collagen cross - linking ( cxl ) has been employed for many years as a means of stabilizing cornea ectasia [ 1 , 2 ] . among the multitude of treatments and technique variations applied
, cxl has been well documented to almost invariably result in some central anterior corneal flattening [ 3 , 4 , 5 , 6 , 7 ] .
disease regression. we present herein a custom application with a novel device , enabling the topographically customizable administration of very high - fluence cxl , applied in a specific toric pattern , in order to achieve , besides ectasia stabilization , predictable corneal astigmatic changes .
this study received approval by the ethics committee of our institution , and adhered to the tenets of the declaration of helsinki . written informed consent
we report herein a case of a 6-month postoperative evaluation of an innovative customized toric application of transepithelial cross - linking . the patient was a 37-year - old female with a preoperative clinical diagnosis of progressive moderate keratoconus of the left eye , minimum corneal pachymetry of 450 m , and uncorrected distance visual acuity ( udva ) between 20/32 and 20/25 .
the patient was enrolled due to keratoconus progression noted over the previous year . in the past , the patient 's other eye ( right ) had a more evident keratoconic manifestation and had been treated a few years ago with the athens protocol procedure [ 8 , 9 ] .
the left eye was not treated at that time due to the patient 's age and because it was less affected ; however , the progression , in combination with the patient 's desire for quick visual rehabilitation played a role in the decision to treat this keratoconic eye with this novel approach .
the riboflavin penetration through the intact epithelium ( transepithelial ) into the stroma involved a two - step process .
the manufacturer cautions against administering paracel for over 4 min to minimize the risk of epithelial sloughing .
the second step was the application of vibex xtra ( avedro inc . ) , 0.25% riboflavin isotonic saline solution .
application time was 6 min , with a drop every 30 s. with this two - step soaking process , the riboflavin passage to the anterior chamber was approximately complete in 10 min .
the kxl ii cross - linking system ( avedro inc . ) was employed for the uva exposure . following alignment and focusing by the surgeon ,
the toric treatment pattern and orientation relative to the astigmatic axes were investigated in preclinical computational modeling studies [ 10 , 11 ] . as shown in fig .
1 , the specific toric irradiation pattern had a  butterfly - wing shape , extending to 5-mm , axis oriented at 129 ( orthogonal to the steep axis of astigmatism ) , with a total energy of 14.0 j / cm applied for 10 min and 22 s. overlapped to this was a circular irradiation area extending to a 6-mm diameter , with a total energy of 4.0 j / cm applied for 2 min and 56 s. the uva power was 45 mw / cm , delivered with a pulsed mode of 1-second on and a 1-second off . during the uva irradiation ,
the cornea was moistened every couple of minutes with a drop of balanced salt solution .
the patient was postoperatively treated with a combination of antibiotic / corticosteroid drops for 10 days .
the patient was examined the first day , the first week , and every month for a total duration of 6 months . at each visit ,
the cornea was assessed with placido topography ( topolyzer vario ; wavelight , erlangen , germany ) by means of curvature maps and simulated keratometry , scheimpflug imaging ( oculyzer ii ; wavelight ) by means of curvature maps and simulated keratometry , anterior surface irregularity indices and keratoconus classification , autorefraction and keratometry ( nidek ar 1 ; nidek co. ltd .
, tokyo , japan ) , anterior segment optical coherence tomography ( oct )   ( rtvue-100 ; optovue inc . ,
usa ) providing corneal pachymetry and epithelial pachymetry maps , and endothelial cell counts measurement with a confocal specular microscopy device ( cellchek xl ; konan , irvine , calif .
the riboflavin penetration through the intact epithelium ( transepithelial ) into the stroma involved a two - step process .
the first step was the application of a paracel solution ( avedro inc . , waltham , mass . , usa ) , a slightly hypotonic specially formulated 0.25%-riboflavin solution with 0.02% benzalconium chloride .
the manufacturer cautions against administering paracel for over 4 min to minimize the risk of epithelial sloughing .
the second step was the application of vibex xtra ( avedro inc . ) , 0.25% riboflavin isotonic saline solution .
application time was 6 min , with a drop every 30 s. with this two - step soaking process , the riboflavin passage to the anterior chamber was approximately complete in 10 min .
the kxl ii cross - linking system ( avedro inc . ) was employed for the uva exposure . following alignment and focusing by the surgeon ,
the toric treatment pattern and orientation relative to the astigmatic axes were investigated in preclinical computational modeling studies [ 10 , 11 ] . as shown in fig .
1 , the specific toric irradiation pattern had a  butterfly - wing shape , extending to 5-mm , axis oriented at 129 ( orthogonal to the steep axis of astigmatism ) , with a total energy of 14.0 j / cm applied for 10 min and 22 s. overlapped to this was a circular irradiation area extending to a 6-mm diameter , with a total energy of 4.0 j / cm applied for 2 min and 56 s. the uva power was 45 mw / cm , delivered with a pulsed mode of 1-second on and a 1-second off . during the uva irradiation ,
the cornea was moistened every couple of minutes with a drop of balanced salt solution .
the patient was postoperatively treated with a combination of antibiotic / corticosteroid drops for 10 days .
the patient was examined the first day , the first week , and every month for a total duration of 6 months . at each visit ,
the cornea was assessed with placido topography ( topolyzer vario ; wavelight , erlangen , germany ) by means of curvature maps and simulated keratometry , scheimpflug imaging ( oculyzer ii ; wavelight ) by means of curvature maps and simulated keratometry , anterior surface irregularity indices and keratoconus classification , autorefraction and keratometry ( nidek ar 1 ; nidek co. ltd . ,
tokyo , japan ) , anterior segment optical coherence tomography ( oct )   ( rtvue-100 ; optovue inc . ,
usa ) providing corneal pachymetry and epithelial pachymetry maps , and endothelial cell counts measurement with a confocal specular microscopy device ( cellchek xl ; konan , irvine , calif .
the patient achieved udva of 20/32 at the first postoperative week and 20/25 at 6 months .
the patient reported no pain ( 0 on a scale of 010 ) and minimal discomfort during the procedure . during the immediate postoperative follow - up visits ,
endothelial cell counts were stable , preoperatively at 2,430 cells / mm and postoperatively at 2,400 cells / mm .
preoperative and postoperative visual acuity , pachymetry and keratometry average data are reported in table 1 .
3 illustrate examples of placido disc and scheimpflug imaging sagittal curvature preoperative , 6-month postoperative and difference maps .
a significant astigmatic reduction was noted ( on average 0.8 d ) as measured by all keratometric modalities employed in the study . topography ( fig .
3 ) , reaching a maximum of 2.5 d at the steepest preoperative location . based on the scheimpflug imaging ( amsler - krumeich criteria ) analysis , preoperatively , the cornea was classified for the topographic keratoconus classification of kc1 and the values for the anterior irregularity indices of height decentration ( ihd ) and surface variance ( isv ) were 0.039 and 43 , respectively ( fig .
poss ( possible kc ) , while the anterior surface irregularity indices of surface variance and height decentration were lower , with values of 32 and 0.024 , respectively , indicating a trend towards a more normalized cornea .
4 illustrates oct - derived corneal and epithelial thickness pachymetry maps preoperatively , at 1-week and 6-month postoperatively .
the significant refractive changes as a result of classic cxl [ 3 , 4 , 5 , 6 , 7 , 14 , 15 , 16 ] , when applying the dresden protocol ( 3 mw / cm for 30 min ) , as well as higher uva fluence , either superficially , via riboflavin placed within a femtosecond laser - created pocket or icrs channels can be established by a number of reports [ 18 , 19 ] .
such flattening , which constitutes a refractive effect resulting from differential cross - linking - induced stiffening effects , has been described by a number of clinicians as  disease regression. we have reported on the use of higher fluence cxl as an agent for refractive stabilization in high - myopic and hyperopic lasik [ 20 , 21 , 22 ] , and have also recently reported significant refractive changes in astigmatic keratotomy , when 
facilitated by the development of a customizable differential uv delivery system by avedro and the ability to perform feasibility studies with the kxl ii device , the current study provides additional evidence for the potential of patterned cxl in the deliberate treatment of refractive error .
we have recently reported in vivo , topographically regular and predictable central cornea flattening effects consistent with a correction of myopia of about 2.5 d .
the available interim data appear promising with regard to the potential for correcting low myopic refractive errors without tissue removal in an excimer - like fashion or other previously described thermal techniques combined with cxl .
myopic , hyperopic and astigmatic corrections are other novel applications that are currently under study with this technology .
the novel toric topographically customized application of cross - linking presented herein ( photorefractive intrastromal cross - linking ) employed preferential corneal flattening along the flat refractive axis .
six months postoperatively , a very specific reduction of astigmatism of 0.8 d ( reaching up to 2.5 d at certain loci ) was observed .
the epithelial remodeling maps in the first 6 months , when compared to normal eyes , suggest that there was some modest change in the epithelial distribution , with the treated area having initially a slight reduction in the average epithelial thickness , and recovering at the 6-month follow - up to a more regular distribution than the preoperative distribution .
the epithelial data suggest that the achieved refractive effect is not a result of epithelial remodeling , and thus may be attributed to direct stromal remodeling . as shown in the oct pachymetry data illustrated in fig .
4 , preoperatively , the difference between the minimum corneal thickness of 503 m to the pupil center corneal thickness of 535 m was 32 m , while 6 months postoperatively , the minimum corneal thickness was 542 m and the center corneal thickness 557 m , with a difference of 15 m . additionally , the procedure has neither an obvious corneal thinning effect nor an apparent haze following treatment .
since it is essentially performed through the intact epithelium , the procedure required minimal postoperative adjustment of the daily activities by the patient and produced essentially no pain or discomfort even within the first few hours after the procedure .
the rapid recovery and relative safety of transepithelial cxl may additionally offer the possibility to titrate the effect through two or more treatments over time as needed . as the patient is under continuous follow - up , and as more
patients are being enrolled for the procedure , we anticipate reporting on the stability of the procedure , as well as on further refinement of treatment patterns , diameter , and centration for specific topographic patterns .
we have herein introduced a novel technique based on refractive cxl application on previously untreated keratoconic cornea as a conservative management option . at 6-month follow - up , a stable reduction in astigmatism
this is a nonablative and nonincisional approach to treat irregular astigmatism in ectatic cornea with rapid visual rehabilitation .
alcon / wavelight , allegran , avedro , i - optics ; optovue ( a.j.k . ) .
 purposeto report a novel application of toric topographically customized transepithelial collagen cross - linking ( cxl ) aiming to achieve refractive astigmatic changes in a keratoconic cornea.methodsspecially formulated riboflavin transepithelial administration and delivery of high - fluence uva in a topographically customized pattern was applied in an eye with progressive keratoconus . 
 visual acuity , cornea clarity , keratometry , topography , and pachymetry with a multitude of modalities , as well as endothelial cell counts were evaluated for > 6 months.resultsuncorrected distance visual acuity changed from preoperative 20/40 to 20/25 at 6 months . a mean astigmatic reduction of 0.8 d , and 
 significant cornea surface normalization was achieved 6 months postoperatively . 
 there was some mild change in the epithelial distribution , with the treated area having a slight normalization in the average epithelial thickness.conclusionswe introduce herein the novel application of a topographically customizable transepithelial cxl in progressive keratoconus in order to achieve an astigmatic refractive effect and ectasia stabilization . 
 this novel technique offers a nonablative and nonincisional approach to treat irregular astigmatism in ectatic cornea with rapid visual rehabilitation . 
Introduction
Case Presentation
Surgical Technique
Results
Discussion
Conclusions
Disclosure Statement