Correspondence

medications are often the preferred method of treatment for ocularsurface squamous neoplasia, especially in diffuse lesions and thoseinvolving large areas of the limbus or cornea. IFN a2b, specifically,is our preferred method of topical treatment because it is not onlyeffective but also, as Huerva and others have shown, extremely welltolerated.3 For patients who have difficulty complying with thetopical drop regimen, IFN a2b injections are also an option,although these patients do need to be warned about the high like-lihood of transient post injection flu-like symptoms and the need forat least weekly injections until resolution. Time to resolution isshortest with surgery, followed by IFN a2b injection, and thentopical IFN a2b, which may also play a role in the decision ofwhich treatment to use. Last, cost and insurance coverage mayfactor in to the decision process. The choice of therapy for ocularsurface squamous neoplasia, therefore, depends on a combinationof lesion characteristics, patient characteristics, and patient prefer-ence. No single modality of treatment has yet proved to be superiorin terms of future recurrence.

AFSHAN A. NANJI, MD, MPHANAT GALOR, MD, MSPHCAROL L. KARP, MDBascom Palmer Eye Institute, Miami, Florida

Financial Disclosure(s):C.K.: Support - NIH Center Core Grant P30EY014801, Research toPrevent Blindness Unrestricted Award and Career Development Award,Department of Defense (DOD; grant no. W81XWH-09-1-0675), TheRonald and Alicia Lepke Grant, The Lee and Claire Hager Grant, TheJimmy and Gaye Bryan Grant (all institutional grants).A. G.: Grants - VA Career Development award, Stanley Glaser award,Genentech; Personal fees - B&L consultant; outside the submitted work.The authors have no proprietary or commercial interest in any materialsdiscussed in this Letter to the Editor.

References

1. Nanji AA, Moon CS, Galor A, et al. Surgical versus medicaltreatment of ocular surface squamous neoplasia: a comparison ofrecurrences and complications. Ophthalmology 2014;121:994–1000.

2. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2beye-drops for ocular surface squamous neoplasia: a dose com-parison study. Br J Ophthalmol 2010;94:551–4.

3. Huerva V, Mangues I. Treatment of conjunctival squamousneoplasias with interferon alpha 2b. J Fr Ophtalmol 2008;31:317–25.

Re: Said et al.: Collagen cross-linkingwith photoactivated riboflavin(PACK-CXL) for the treatment ofadvanced infectious keratitis withcorneal melting (Ophthalmology

2014;121:1377-82)

Dear Editor:We read with interest the article entitled “Collagen cross-linkingwith photoactivated riboflavin (PACK-CXL) for the treatment ofadvanced infectious keratitis with corneal melting” by Said et al.1

Although the authors concluded that PACK-CXL is an effective

adjuvant therapy in the management of severe infectious keratitis,we would like to draw attention to several issues.

First, the authors provided no rationale for the sample size. Itseems that they arbitrarily included 40 eyes in their study. The sta-tistical power of the study, therefore, remains questionable. Themethod of randomization used in the study is not appropriate. With“quasi” randomization, there is no scope for allocation concealment,which therefore adds an element of bias into the study. Further, themanuscript does not provide any information on masking.

Second, the 2 arms in the study are not similar, with the controlgroup having significantly more aged individuals than the treatmentgroup. It is well known that age-related glycation cross-links canenhance the mechanical property of collagen fibrils resulting instronger fibrils than normal2,3 Therefore, comparison betweengroups with such different corneal characteristics may not beappropriate. For the same reason, patients with diabetes mellitusshould have been excluded from the study.2,3

Third, with regard to corneal thickness measurement, themanuscript does not provide details of the technique used formeasuring corneal thickness. These details are crucial, because thestudy enrolled patients with corneal melts and the corneal thicknessis expected to be reduced at the site of melt. It can be argued that thecontrol arm subjects had areas of extreme corneal thinning, whichin turn predisposed these corneas for perforation.

Finally, in their analysis of the results, even if we consider thatthe groups were similar at the point of enrollment in the study, the95% CIs around the rate of perforation in 2 groups are overlapping.Although 3 of 19 eyes (15.9%) perforated in the control group, thetrue rate of perforation is likely to be somewhere between 5.5% and37.5% (95% CI). On the other hand, with no perforation in thetreatment group the true rate of perforation is likely to be somewherebetween 0% and 15.4%. Therefore, statistically there is no truedifference in the rate of perforation between the treatment and thecontrol group. If we go by the worst case scenario, it is possible thatthe treatment could be harmful. Thus, it would be inappropriate toconclude that collagen cross-linking may minimize or avoid severecomplications such as corneal perforation. Moreover, a careful lookat the clinical photographs of the eyes treated with PACK-CXLreveals that the treatment results in a densely vascularized scar,which would render the prospects of a future graft very gloomy.

Although the authors sought to study an important questionusing one of the best study designs, the investigation failed toprovide an answer because of serious flaws in the study design andthe analysis of the results.

RASHMI MITTAL, MDPRASHANT GARG, MDCornea and Anterior Segment Services, LV Prasad Eye Institute, KallamAnji Reddy Campus, Hyderabad, India

Financial Disclosure(s):P.G.: Consultant - Alcon, Santen, Allergan India Ltd; Grants - WellcomeTrust, Department of Biotechnology India, SightLife, WA.The authors have no proprietary or commercial interest in any materialsdiscussed in this Letter to the Editor.

References

1. Said D, Elalfy M, Gatzioufas Z, et al. Collagen cross-linkingwith photoactivated riboflavin (PACK-CXL) for the treatment of

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Ophthalmology Volume 121, Number 12, December 2014

advanced infectious keratitis with corneal melting. Ophthal-mology 2014;121:1377–82.

2. Kuo IC, Broman A, Pirouzmanesh A, Melia M. Is there anassociation between diabetes and keratoconus? Ophthalmology2006;113:184–90.

3. Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes andkeratoconus: a retrospective case-control study. Graefes ArchClin Exp Ophthalmol 2000;238:822–5.

Author reply

Dear Editor:We thank Mittal and Garg for their interest in our recent study.1 Weare grateful for the opportunity to address their comments.

Regarding methodology, a power analysis was performed withrespect to the main outcome measure, time to reepithelialization ofthe infiltrate/sulcus. This was not a randomized, masked study. Allinvestigators and participants were unmasked. Thus, no “active”information on masking was included.

Mittal and Garg noted that the control group was composed ofsignificantly older individuals than the treatment group. They statethat age-related glycation cross-links may enhance the mechanicalproperties of collagen fibers, which may have influenced the out-comes. Although we fully agree with this statement, we respectfullydisagree with their conclusion. We did not investigate biome-chanical changes induced by cross-linking (CXL), but the antimi-crobial efficacy (killing rate) of collagen cross-linking withphotoactivated riboflavin (PACK-CXL). Our group provides evi-dence that CXL and PACK-CXL may follow distinctly differentpathways: Whereas CXL shows oxygen dependency and does notfollow the Bunsen Roscoe law of reciprocity,2,3 PACK-CXL seemsto act via both oxygen-dependent and oxygen-independent mech-anisms, and respects the Bunsen Roscoe law. Thus, extrapolatingfrom changes in corneal biomechanics to antimicrobial efficacy isnot appropriate. Although the same argument would theoreticallyalso apply for diabetes, none of the participants in this study wasdiabetic. Even if one would not consider our hypothesis ofdistinctly different pathways for CXL and PACK-CXL, one couldargue that the age-related increase in stiffness in the control grouprepresents a clear advantage rather than a disadvantage, becausestrengthening of the stroma could mean increased resistance toenzymatic digestion.

Regarding corneal thickness measurements, as stated in themanuscript, all thickness measurements were performed using ul-trasound pachymetry. As also stated, all corneas showed a minimalthickness of 400 mm at the time of inclusion.

For treatment results in dense scarring, our colleagues state thatPACK-CXL treatment resulted in a dense vascularized scar, whichwould render the prospects of a future graft gloomy. We cannotfollow this argument; in this study, we only included cases withadvanced melting. Our effort was aimed at preserving the eye. Inthe eyes we studied, a calm anterior segment, even in the presenceof a dense vascularized scar, is a favorable outcome, in both the“medication only” and in the “PACK-CXL plus medication”groups.

We discussed the rate of perforation between the treatment andthe control group in our paper (3 perforations and 1 recurrentinfection [21%]). The small sample size and low occurrences doindeed present a statistical problem: We had indicated that the

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complication rate was significantly higher (P ¼ 0.03) in the controlgroup (21%) than in the PACK-CXL group (0%), using a 95% CI.This calculation was based on a Z-test, which is the correct statis-tical test for this type of calculation. However, we did not include aYates correction for low occurrences in the samples. When recal-culating the Z-test using a Yates correction, the P value increasesfrom 0.03 to 0.09 indicating a clear but nonsignificant trend. Weapologize for this. Nevertheless, this does not affect the conclusionof the study.

In conclusion, our study showed that PACK-CXL represents avaluable adjuvant therapy in advanced melting keratitis. We havebeen investigating the depth-dependent efficacy of PACK-CXL inthe laboratory and strongly believe, together with others,4 thatPACK-CXL will be very useful in early keratitis in addition to itsadjuvant effect in severe melting keratitis.

DALIA G. SAID, MD, FRCS1

ZISIS GATZIOUFAS, MD, PHD2

FARHAD HAFEZI, MD, PHD2,3

1Research Institute of Ophthalmology, Cairo, Egypt; 2Division ofOphthalmology, Department of Clinical Neurosciences, GenevaUniversity Hospitals, Geneva, Switzerland; 3Department ofOphthalmology, Keck School of Medicine, University of SouthernCalifornia, Los Angeles, California States

Financial Disclosure(s):The authors have made the following disclosures: Farhad Hafezi eCo-inventor e PCT/CH 2012/000090 application (UV light source).

References

1. Said D, Elalfy M, Gatzioufas Z, et al. Collagen cross-linkingwith photoactivated riboflavin (PACK-CXL) for the treatment ofadvanced infectious keratitis with corneal melting. Ophthal-mology 2014;121:1377–82.

2. Hammer A, Richoz O, Mosquera S, et al. Corneal biomechanicalproperties at different corneal collagen cross-linking (CXL)irradiances. Invest Ophthalmol Vis Sci 2014;55:2881–4.

3. Richoz O, Hammer A, Tabibian D, et al. The biomechanical ef-fect of corneal collagen cross-linking (CXL) with riboflavin andUV-A is oxygen dependent. Transl Vis Sci Technol 2013;2:6.

4. Price MO, Tenkman LR, Schrier A, et al. Photoactivatedriboflavin treatment of infectious keratitis using collagencross-linking technology. J Refract Surg 2012;28:706–13.

Re: Pakravan et al.: Effect of earlytreatment with aqueous suppressants onAhmed glaucoma valve implantationoutcomes (Ophthalmology 2014;121:1693-8)

Dear Editor:After glaucoma drainage device (GDD) implantation, an initialreduction of intraocular pressure (IOP) is frequently followed by arebound IOP increase called the hypertensive phase. Such a rise ofIOP has been observed with GDDs of various designs and can bedetrimental to the health of the optic nerve. A recent publication byPakravan et al1 demonstrated that early treatment with aqueoussuppressants after Ahmed glaucoma valve (AGV) implantation mayreduce the hypertensive phase frequency, and improve the AGVoutcomes in terms of IOP and success rate. The results would be