Recent eLetters

Dear Editor,

In a thought-provoking editorial in BJO entitled “Why is the amblyopic eye unstable?” C. Hoyt raised two very important issues relating to the treatment of human amblyopia. First, there is currently no effective alternative to occlusion therapy for treating amblyopia. Second, there is considerable “slippage” of visual acuity after cessation of occlusion therapy. Our sole purpose in responding to this editorial is to draw attention to some very recent work, showing significant long-term improvements in visual performance in the adult amblyopic eye that, potentially, could be adapted for use as an effective alternative to occlusion therapy.

Visual perceptual learning – improved visual performance on a given psychophysical task after extensive training – is a well-established phenomenon in the normal visual system1. This form of learning is often tightly coupled to stimulus characteristics encoded early in visual cortex, such as the orientation or spatial frequency (size) of a visual stimulus. The stimulus specificity of perceptual improvements through training suggests that some aspect of neural processing -whether it be the tuning of individual neurons or the weighting of synaptic connections - remains malleable or ‘plastic’, even in the adult visual system.

Recent studies have shown that this form of neural plasticity is not restricted to the normal visual system. Indeed, with an appropriate training regime one can produce a marked improvement in visual performance of the adult amblyopic eye. Perceptual learning produces a 50-60% improvement in Vernier acuity (positional acuity) of the adult amblyopic eye2. Crucially, in some subjects this improvement in Vernier acuity transfers to other forms of spatial discrimination such as Snellen acuity. By way of example, one amblyopic observer improved from a pre-training value of 20/42 (~6/12), attaining 20/20 (6/6) after extensive training on the Vernier task2. This suggests that the adult amblyopic visual system retains a great deal more neural plasticity than previously supposed. Such improvements in visual performance are not limited to acuity tasks. A longitudinal study found that training on a contrast detection task led to a 2-fold improvement in the contrast sensitivity of the amblyopic eye, with minimal “slippage” 12 months after the cessation of training3.

At present, relatively little is known about the benefits of perceptual learning in childhood amblyopia during the “sensitive period”. Given the greater degree of neural plasticity in the developing visual system, one would imagine that the benefits of perceptual learning might greatly outstrip those observed in the adult population. Having said this, a recent study on the efficacy of perceptual learning in previously treated amblyopic children did not support this supposition4. While the children (aged 7 to 10 – beyond the sensitive period as defined by Professor Hoyt) showed significant improvements after 7 to 10 sessions, the results were no better than those of adults. Further work with “fresh” (untreated) and younger amblyopes is required to corroborate and extend these initial findings to younger children, and to determine the “dose- response” function for perceptual learning.

Several large-scale clinical studies in the UK and USA have shown that standard occlusion therapy is effective in treating human amblyopia. However, the benefits are far from universal and a significant number of children (~ one third) gain little or no visual benefit despite protracted treatment5. This is unfortunate given that occlusion therapy is difficult to implement, is often associated with some degree of distress to the child and may have an impact on educational development. As Professor Hoyt correctly notes in his original editorial, no alternative treatment strategies currently exist for these individuals. The development of perceptual learning as a clinical tool may rectify this situation and provide an alternative method both for the treatment of amblyopia and for eliminating or reversing “slippage” once treatment has ceased. Moreover, if the initial perceptual learning studies in children with amblyopia withstand further experimental scrutiny and deliver encouraging results in younger and previously untreated children, the 250-year old practice of ‘patching’ the amblyopic eye may be supplanted or at the least supplemented by a new treatment protocol.

References

1. Fine, I & Jacobs, R.A. (2002) Comparing perceptual learning tasks: A review. Journal of Vision 2, 190-203.

2. Levi DM (2005) Perceptual learning in adults with amblyopia: A reevaluation of the critical periods in human vision. Developmental Psychobiology. 46, 222-232

3. Polat, U., Ma-Naim, T., Belkin, M. & Sagi, D. (2004) Improving vision in adult amblyopia by perceptual learning. Proceedings of the National Academy of Sciences of the United States of America 101, 6692- 6697.

4. Li, R.W., Young, K.G., Hoenig, P. & Levi, D.M. (2005) Perceptual learning improves visual performance in juvenile amblyopia. Investigative Ophthalmology and Visual Science. 46, 3161-3168.

5. Clarke MP, Wright CM, Hrisos S, Anderson JD, Henderson J, Richardson SR. (2003). Randomised controlled trial of treatment of unilateral visual impairment detected at preschool vision screening. BMJ 327, 1251-1256.

Ben S. Webb, Paul V. McGraw
Visual Neuroscience Group
School of Psychology
University of Nottingham, UK

Dennis M. Levi
School of Optometry
UC Berkeley, USA

Dear Editor,

We thank Drs. Tsai et al. for their interest in our article and for the opportunity to clarify the data of our study. Drs. Tsai et al. correctly point out that intraocular pressures (IOP), axial lengths (AL), corneal curvatures, and refractive errors change overtime following glaucoma surgery. The purpose of our study was not to follow the changes of ocular dimensions after combined cataract operation and trabeculectomy with mitomycin C using separate incisions (combined operation) overtime, but to characterize these changes when the ocular dimensions were relatively stable.

The large majority (75%) of our patients who received combined operations had the ocular dimension measured and the IOP recorded for analysis 6 months of more after the combined operation. Eight patients (33%) had measurements obtained 12 months or more after the operation, 10 patients (42%) obtained between 6 to 11 months, and 6 patients (25%) obtained between 1 to 2 months. With the possibility that these 6 patients with a short follow-up may have unstable ocular dimensions and affect the interpretation of the results, we re-analyze our data of the 18 patients who had the data collected at 6 months or more after the combined operation. The significances of the results remain unchanged.

After a combined operation in these 18 patients, the mean axial length is significantly shortened from 24.13 (1.04) mm to 24.02 (1.06) mm (p<0.00001). The mean axial length reduction after combined operation (109 (61) µm) is still larger than the reduction after cataract operation alone (75 (38) µm), but does not remain statistical significant (p=0.07) with a smaller sample size. The axial length reduction after combined operation correlates significantly with the postoperative IOP (p=0.008). There is a mean with the rule (WTR) surgically induced corneal astigmatism of 0.42 (0.71) D by vector analysis, and a significant increase of mean keratometry reading of 0.24 (0.42) D after a combined operation. There is no significant difference between the expected and observed refractive errors.

In addition, all patients in this study received a standard regimen of topical steroid and antibiotic after the combined operation. Topical steroid was started with 4 times daily and tapered 1 drop per week for 4 weeks. Topical antibiotic was used 4 times daily for 1 week from postoperative day 1.

Previous studies on changes of axial length after trabeculectomy were based on ultrasound biometry, which requires physical contact with the eye by a transducer or a saline immersion bath. The use of a more precise non- contact method of measurement, avoiding indentation or deformation of a soft globe after trabeculectomy has clear advantage. Although induction of a mean WTR corneal astigmatism after trabeculectomy with or without using mitomycin C had been reported, studies on corneal astigmatism induction after combined operation with more recent surgical technique were few. It may not be directly applicable to compare results of ocular dimension changes in trabeculectomy alone or cataract operation alone to combined cataract operation and trabeculectomy.

In the study by Claridge et al., polar values as a balance between with the rule (WTR) and against the rule (ATR) components of any given astigmatism were calculated.[1] An increase in polar value indicates a shift towards WTR astigmatism whereas a decrease indicates a move towards ATR astigmatism. Authors described three patterns of postoperative corneal topography changes: superior corneal steepening, superior corneal flattening, and complex regional variations in corneal topography that did not fit any particular pattern. In the superior corneal steepening, the polar value of the simulated keratometry increased from preoperative value of 0.6 D to 1.0 D at 1 month and 3 months postoperatively, which was a 0.4 D WTR change. For the superior flattening group, the polar value increased from -0.3 D preoperatively to +0.1 D at 1 month and 0.0 D at 3 months postoperatively. The WTR change was 0.7 to 0.8 D.[1] The overall mean induced astigmatism reported by Kook and coauthors in patients who had trabeculectomy with mitomycin C application was larger at 1 month (+1.08 D x 90 degree) and 3 months (+1.23 D x 90 degree) after operation, and smaller at 6 months (+0.94 D x 90 degree) and 12 months (+0.65 D x 90 degree) after operation.[2] By re-analyzing our data excluding patients with less than 6 months of follow-up, we were able to characterize the changes when the ocular dimension became more stable after the operation. However, we agree with Drs Tsai at al that the intraoperative use of mitomycin C may affect wound healing and has long-lasting influences on AL and corneal curvature than operation without the use of antimetabolite, and future study with a long-term follow-up is warrant.

Sincerely Yours,

Simon K. Law, MD

Glaucoma Division
Ophthalmology Department
Jules Stein Eye Institute
University of California Los Angeles

References:

1. Claridge KG, Galbraith JK, Karmel V, Bates AK. The effect of trabeculectomy on refraction, keratometry and corneal topography. Eye. 1995;9 ( Pt 3):292-298.

2. Kook MS, Kim HB, Lee SU. Short-term effect of mitomycin-C augmented trabeculectomy on axial length and corneal astigmatism. J Cataract Refract Surg. 2001 Apr;27(4):518-523.

Dear Editor

We read with great interest the article by Vysniauskiene et al.1 Their efforts in evaluating the intraocular pressure (IOP) changes of the contralateral eyes after trabeculectomy with mitomycin C (MMC) is appreciated. They concluded that a month after trabeculectomy, the mean IOP in contralateral eyes decreased. Of note, among the 24 fellow eyes in the study, 11 (45.8%) had topical ocular hypotensive therapy. Among the remaining 13 (54.2%) who had not, 12 of them had undergone trabeculectomy with MMC. We would be grateful if the authors may like to share with us their opinions as to whether the presumed “ophthalmotonic consensual reaction?may be modified in an unknown way by the topical medications or surgery, thereby affecting the interpretation of their results.

The decision by ophthalmologist to offer trabeculectomy is likely to be made at a point when the IOP is high on the variation curve. Therefore the decreased IOP in the fellow eye could be due to the “regression to the mean effect. The IOP of the fellow eye was measured 1 day before surgery, as well as 1 day and 1 month after surgery. As the study was conducted between 1995 and 2000, we would be interested to know the long term IOP changes after surgery. We suggest that this may help to lessen the effect of regression to the mean, as well as to see how long will the “ophthalmotonic consensual reaction? persist beyond 1 month.

As the IOP in glaucoma patients is unlikely to follow a normal Gaussian distribution, and it appeared that the data set was not yet tested for normality, the use of non-parametric counterparts such as Wilcoxon signed rank test is probably more appropriate.

We would like to commend the authors for conducting the study on this interesting topic. We wish that the issues raised will help broaden the discussion.

References

1 I Vysniauskiene, T Shaarawy, J Flammer, IO Haefliger. Intraocular pressure changes in the contralateral eye after trabeculectomy with mitomycin C.

2 Weekers L. Modification experimentales de l'ophtalmotonous. Reaction ophtalmotonique consenuelle. Arch Ophthalmol (Paris) 1924;41:641- 58.

Dear Editor,

We read with interest the article by Gupta and colleagues describing their findings in an investigation of the utility loss associated with glaucoma. When considered in light of previous investigations this work makes an important contribution to our limited understanding of the influence of culture, socio-economic status, and ethnic background on health state preference. It is particularly gratifying to see this done in glaucoma, a disease where there has been very limited work done towards utility estimate.

There are some aspects of the results of this study that bear clarification. First, we ask that they comment on staging glaucoma using visual acuity rather than visual field loss. Clinical staging of glaucoma by loss of visual field is the method preferred by glaucoma specialists,[1] and both utility loss (as measured by the EQ-5D)[2] and cost of care[3] have been shown to be responsive to this measure. Second, it would be good to report the number of study participants who refused to trade any time (or risk blindness or death due to surgery). In previous work, this proportion has substantial.[4] Finally, we ask that they comment more fully what some may consider an inconsistency in the findings. They found that on average people with glaucoma are willing to accept a 14% risk of death to eliminate their disease, but only a 3% risk of blindness, leading us to assume that among the people in this sample, being blind is worse than being dead. This has not been found in previous studies of the utility associated with blindness.

Just as Dr. Gupta and his colleagues speculate that there might be a cultural or socio-economic basis for the substantially higher utility loss associated with glaucoma he found in his sample (when contrasted with the work of Jampel4), it is possible that these apparently “inconsistent” findings might be the result of differing views of visual disability in our industrialized society (with nearly universal access to—although not necessarily utilization of—health care and rehabilitative services), versus that found in a developing country. If these findings are indeed valid and supported by additional research, it would make an important contribution to our understanding of preference based measures by providing evidence that preferences for health states (and thus variance in reported utility) may vary based upon socio-economic factors. While some have suggested that this is not the case,[5] such a finding would be consistent with recent reports that reported utility varies by race and other factors.[6,7]

References:

1. Hodapp E, Parrish RK, Anderson DR. Clinical Decisions in Glaucoma. St. Louis: Mosby, 1993.

2. Alm A, Kobelt G, Bergstrom A, Chen E, Linden C. Measuring Utility in Glaucoma. 2005 Annual Meeting Association for Research in Vision and Ophthalmology Fort Lauderdale, Florida.

3. Lee PP, Walt J, Doyle JJ, Kotak SV, Evans SJ, Budenz DL, et al. A Multi -center, Retrospective Pilot Study of Resource Utilization and Costs Associated with Severity of Disease in Glaucoma. Archives of Ophthalmology 2005;Accepted for Publication.

4. Jampel HD, Schwartz A, Pollack I, Abrams D, Weiss H, Miller R. Glaucoma Patients' Assessment of Their Visual Function and Quality of Life. Journal of Glaucoma 2002;11(2):154-63.

5. Brown GC, Brown MM, Sharma S, Beauchamp GR, Hollands H. The reproducibility of ophthalmic utility values. Transactions of the American Ophthamological Society 2001;99:199-204.

6. Bravata DM, Nelson LM, Garber AM, Goldstein MK. Invariance and Inconsistency in Utility Ratings. Medical Decision Making 2005;25(2):158- 67.

7. Wittenberg E, Divi N, Halpern E, Araki SS, Prosser L, Weeks JC. The Effect of Age, Race and Gender on Utility Values for Hypothetical Health States. 2004 Annual Meeting Society for Medical Decision Making Atlanta Georgia.

Dear Editor,

An aim to provide an optimised keratoprosthesis, with excellent biointegration, and all other properties meeting ideal requirements, is one we share with the authors of the recent article entitled “Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials”.[1] However, the current paper includes some points that require clarification.

PHEMA (spelled in full: poly(2-hydroxyethyl methacrylate)is a non-toxic polymer of the toxic monomer HEMA, though cytotoxicity is still possible if non-reacted monomer has not been fully removed. The ' polyhydroxyethyl methacrylate' the authors obtained for their study was not fully described, and may have been contact lens blanks, unlikely to have been processed for 'implantable quality'. Whether the samples had been fully extracted was not stated, nor was the hydration of the samples when used for the study. Contact lens blanks are not designed for cell adhesion and the results of this study, with regard to PHEMA, are entirely predictable and have been previously reported.

The commercially available keratoprosthesis AlphaCor is made from a form of PHEMA, specifically modified for its intended purpose within the cornea. In particular, the AlphaCor OPTIC is made from a relatively low water content, but hydrated, microporous form, similar to the samples evaluated by the authors, specifically because it does not encourage cellular adhesion (epithelial coverage is not desired for this model, nor would adherent posterior cells and membranes be desirable).

In contradistinction, the biointegratable SKIRT region of AlphaCor is made from a macroporous form of PHEMA with a very high water content; this material, with its interconnecting channels, has been optimised to promote viable biocolonisation, which has been extensively described in the literature. The authors of the present article do concede that cells 'may behave differently in colonising a 3-D porous keratoprosthesis skirt': indeed they do. Further, very subtle modifications of the sponge structure significantly affect all aspects of biointegration.

Both early trial results, such as the preliminary cases cited by the authors, and current results for over 250 AlphaCor devices, have been extensively presented and made available to all device users. Histology now available from AlphaCor devices explanted from human recipients confirms that the biointegration process in humans is similar to that previously shown in the animal model, and maintained in the long term. As expected, specific inflammatory processes can cause localised reversal of biointegration in areas of stromal melting. Certainly, porosity itself does not prevent melting processes, as is also seen in relation to hydroxyapatite keratoprostheses and orbital implants.

There is no argument that keratoprosthesis materials and design require ongoing revision and improvement. The authors' findings in relation to hydroxyapatite are interesting, although as they note, this rigid material has its own limitations. Novel approaches are undergoing early evaluation and may offer benefits. However, at present, in our view, AlphaCor is a device worthy of consideration for those in whom a donor graft would fail.

Disclosure: Celia Hicks is Medical Director of CooperVision Surgical, manufacturer of AlphaCor. The Biomaterials and Polymer Research department of the Lions Eye Institute has a financial interest with CooperVision Surgical through support of departmental funding, travel and research.

References

1. J S Mehta, C E Futter, S R Sandeman, R G A F Faragher, K A Hing, K E Tanner, and B D S Allan. Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials. Br. J. Ophthalmol. 2005; 89: 1356 – 1362.