ARTICLE

Photorefractive keratec

tomy with mitomycin-Cafter corneal transplantation for keratoconus

Chris Hodge, BAppSc, Gerard Sutton, MB BS, MD, FRANZCO, FRACS,Michael Lawless, MB BS, FRANZCO, FRACS, FRCOphth, Chris Rogers, MB BS, FRANZCO, FRACS

Q

P

1884

2011 A

ublished

PURPOSE: To evaluate the efficacy of photorefractive keratectomy (PRK) for residual refractiveerror after penetrating keratoplasty (PKP) for keratoconus.

SETTING: Private ophthalmic clinic.

DESIGN: Case series.

METHOD: Consecutive patients who had PRK augmented with topical mitomycin-C (MMC) afterPKP for keratoconus were retrospectively reviewed. Patients were divided into a a low cylindergroup (refractive cylinder %6.00 D) and a high cylinder group (refractive cylinder >6.00 D).Visual acuity, refraction, and keratometry were analyzed preoperatively and 1, 3, 6, and 12months postoperatively.

RESULTS: The study comprised 47 eyes (41 patients). The spherical equivalent (SE) decreasedfrom �4.24 D G 3.23 (SD) preoperatively to �0.71 G 1.03 D 12 months postoperatively in thelow cylinder group and from�4.19G 3.54 D to�2.45G 3.42 D, respectively, in the high cylindergroup. The refractive cylinder decreased from �4.27G 1.4 D to �1.71G 1.55 D, respectively, inthe low cylinder group and from �7.78 G 1.21 D to �4.6 G 2.54 D, respectively, in the high cyl-inder group. By the last follow-up, 8.3% of patients had lost 2 lines of corrected distance visualacuity. There were no cases of corneal haze greater than 2C or of graft rejection.

CONCLUSIONS: Penetrating keratoplasty with adjunctive MMC decreased several refractivevariables in patients with previous PKP. These results compare well with those in the publishedliterature and suggest PRK is as effective as, and probably safer than, laser in situ keratomileusisin treating refractive error in these cases.

Financial Disclosure: No author has financial or proprietary interests in any material or methodmentioned.

J Cataract Refract Surg 2011; 37:1884–1894 Q 2011 ASCRS and ESCRS

The primary measure of success of penetrating kerato-plasty (PKP) has generally been defined in terms of vi-sual acuity, graft clarity, and survival. These measuresreflect the 2 major problems with the surgery; that is,debilitating astigmatism and graft rejection.1–5

Secondary measures of success in PKP for keratoco-nus include astigmatism and the mean sphericalequivalent (SE). Olson et al.6 report the lowest meanastigmatism (2.76 diopters [D]) after PKP for keratoco-nus, with only 15% of eyes having astigmatism greaterthan 5.00 D. They also found that 77% of eyesachieved a corrected distance visual acuity (CDVA)of 6/7.5 or better. In a study by Javadi et al.3 of 164eyes that had PKP for keratoconus, the mean astigma-tismwas 3.4G 1.8 D and the mean spherical error was�0.61G 2.6 D. They found no correlation between the

SCRS and ESCRS

by Elsevier Inc.

results and trephination or suturing technique, sup-porting the later findings in a 2006 metaanalysis byFrost et al.7

Astigmatism as a measure of success appears to berelatively constant, with a reported mean value be-tween 2.75 D and 4.00 D.3,5–11 The management of sig-nificant postoperative astigmatism and anisometropiahas been most commonly treated with gas-permeablecontact lenses.12–15 Although lens designs have im-proved, many keratoconic patients have corneal trans-plantation because of their initial intolerance to contactlens wear.16 Refractive surgical procedures, such asarcuate incisions, resuturing, retrephination, wedgeexcisions, and Ruiz-type techniques, have been usedto treat post-graft astigmatism.17–24 In general, theycorrect various amounts of astigmatism but with

0886-3350/$ - see front matter

doi:10.1016/j.jcrs.2011.05.029

1885PRK WITH MMC AFTER PKP FOR KERATOCONUS

limited predictability and without allowing treatmentof anisometropia.

After the advent of photorefractive keratectomy(PRK), the technique was used to treat post-PKP re-fractive errors.25,26 The early results were variableand restricted by the development of the haze and re-gression commonly associated with significant correc-tions with all surface excimer laser procedures.27–29 Itis possible that the effect of haze was accentuated inthese cases because of the presence of already acti-vated keratocytes.30 This problem, however, can beameliorated, at least to some degree, by the use of post-operative mitomycin-C (MMC).30

Laser in situ keratomileusis (LASIK) has also beenused to treat post-PKP refractive errors again; how-ever, the results have been variable.31–39 The creationof the LASIK flap further weakens the wound andhas been suggested as a cause of unusual refractiveoutcomes and loss of CDVA.40 Intraoperative compli-cations leading to reduced visual outcomes have alsobeen reported.37,40,41

In this study, we evaluated the effects and overallsafety of PRKwithMMC 0.02% to treat residual refrac-tive errors in patients who had previous PKP for kera-toconus. We believe this is the largest published seriesto date of PRK after PKP.

PATIENTS AND METHODS

Eyes of consecutive patients who had PRK for refractive er-ror after previous PKP to treat keratoconus between 2006and 2008 were assessed in a retrospective chart analysis.Data collected included age, sex, manifest refraction, SErefraction, topographic cylinder, pachymetry, CDVA, anduncorrected distance visual acuity (UDVA) preoperativelyand 1, 3, 6, and 12 months postoperatively. The CDVA wasobtained through the phoropter or with the patient's glasses.Vector analysis was calculated at 12 months.

Inclusion criteria included a clear corneal graft for kerato-conus with no current signs of allograft rejection, suture re-moval before surgery, and a stable refraction for 3 months.Exclusion criteria were similar to those in all patients havingPRK and included pregnancy and ocular comorbidities thatmay affect vision or the healing process (eg, cataract or sig-nificant dry eye).

Submitted: January 9, 2011.Final revision submitted: April 6, 2011.Accepted: May 2, 2011.

From Vision Eye Institute (Hodge, Sutton, Lawless, Rogers),Chatswood, Sydney Medical School (Hodge, Sutton), Universityof Sydney, and Save Sight Institute (Sutton), Sydney MedicalSchool Foundation, Sydney University, Sydney, Australia.

Corresponding author: Chris Hodge, Vision Eye InstituteChatswood, NSW, Australia 2067. E-mail: christopher.hodge@vgaustralia.com.

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The minimum gap between surgeries was 6 weeks. Theupper limit of treatment for the 2 laser units used in the studywas 6.00 D of cylinder; therefore, patients were divided into2 groups for data analysis. The low cylinder group com-prised patients with a refractive cylinder of 6.00 D or lowerand the high cylinder group, patientswith refractive cylinderabove 6.00 D. The patients were grouped to compartmental-ize the effect on the overall statistics of the expected under-correction and planned undercorrection in patients withpreoperative refractive cylinder above 6.00 D.

All refractive errors were reduced by 10% when pro-grammed for ablation because patients with PRK proceduresin conjunction with MMC have shown a tendency towardovercorrection and consecutive hyperopia. This is presum-ably due to MMC's attenuation of the wound-healingresponse.

The PRKwas performed using a LadarVision laser (AlconLaboratories, Inc.) or an Allegretto laser (Wavelight AG). Allsurgeries were performed by 1 of 3 surgeons (G.S., M.L.,C.R.). The protocol for treating astigmatism was to markthe patient's sclera before surgery with the patient seated.Marks were made with a medium Codman marker pen(Johnson & Johnson) at 0 degree and 180 degrees. Immedi-ately before the ablation with the LadarVision laser, the hor-izontal axis line on the unit was rotated to align with the 2limbal markings to ensure proper registration and ablationonto the cornea. The marking procedure before ablationwas the same in eyes having PRK with the Allegretto laser;at the ablation, the surgeon manipulated the patient's headto ensure the marks were located across the horizontalmedium. No additional procedures, for example arcuate T,were performed in eyes with a refractive cylinder above6.00 D. Immediately after the laser treatment, a sponge(Corneal Light Shield, BD Visitec, Beaver-Visitec Interna-tional) impregnated with MMC 0.02% was applied to alleyes for between 15 seconds and 60 seconds. The titrationof MMC application was dependent primarily on the levelof correction treated.

After surgery, a bandage contact lens (Focus Night &Day,Ciba Vision) was placed on the operated eye for 4 days.Patients received ciprofloxacin 0.3% (Ciloxan) 4 times dailyfor 1 week after surgery. Diclofenac sodium (VoltarenOphthalmic) was instilled the morning after surgery. Fluoro-metholone (FML) was started after contact lens removal andcontinued for 1 week 4 times per day.

Statistical analysis was performed using SPSS software(version 16.0, SPSS, Inc.). Student t tests were used to analyzeresults.

RESULTS

The study comprised 47 eyes of 41 consecutive pa-tients (25 in low cylinder group; 16 in high cylindergroup). The mean age of the 16 women and 25 menwas 40 years G 12 (SD) (range 22 to 67 years).Thirty-two eyes were treated with the LadarVisionlaser and 15 eyes with the Allegretto laser. The meanlength of MMC application was 40.1 G 14.8 seconds(median 30 seconds).

Refraction

Table 1 shows the preoperative and postoperativerefractive data by group. Although a final

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Table 1. Preoperative and postoperative refraction.

Group

Mean (D) G SD

Preoperative*

Postoperative†

1 Month 3 Months 6 Months 12 Months

Low cylinderSphere �2.10 G 3.55 0.30 G 0.99 0.46 G 1.05 0.16 G 0.86 0.14 G 1.15Cylinder �4.27 G 1.40 �1.16 G 1.04 �1.57 G 1.14 �1.33 G 1.31 �1.71 G 1.55

High cylinderSphere �0.30 G 3.66 1.30 G 2.62 0.98 G 1.80 �0.93 G 5.30 �0.15 G 2.48Cylinder �7.78 G 1.21 �2.70 G 1.77 �3.48 G 2.41 �3.73 G 3.21 �4.60 G 2.54

*31 eyes, low cylinder group; 16 eyes, high cylinder group†At 1 month, 30 eyes, low cylinder group and 15 eyes, high cylinder group; at 3 months, 23 eyes and 13 eyes, respectively; at 6 months, 20 eyes and 11 eyes,respectively; at 12 months, 19 eyes and 10 eyes, respectively

1886 PRK WITH MMC AFTER PKP FOR KERATOCONUS

undercorrection of effect was apparent in both groups,the change from preoperative levels was statisticallysignificant at most postoperative time points. Further-more, the high cylinder group appeared to regressover time compared with the low cylinder group,albeit in terms of overall spherical ablation(Figure 1). Table 2 shows the mean preoperative and

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postoperative topographic keratometry and cylindervalues. Statistical significance varied between groupsfor both topographic parameters. Figure 2 shows thepostoperative astigmatism outcomes in graph form.

Pachymetry derived from corneal topographyshowed a mean preoperative central thickness of575.7 G 49.1 mm (range 450 to 692 mm). The mean

Figure 1. Stability of SE refraction. Top: Lowcylinder group. Bottom: High cylinder group(SE Z spherical equivalent).

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Table 2. Preoperative and postoperative topography results.

Group

Mean (D) G SD

Preoperative*

Postoperative†

1 Month 3 Months 6 Months 12 Months

Low cylinderSphere 46.15 G 2.99 42.11 G 4.21 44.97 G 5.50 42.33 G 3.06 43.14 G 2.83Cylinder 5.18 G 2.61 2.63 G 0.60 4.86 G 4.19 3.46 G 2.67 3.73 G 3.30

High cylinderSphere 46.83 G 2.99 43.79 G 2.06 42.89 G 1.93 43.28 G 1.92 43.51 G 1.65Cylinder 9.09 G 3.04 5.48 G 1.69 4.78 G 2.56 5.30 G 5.25 7.17 G 5.07

*30 eyes, low cylinder group; 16 eyes, high cylinder group†At 1 month, 5 eyes, low cylinder group and 4 eyes, high cylinder group; at 3 months, 10 eyes and 6 eyes, respectively; at 6 months, 16 eyes and 6 eyes, respec-tively; at 12 months, 17 eyes and 9 eyes, respectively

1887PRK WITH MMC AFTER PKP FOR KERATOCONUS

thinnest preoperative thickness was 555.1 G 54.4 mm(range 423 to 690 mm). The mean maximum surgicalablation depth was 103.5 G 25.2 mm (range 47.2 to164.9 mm). The mean postoperative thinnest pachyme-try was 443.7 G 67.9 mm (range 331 to 582 mm).Figure 3 shows the percentage of all patients who

lost or gained lines of CDVA. Fifteen patients(51.8%) at 6 months and 12 patients (41.3%) at12 months gained lines of CDVA postoperatively.There was no difference in safety between the lowcylinder group and the high cylinder group.

Figure 4 shows the CDVA at the preoperative and6-month and 12-month postoperative visits. Ten pa-tients (52.6%) in the low cylinder group and 1 patient(10.0%) in the high cylinder group achieved a UDVAof 20/40 or better at 12 months.

Vector Analysis

Table 3 shows the distribution of manifest refractiveerrors before and after refractive surgery at 12 months(referenced to spectacle plane) by group. The SE (M)was statistically significantly lower after surgery inthe low cylinder group (P!.001) but not in the highcylinder group. The power vectors (J0 and J45) werenot statistically significantly different between groups.As a measure of the overall effect of surgery, theblurring strength (B) of the spherocylindrical refrac-tive error was significant from preoperatively to post-operatively in both groups (P!.001 and P!.01 for lowcylinder and high cylinder, respectively). Figure 5shows the projection of the power vectors into the as-tigmatic plane based on the coordinate axes J0 and J45.Although the difference between the preoperative andpostoperative values was not statistically significant,the postoperative results indicate a tighter groupingaround the zero axis point, which suggests an im-provement after surgery.

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The mean relative index of success, calculated usingrefractive cylinder data, was 0.33 G 0.30 in the entirecohort. The mean was 0.30 (median 0.19) in the lowcylinder group and 0.34 (median 0.31) in the high cyl-inder group.

Complications

Nopatient developed haze greater than grade 2, andthere were no significant differences in the presence ofhaze between the low cylinder group and high cylin-der group. The loss of CDVA at 1month was the resultof unsettled epithelium, presumably caused by the ep-ithelial remodeling associated with PRK.

Two patients had repeat corneal transplantation3 years after PRK surgery. In 1 patient, the anteriorstromal scarring present after PKP persisted afterPRK. The preoperative CDVA was 20/150. Althoughthe CDVA in this patient improved at 1 month and3 months, it returned to the preoperative level at12 months. The second patient had an injury unrelatedto laser surgery and was left with central scarring; thepatient required surgery for visual rehabilitation.

DISCUSSION

The advent of femtosecond technology allows thecreation of a safer, more predictable LASIK flap.42 Incombination with new-generation excimer lasers,LASIK offers patients excellent clinical and safetyoutcomes. However, postoperative refractive casespresent challenges to the surgeon and may requirea different approach.

After PKP for keratoconus, high degrees of ametro-pia are relatively common and can be limiting to thepatient on several levels.3,5–11 Several methods to cor-rect these errors have been suggested, and the resultshave been variable.17–24 We present a large series of

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Figure 2. Refractive astigma-tism. Top: Low cylinder group.Bottom: High cylinder group.

1888 PRK WITH MMC AFTER PKP FOR KERATOCONUS

patients having PRK with the corresponding applica-tion of MMC.

In our study, there was a 60% decrease in refractivecylinder at 12months and an overall reduction in SE in83.3% of patients with low refractive cylinder.Although patients with high refractive cylinder alsohad a decrease in cylinder and SE, the reduction wasnot as pronounced (40.9% and 41.5% respectively).

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Although the results show statistically significantimprovements after surgery, they confirm a tendencytoward undercorrection. The maximum astigmaticcorrection in all patients with both laser platformswe used was 6.00 D; therefore, the undercorrectionin patients with high refractive cylinder was not unex-pected. There was a significant variance in the highcylinder group results, reflected by the high standard

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Figure 3. Change in the CDVA overtime.

1889PRK WITH MMC AFTER PKP FOR KERATOCONUS

deviations. This suggests that eyes with extreme levelsof refractive cylinder are unstable over time, whichmay reflect a more irregular host cornea. Patientswith all levels of refractive error must have appropri-ate counseling before surgery to ensure they have real-istic expectations of the outcomes.

Comparative results for PRK after PKP are availablein the literature. Forseto et al.43 describe 36 eyes thathad PRK with MMC to correct post-PKP refractive er-rors; the primary indication for PKP was varied, with80.6% of patients having keratoconus previously. Themean SE decreased from �3.95 G 4.11 D before PRKto �1.07 G 1.45 D after PRK and the refractive cylin-der, from 4.42 G 1.69 to �1.88 G 1.75 D, respectively.Leccisotti44 report 10 eyes that had a reduction in SEfrom �4.98 G 1.75 D preoperatively to 0.28 G0.61 D postoperatively. The postoperative values inour low cylinder group compare favorably with thesereports.

If LASIK serves as a benchmark procedure, our re-sults in patients with preoperative refractive cylinderless than 6.00 D compare well with the post-LASIKresults available in the literature, which report a re-duction of 40.0% to 79.3% in refractive cylinder andof 74.8% to 92.0% in SE.35,45–49 Mann et al.30 presenta small series of previously keratoconic eyes thatobtained a 90% reduction in refractive cylinder afterLASIK. This represents an unusually good result;however, the mean refractive cylinder preoperativelywas –3.25 D, which is considerably lower than inmost post-PKP refractive studies. This highlights theconsiderable differences preoperatively in various

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published cohorts, which presents difficulties in de-riving valid comparisons about the success of a tech-nique. Williams et al.49 report a significant variationin PKP outcomes in patients with various preopera-tive corneal diseases. Our cohort was limited to pa-tients with keratoconus. This design was intendedto reduce the influence of preoperative variablesand to allow comparison with other similar studies.Application of these results to patients having PKPfor other reasons may prove misleading and shouldbe avoided.

As Koch states in a 2001 editorial,50 simple analysisis not enough to confirm the success of astigmatic sur-gery. We used the vector analysis method describedby Thibos and Horner.51 Analysis of our results sug-gests an overall decrease in most values, validatingthe procedures. The index of success confirms the im-provement in all cases after PRK. There are few com-parisons available in the literature. Mularoni et al.31

report a mean relative index of success of 0.26 in 15eyes that had LASIK following PKP. Our result (0.33)compares well with this value. Further standardiza-tion of postoperative astigmatic calculations willimprove the legitimacy of these results and furtherconsolidate comparisons.

As a measure of safety, the percentage of patients inour study losing 2 lines or more of CDVA decreasedfrom 1 month to 3 months postoperatively. The lossof CDVAwas attributed to unsettled epithelium ratherthan to corneal haze. Therefore, the improvement from1 month was likely a reflection of an improvement inepithelial surface remodeling, which is typical in all

VOL 37, OCTOBER 2011

Figure 4. The UDVA preoperatively 6months and 12 months postoperatively.

1890 PRK WITH MMC AFTER PKP FOR KERATOCONUS

PRK patients over time. Perhaps just as important,there was a much greater chance of patients gaininglines of CDVA than losing lines.

A limitation of our study was that we do not reportpreoperative and postoperative endothelial cellcounts. Measurements were taken in most eyes;however, the subjective nature of our measuringunit, combined with a range of technician experience,provided significant variation in the postoperative

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results. We thought that including erroneous resultsmay be misleading and therefore excluded these find-ings from the article. We have made significant adjust-ments to our procedures, and it is likely that futurepresentations will include more accurate long-termdata.

There were no intraoperative complications in ourgroup, nor were there significant variances in poly-morphism after surgery, as confirmed by the surgeons.

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Table 3. Vector analysis results.

Group

Mean G SD

M J0 J45 B

Low cylinderPreop �4.22 G 3.18 �0.70 G 1.71 �0.18 G 1.57 5.27 G 2.29Postop �0.75 G 1.06* �0.70 G 0.48 �0.28 G 1.07 1.51 G 0.87*

High cylinderPreop �4.19 G 3.54 �0.73 G 3.02 0.16 G 2.61 6.42 G 1.93Postop �2.45 G 3.42 �0.10 G 1.94 0.29 G 1.90 4.02 G 2.82†

BZ blurring strength of the spherocylindrical refractive error; J0 and J45Z Jackson cross cylinders equivalent to the conventional cylinder; MZ spherical lensequal to the spherical equivalent*P!.001†P!.05

1891PRK WITH MMC AFTER PKP FOR KERATOCONUS

Several studies describe complications after LASIK inpatients with previous PKP. These can decrease visualacuity and diminish the overall effectiveness of thesurgery. Complications include microdehiscence ofthe wound, buttonhole flaps, fluid on the interface,and flap retraction, all of which are reported to causeloss of CDVA.33,37,40,41 In a large study by Hardtenet al.,33 up to 16% of patients developed epithelial in-growth after LASIK. Some authors attribute the in-creased incidence of ingrowth to factors such aswound override and subsequent issues with woundadherence at the graft–host interface.33,38 The use ofa 2-step procedure has been suggested as a means ofovercoming thepotentially significant changes a lamel-lar cut may induce.52–54 However, the potential visualacuity benefits of this technique may be negatedsomewhat by the potentially increased risk for epithe-lial ingrowth occurring in these retreated patients.33 Itis possible that the PRK technique has an advantage interms of safety in these cases.

Previously, a major limiting factor of PRK was thehigh incidence of corneal haze, which led to loss ofCDVA, regression, or both. Many early stud-ies24,25,32,55–58 describe the incidence and severity ofthese complications and the subsequent visual andrefractive results, all of which compare poorly withthe results of other techniques. Risk factors includethe high degree of ablation required for the level ofspherical and astigmatic corrections common in thepost-PKP population.27,28 Also, it has been suggestedthat the activation of the already large number of ker-atocytes in post-PKP eyes further increases the riskfor stromal haze.30 Mitomycin-C is an alkylatingagent that reduces the myofibroblast repopulationpostoperatively; this is thought to reduce the inci-dence and severity of haze.59 Thus, use of MMC isprobably essential to the success of this technique.In this series, no patient developed haze greaterthan grade 2 by 12 months. Although uncommon,

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corneal haze can occur after this time period. Longerfollow-up would prove useful to confirm the validityof these results. Mitomycin-C is highly cytotoxic, andthere is risk to the cornea in the short term and longterm. Undesirable long-term effects are reduced ante-rior stromal keratocyte density and endothelial celldeath, leading to possible corneal melting, ectasia,and long-term endothelial failure.60,61 Althougha growing number of studies confirm the judicioususe of MMC as safe in terms of possible complica-tions, they must be taken into account when weigh-ing the relative merits of PRK against those of othertechniques.62–66

Barreto et al.67 recently described positive results ina case of a topography-guided ablation with MMC af-ter PKP for keratoconus. The ability to correct irregularastigmatism is a limiting factor in achieving the best re-sults in the post-PKP eye. The emerging technology oftopography-guided ablationmay help address the dis-crepancy between refractive and topographic informa-tion that commonly exists and improve the surgeon'sability to correct these refractive errors. Further studieswith larger samples are required to analyze the bene-fits of this technology.

In conclusion, PRK with adjunctive MMC andLASIK are successful in reducing refractive errorsin patients who had previous PKP. Patients withhigh refractive cylinder after PKP appear to bemore likely to have a reduced final effect. Photore-fractive keratectomy, however, may be safer thanLASIK in treating these errors and, combined withappropriate laser technology, may be the preferredmethod in these cases. Further analysis oftopography-guided ablation by LASIK and byPRK and the long-term effects of MMC is neededto support these conclusions. Patients should becounseled preoperatively to avoid unrealistic expec-tations, particularly in cases of extreme refractiveerror.

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Figure 5. Projections of the vectors into theastigmatic plane based on the coordinateaxes J0 and J45 for the low refractive cylinderand high refractive cylinder groups Top:Low cylinder group. Bottom: High cylindergroup.

1892 PRK WITH MMC AFTER PKP FOR KERATOCONUS

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VOL

37, OCTOBER 2011

First author:Chris Hodge, BAppSc

Vision Eye Institute, Chatswood,Sydney, Australia