optic nerve/lamina cribrosa complex to intraocular pressure elevation, bringing hope as a possible future treatment for low. tension glaucoma." DISCUSSION Although the case series outlined validate the use of CXL as an adjuvant therapy, randor are noeded 10 « id control trials mpare CXL to the standard of care standardized protocol for ng CXL for its different indications is also needed, particularly regarding duration and number of troatmont sessions required. Currently, other meth- inkago aro under investigation, i flash-linking” and protocols using gluteraldehyde or glycoaldohyde."*™ It will be intriguing to soo these ap- pliod, as it may prove that separate protocols may be more or loss beneficial for differont indications. Although CXL appears to be woll tolerated, a paucity oflong-torm safety data remains. Of note, itis unknown over time how CXL may affect ocular parameters such as tear function and corneal sensitivity or what altera- tions it may induce in conjunctival epithelium, goblet and coll . Patients should le increasing occur- surface limbal stem ¢ be monitored long-term for po: rence of metaplastic disorders of the ocular surface.°* Furthermore, it is unknown if or to what extent CXL. may affect absorption of topical medications. As CXL. is also a naturally occurring phenomenon,” there is some concern as to the additive effect of induced CXL, in patients with diabetes, or as patients age. Several studies have shown a limited duration of effect when using CXL for comeal edema." Because the tumn- over rate of stromal collagen fibers is several years, long-term stability of treatment effect in other disease states is yet to be verified. Collagen cross-linking with riboflavin and UVA light is a promising, minimally invasive treatment for comeal ectasia, A growing number of case reports sug- gest additional application in corneal edema and infec~ tious keratitis may be beneficial. However, more studies are needed to standardize the most efficient approach in these settings and to address long-term outcomes. AUTHOR CONTRIBUTIONS. Study concopt and design (DLB., ML, MM); data collection (DB); analysis and interpretation of data (D.LB): drafting of the manuscript (D.LB.);ertical revision ofthe manuscript (DILB., MHL MAM); supervision (MM) REFERENCES 1. Spoor E, Huhlo M, Soler. Induction of eross- links in corneal tissue. Exp Bye Hes. 1008;66(1):97-103 2, Wollensak G, Spoerl B, Seller T.. Ribollavin/altaviolet induced collagen crosslinking forthe woatment of keratoconus, ‘Am J Ophthalmol. 2003;135(5):620-627 Es ‘Copyright © SLACK Incorporated Comeal Collagen CXL for Nonectatic Disorders/Bettis et al 1. 16, 16 1 0 20, 21. Ashwin PI, McDonnell PJ. Collagon cross-linkage: a com- prehensive review and directions for future research, Be J Ophthalmol. 2010;94{8) 965-970. 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