Correspondence medications are often the preferred method of treatment for ocular surface squamous neoplasia, especially in diffuse lesions and those involving large areas of the limbus or cornea. IFN a2b, specifically, is our preferred method of topical treatment because it is not only effective but also, as Huerva and others have shown, extremely well tolerated.3 For patients who have difficulty complying with the topical drop regimen, IFN a2b injections are also an option, although these patients do need to be warned about the high likelihood of transient post injection flu-like symptoms and the need for at least weekly injections until resolution. Time to resolution is shortest with surgery, followed by IFN a2b injection, and then topical IFN a2b, which may also play a role in the decision of which treatment to use. Last, cost and insurance coverage may factor in to the decision process. The choice of therapy for ocular surface squamous neoplasia, therefore, depends on a combination of lesion characteristics, patient characteristics, and patient preference. No single modality of treatment has yet proved to be superior in terms of future recurrence.

AFSHAN A. NANJI, MD, MPH ANAT GALOR, MD, MSPH CAROL L. KARP, MD Bascom Palmer Eye Institute, Miami, Florida Financial Disclosure(s): C.K.: Support - NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Award and Career Development Award, Department of Defense (DOD; grant no. W81XWH-09-1-0675), The Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Jimmy 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 materials discussed in this Letter to the Editor.

References 1. Nanji AA, Moon CS, Galor A, et al. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology 2014;121: 994–1000. 2. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2b eye-drops for ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol 2010;94:551–4. 3. Huerva V, Mangues I. Treatment of conjunctival squamous neoplasias with interferon alpha 2b. J Fr Ophtalmol 2008;31: 317–25.

Re: Said et al.: Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting (Ophthalmology 2014;121:1377-82) Dear Editor: We read with interest the article entitled “Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced 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. It seems that they arbitrarily included 40 eyes in their study. The statistical power of the study, therefore, remains questionable. The method 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, the manuscript does not provide any information on masking. Second, the 2 arms in the study are not similar, with the control group having significantly more aged individuals than the treatment group. It is well known that age-related glycation cross-links can enhance the mechanical property of collagen fibrils resulting in stronger fibrils than normal2,3 Therefore, comparison between groups with such different corneal characteristics may not be appropriate. For the same reason, patients with diabetes mellitus should have been excluded from the study.2,3 Third, with regard to corneal thickness measurement, the manuscript does not provide details of the technique used for measuring corneal thickness. These details are crucial, because the study enrolled patients with corneal melts and the corneal thickness is expected to be reduced at the site of melt. It can be argued that the control arm subjects had areas of extreme corneal thinning, which in turn predisposed these corneas for perforation. Finally, in their analysis of the results, even if we consider that the groups were similar at the point of enrollment in the study, the 95% CIs around the rate of perforation in 2 groups are overlapping. Although 3 of 19 eyes (15.9%) perforated in the control group, the true rate of perforation is likely to be somewhere between 5.5% and 37.5% (95% CI). On the other hand, with no perforation in the treatment group the true rate of perforation is likely to be somewhere between 0% and 15.4%. Therefore, statistically there is no true difference in the rate of perforation between the treatment and the control group. If we go by the worst case scenario, it is possible that the treatment could be harmful. Thus, it would be inappropriate to conclude that collagen cross-linking may minimize or avoid severe complications such as corneal perforation. Moreover, a careful look at the clinical photographs of the eyes treated with PACK-CXL reveals 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 question using one of the best study designs, the investigation failed to provide an answer because of serious flaws in the study design and the analysis of the results.

RASHMI MITTAL, MD PRASHANT GARG, MD Cornea and Anterior Segment Services, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India Financial Disclosure(s): P.G.: Consultant - Alcon, Santen, Allergan India Ltd; Grants - Wellcome Trust, Department of Biotechnology India, SightLife, WA. The authors have no proprietary or commercial interest in any materials discussed in this Letter to the Editor.

References 1. Said D, Elalfy M, Gatzioufas Z, et al. Collagen cross-linking with 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. Ophthalmology 2014;121:1377–82. 2. Kuo IC, Broman A, Pirouzmanesh A, Melia M. Is there an association between diabetes and keratoconus? Ophthalmology 2006;113:184–90. 3. Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol 2000;238:822–5.

Author reply Dear Editor: We thank Mittal and Garg for their interest in our recent study.1 We are grateful for the opportunity to address their comments. Regarding methodology, a power analysis was performed with respect to the main outcome measure, time to reepithelialization of the infiltrate/sulcus. This was not a randomized, masked study. All investigators and participants were unmasked. Thus, no “active” information on masking was included. Mittal and Garg noted that the control group was composed of significantly older individuals than the treatment group. They state that age-related glycation cross-links may enhance the mechanical properties of collagen fibers, which may have influenced the outcomes. Although we fully agree with this statement, we respectfully disagree with their conclusion. We did not investigate biomechanical changes induced by cross-linking (CXL), but the antimicrobial efficacy (killing rate) of collagen cross-linking with photoactivated riboflavin (PACK-CXL). Our group provides evidence that CXL and PACK-CXL may follow distinctly different pathways: Whereas CXL shows oxygen dependency and does not follow the Bunsen Roscoe law of reciprocity,2,3 PACK-CXL seems to act via both oxygen-dependent and oxygen-independent mechanisms, and respects the Bunsen Roscoe law. Thus, extrapolating from changes in corneal biomechanics to antimicrobial efficacy is not appropriate. Although the same argument would theoretically also apply for diabetes, none of the participants in this study was diabetic. Even if one would not consider our hypothesis of distinctly different pathways for CXL and PACK-CXL, one could argue that the age-related increase in stiffness in the control group represents a clear advantage rather than a disadvantage, because strengthening of the stroma could mean increased resistance to enzymatic digestion. Regarding corneal thickness measurements, as stated in the manuscript, all thickness measurements were performed using ultrasound pachymetry. As also stated, all corneas showed a minimal thickness of 400 mm at the time of inclusion. For treatment results in dense scarring, our colleagues state that PACK-CXL treatment resulted in a dense vascularized scar, which would render the prospects of a future graft gloomy. We cannot follow this argument; in this study, we only included cases with advanced melting. Our effort was aimed at preserving the eye. In the eyes we studied, a calm anterior segment, even in the presence of 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 and the control group in our paper (3 perforations and 1 recurrent infection [21%]). The small sample size and low occurrences do indeed present a statistical problem: We had indicated that the

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complication rate was significantly higher (P ¼ 0.03) in the control group (21%) than in the PACK-CXL group (0%), using a 95% CI. This calculation was based on a Z-test, which is the correct statistical test for this type of calculation. However, we did not include a Yates correction for low occurrences in the samples. When recalculating the Z-test using a Yates correction, the P value increases from 0.03 to 0.09 indicating a clear but nonsignificant trend. We apologize for this. Nevertheless, this does not affect the conclusion of the study. In conclusion, our study showed that PACK-CXL represents a valuable adjuvant therapy in advanced melting keratitis. We have been investigating the depth-dependent efficacy of PACK-CXL in the laboratory and strongly believe, together with others,4 that PACK-CXL will be very useful in early keratitis in addition to its adjuvant effect in severe melting keratitis.

DALIA G. SAID, MD, FRCS1 ZISIS GATZIOUFAS, MD, PHD2 FARHAD HAFEZI, MD, PHD2,3 1

Research Institute of Ophthalmology, Cairo, Egypt; 2Division of Ophthalmology, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland; 3Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California States Financial Disclosure(s): The authors have made the following disclosures: Farhad Hafezi e Co-inventor e PCT/CH 2012/000090 application (UV light source).

References 1. Said D, Elalfy M, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology 2014;121:1377–82. 2. Hammer A, Richoz O, Mosquera S, et al. Corneal biomechanical properties 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 effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol 2013;2:6. 4. Price MO, Tenkman LR, Schrier A, et al. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg 2012;28:706–13.

Re: Pakravan et al.: Effect of early treatment with aqueous suppressants on Ahmed glaucoma valve implantation outcomes (Ophthalmology 2014;121:1693-8) Dear Editor: After glaucoma drainage device (GDD) implantation, an initial reduction of intraocular pressure (IOP) is frequently followed by a rebound IOP increase called the hypertensive phase. Such a rise of IOP has been observed with GDDs of various designs and can be detrimental to the health of the optic nerve. A recent publication by Pakravan et al1 demonstrated that early treatment with aqueous suppressants after Ahmed glaucoma valve (AGV) implantation may reduce the hypertensive phase frequency, and improve the AGV outcomes in terms of IOP and success rate. The results would be

Re: Said et al.: Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting (Ophthalmology 2014;121:1377-82).

Re: Said et al.: Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting (Ophthalmology 2014;121:1377-82). - PDF Download Free
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