A year of cornea in review: 2013.

ANNUAL REVIEW

A Year of Cornea in Review: 2013 Juan G. Arbelaez, MD,*Þ Matthew T. Feng, MD,* Tomas J. Pena, MD,*Þ Marianne O. Price, PhD, MBA,Þ and Francis W. Price, Jr, MD*

Purpose: The goal of this study was to provide an update of significant corneal literature published in 2013.

Design: This study is a systematic literature review. Methods: We conducted a systematic review of the English-language literature published from January 1, 2013, to December 31, 2013, using the following PubMed search and Medical Subject Headings terms: cornea transplantation, keratoplasty, Descemet membrane endothelial keratoplasty, Descemet stripping endothelial keratoplasty, cross linking, pre-Descemet’s layer, Rho-associated kinase, keratoprosthesis, infectious keratitis, corneal dystrophy, corneal astigmatism, and keratoconus. Results: This review summarizes relevant and innovative original articles, review articles, and novel techniques from the following journals: American Journal of Ophthalmology, British Journal of Ophthalmology, Cornea, Graefe’s Archive for Clinical and Experimental Ophthalmology, Investigative Ophthalmology & Visual Science, JAMA Ophthalmology, Journal of Cataract and Refractive Surgery, Journal of Refractive Surgery, and Ophthalmology. Case reports, abstracts, letters to the Editor, and unpublished work were excluded, as well as articles e-published ahead of print in 2012 that were discussed in the previous review. One hundred twenty-seven articles met the criteria for this review. Conclusions: This review summarizes significant cornea-related literature from 2013. Key Words: cornea, keratoplasty, Descemet membrane endothelial keratoplasty, Descemet stripping endothelial keratoplasty, Descemet membrane endothelial transfer, cross-linking, pre-Descemet layer, Q-associated kinase, limbal stem cell, keratoprosthesis, infectious keratitis, corneal dystrophy, corneal astigmatism, keratoconus (Asia Pac J Ophthalmol 2015;4: 40Y50)

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t is difficult to miss the accelerating pace of scientific discovery around us. The field of ophthalmology and the subspecialty of cornea are no exceptions, increasing the importance of periodic literature reviews to synthesize and summarize published data. Herein, we continue the previous update by Chew et al1 by discussing significant corneal articles from 2013.

CORNEAL TRANSPLANTATION In 2013, the focus in keratoplasty was on lamellar techniquesVendothelial keratoplasty (EK) and anterior lamellar keratoplasty (ALK). Relative to traditional penetrating keratoplasty (PKP), lamellar techniques provide faster rehabilitation and more targeted replacement of the dysfunctional layers of the cornea. The EK technique with the lowest risk for rejection [Descemet membrane EK (DMEK)] and the ALK technique that From the *Price Vision Group; and †Cornea Research Foundation of America, Indianapolis, IN. Received for publication September 24, 2014; accepted January 12, 2015. The authors have no funding or conflicts of interest to disclose. Reprints: Francis W. Price, Jr, MD, Price Vision Group, 9002 N Meridian St, Suite 100, Indianapolis, IN 46260. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000110

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provides the best vision [deep ALK (DALK)] are also the most challenging to perform, so interest in the development and evaluation of new modifications was high.

Descemet Stripping Automated Endothelial Keratoplasty Descemet stripping automated EK (DSAEK) currently remains the most popular method of targeted endothelial replacement. Aspects of particular interest in 2013 were tissue preparation, tissue insertion devices, expanding indications, and further characterization of DSAEK outcomes and complications.

Tissue Preparation Methods to more consistently control graft thickness as well as eye bank preparation and shipping of tissue were the key topics last year. Using a double-pass technique to reduce the depth and standard deviation of the final cut, Busin et al2 reported visual outcomes of ultrathin (UT) DSAEK comparable with DMEK and better than standard thickness DSAEK in terms of speed of visual recovery and percentage of patients with 20/20 final visual acuity. They reported that preparation and delivery of UT-DSAEK donor tissue were neither difficult nor time-consuming and that complications did not differ substantially from standard DSAEK. Bucher et al3 performed osmotic deswelling using THIN-C medium on 17 human corneas before UT-DSAEK graft preparation. This improved the quality of the graft interface but did not significantly improve the cut precision of the microkeratome. In a variation of the double-pass technique, Rosa et al4 prepared 25 grafts using a femtosecond laser for the first cut only and a 300-Km microkeratome head for the second cut. They obtained grafts of less than 100 Km, excellent visual acuity results, and good endothelial cell counts without any tissue wastage; however, this is a relatively expensive and time-consuming approach. A femtosecond laser can target a given depth more precisely, whereas a microkeratome produces a smoother dissection plane. Most femtosecond lasers applanate the curved cornea against a flat reference surface, creating undulations in the posterior cornea and, in turn, an undulating dissection plane and suboptimal vision. In addition, the soft posterior stroma does not cut as smoothly as the tightly packed collagen of the anterior stroma. Although multiple studies have shown that visual outcomes are disappointing with completely femtosecond laserYdissected DSAEK grafts, people continue to try it with uniformly poor results. Among those who tried laser-assisted DSAEK last year, Phillips et al5 evaluated endothelial survival and stromal bed quality when creating deep stromal cuts with low-pulse energy, high-frequency femtosecond laser. They obtained a mean thickness of 61 Km with minimal endothelial cell damage, but the stromal surface quality was suboptimal. Likewise, Vetter et al6 reported a series of 22 uncomplicated DSAEK cases in which the donor corneas were prepared with the VisuMax femtosecond laser (Carl Zeiss Meditec AG, Jena, Germany) or the Amadeus II microkeratome (Ziemer Ophthalmic Systems AG, Port, Switzerland). Graft thickness was similar in both groups, but visual acuity was better in the microkeratome group, whereas posterior corneal irregularities were notable in the femtosecond group. Similarly,

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A Year of Cornea in Review: 2013

Heinzelmann et al7 found that microkeratome-assisted DSAEK produced better visual outcomes than femtosecond laserYassisted DSAEK. Femtosecond laserYassisted DSAEK also had a higher rate of graft failure. Eye bank predissection of DSAEK donor tissue is increasingly popular because it allows surgeons who do not have a microkeratome to readily perform DSAEK and precludes the possibility of unsuccessful graft preparation in the operating room. Several studies assessed the effect of storing and transporting precut tissue. Tang et al8 evaluated precut DSAEK graft deturgescence during storage at 4-C using optical coherence tomography (OCT). The average central graft thickness decreased from 189 Km (range, 146Y255 Km) immediately after microkeratome dissection to 148 Km (range, 116Y190 Km) after 4 hours in preservation medium (P < 0.001). Because steady state was reached after 2 hours, the authors suggested that preoperative DSAEK graft thickness be measured at that time. Ruzza et al9 reported that precut DSAEK grafts preserved in organ culture medium for 2 weeks had an endothelial cell density (ECD) loss of 19.9% with intact cellular organization. They concluded that precut DSAEK grafts may be stored in organ culture medium for up to 2 weeks. However, these corneas had not been trephined yet, which can cause additional cell loss. Imported precut donor corneas from overseas eye banks are a valuable source of DSAEK donors where the domestic donor corneal supply is insufficient. Therefore, Yamazoe et al10 evaluated change in ECD caused by the precutting and long-distance transportation of 124 DSAEK grafts. The average endothelial cell loss was 1.8% after precutting and 3.9% after transport, for a total mean loss of 5.7%, which was considered acceptable.

well as 1, 3, 6, and 12 months after DSAEK to assess the visual impact of wave front aberrations, corneal thickness, and corneal light scatter. Visual performance improved during the first year after DSAEK mainly in association with decreased (but not normalized) light scatter because higher-order aberrations (HOAs) remained increased without significant change. The debate about the influence of DSAEK graft thickness on visual acuity outcomes continued with additional centers weighing in on the question. Daoud et al16 retrospectively reviewed 460 DSAEK cases and did not detect a significant association between graft thickness and final best corrected visual acuity (BCVA) or refractive error. Likewise, Phillips et al17 found no significant correlation between preoperative graft thickness and visual acuity after DSAEK in 144 eyes. Woodward et al18 retrospectively reviewed 64 DSAEK cases with a mean follow-up of 2 years and found that BCVA was not significantly correlated with preoperative or postoperative graft thickness. In contrast, Dickman et al19 found that visual gain after DSAEK was significantly correlated with graft thickness in patients without vision-limiting comorbidities. The relationship was strongest in patients with pseudophakic bullous keratopathy. Graft thickness also correlated with graft asymmetry, which, in turn, correlated with all posterior corneal HOAs, except spherical aberrations. The disparity in findings and ongoing debate may be attributable to differences in how and when graft thickness is measured, differing methods of data analysis, and the multiplicity of factors that can influence vision, including light scattering, HOAs, and the inherent irregularity of a microkeratome cut.

Outcomes

Transplanting a larger area of healthy donor tissue may result in less endothelial cell loss over time on the basis of the assumption that migration of healthy endothelial cells from the donor tissue compensates for dysfunctional host endothelium surrounding the graft. Anshu et al20 retrospectively evaluated the potential influence of DSAEK graft diameter on endothelial cell loss in 695 eyes with FED that had at least 1-year follow-up and no prior glaucoma surgery. Graft diameters ranged from 7.5 to 9.5 mm, with 8.5- and 9.0-mm grafts being the most common. In the group with 8.5-mm diameter grafts, the mean endothelial cell loss increased from 32% at 1 year to 47% at 5 years, whereas in the group with 9.0-mm grafts, cell loss increased from 30% at 1 year to 46% at 5 years. Differences between groups were not statistically significant at any time point. Although a larger graft diameter (9.0 mm) theoretically provides a larger reservoir of healthy endothelial cells, it did not slow the rate of cell loss as compared with a smaller diameter (8.5 mm).

Corneal hypoesthesia in post-PKP eyes is a known risk factor for epithelial damage and ocular surface disease. In contrast, DSAEK uses a much smaller incision that preserves corneal nerves. Hirayama et al11 compared changes in corneal sensation, epithelial damage, and tear film after DSAEK and PKP and found that compared with the PKP eyes, DSAEK eyes had significantly better corneal sensation which was even better than before surgery. No tear film differences were detected between procedures. These findings were not entirely novel but provide important independent confirmation that preservation of corneal sensation assists in early recovery of visual function and long-term maintenance of ocular surface health after DSAEK. Several centers reported interesting new insights regarding factors that impact vision after DSAEK. Patel and McLaren12 analyzed 49 corneas of 42 patients with Fuchs endothelial dystrophy (FED) before DSAEK and during 3 years of postoperative follow-up using confocal microscopy. The reduced cellularity of the anterior stroma had not recovered 3 years after DSAEK and abnormal subepithelial cells, presumably fibroblasts, were present. Arnalich-Montiel et al13 used Scheimpflug densitometry to demonstrate increased central corneal light scattering after DSAEK regrafts as compared with primary DSAEK. They hypothesized that acute corneal edema may cause irreversible changes. De Sanctis et al compared post-DSAEK with fellow eyes and found a moderate reduction in true net corneal power by corneal tomography after DSAEK. The change was primarily caused by changes in the posterior corneal curvature. They suggested that knowledge of true net power changes could guide intraocular lens power calculations for DSAEK triple procedures.14 The addition of DSAEK donor tissue changes the host posterior corneal surface such that wave front aberrations, especially those arising from the posterior corneal surface, increase afterward. Hindman et al15 prospectively evaluated 20 eyes before DSAEK as * 2015 Asia Pacific Academy of Ophthalmology

Endothelial Cell Loss

Complications Unlike PKP, DSAEK creates a lamellar interface, which creates the potential for a unique set of complications associated with interface abnormalities. Previously reported abnormalities include epithelial downgrowth, infection, retention of fibers or Descemet membrane (DM) in the host-donor interface, calcareous deposition, interface blood, persistent interface fluid, and reticular or interface haze associated with retained viscoelastic in the interface. Vira et al21 described findings of textural interface opacity (TIO) at the graft-host interface after DSAEK in 30 patients from 7 institutions. This interface opacity was not inflammatory, did not respond to topical corticosteroids, and did not seem to be cellular. Two clinical types of TIO were seen: an elongated type and a punctate type. The authors proposed that the elongated type could be secondary to an irregular cut of the donor with the microkeratome blade. Six patients had small pockets of www.apjo.org


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interface fluid noted on slit-lamp examination. The authors suggested that the fluid could have been retained viscoelastic because 29 of the 30 cases had Descemet membrane stripped under viscoelastic with a small amount of viscoelastic placed on the endothelium during graft insertion, or it might have been a pocket of trapped aqueous or balanced salt solution. In many cases, the TIO spontaneously improved without intervention and most patients obtained good visual outcomes. The long-term use of postoperative steroids to prevent corneal transplant rejection can be associated with steroid-responsive intraocular pressure (IOP) elevation after any type of keratoplasty procedure. Maier et al22 reported a 29% incidence of IOP elevation and 12% incidence of post-DSAEK glaucoma and found that steroid-induced IOP elevation was the most frequent cause, with an incidence of 19%. This could be treated effectively by tapering down steroid medication. Preexisting glaucoma increased the risk for developing IOP elevation and post-DSAEK glaucoma. Management by medical treatment resulted in good visual acuity and graft survival. This study confirmed previous findings from our center. Yin et al23 assessed the prevalence of herpes simplex virus type 1 (HSV-1) in failed DSAEK grafts. They studied 51 failed DSAEK grafts and isolated HSV-1 DNA from 2 grafts (3.9%); furthermore, the corresponding donor rims did not demonstrate HSV-1. This suggests that HSV-1 infection plays a minor role in DSAEK failure and that viral reactivation from the recipient cornea is more likely than transmission from the donor. Similarly, Ang et al24 suggested that Asian patients with corneal endotheliitis may benefit from preoperative aqueous polymerase chain reaction (PCR) analysis before corneal transplantation. Such patients were more likely to have a recurrence of endotheliitis if they were cytomegalovirus positive, despite successful antiviral treatment preoperatively.

Descemet Stripping Automated Endothelial Keratoplasty Versus Penetrating Keratoplasty Several studies agreed that DSAEK enjoys a lower rejection rate than PKP. Price et al25 compared the outcomes of DSAEK with PKP from the Cornea Donor Study in a retrospective, multicenter, nonrandomized clinical trial. The 3-year survival rate did not differ significantly between DSAEK and PKP performed for either FED cases (96%) or non-FED cases (84%Y86%). Principal causes of graft failure or regraft within 3 years after DSAEK and PKP were immunologic graft rejection (0.6% versus 3.1%), endothelial decompensation in the absence of documented rejection (1.7% versus 2.1%), unsatisfactory visual or refractive outcome (1.7% versus 0.5%), and infection (0% versus 1.1%), respectively. The median 3-year cell loss for DSAEK and PKP was 46% and 51% in FED and 59% and 61% in the non-FED cases. At 3 years, use of a smaller DSAEK insertion incision was associated with significantly higher cell loss (60% versus 33% for 3.2- and 5.0-mm incisions, respectively) but not with differences in graft survival. The 3-year predicted probability of a rejection episode was significantly lower for DSAEK (9%) than PKP (20%). Hjortdal et al26 compared rejection and graft failure frequencies after DSAEK and PKP for 201 eyes with FED. All rejections and most graft failures occurred within the first 2 years, during which rejection episodes were significantly more common in PKP (16%) than DSAEK (5%). By 5 years, more DSAEK than PKP grafts had failed, but no DSAEK had failed secondary to rejection. In the PKP group, 2 grafts failed after rejection episodes and 1 graft failed because of bacterial keratitis. The DSAEK group had 3 primary failures, 2 secondary failures from endothelial decompensation in the absence of observed rejection episodes, and 2 grafts that failed because of progressive fibrous contraction of the

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graft and 1 femtosecond laserYprepared graft was exchanged for a microkeratome-prepared graft because of visually disturbing interface haze. The DSAEK group included the surgeon’s learning curve with the procedure. Finally, Ezon et al27 retrospectively compared first-episode immunologic graft rejection after more than 100 cases each of DSAEK and PKP. When glaucoma was excluded, the rejection risk for PKP was higher (hazard ratio, 5.56). Prior incisional glaucoma surgery increased the rejection risk by a factor of 3.15 regardless of the transplant type. When PKP rejections occurred, graft failure followed within 6 months in 31%. In contrast, no DSAEK rejections resulted in failure within the follow-up period.

Descemet Membrane Endothelial Keratoplasty Tissue Preparation Multiple high-volume DMEK centers have demonstrated that experience and standardization of techniques result in lower rates of tissue loss and donor detachment. Droutsas et al28 described a single surgeon’s learning curve encompassing 25 ‘‘no touch’’ DMEK graft preparations and surgeries. Two (8%) grafts had peripheral tears, but no tissue was lost. Rebubbling for partial graft detachment occurred in 9 (36%) cases. Primary graft failure occurred in 1 (4%) case. Schlo¨tzer-Schrehardt et al29 described 350 DMEK donor preparations using a bimanual submerged preparation technique. Tissue loss of 2% was attributed to interindividual variations in DM structure and composition. To hedge against even low rates of tissue loss, some surgeons may wish to have their donor tissue prepared ahead of time, whether personally or by an eye bank. Feng et al30 prospectively examined the effect of preparing DMEK donor tissue up to 2 days before surgery. Group 0 donors were prepared on the day of surgery, group 1 donors were prepared the day before surgery, and group 2 donors were prepared 2 days before surgery. Groups 1 and 2 were stored in refrigerated corneal storage solution until use. In groups 0, 1, and 2, the rate of failure to clear was 1.5%, 1.9%, and 2.8%, respectively, and the rebubbling rate was 15%, 13%, and 14% in the grafts that cleared successfully. The median endothelial cell loss at 3 months was 28%, 29%, and 29%. The groups were not significantly different, suggesting that DMEK donors can be prepared 1 to 2 days preoperatively. Heindl et al31 retrospectively studied the relationship between storage time of split donor tissue and outcomes after DALK and DMEK. No significant associations were observed with BCVA, endothelial cell loss, or complication rate within 1 year of followup. They concluded that anterior and posterior donor tissue may be stored safely for up to 1 week in organ culture before use in DALK and DMEK surgery.

Techniques In 2013, efforts to simplify, improve, and standardize the DMEK procedure continued. Muraine et al32 described a new method to prepare and inject DMEK grafts. Donors were punched first using a specially designed partial-thickness trephine, then inverted on an artificial anterior chamber where Descemet membrane was hydrodissected from the posterior stroma. Although the graft was still endothelial-side up, viscoelastic was applied centrally before the graft was folded endothelium-inward around the viscoelastic. The folded graft was slid onto a Busin glide and into the recipient eye, where it opened endothelial-side down with irrigation, which was much like a DSAEK graft. Guëll et al33 described a new bimanual infusion technique for the insertion and positioning of DMEK grafts in pseudophakic eyes using very low pressure irrigation flow. Liarakos et al34 retrospectively analyzed * 2015 Asia Pacific Academy of Ophthalmology



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surgical videos from 100 consecutive DMEK cases and distilled graftYunfolding methods into 4 basic and 3 auxiliary techniques. Perhaps the most crucial intraoperative step is the identification and confirmation of graft orientation. Burkhart et al35 described the use of a handheld slit beam for this purpose. The device was more flexible and more cost-effective than a microscope-mounted slit beam. Steven et al36 described the use of intraoperative OCT. Both methods worked by viewing the graft in cross section and using the knowledge that scrolled DMEK grafts curl endothelium outward. Descemet membrane EK represents an evolution in keratoplasty that, in many ways, parallels the evolution that phacoemulsification brought to cataract extraction. McKee et al37 reported that, because of rapid visual recovery and small incisions, DMEK of fellow eye can be performed within 1 to 2 weeks of DMEK of the first eye without an increased risk for complications. Rapid sequential DMEK, similar to rapid sequential modern cataract surgery, can offer prompt recovery, safety, patient convenience, and excellent visual outcomes.

Special Considerations Endothelial keratoplasty to rescue a failed PKP can be technically challenging. The often uneven profile of the PKP’s posterior surface and curvature mismatch can lead to DSAEK graft detachment and DMEK is no different. Anshu et al38 retrospectively examined the outcomes of DMEK and Descemet membrane automated EK for failed PKP. The small series included 4 DMEKs and 2 Descemet membrane automated EKs. The EK grafts were 8 or 9 mm, whereas the failed PKP diameter was 8 mm in all cases. The median BCVA improved from 20/70 to 20/50, 20/40, and 20/ 30 at 1, 3, and 6 months, respectively. The median donor ECD decreased from 2801/mm2 to 1906/mm2 and 1880/mm2 at 3 and 6 months. However, 75% of the DMEK had peripheral detachments requiring a single rebubbling. There was 1 primary failure that was managed with DSAEK. Quilendrino et al39 reported the outcomes of large diameter (10Y10.5 mm) DMEK grafts in 4 buphthalmic eyes. Descemet membrane EK was performed successfully and all corneas were cleared. BCVA improved in all cases with good visual potential. Endothelial cell loss ranged from 37% to 42%. No primary graft failures or rejections were observed. Three eyes required additional medication for elevated IOP but none required further glaucoma surgery.

Outcomes Timing may be a key in maximizing visual rehabilitation after DMEK. Although Kobayashi et al40 showed that residual corneal abnormalities seen with in vivo laser confocal microscopy are fewer after DMEK than DSAEK, van Dijk et al41 nevertheless found that long-standing stromal edema may induce irreversible changes in the anterior stroma. Specifically, preexisting corneal scarring or preoperative corneal edema for more than 12 months may be a risk factor for diffuse irregular astigmatism after DMEK. Therefore, patients with endothelial dysfunction should be managed aggressively. In another outcomes study, Dapena et al42 reviewed 200 consecutive DMEKs to determine the causes of unexpectedly poor visual rehabilitation. Graft failure and concomitant ocular pathology were the main causes.

Penetrating Keratoplasty Cornea Donor Study Ten-year success rates for PKP using donors between the ages of 12 and 65 years versus 66 and 75 years were not significantly different (77% versus 71%, respectively, P = 0.11). * 2015 Asia Pacific Academy of Ophthalmology


There was evidence for a possible donor age effect at the extremes of the age range. However, for donors between ages 34 and 71 years, which account for approximately 75% of the transplantable corneas in the United States, the success rate was fairly constant. These results suggest that graft selection should be largely independent of donor age considerations in PKP for endothelial disease.43 The median endothelial cell loss was 76% to 79% in eyes with clear grafts at 10 years. Higher preoperative ECD and larger donor tissue size were associated with higher ECD at 10 years.44 However, preoperative donor ECD itself was not a significant predictor of 5-year PKP survival, whereas 6-month postoperative ECD was a significant predictor.45 Postoperative pachymetry was predictive of graft survival within the first 5 years, but ECD was independently predictive as well, such that neither measurement should substitute for the other.46

Eye Banking Demand for donor tissue continues to increase. Woodward et al47 examined the potential effects of more restrictive donor acceptance parameters on cost and tissue availability. If all surgeons requested ECD of 2500 cells/mm2 and greater and donor age of 65 years and younger, the donor supply was projected to shrink by 45%. The estimated effect was an 83% increase in tissue processing fees. Infectious surveillance continued to be a priority. Aldave et al48 investigated the incidence of postkeratoplasty fungal infections to determine whether storage media supplementation with an antifungal agent was appropriate. The trend was rising, but difference did not reach statistical significance. The Eye Bank Association of America medical advisory board did not recommend addition of an antifungal agent to cold storage media at this time. Linke et al49 analyzed contamination rates and risk factors for corneas stored in organ culture medium from 1998 to 2010. Most contamination was fungal (62%), which was predominantly from Candida (45%). Bacterial contaminations (34%) were dominated by Staphylococcus (13%). Skin floras were major contributors. The median death-to-explantation interval of contaminated corneas (44 hours) was significantly longer than that of sterile corneas (39 hours). Cardiopulmonary failure was associated with the highest contamination rate (14%) of all death causes, whereas average temperature was not significantly associated. Endothelial status is one of the most important factors in the selection of donor tissue. Bruinsma et al50 studied immediate postmortem corneas and assessed the validity of polymegethism and pleomorphism as tissue discard parameters. They retrospectively evaluated endothelial quality immediately after procurement of the corneoscleral rim and again after 1 to 3 weeks in organ culture. Although 21% showed polymegethism, pleomorphism, and ‘‘poor swelling’’ after procurement, 86% of those converted to a normal mosaic after culture. This suggested that cellular contour parameters may reflect acute reactions to cellular stress more than tissue viability, at least when organ culture storage medium is available.

Tacrolimus for High-Risk Penetrating Keratoplasty Magalhaes et al51 retrospectively examined PKP grafts performed for previous failed PKP or severe chemical burn that were treated with 1% prednisolone acetate with or without 0.03% topical tacrolimus. Tacrolimus was effective in preventing irreversible rejection in these high-risk grafts without increasing IOP.

Deep Anterior Lamellar Keratoplasty Dua Layer Big bubble pneumodissection is an elegant technique for separating Descemet membrane from posterior stroma. Big www.apjo.org


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bubbles have therefore been used to bare recipient DM during DALK or detach DM during DMEK donor preparation. However, the variability of big bubble creation prompted closer histological examination by Dua et al. The result was the muchdiscussed identification of a putatively novel pre-Descemetic layer in adults that the authors named Dua layer.52 In brief, socalled type 1 big bubbles dissected DM together with an additional, immediately anterior layer, as evidenced by the ability to peel DM without perforating the bubble. Type 1 big bubbles were smaller (maximum, 8.5 mm), more central, and more resistant to popping pressure (1.45 bar) than type 2 big bubbles, which were larger diameter (maximum, 10.5 mm) and thin-walled without the additional layer anterior to DM. The layer anterior to DM was characterized as being a strong, acellular, 10-Km thick collection of 5 to 8 lamellae of type 1 collagen, such that its selective inclusion or exclusion would conceivably allow surgeons to modulate posterior corneal biomechanics. Dua layer spawned controversy on nearly every level ranging from its validity to its eponym.53,54 In an accompanying editorial, Jester et al53 called into question a supposed hallmark of the layer, namely, the acellularity. They were of the opinion that the data presented did not warrant the assignation of a new anatomic layer to the cornea and that the proposed terminology was not in keeping with the recommended descriptive terminology in Terminologia Anatomica.53

Deep Anterior Lamellar Keratoplasty Versus Penetrating Keratoplasty In a contralateral eye study, Kim et al55 retrospectively compared ECD, visual outcomes, and complications in 8 patients who had paired DALK and PKP. They found no significant differences in uncorrected visual acuity, BCVA, or refractive error and concluded that DALK is an effective alternative to PKP for stromal pathologies. Cheng et al56 compared DALK and PKP for macular corneal dystrophy (MCD; n = 78) using a manual dissection technique for DALK. The 1-year incidence of complications was less with DALK (5% versus 21%). In addition, endothelial cell loss was less with DALK, whereas visual outcomes were superior with PKP through 5 years. The rate of MCD recurrence was 1%, 8%, and 40% at 1, 5, and 10 years after PKP and 14% and 50% at 1 and 5 years after DALK. Thus, the recurrence rate was 5 times higher in the DALK cohort. Recurrence was more likely in those with a younger age of onset. Sogutlu Sari et al57 also compared big bubble DALK and PKP for MCD in 76 eyes. Deep ALK provided comparable visual and optical results as PKP with less endothelial cell loss and eliminated endothelial rejection.

Techniques The plethora of new technique articles in 2013 is a testament to the challenging nature of DALK in its current forms. Areas that were addressed covered nearly every surgical aspect, from donor preparation to recipient lamellar dissection and margin creation. In a prospective randomized study, Baradaran-Rafii et al58 compared Anwar big bubble and Melles viscoelastic dissection in 57 patients with keratoconus (KCN). Both techniques produced comparable visual acuity and refractive outcomes, aberrometric profiles, biomechanical properties, pachymetries, as well as ECD. However, the big bubble technique resulted in better contrast sensitivity. In terms of complications, Descemet membrane was not bared in 1 big bubble case, and Descemet membrane rupture occurred in 2 big bubble cases and 1 viscoelastic dissection case.58 Zare et al59 retrospectively assessed the effects of retaining donor DM on visual outcomes, contrast sensitivity, HOAs, and

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central graft thickness after big bubble DALK for KCN. Donor DM was removed in 48 grafts and left intact in 22 grafts. All grafts were sutured to the recipient bed. Both groups had comparable postoperative keratometric astigmatism, spherical equivalent refraction, and HOAs. However, the group without DM had better contrast sensitivity. Muftuoglu et al60 described a hybrid technique for use when air injection results in a small bubble only. Viscoelastic was injected from a new site using a 27-gauge cannula to further detach DM. In this so-called air-visco bubble DALK technique, the small air bubble migrates quickly to the periphery in a ‘‘kidney bean’’ configuration as a mixed air-viscoelastic big bubble is formed. In a series of 210 eyes, 141 had successful DALK with only air injection and the remaining 69 eyes had successful airvisco bubble DALK when a big bubble was not achieved with only air injection.60 Scorcia et al61 reported intraoperative OCT findings during DALK in 100 patients with KCN. When pneumatic dissection was attempted at a sufficient depth, big bubbles formed more consistently. Although the ideal depth could not be defined, OCT allows objective evaluation of the depth reached by the cannula tip used for pneumatic dissection. Intraoperative OCTguided cannula repositioning may allow surgeons to more reliably achieve target depth and improve the success rate for big bubble formation. Vajpayee et al62 described a diamond knifeYassisted manual dissection technique and compared it with big bubble DALK in KCN. Although the new technique leaves a very thin layer of corneal stroma, visual and refractive outcomes were reported to be comparable with those of big bubble DALK. Rama et al63 similarly reported that diamond knifeYassisted manual dissection provided visual, refractive, and clinical results comparable with other DALK techniques. As in previous studies, less residual host stromal thickness was associated with better visual acuity. Lange et al64 described enzymatic digestion of the corneal stroma and extracellular matrix as a novel method of lamellar dissection. In this ex vivo pilot study, they used hyaluronidase and trypsin on 17 cadaveric human corneas with no deleterious effects on residual host tissue observed using light microscopy. No significant endothelial cell loss was observed in tissues where a predissection cell count was obtainable. These promising preliminary results suggest that further studies into enzymolysis are needed. Shehadeh-Mashor et al reported 1-year outcomes using a femtosecond laser to create interlocking corneal side cuts in a mushroom configuration in 19 eyes. All cases were completed without conversion to PKP. The authors concluded that this procedure was reliable and reproducible in agreement with previous reports.65

Boston Keratoprosthesis The Boston Keratoprosthesis (KPro) type I remains as the most commonly implanted artificial cornea worldwide. It is a useful alternative to traditional keratoplasty in high-risk eyes and may be the primary procedure of choice in congenital aniridia.66 A large multicenter study of 300 eyes found that the probability of retention was 94% at 1 year and 89% at 2 years. The lowest retention rates were associated with ocular surface disease, particularly autoimmune-related disease.67 The Boston KPro has undergone several iterative improvements since its inception. The back plate is now available in titanium, which has been touted to improve design and biocompatibility. In an effort to improve cosmesis and therefore patient acceptance of the new titanium back plate, blue and brown coloration surface modification is possible via electrochemical anodization.68 Not surprisingly, much of the KPro literature covered its most common complications: retroprosthetic membrane (RPM), glaucoma, and infection. * 2015 Asia Pacific Academy of Ophthalmology



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Retroprosthetic membrane not involving the optic may not be visually significant, but extensive involvement over the back plate was associated with sterile melts in a retrospective study (risk ratio, 2.9).69 The proposed mechanism is decreased aqueous nutrition. In the melt group, all eyes had retroYback plate membranes that were significantly thicker on average (278 Km), which could impede aqueous diffusion to a greater degree. The authors used anterior segment optical coherence tomography (AS-OCT) to identify and measure the RPM. New oversized (9.5 mm) back plates were imaged in vivo with AS-OCT and noted to improve wound apposition at the internal graft-host junction.70 The authors theorized that covering the wound with a larger back plate may decrease the likelihood of RPM formation. At an average follow-up of 1 year, no RPM was seen versus 20% in the standard (8.5 mm) back plate comparison group. The ability of Fourier domain ASOCT to visualize RPM, periprosthetic cysts, and donor carrier melts was illustrated nicely by Shapiro et al.71 Donor carrier melts can be refractory, recurrent, and challenging to manage. The limitations of previously available medical and surgical options resulted in the description of new techniques for the surgical treatment of donor carrier melts. Ziai et al72 combined 2 existing techniques: lamellar grafting to fill the defect with adjunctive buccal mucosal allografting to cover it. The treatment may be temporizing only, but fortunately, the supply of oral buccal mucosa regenerates to allow repeated treatments. An alternative is the complete exchange of the donor carrier in such a way that the KPro hardware is left intact and reused.73 The technique uses small relaxing incisions in the new donor and exploits the relationship between corneal hydration status and thickness. A new donor can be collared over the front plate and into sandwiched position in a fully assembled KPro in this way. The authors emphasized that no additional sutures beyond the standard number in the standard locations are needed. In their experience, techniques that require sutures within the donor carrier often lead to recurrent melts associated with the said sutures. In some cases, a type II KPro may fare better, such as in mucous membrane pemphigoid.74 Glaucoma is common in candidate eyes for KPro and progression is common after KPro. Simultaneous glaucoma tube placement is often recommended. A retrospective study examined a subset of KPro patients who underwent combined glaucoma tube placement at the time of KPro.75 Glaucoma progression nevertheless occurred in 39% of the patients. Certain complications were higher in the KPro-alone group, such as suprachoroidal hemorrhage and tube occlusion. The authors cautioned that combined surgery should be reserved for select patients and a complete vitrectomy should be performed to avoid vitreous incarceration as an etiology of tube occlusion. Serial AS-OCT demonstrates progressive angle closure after KPro and can be used to monitor anterior chamber shallowing and synechiae formation otherwise difficult to appreciate behind the back plate.76 Because protrusion of the posterior graft-host junction seen on AS-OCT may initiate synechial closure of the angle, an oversized (9.5 mm) back plate that covers the junction might decrease the rate of progressive angle closure; however, longer follow-up is needed.70 Another feared complication of KPro is infection. One prospective study characterized the microbial colonization patterns in KPro eyes receiving topical antibiotics.77 Despite appropriate coverage, conjunctival cultures were significantly more likely to be positive in fellow eyes without KPro. Furthermore, despite grampositive coverage such as with vancomycin, the predominant organisms isolated were gram positive. Another study found that KPro culture positivity rates were no different from PKP and control eyes.78 Gram-positive bacteria were recovered most frequently. However, these isolates were more likely to be resistant to * 2015 Asia Pacific Academy of Ophthalmology


fourth-generation fluoroquinolones in KPro eyes (44%). The authors attribute these resistance patterns to chronic fluoroquinolone prophylaxis. In a large retrospective study, the infectious keratitis rate was 13.6%.79 Bacteria and fungi were recovered at similar rates. Prolonged topical vancomycin use was associated with increased rates of fungal and overall keratitis. In a multicenter study of device retention in 300 eyes, 9 infections resulted in KPro loss.67 Seven cases were fungal keratitis. One case each was fungal or bacterial endophthalmitis. These reports demonstrate an ongoing challenge facing clinicians caring for KPro patients.

INFECTIOUS KERATITIS Diagnosis Inoue and Ohashi80 reviewed noteworthy examples of realtime PCR for the successful diagnosis of infectious keratitis. This included Acanthamoeba that was undetected by histological examination and culture, zoster sine herpete with atypical pseudodendrite, acyclovir-resistant herpesvirus, and corneal endotheliitis caused by cytomegalovirus, human herpesvirus 7, or human herpesvirus 8. DNA was extracted from scraped corneal epithelium and aliquots (0.1 mL) of aqueous humor from the affected eye. They concluded that a variety of pathogen-specific DNA can be assessed using realtime PCR, making it useful for both diagnosis and monitoring. Polymerase chain reaction has high sensitivity and speed and can identify multiple pathogens simultaneously from minute samples, making early diagnosis and treatment more likely. Bhadange et al81 examined whether liquid culture media are helpful in the diagnosis of infectious keratitis via a retrospective review of microbiology records from 114 corneal scraping samples. Thirty-eight (86%) of 44 cases of bacterial keratitis were diagnosed using solid media alone and 6 (14%) of the 44 cases required liquid media for diagnosis (P < 0.001). In fungal keratitis, 61 (98%) of 62 cases were diagnosed using solid media alone, whereas 1 case required liquid media for diagnosis. In mixed infection, no cases required liquid media for diagnosis of the fungal component; however, all 8 cases required liquid media for the bacterial component. In conclusion, liquid culture media improved the isolation of bacteria in pure bacterial and mixed keratitis; however, their role in isolating fungus was limited.

Treatment and Outcomes Hoffmann et al82 studied amniotic membrane transplantation (AMT) to stabilize severe infectious keratitis before elective PKP. Seven to 41 days after initiating intensive antimicrobial therapy for herpetic, bacterial, or combined keratitis, AMTwas performed (n = 12). Elective PKP was subsequently performed in 10 eyes, whereas 2 eyes required emergency PKP to treat perforations. With a median follow-up of 20 months (range, 4Y38 months), 10 (83%) of the 12 grafts and 9 (90%) of the 10 elective grafts remained clear. The authors concluded that AMT for ulcerative keratitis seemed to help avoid emergency keratoplasty and improve the anatomical and optical results of sequential PKP. Kowalski et al83 examined combination versus monotherapy antibiotics, concluding that cefazolin-tobramycin, cefuroximegentamicin, and moxifloxacin monotherapy were all equivalent for the empiric topical treatment of bacterial keratitis. Similarly, Sharma et al84 compared 0.5% moxifloxacin against a combination of fortified 5% cefazolin sodium and 1.3% tobramycin sulfate eye drops in the treatment of moderate bacterial keratitis. Corneal healing was equivalent between groups. Suzuki and Ohashi85 studied the in vitro interaction of fluoroquinolones such as levofloxacin, gatifloxacin, or moxifloxacin in combination with tobramycin or cefmenoxime against clinical isolates of bacteria from keratitis www.apjo.org


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and postulated that these combinations may improve coverage and decrease the growing fluoroquinolone resistance seen in bacteria. Tu and Jain86 reported a small case series of 0.2% topical linezolid in the treatment of gram-positive bacterial keratitis as an alternative to topical vancomycin. Linezolid was effective, whereas vancomycin was ineffective, poorly tolerated, or both. Linezolid was reportedly comfortable to use and did not result in exacerbation of an already compromised ocular surface. In the mycotic ulcer treatment trial, Prajna et al87 compared topical treatments for filamentous fungal keratitis. This phase 3, double-masked, multicenter trial enrolled 323 patients, who were randomized to 1% voriconazole or 5% natamycin, which was applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Natamycin-treated cases were less likely to have perforation or require therapeutic PKP. Fusarium cases fared better with natamycin than with voriconazole, whereas there was no difference in non-Fusarium cases. Natamycin was associated with significantly better clinical and microbiological outcomes for smear-positive filamentous fungal keratitis. The authors concluded that voriconazole should not be used as monotherapy in filamentous keratitis. Rogers et al88 retrospectively evaluated the outcomes of medical and surgical management of fungal keratitis at a tertiary care eye center. The main outcome measure was a microbiological cure with either medical therapy alone or in combination with therapeutic keratoplasty. All eyes (n = 73) were initially treated with antifungal agents such as topical polyene, triazole, or imidazole. Among the 32 eyes treated with keratoplasty, 17 (53.1%) eyes maintained a clear graft. Among the 15 eyes with failed grafts, 12 eyes ultimately achieved clear grafts after subsequent repeated grafts. The median BCVA was 20/30 in the medical therapy group and 20/40 in the keratoplasty group. Young et al89 reported the risk factors and microbiological profile of pediatric (younger than 18 years old) microbial keratitis cases at a tertiary care hospital in Hong Kong. Pseudomonas was the most commonly isolated organism (62%), followed by coagulasenegative Staphylococcus (31%) and Corynebacterium (12%). Fourteen (78%) of 18 cases were treated with fortified antibiotics and 4 (22%) cases were treated with intensive topical 0.3% levofloxacin eye drops. Ceftazidime (50 mg/mL) and tobramycin (14 mg/mL) were used in combination, alternating every half-hour in 13 eyes. In addition, hourly 0.3% ofloxacin ointment was used in 5 cases. Overall, 17 (94%) of the 18 cases responded to medical management alone. One case secondary to trauma required multiple surgeries, including retinal detachment repair. The study highlighted contact lensYrelated microbial keratitis in children, especially those related to orthokeratology.

CORNEAL DYSTROPHIES Fuchs Endothelial Dystrophy The Fuchs’ Genetics Multi-Center Study Group reported that female sex and smoking were associated significantly with advanced FED. Diabetes was associated with higher central corneal thickness (CCT), whereas female sex was associated with lower CCT. As shown previously, advanced FED was associated with large increases in CCT.90 Schrems-Hoesl et al91 reported the use of in vivo confocal microscopy to analyze the corneas of 30 patients with early FED. They found alterations in corneal innervation in patients with earlystage FED, suggesting a potential role of corneal nerves in the pathogenesis of FED. Additional studies are required to investigate whether subbasal nerve alterations are caused by nonspecific corneal edema from FED-induced decrease in ECD, or potentially lead to loss of endothelial cells.

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Q-Associated Kinases Inhibitor

Q-Associated kinases (known as ‘‘Rho-associated protein kinase’’ [ROCK]) are protein serine/threonine kinases that are the best-characterized Q downstream effectors. The Q/ROCK pathways are involved in regulating the cytoskeleton and influence cell migration, apoptosis, and proliferation. Building on their earlier studies showing that the selective ROCK inhibitor, Y-27632, promoted the proliferation of primate corneal endothelial cells in vitro and the healing of primate corneal endothelium in vivo, Koizumi et al92 reported the first use of Y-27632 as a topical treatment in a patient with FED. The treatment was applied after transcorneal freezing of the central corneal endothelium. Endothelial function and vision were maintained through the 2-year follow-up period. The results suggested that in vivo proliferation/redistribution of corneal endothelium may be stimulated by medical/pharmaceutical treatment after the destruction of diseased endothelium. Guttae, which scatter light, are a prominent feature of FED, certainly in whites, so additional studies are needed to assess the ability to stimulate repopulation of the central corneal endothelium after removal of Descemet membrane and guttae. Ziaei et al93 reported that oxidative stress and degenerative changes in FED may be blocked by targeting the Nrf2-ARE pathway. Studies were done on ex vivo corneas and human corneal endothelial cell lines.

Posterior Polymorphous Corneal Dystrophy Aldave et al94 reported that abnormally steep corneal curvatures are found in 37% of individuals with posterior polymorphous corneal dystrophy and in 86% when secondary to zinc finger Ebox-binding homeobox 1 (ZEB1) mutations. ZEB1 was present in keratocyte nuclei, suggesting a role for ZEB1 in keratocyte function. Therefore, ZEB1 may play a role in both corneal stromal and endothelial development and function. They concluded that posterior polymorphous corneal dystrophy should be considered both an endothelial dystrophy and an ectatic disorder.

CORNEAL CROSS-LINKING Corneal cross-linking (CXL) was a hot topic again last year. One common theme was the relationship between treatment efficacy as well as cone location and severity. Specifically, CXL is more effective for central cones and milder KCN. For example, improvement in BCVA is more likely when the keratometric apex lies within the central 3-mm zone.95 Posttreatment stromal demarcation lines are often seen clinically and used to estimate depth of treatment. When measured using AS-OCT, they were found to be approximately 50% deeper centrally (300 Km) than peripherally (200 Km) by 2 independent groups.96,97 In a prospective 12-month study of 30 eyes, progression stopped after CXL in cases defined as early KCN (mean central K, e53 diopters, (D)); however, the authors noted that the cases defined as advanced KCN (mean central K, >53 D) were associated with significant regression in several indices and recommended CXL earlier in the course of KCN.98 However, this is not to say that CXL is ineffective for advanced KCN. In a retrospective study of 28 eyes with steepest K of 55+ D (average, 61.2 T 3.7 D), progression was halted in 27 (96%) eyes. The authors suggested that CXL may not have a failure rate in advanced progressive KCN as high as previously thought.99 One decade after the first human studies were reported from Dresden, more long-term and safety CXL outcomes are available and they support previous work showing stability. A large retrospective study of epithelium-off CXL with 4 years of follow-up found improved BCVA, decreased coma, and stabilization of progression across all age groups but particularly for 18 to 39 year olds.100 Forty eyes that were observed prospectively 5 years after * 2015 Asia Pacific Academy of Ophthalmology



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epithelium-off CXL did not progress.101 A study of 30 eyes showed significant improvement within 1 year in spherical equivalent, BCVA, and keratometry after epithelium-off CXL, with continued improvement at 4 to 6 years; no treated eyes progressed, whereas progression was noted in 7 untreated fellow eyes.102 A retrospective study found that postrefractive ectasia arrested or occasionally improved after a mean follow-up of 2 years.103 In 1 epithelium-off prospective study, there was no increase in dry eye104 perhaps because, after a transient denervation period, corneal nerves regenerated by 6 months with no significant change in the tear film.105 Endothelial cell density and epithelial healing were unaffected in a small prospective cohort that evaluated high-fluence and shorter duration CXL.106 Several basic science studies examined CXL at a mechanistic level. Human keratocyte cell cultures expressed increased fibronectin and tissue transglutaminase after CXL.107 The latter is an enzyme cross-linking extracellular matrix protein and its induction offers insight into the mechanism of CXL. The effect was not seen with either riboflavin or UV-A radiation alone. The pathologic analysis of 6 eyes 5 to 30 months after CXL found significant loss of keratocytes from the anterior stroma and midstroma compared with untreated eyes and normal controls.108 The difference was less significant in the corneal periphery. Another small study addressed the ongoing question of transepithelial versus epitheliumoff (traditional) CXL. It showed that iontophoresis enhanced riboflavin saturation and penetration compared with conventional transepithelial techniques, but the highest concentrations were still achieved using epithelium-off techniques.109 Clinically, the epithelium-on versus epithelium-off debate continued. In 23 pediatric KCN eyes, Magli et al110 found transepithelial and epithelium-off CXL to have similar efficacy in improving keratometric indices at up to 1 year. Vision was unchanged, with no difference between the 2 groups. The children reported less pain and had fewer complications with epithelium-on CXL. Younger patients had significantly more pain 3 to 4 days after epithelium-off CXL in a study of 178 adult eyes.111 In a randomized study, in vivo confocal microscopy and OCT showed greater and deeper stromal inflammation and resultant keratocyte loss in the epithelium-off versus epithelium-on treatment arm; visual and keratometric results were not reported.112 One small study demonstrated normalization or trends toward normalization in epithelial protein expression, anterior stromal keratocyte density, and collagen fiber organization in eyes with KCN that underwent transepithelial CXL 3 months before PKP.113 These and earlier reports support epithelium-on as being less invasive, but more studies are needed to compare efficacy versus the traditional epithelium-off technique.

Future Directions A potpourri of interesting proof-of-concept studies in rabbit eyes may lead to improvements in CXL safety and are worth mentioning. Ultrasound was found to increase uptake of riboflavin in rabbit eyes with epithelium-on.114 The substitution of green for UV-A light, together with rose bengal for riboflavin, was found to have oxygen-dependent cross-linking effects without evident corneal toxicity and a stromal penetration depth of only 120 Km. The authors suggest that this technique could be advantageous in especially thin corneas.115 Finally, some investigations may change the way we stage and treat KCN. A prospective trial confirmed that photorefractive keratectomy combined with CXL significantly improved BCVA in progressive KCN versus CXL alone.116 The effect was stable within the follow-up period of 2 years. Corneal cross-linking was performed epithelium-off, with the epithelium having been ablated through photorefractive keratectomy. Meanwhile, a novel * 2015 Asia Pacific Academy of Ophthalmology


OCT-based classification system of keratoconus staging was proposed based on a cross-sectional study of 218 eyes.117 Interestingly, OCT revealed that the corneal epithelium thins in early-stage KCN and thickens in later stages. The latter can mask advanced stromal thinning when pachymetry is considered alone. This may explain CXL cases where pachymetry becomes unexpectedly thin after routine epithelial debridement. Screening with OCT, particularly an epithelial thickness map, may allow surgeons to anticipate such cases and plan accordingly.

Other Indications The CXL data for infectious keratitis and bullous keratopathy continue to be mixed. Regarding infectious keratitis, 1 study noted that the frequent use of fluorescein (eg, to monitor ulcer size) may compete with riboflavin and explain inconsistencies in efficacy.118 The authors recommend not staining the cornea with fluorescein before CXL. A protocol using hypoosmolar riboflavin through the epithelial defect without additional deepithelialization, which was dubbed as CXL window absorption by the authors, was successful in a small series of infectious keratitis refractory to topical and systemic antibiotics.119 Meanwhile, in vitro studies did not show antimicrobial efficacy of CXL against Candida albicans or Fusarium solani,120 or Acanthamoeba.121 Some of the reported activity of CXL in infectious keratitis may be caused by other mechanisms, such as inhibition of corneal melting per 1 meta-analysis.122 The mechanism of inhibition may be via the matrix metalloproteinase resistance of cross-linked collagen types I and IV.123 Finally, a prospective study of CXL for pseudophakic bullous keratopathy found that improvements in symptoms, vision, and central pachymetry were greatest at 1 month and appeared temporary.124

CONCLUSIONS This annual installment reviews noteworthy cornea-related literature that the authors deem particularly relevant. The review is limited by the key words and journals included in the literature search and the exclusion of other excellent studies published within the same period, which in itself highlights the pace of discovery in the field. These are exciting times to care for corneal disease. The ophthalmologist’s growing armamentarium allows increasingly targeted therapy especially in the areas of keratoplasty, infectious keratitis, and cross-linking. As always, each answer leads to more new questions such that further studies are needed. REFERENCES 1. Chew AC, Mehta JS, Tan DT. One year of cornea research in reviewV2012. APJO. 2013;2:401Y413. 2. Busin M, Madi S, Santorum P, et al. Ultrathin Descemet’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique/two-year outcomes. Ophthalmology. 2013;120:1186Y1194. 3. Bucher F, Roters S, Mellein A, et al. ‘‘OSMO-UT-DSAEK’’ using THIN-C medium. Graefes Arch Clin Exp Ophthalmol. 2013;251:2181Y2185. 4. Rosa AM, Silva MF, Quadrado MJ, et al. Femtosecond laser and microkeratome-assisted Descemet stripping endothelial keratoplasty/ first clinical results. Br J Ophthalmol. 2013;97:1104Y1107. 5. Phillips PM, Phillips LJ, Saad HA, et al. ‘‘Ultrathin’’ DSAEK tissue prepared with a low-pulse energy, high-frequency femtosecond laser. Cornea. 2013;32:81Y86. 6. Vetter JM, Butsch C, Faust M, et al. Irregularity of the posterior corneal surface after curved interface femtosecond laser-assisted versus microkeratome-assisted Descemet stripping automated endothelial keratoplasty. Cornea. 2013;32:118Y124. 7. Heinzelmann S, Maier P, Bo¨hringer D, et al. Visual outcome and histological findings following femtosecond laser-assisted versus

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microkeratome-assisted DSAEK. Graefes Arch Clin Exp Ophthalmol. 2013;251:1979Y1985. 8. Tang M, Stoeger C, Galloway J, et al. Evaluating DSAEK graft deturgescence in preservation medium after microkeratome cut with optical coherence tomography. Cornea. 2013;32:847Y850. 9. Ruzza A, Salvalaio G, Bruni A, et al. Banking of donor tissues for Descemet stripping automated endothelial keratoplasty. Cornea. 2013;32:70Y75. 10. Yamazoe K, Yamazoe J, Shinozaki N, et al. Influence of the precutting and overseas transportation of corneal grafts for Descemet stripping automated endothelial keratoplasty on donor endothelial cell loss. Cornea. 2013;32:741Y744. 11. Hirayama Y, Satake Y, Hirayama M, et al. Changes in corneal sensation, epithelial damage, and tear function after Descemet stripping automated endothelial keratoplasty. Cornea. 2013;32:1255Y1259. 12. Patel SV, McLaren JW. In vivo confocal microscopy of Fuchs endothelial dystrophy before and after endothelial keratoplasty. JAMA Ophthalmol. 2013;131:611Y618. 13. Arnalich-Montiel F, Hernańdez-Verdejo JL, Oblanca N, et al. Comparison of corneal haze and visual outcome in primary DSAEK versus DSAEK following failed DMEK. Graefes Arch Clin Exp Ophthalmol. 2013;251:2575Y2584.

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26. Hjortdal J, Pedersen IB, Bak-Nielsen S, et al. Graft rejection and graft failure after penetrating keratoplasty or posterior lamellar keratoplasty for Fuchs endothelial dystrophy. Cornea. 2013;32:e60Ye63. 27. Ezon I, Shih CY, Rosen LM, et al. Immunologic graft rejection in Descemet’s stripping endothelial keratoplasty and penetrating keratoplasty for endothelial disease. Ophthalmology. 2013;120: 1360Y1365. 28. Droutsas K, Giallouros E, Melles GR, et al. Descemet membrane endothelial keratoplasty: learning curve of a single surgeon. Cornea. 2013;32:1075Y1079. 29. Schlo¨tzer-Schrehardt U, Bachmann BO, Tourtas T, et al. Reproducibility of graft preparations in Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2013;120:1769Y1777. 30. Feng MT, Burkhart ZN, Price FW Jr, et al. Effect of donor preparation-to-use times on Descemet membrane endothelial keratoplasty outcomes. Cornea. 2013;32:1080Y1082. 31. Heindl LM, Riss S, Adler W, et al. Split cornea transplantation/ relationship between storage time of split donor tissue and outcome. Ophthalmology. 2013;120:899Y907. 32. Muraine M, Gueudry J, He Z, et al. Novel technique for the preparation of corneal grafts for Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2013;156:851Y859.

14. de Sanctis U, Damiani F, Brusasco L, et al. Refractive error after cataract surgery combined with Descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2013;156:254Y259.

33. Guëll JL, Morral M, Gris O, et al. Bimanual technique for insertion and positioning of endothelium-Descemet membrane graft in Descemet membrane endothelial keratoplasty. Cornea. 2013;32:1521Y1526.

15. Hindman HB, Huxlin KR, Pantanelli SM, et al. Post-DSAEK optical changes: a comprehensive prospective analysis on the role of ocular wavefront aberrations, haze, and corneal thickness. Cornea. 2013;32:1567Y1577.

34. Liarakos VS, Dapena I, Ham L, et al. Intraocular graft unfolding techniques in Descemet membrane endothelial keratoplasty. JAMA Ophthalmol. 2013;131:29Y35.

16. Daoud YJ, Munro AD, Delmonte DD, et al. Effect of cornea donor graft thickness on the outcome of Descemet stripping automated endothelial keratoplasty surgery. Am J Ophthalmol. 2013;156:860Y866. 17. Phillips PM, Phillips LJ, Maloney CM. Preoperative graft thickness measurements do not influence final BSCVA or speed of vision recovery after Descemet stripping automated endothelial keratoplasty. Cornea. 2013;32:1423Y1427.

35. Burkhart ZN, Feng MT, Price MO, et al. Handheld slit beam techniques to facilitate DMEK and DALK. Cornea. 2013;32:722Y724. 36. Steven P, Le Blanc C, Velten K, et al. Optimizing Descemet membrane endothelial keratoplasty using intraoperative optical coherence tomography. JAMA Ophthalmol. 2013;131:1135Y1142. 37. McKee Y, Price MO, Gunderson L, et al. Rapid sequential endothelial keratoplasty with and without combined cataract extraction. J Cataract Refract Surg. 2013;39:1372Y1376.

18. Woodward MA, Raoof-Daneshvar D, Mian S, et al. Relationship of visual acuity and lamellar thickness in Descemet stripping automated endothelial keratoplasty. Cornea. 2013;32:e69Ye73.

38. Anshu A, Price MO, Price FW Jr, et al. Descemet membrane endothelial keratoplasty and hybrid techniques for managing failed penetrating grafts. Cornea. 2013;32:1Y4.

19. Dickman MM, Cheng YY, Berendschot TT, et al. Effects of graft thickness and asymmetry on visual gain and aberrations after Descemet stripping automated endothelial keratoplasty. JAMA Ophthalmol. 2013;131:737Y744.

39. Quilendrino R, Yeh RY, Dapena I, et al. Large diameter Descemet membrane endothelial keratoplasty in buphthalmic eyes. Cornea. 2013;32:e74Ye78.

20. Anshu A, Price MO, Price FWJr. Descemet stripping automated endothelial keratoplasty for Fuchs endothelial dystrophyVinfluence of graft diameter on endothelial cell loss. Cornea. 2013;32:5Y8. 21. Vira S, Shih CY, Ragusa N, et al. Textural interface opacity after Descemet stripping automated endothelial keratoplasty: a report of 30 cases and possible etiology. Cornea. 2013;32:e54Ye59. 22. Maier AK, Klamann MK, Torun N, et al. Intraocular pressure elevation and post-DSEK glaucoma after Descemet’s stripping endothelial keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2013;251:1191Y1198. 23. Yin D, Huang A, Warrow D, et al. Detection of herpes simplex virus type 1 in failed Descemet stripping automated endothelial keratoplasty grafts. Cornea. 2013;32:1189Y1192. 24. Ang M, Sng CC, Chee SP, et al. Outcomes of corneal transplantation for irreversible corneal decompensation secondary to corneal endotheliitis in Asian eyes. Am J Ophthalmol. 2013;156:260Y266. 25. Price MO, Gorovoy M, Price FW Jr, et al. Descemet’s stripping automated endothelial keratoplasty/three-year graft and endothelial cell survival compared with penetrating keratoplasty. Ophthalmology. 2013;120:246Y251.

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40. Kobayashi A, Yokogawa H, Yamazaki N, et al. In vivo laser confocal microscopy after Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2013;120:923Y930. 41. van Dijk K, Parker J, Liarakos VS, et al. Incidence of irregular astigmatism eligible for contact lens fitting after Descemet membrane endothelial keratoplasty. J Cataract Refract Surg. 2013;39:1036Y1046. 42. Dapena I, Yeh RY, Baydoun L, et al. Potential causes of incomplete visual rehabilitation at 6 months postoperative after Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2013;156:780Y788. 43. Mannis MJ, Holland EJ, Gal RL, et al. The effect of donor age on penetrating keratoplasty for endothelial disease: graft survival after 10 years in the Cornea Donor Study. Ophthalmology. 2013;120:2419Y2427. 44. Lass JH, Benetz BA, Gal RL, et al. Donor age and factors related to endothelial cell loss 10 years after penetrating keratoplasty: Specular Microscopy Ancillary Study. Ophthalmology. 2013;120:2428Y2435. 45. Benetz BA, Lass JH, Gal RL, et al. Endothelial morphometric measures to predict endothelial graft failure after penetrating keratoplasty. JAMA Ophthalmol. 2013;131:601Y608. 46. Verdier DD, Sugar A, Baratz K, et al. Corneal thickness as a predictor of corneal transplant outcome. Cornea. 2013;32:729Y736.

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47. Woodward MA, Ross KW, Requard JJ, et al. Impact of surgeon acceptance parameters on cost and availability of corneal donor tissue for transplantation. Cornea. 2013;32:737Y740. 48. Aldave AJ, DeMatteo J, Glasser DB, et al. Report of the Eye Bank Association of America medical advisory board subcommittee on fungal infection after corneal transplantation. Cornea. 2013;32:149Y154. 49. Linke SJ, Fricke OH, Eddy MT, et al. Risk factors for donor cornea contamination: retrospective analysis of 4546 procured corneas in a single eye bank. Cornea. 2013;32:141Y148. 50. Bruinsma M, Lie JT, Groeneveld-van Beek EA, et al. Are polymegethism, pleomorphism, and ‘‘poor swelling’’ valid discard parameters in immediate postmortem evaluation of human donor corneal endothelium? Cornea. 2013;32:285Y289. 51. Magalhaes OA, Marinho DR, Kwitko S. Topical 0.03% tacrolimus preventing rejection in high-risk corneal transplantation: a cohort study. Br J Ophthalmol. 2013;97:1395Y1398. 52. Dua HS, Faraj LA, Said DG, et al. Human corneal anatomy redefined: a novel pre-Descemet’s layer (Dua’s layer). Ophthalmology. 2013;120: 1778Y1785. 53. Jester JV, Murphy CJ, Winkler M, et al. Lessons in corneal structure and mechanics to guide the corneal surgeon. Ophthalmology. 2013;120: 1715Y1717. 54. Schwab IR. Who’s on first? Ophthalmology. 2013;120:1718Y1719. 55. Kim MH, Chung TY, Chung ES. A retrospective contralateral study comparing deep anterior lamellar keratoplasty with penetrating keratoplasty. Cornea. 2013;32:385Y389. 56. Cheng J, Qi X, Zhao J, et al. Comparison of penetrating keratoplasty and deep lamellar keratoplasty for macular corneal dystrophy and risk factors of recurrence. Ophthalmology. 2013;120:34Y39. 57. Sogutlu Sari E, Kubaloglu A, Unal M, et al. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for macular corneal dystrophy: a randomized trial. Am J Ophthalmol. 2013;156:267Y274. 58. Baradaran-Rafii A, Eslani M, Sadoughi MM, et al. Anwar versus Melles deep anterior lamellar keratoplasty for keratoconus: a prospective randomized clinical trial. Ophthalmology. 2013;120:252Y259. 59. Zare M, Feizi S, Hasani H, et al. Comparison of Descemet-on versus Descemet-off deep anterior lamellar keratoplasty. Cornea. 2013;32: 1437Y1440. 60. Muftuoglu O, Toro P, Hogan RN, et al. Sarnicola air-visco bubble technique in deep anterior lamellar keratoplasty. Cornea. 2013;32: 527Y532. 61. Scorcia V, Busin M, Lucisano A, et al. Anterior segment optical coherence tomography-guided big-bubble technique. Ophthalmology. 2013;120:471Y476. 62. Vajpayee RB, Maharana PK, Sharma N, et al. Diamond knife-assisted deep anterior lamellar keratoplasty to manage keratoconus. J Cataract Refract Surg. 2014;40:276Y282. 63. Rama P, Knutsson KA, Razzoli G, et al. Deep anterior lamellar keratoplasty using an original manual technique. Br J Ophthalmol. 2013;97:23Y27. 64. Lange AP, Moloney G, Arino M, et al. Enzyme-assisted deep anterior lamellar keratoplastyVa new method of lamellar dissectionVa wetlab-based pilot study. Cornea. 2013;32:98Y103. 65. Shehadeh-Mashor R, Chan C, Yeung SN, et al. Long-term outcomes of femtosecond laserYassisted mushroom configuration deep anterior lamellar keratoplasty. Cornea. 2013;32:390Y395.


68. Paschalis EI, Chodosh J, Spurr-Michaud S, et al. In vitro and in vivo assessment of titanium surface modification for coloring the backplate of the Boston keratoprosthesis. Invest Ophthalmol Vis Sci. 2013;54:3863Y3873. 69. Sivaraman KR, Hou JH, Allemann N, et al. Retroprosthetic membrane and risk of sterile keratolysis in patients with type 1 Boston keratoprosthesis. Am J Ophthalmol. 2013;155:814Y822. 70. Cruzat A, Shukla A, Cohlman CH, et al. Wound anatomy after type 1 Boston KPro using oversized back plates. Cornea. 2013;32:1531Y1536. 71. Shapiro BL, Cortes DE, Chin EK, et al. High-resolution spectral domain anterior segment optical coherence tomography in type 1 Boston keratoprosthesis. Cornea. 2013;32:951Y955. 72. Ziai S, Rootman DS, Slomovic AR, et al. Oral buccal mucous membrane allograft with a corneal lamellar graft for the repair of Boston type 1 keratoprosthesis stromal melts. Cornea. 2013;32:1516Y1519. 73. Feng MT, Burkhart ZN, McKee Y, et al. A technique to rescue keratoprosthesis melts. Cornea. 2013;32:1407Y1411. 74. Palioura S, Kim B, Dohlman CH, et al. The Boston keratoprosthesis type 1 in mucous membrane pemphigoid. Cornea. 2013;32:956Y961. 75. Robert MC, Pomerleau V, Harissi-Dagher M. Complications associated with Boston keratoprosthesis type 1 and glaucoma drainage devices. Br J Ophthalmol. 2013;97:573Y577. 76. Kang JJ, Allemann N, Cruz JD, et al. Serial analysis of anterior chamber depth and angle status using anterior segment optical coherence tomography after Boston keratoprosthesis. Cornea. 2013;32:1369Y1374. 77. Lee SH, Mannis MJ, Shapiro B, et al. Evaluation of microbial flora in eyes with a Boston type 1 keratoprosthesis. Cornea. 2013;32:1537Y1539. 78. Robert MC, Eid EP, Saint-Antoine P, et al. Microbial colonization and antibacterial resistance patterns after Boston type 1 keratoprosthesis. Ophthalmology. 2013;120:1521Y1528. 79. Kim MJ, Yu F, Aldave AJ. Microbial keratitis after Boston type 1 keratoprosthesis implantation: incidence, organisms, risk factors, and outcomes. Ophthalmology. 2013;120:2209Y2216. 80. Inoue T, Ohashi Y. Utility of real-time PCR analysis for appropriate diagnosis for keratitis. Cornea. 2013;32:S71YS76. 81. Bhadange Y, Sharma S, Das S, et al. Role of liquid culture media in the laboratory diagnosis of microbial keratitis. Am J Ophthalmol. 2013;156:745Y751. 82. Hoffmann S, Szentma´ry N, Seitz B. Amniotic membrane transplantation for the treatment of infectious ulcerative keratitis before elective penetrating keratoplasty. Cornea. 2013;32:1321Y1325. 83. Kowalski RP, Kowalski TA, Shanks RM, et al. In vitro comparison of combination and monotherapy for the empiric and optimal coverage of bacterial keratitis based on incidence of infection. Cornea. 2013;32: 830Y834. 84. Sharma N, Goel M, Bansal S, et al. Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial. Ophthalmology. 2013;120:1173Y1178. 85. Suzuki T, Ohashi Y. Combination effect of antibiotics against bacteria isolated from keratitis using fractional inhibitory concentration index. Cornea. 2013;32:e156Ye160. 86. Tu EY, Jain S. Topical linezolid 0.2% for the treatment of vancomycin-resistant or vancomycin-intolerant gram-positive bacterial keratitis. Am J Ophthalmol. 2013;155:1095Y1098.

66. Rixen JJ, Cohen AW, Kitzmann AS, et al. Treatment of aniridia with Boston type 1 keratoprosthesis. Cornea. 2013;32:947Y950.

87. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131:422Y429.

67. Ciolino JB, Belin MW, Todani A, et al. Retention of the Boston keratoprosthesis type 1: multicenter study results. Ophthalmology. 2013;120:1195Y1200.

88. Rogers GM, Goins KM, Sutphin JE, et al. Outcomes of treatment of fungal keratitis at the University of Iowa Hospitals and Clinics: a 10-year retrospective analysis. Cornea. 2013;32:1131Y1136.


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89. Young AL, Leung KS, Tsim N, et al. Risk factors, microbiological profile, and treatment outcomes of pediatric microbial keratitis in a tertiary care hospital in Hong Kong. Am J Ophthalmol. 2013;156:1040Y1044.

107. Kopsachilis N, Tsaousis KT, Tsinopoulos IT, et al. A novel mechanism of UV-A and riboflavin-mediated corneal cross-linking through induction of tissue transglutaminases. Cornea. 2013;32:1034Y1039.

90. Zhang X, Igo RP Jr, Fondran J, et al. Association of smoking and other risk factors with Fuchs’ endothelial corneal dystrophy severity and corneal thickness. Invest Ophthalmol Vis Sci. 2013;54:5829Y5835.

108. Messmer EM, Meyer P, Herwig MC, et al. Morphological and immunohistochemical changes after corneal cross-linking. Cornea. 2013;32:111Y117.

91. Schrems-Hoesl LM, Schrems WA, Cruzat A, et al. Cellular and subbasal nerve alterations in early stage Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study. Eye (Lond). 2013;27:42Y49.

109. Mastropasqua L, Nubile M, Calienno R, et al. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol. 2014;157:623Y630.

92. Koizumi N, Okumura N, Ueno M, et al. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea. 2013;32:1167Y1170. 93. Ziaei A, Schmedt T, Chen Y, et al. Sulforaphane decreases endothelial cell apoptosis in Fuchs endothelial corneal dystrophy: a novel treatment. Invest Ophthalmol Vis Sci. 2013;54:6724Y6734. 94. Aldave AJ, Ann LB, Frausto RF, et al. Classification of posterior polymorphous corneal dystrophy as a corneal ectatic disorder following confirmation of associated significant corneal steepening. JAMA Ophthalmol. 2013;131:1583Y1590. 95. Lamy R, Netto CF, Reis RG, et al. Effects of corneal cross-linking on contrast sensitivity, visual acuity, and corneal topography in patients with keratoconus. Cornea. 2013;32:591Y596. 96. Yam JC, Cheng AC. Reduced cross-linking demarcation line depth at the peripheral cornea after corneal collagen cross-linking. J Refract Surg. 2013;29:49Y53. 97. Kymionis GD, Grentzelos MA, Plaka AD, et al. Evaluation of the corneal collagen cross-linking demarcation line profile using anterior segment optical coherence tomography. Cornea. 2013;32:907Y910. 98. Arora R, Jain P, Goyal JL, et al. Comparative analysis of refractive and topographic changes in early and advanced keratoconic eyes undergoing corneal collagen crosslinking. Cornea. 2013;32:1359Y1364. 99. Ivarsen A, Hjortdal J. Collagen cross-linking for advanced progressive keratoconus. Cornea. 2013;32:903Y906. 100. Vinciguerra R, Romano MR, Camesasca FI, et al. Corneal cross-linking as a treatment for keratoconus: four-year morphologic and clinical outcomes with respect to patient age. Ophthalmology. 2013;120: 908Y916. 101. Hashemi H, Seyedian MA, Miraftab M, et al. Corneal collagen cross-linking with riboflavin and ultraviolet a irradiation for keratoconus: long-term results. Ophthalmology. 2013;120:1515Y1520. 102. O’Brart DP, Kwong TQ, Patel P, et al. Long-term follow-up of riboflavin/ultraviolet A 9370 nm) corneal collagen cross-linking to halt the progression of keratoconus. Br J Ophthalmol. 2013;97:433Y437. 103. Richoz O, Mavrakanas N, Pajic B, et al. Corneal collagen cross-linking for ectasia after LASIK and photorefractive keratectomy: long-term results. Ophthalmology. 2013;120:1354Y1359.

110. Magli A, Forte R, Tortori A, et al. Epithelium-off corneal collagen cross-linking versus transepithelial cross-linking for pediatric keratoconus. Cornea. 2013;32:597Y601. 111. Ghanem VC, Ghanem RC, de Oliveira R. Postoperative pain after corneal collagen cross-linking. Cornea. 2013;32:20Y24. 112. Mastropasqua L, Nubile M, Lanzini M, et al. Morphological modification of the cornea after standard and transepithelial corneal cross-linking as imaged by anterior segment optical coherence tomography and laser scanning in vivo confocal microscopy. Cornea. 2013;32:855Y861. 113. Mencucci R, Paladin I, Sarchielli E, et al. Transepithelial riboflavin/ ultraviolet a corneal cross-linking in keratoconus: morphologic studies on human corneas. Am J Ophthalmol. 2013;156:874Y884. 114. Lamy R, Chan E, Zhang H, et al. Ultrasound-enhanced penetration of topical riboflavin into the corneal stroma. Invest Ophthalmol Vis Sci. 2013;54:5908Y5912. 115. Cherfan D, Verter EE, Melki S, et al. Collagen cross-linking using rose bengal and green light to increase corneal stiffness. Invest Ophthalmol Vis Sci. 2013;54:3426Y3433. 116. Alessio G, L’Abbate M, Sborgia C, et al. Photorefractive keratectomy followed by cross-linking versus cross-linking alone for management of progressive keratoconus: two-year follow-up. Am J Ophthalmol. 2013;155:54Y65. 117. Sandali O, El Sanharawi M, Temstet C, et al. Fourier-domain optical coherence tomography imaging in keratoconus: a corneal structural classification. Ophthalmology. 2013;120:2403Y2412. 118. Richoz O, Gatzioufas Z, Francois P, et al. Impact of fluorescein on the antimicrobial efficacy of photoactivated riboflavin in corneal collagen cross-linking. J Refract Surg. 2013;29:842Y845. 119. Rosetta P, Vinciguerra R, Romano MR, et al. Corneal collagen cross-linking window absorption. Cornea. 2013;32:550Y554. 120. Kashiwabuchi RT, Carvalho FR, Khan YA, et al. Assessment of fungal viability after long-wave ultraviolet light irradiation combined with riboflavin administration. Graefes Arch Clin Exp Ophthalmol. 2013;251:521Y527. 121. Berra M, Galperin G, Boscaro G, et al. Treatment of Acanthamoeba keratitis by corneal cross-linking. Cornea. 2013;32:174Y178.

104. Taneri S, Oehler S, Asimellis G, et al. Influence of corneal cross-linking for keratoconus on several objective parameters of dry eye. J Refract Surg. 2013;29:612Y616.

122. Alio JL, Abbouda A, Valle DD, et al. Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect. 2013;3:47.

105. Kontadakis GA, Kymionis GD, Kankariya VP, et al. Effect of corneal collagen cross-linking on corneal innervation, corneal sensitivity, and tear function of patients with keratoconus. Ophthalmology. 2013;120: 917Y922.

123. Zhang Y, Mao X, Schwend T, et al. Resistance of corneal RFUVA-cross-linked collagens and small leucine-rich proteoglycans to degradation by matrix metalloproteinases. Invest Ophthalmol Vis Sci. 2013;54:1014Y1025.

106. Gatzioufas Z, Richoz O, Brugnoli E, et al. Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. J Refract Surg. 2013;29:846Y848.

124. Arora R, Manudhane A, Saran RK, et al. Role of corneal collagen cross-linking in pseudophakic bullous keratopathy: a clinicopathological study. Ophthalmology. 2013;120:2413Y2418.

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Artificial Organs 2013: a year in review.

Clinical trials update - 2013: year in review.

The year in review: perioperative medicine 2013.

Clinical trials update. 2013: year in review.

Year in review 2013: Critical Care - nephrology.

One Year of Glaucoma Research in Review: 2012 to 2013.

The year in review: anesthesia for congenital heart disease 2013.

Year in review 2013: basic science and epidemiology.

2013, a very good year.

A review of collagen cross-linking in cornea and sclera.

A Two-Year Review on Epidemiology and Clinical Characteristics of Dengue Deaths in Malaysia, 2013-2014.

Highlights of the year in JACC 2013.

A year in review.

Journal of Artificial Organs 2013: the year in review : Journal of Artificial Organs Editorial Committee.

[Student program 2013 : a review].

2013 in review.

Lung transplantation: SEPAR year 2013.

The Year in Cardiology 2013: coronary intervention.

The Year in Cardiology 2013: arrhythmias.

The Year in Cardiology 2013: heart failure.

Year in review 2013: Acute lung injury, interstitial lung diseases, sleep and physiology.

Year in review 2013: Chronic obstructive pulmonary disease, asthma and airway biology.

Respiratory Care year in review 2013: airway management, noninvasive monitoring, and invasive mechanical ventilation.

RCGP Research Paper of the Year 2013.