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Persistent Corneal Edema after Collagen Cross-Linkingfor Keratoconus

ASHOK SHARMA, JENNIFER MARIE NOTTAGE, KANISH MIRCHIA, RAJAN SHARMA, KANWAR MOHAN,

AND VERINDER SINGH NIRANKARI

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● PURPOSE: To present a new complication of persistentorneal edema after collagen cross-linking (CXL) ineratoconus patients.

● DESIGN: Retrospective case series of postoperativeorneal edema after CXL.

● METHODS: STUDY POPULATION: All patients who under-went CXL treatment with subsequent corneal edema.Patients with stromal haze were excluded. INTERVENTION:The CXL treatments used the Dresden protocol withcorneal thickness of more than 400 �m after epitheliumwas removed. MAIN OUTCOME MEASURE: The resolution ofcorneal edema after surgery.● RESULTS: Postoperative corneal edema was identifiedn 10 (2.9%) of 350 patients who were followed up for

mean of 14 � 4 months. The edema started onostoperative day 1 (10/10) and increased for 3 weeks.dditional findings included: deep vascularization (2

yes; 20%), iris atrophy (6 eyes; 60%), pigment disper-ion (5 eyes; 50%), persistent epithelial defect (3 eyes;0%), and infectious keratitis (1 eye; 10%). Specularicroscopy was unsuccessful, but the fellow untreated

yes had normal endothelial counts. Intraocular pressurend lenticular evaluations were normal. Corneal edemamproved in 4 patients and resolved in 1 patient. In these

patients, the logarithm of the minimal angle of resolu-ion best-corrected visual acuity was 0.5 � 0.18. Pene-rating keratoplasty was offered to 5 patients whenmprovement plateaued at 3 months, but only 2 patientsnderwent penetrating keratoplasty.

● CONCLUSIONS: CXL is a safe and effective procedureith few known side effects. This case series reports theossibility of corneal endothelial damage with visuallyignificant corneal edema after CXL treatment. Based onhe extent of endothelial damage, patients may requireenetrating keratoplasty. (Am J Ophthalmol 2012;54:922–926. © 2012 by Elsevier Inc. All rightseserved.)

Accepted for publication June 6, 2012.From the Cornea Centre, Chandigarh, India (A.S., K.Mo.); the

Cornea Service, Eye Consultants of Maryland, Owings Mills, Maryland(J.M.N., V.S.N.); the Government Medical College and Hospital, Chan-digarh, India (K.Mi.); the Maharishi Markandeshwar Institute of MedicalScience and Research, Haryana, India (R.S.); and the Department ofOphthalmology, University of Maryland, Baltimore, Maryland (V.S.N.).

Inquiries to Verinder S. Nirankari, Cornea Service, Eye Consultants ofMaryland, 21 Crossroads Drive, Suite 425, Owings Mills, MD 21117;

e-mail: vnirankari@aol.com

© 2012 BY ELSEVIER INC. A22

K ERATOCONUS IS A BILATERAL, ASYMMETRIC, NON-

inflammatory, progressive ectatic degeneration re-sulting in stromal thinning and distortion of the

ornea. Depending on the severity and progression of theisease, it can be treated with spectacles, rigid gas perme-ble contact lenses, intracorneal ring segments, deep an-erior lamellar keratoplasty, or penetrating keratoplasty.1–5

Recently, collagen cross-linking (CXL) with riboflavindrops has been reported to be effective in increasing thebiomechanical strength and stability of the cornea.6–8

CXL, if preformed according to standard protocols, hasbeen found to be a safe procedure.9,10 Despite the highsafety profile reported, there are a few reports of adverseevents after CXL. Persistent corneal haze is one of themore frequently reported complications of CXL.11–13 Inaddition, a few cases of infectious keratitis after CXL havebeen reported.14,15 Furthermore, Gokhale recently re-orted a single case of CXL-induced corneal endothelialell damage resulting in corneal edema.16 We observedeveral cases of persistent corneal edema after CXL forreatment of progressive keratoconus and have evaluatedhis case series of 10 patients.

METHODS

AFTER APPROVAL FROM THE CORNEA CENTRE INSTITU-

tional Review Board, a retrospective chart review of allpatients treated with CXL for progressive keratoconus fromJuly 1, 2008, through June 30, 2011, was conducted. Thesecharts were reviewed for any complications of the treat-ment. Patients who were treated for persistent stromal hazewere excluded from the study. Patients in whom cornealedema developed that persisted for more than 3 weeks wereincluded in the study.

Data acquisition included preoperative and postopera-tive best-corrected visual acuity, refraction, keratometry,pachymetry, and corneal topography. Pachymetry readingswere obtained from a Pentacam (Pentacam Oculyzer;Oculus Optikgerate GmbH, Heidelberg, Germany) toeliminate the chance of missing the thinnest point in thecornea that could be missed by ultrasonic pachymeter. Thedetails of the surgical procedure, including frequency ofriboflavin drops, total energy delivered, and any deviation

from the Dresden protocol, were recorded. The postoper-

LL RIGHTS RESERVED. 0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2012.06.005

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ative anterior segment findings and duration of symptomsalso were evaluated.

● COLLAGEN CROSS-LINKING PROCEDURE: The CXLtreatment was preformed as an outpatient procedure fol-lowing the Dresden protocol by an experienced ophthal-mologist (K.Mi.).17 The treatment was performed underterile conditions in an operating theater. After obtainingnformed consent, the ocular surface was anesthetized withopical proparacaine hydrochloride 0.5% solution. Anyelid speculum was inserted, and the corneal epitheliumas removed using a hockey stick blade (Grieshaber;lcon, Schaffhausen, Switzerland). The epithelium was

ebrided to expose 80% to 90% of the central cornea. Theorneal thickness was measured after the epithelium wasemoved to confirm a thickness of more than 400 �m in allases. Next, isotonic riboflavin 0.1% drops (Medio-Cross;edizinprodukte GmbH, Neudorf, Germany) were in-

tilled every 2 minutes for 30 minutes, concurrent withnstillation of topical proparacaine. The corneas then werexposed to ultraviolet A light (UV-X System; Peschkeeditrade GmbH, Huenenberg, Switzerland) for 30 min-

tes. Administration of additional isotonic riboflavin dropsccurred every 3 minutes during the ultraviolet A expo-ure. The parameters of emitted ultraviolet light included:avelength, 370 nm; irradiance, 3 mW/cm2; and diameter,.5 mm. A calibrated ultraviolet meter was used to confirmhe irradiance (3.0 mW/cm2) before each treatment ses-ion; however, the corneal thickness was not remeasureduring the ultraviolet exposure. After completion of ultra-iolet A exposure, the eyelid speculum was removed and arop of moxifloxacin hydrochloride ophthalmic solution

TABLE. Investigational Parameters for Patients in Whom PeTreatment for Pro

Patient

No.

Age

(y) Sex

VA Max K

Preoperative Postoperative Preoperative Postope

1 17 M 0.00 0.20 53.8 48

2a 21 F 0.00 0.80 51.2 50

3a 24 M 0.00 0.20 59.8 49

4b 20 M 0.20 1.00 59.4 56

5 29 F 0.00 0.50 57.9 55

6b 16 M 0.00 1.00 53.8 54

7 32 F 0.00 0.30 58.3 55

8 26 M 0.00 0.60 56.9 54

9 16 M 0.00 0.60 59.5 57

10b 22 M 0.20 0.80 56.9 54

CCT � central or minimal corneal thickness; F � female; M � ma

y � year.aPatients who underwent penetrating keratoplasty after cross-linbPatients offered penetrating keratoplasty after cross-linking, but

.5% (Cipla Ltd, Roorkee, India) was instilled. An eye pad

PERSISTENT CORNEAL EDEMA AFTEVOL. 154, NO. 6

nd shield then were applied. The standard postoperativereatment included both moxifloxacin hydrochloride oph-halmic solution 0.5% and carboxymethyl cellulose (Al-ergan, Karnataka, India) 4 times daily. For pain control,he patient also was prescribed Combiflam (combinationill of ibuprofen and acetaminophen; Aventis, Akhlesh-ar, India) as needed for 2 to 3 days. After the cornealpithelium healed, fluorometholone drops were addedwice daily for 2 weeks followed by a taper to once daily forweeks. If the patient had a nonhealing epithelial defect,

hen a bandage contact lens was placed.Those patients in whom corneal edema developed were

rescribed prednisolone acetate 1.0% drops (Allergan) 3imes daily, carboxymethylcellulose 1% (Allergan) 4 timesaily, and homatropine 1% (Bell Pharma, Mumbai, India)wice daily. Topical steroids were stopped after 6 weeks ofreatment.

RESULTS

OF THE 520 CHARTS OF PATIENTS WITH PROGRESSIVE KERA-

toconus that were reviewed, 350 consecutive patients re-ceived CXL from a referring ophthalmologist. Of these,postoperative corneal edema developed in 10 (10/350; 2.9%).Three patients (3/350; 0.9%) were excluded: 1 because ofstromal haze, 1 because of infectious keratitis without cornealedema, and 1 because of corneal melt. No intraoperativecomplications were noted at the time of CXL treatment. Theaverage age was 22 � 5 years (range, 16 to 32 years). Patientswere followed up for mean of 14 � 4 months (range, 8 to 22months). Before surgery, the median logarithm of the mini-

nt Corneal Edema Developed after Collagen Cross-Linkingive Keratoconus

CCT

Follow-up

(mos)Preoperative

3 Weeks

after

Surgery

3 Months

after

Surgery

6 Months

after

Surgery

12 Months

after

Surgery

493 621 596 586 565 22

482 698 693 682 664 12

484 656 645 594 585� 18

480 695 685 663 657 8

496 598 587 585 572 10

474 687 659 633 585 15

463 620 582 571 569 16

447 678 674 628 590 14

449 634 626 597 575 16

458 658 632 609 584 12

ax K � maximum keratometry; mos � months; VA � visual acuity;

ined.

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rative

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mal angle of resolution (logMAR) best-corrected visual acu-

R COLLAGEN CROSS-LINKING 923

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ity was 0.00 � 0.08, the median maximum keratometry was7.4 � 2.90 diopters, and the mean pachymetry was 472.6 �7.5 �m. Preoperative specular microscopy was not per-ormed (Table).

In all cases, the onset of corneal edema occurred withinhe first 24 hours after the procedure, and both the cornealdema and anterior chamber inflammation increased for 2o 3 weeks. Descemet membrane was not ruptured, nor wasntraocular pressure elevated after surgery in any cases. Allatients were phakic, and there were no lens opacities afterXL. Additional anterior segment findings in the 10atients included: marked deep corneal vascularization (2yes; 22%), iris atrophy (6 eyes; 67%), pigment dispersion5 eyes; 56%), corneal epithelial defect present for more

FIGURE 1. Photograph showing corneal edema and iris atro-phy in a keratoconus patient after collagen cross-linkingtreatment.

FIGURE 2. Photograph showing corneal edema and peripheralanterior synechiae after collagen cross-linking treatment forprogressive keratoconus.

han 6 days (3 eyes; 33%), and infectious keratitis (1 eye;

AMERICAN JOURNAL OF924

1%; Figures 1 and 2). The infectious keratitis occurred inpatient with a persistent corneal epithelial defect.Specular microscopy after CXL was attempted in all

ases, but was unsuccessful because of the degree ofdema or residual stromal haze. The fellow untreatedye did not have any guttata on postoperative examina-ion. Specular microscopy was performed on the non-reated eye with an average endothelial cell count of610 � 128 cells/mm2.The median postoperative logMAR best-corrected vi-

sual acuity at the last follow up was 0.60 � 0.30 (P �.0001, Mann–Whitney U test). The postoperative visionincluded patients who required penetrating keratoplasty(PK) to obtain improved vision. The median postoperativemaximum keratometry at the last follow-up visit wasreduced to 54.7 � 3.36 diopters (P � .0043, Mann–Whitney U test). The mean postoperative pachymetrydeclined from 654.5 � 35.1 �m at 3 weeks after CXL (P �.0001, Mann–Whitney U test) to 637.9 � 40.4 �m at 3months (P � .0001, Mann–Whitney U test). It decreasedfurther to 614.8 � 36.2 �m at 6 months (P � .0001,Mann–Whitney U test) and 595.7 � 37.7 �m at 12months (P � .0001, Mann–Whitney U test). The 12-month pachymetry excluded 1 patient who underwent PKbefore this time point.

Corneal edema improved in 4 patients and resolved in 1patient. The posttreatment logMAR visual acuity for thisgroup of patients was 0.5 � 0.18. One patient hadcomplete resolution of the corneal edema and was able toresume rigid gas permeable contact lens wear withoutsequelae. Surgical options were offered to patients whenimprovement plateaued for 3 months. PK was recom-mended for 5 patients, but only 2 patients underwent PK at8 and 13 months after CXL treatment (Figure 3). For the2 patients who underwent PK, they had significant iris

FIGURE 3. Photograph showing nonresolving corneal edemaafter collagen cross-linking for progressive keratoconus treatedby penetrating keratoplasty with good visual results.

atrophy, iris prolapse, and iris billowing in response to

OPHTHALMOLOGY DECEMBER 2012

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ordinary intraocular fluid currents. This condition resem-bled intraoperative floppy iris syndrome. These 2 patientswere not taking an �-1-adrenergic blocker, and theirathology reports showed only stromal scarring and inflam-ation. Their posttreatment logMAR visual acuities were

.2 and 0.8. For the 3 patients with significant edema whoeclined PK, their posttreatment logMAR visual acuityas 1 � 0.12.

DISCUSSION

CXL HAS BEEN REPORTED TO BE A SAFE AND EFFECTIVE

treatment to increase the biomechanical strength of thecornea in keratoconus patients.18,19 The combined use ofultraviolet A irradiation with riboflavin decreases thecytotoxic irradiance level to 10 times lower than that ofultraviolet A irradiation alone.20 Studies have shown thatthe standard surface ultraviolet A irradiance of 3 mW/cm2

penetrates human keratocytes up to a depth of 300 �m.20

At the endothelial level, the irradiance is reduced to 0.15mW/cm2, which is well below the threshold consideredcytotoxic (0.36 mW/cm2).13,20–24 Despite following theseuidelines, Gokhale reported one case of CXL-inducedorneal edema in a cornea thicker than 400 �m beforeurgery.16 To our knowledge, this case is the only previ-usly reported incident of persistent corneal edema afterXL for keratoconus.It is difficult to speculate about the pathophysiologic

eatures of the corneal edema in our case series. Variousossibilities were entertained, including inadvertent deliv-ry of excessive energy, intraoperative corneal thinningesulting from corneal dehydration, inaccurate pachymetryeading during surgery, acute hydrops, and pre-existinguchs endothelial dystrophy.Several safety factors were followed to prevent inad-

ertent delivery of excessive energy, including checkinghe accuracy of the calibration device, confirming theltraviolet output, ensuring patient stability, consistentocus of the ultraviolet light source, and verifyingachymetry measurements of more than 400 �m in all

cases. Despite these measures, it is always possible thatan excessive amount of energy was applied to thecorneas in this series.

Intraoperative corneal thinning resulting from cornealdehydration from epithelial debridement is another possi-ble cause of corneal endothelial damage during CXL. In arecent study by Holopainen and Krootila, the cornealthickness decreased from more than 400 �m to 350 �m in80% of eyes over a 60-minute CXL treatment (30 minutesof riboflavin instillation without a lid speculum in placeand 30 minutes of ultraviolet treatment).25 The study didnot report any cases of corneal edema or endothelial celldamage. Corneal thinning in our patients may be higherthan that reported by Holopainen and Krootila because

the lid speculum was left in place for the 30-minute

PERSISTENT CORNEAL EDEMA AFTEVOL. 154, NO. 6

riboflavin instillation period. The corneal thickness wasnot rechecked during the ultraviolet exposure. It is possiblethat extreme intra-CXL treatment corneal thinning occur-ring during CXL in our patients may be responsible forcorneal endothelial damage. Based on this potential causeof ultraviolet light toxicity, we recommend removal of thelid speculum during the riboflavin instillation and recheck-ing the pachymetry during the ultraviolet exposure period.

Pre-existing Fuchs endothelial dystrophy also may causecorneal edema after CXL. Given the associated link betweenFuchs endothelial dystrophy and keratoconus,26 all studycorneas were evaluated before surgery for guttata by slit lamp.Preoperative specular microscopy was not performed. Postop-erative evaluation of the corneas with slit-lamp examinationand specular microscopy of the fellow eye also revealed anormal endothelium and endothelial cell count.

Of the 2 patients who underwent PK, corneal buttonspecimens were available, and stromal scarring and inflam-mation were the only reported findings. These data did notcontribute to a viable reason that patients experiencedcornea edema after CXL.

In addition to corneal edema, many patients had otheranterior segment changes that could be attributed to exces-sive ultraviolet light exposure. These changes included cor-neal neovascularization, pigment clumps on the back of thecornea, and iris atrophy. Two eyes had significant iris atrophyand intraoperative floppy iris syndrome-like changes. Persis-tent epithelial defect in 1 patient extended beyond thelimbus, suggesting limbal stem cell damage. The intraocularpressure and crystalline lens were not altered by the ultravi-olet exposure. There were no cases of uveitis in our series.Previous studies have proven that exposure to excessiveultraviolet light can cause stromal haze, endothelial dysfunc-tion, lenticular opacities, uveitis, iris changes, and retinalphototoxicity.27–30

Despite multiple anterior segment changes, half of thestudy patients (5/10) recovered endothelial functionenough to reduce corneal edema and regain functionalvision. The best-corrected logMAR visual acuity at the lastfollow-up in this subgroup was 0.60 � 0.30.

CXL is a well-known procedure that is gaining popular-ity as a treatment option for progressive keratoconus,especially given its relatively safe side-effect profile. Thiscase series reports the possibility of corneal endothelialdamage with visually significant corneal edema after CXLtreatment. Although rare, corneal endothelial damagewith subsequent corneal edema is a possible complication.Based on the extent of the endothelial damage, patientsmay require PK to obtain optimal vision. Possible means ofprevention include: ensuring that the corneal thickness ismore than 400 �m, removal of the lid speculum duringinstillation of riboflavin drops to prevent excessive thin-ning secondary to evaporation, frequent equipment cali-bration, and frequent intratreatment checks of the cornealthickness with readministration of hypotonic solution if

the thickness drops to less than 350 �m.

R COLLAGEN CROSS-LINKING 925

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OFinterest and none were reported. Involved in Design and conduct of study (A.S., J.M.N., K.Mi., R.S., K.Mo., V.S.N.); Collection, management, andanalysis of data (A.S.); and Preparation (A.S.) and review or approval (A.S., J.M.N., K.Mi., R.S., K.Mo., V.S.N.) of manuscript. This retrospective studyof patient data was approved by the Institutional Review Board from the Cornea Centre, Chandigarh.

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OPHTHALMOLOGY DECEMBER 2012

Biosketch

Ashok Sharma is the Director of Cornea Centre in Chandigarh, India, where he has served on the faculty for 11 years.He is also the founder and honorary secretary of Eye Bank Society, Chandigarh, India, and has over 80 peer-reviewedpublications. Dr Sharma also received the Achievement Award and the International Ophthalmologist Education Awardfrom the American Academy of Ophthalmology. His research interests include cornea and external diseases.

PERSISTENT CORNEAL EDEMA AFTER COLLAGEN CROSS-LINKINGVOL. 154, NO. 6 926.e1