Risk Factors for Posterior Capsule Opacification

EDITORIALS 1389

Posterior capsule opacification digitised photographs, capsule opacity Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from ...... has fibrotic and lens epithelial proliferative components that require three dimensional measurement. In order to Risk factors for posterior capsule assess the extent of opacification, researchers such as Sacu and colleagues opacification have resorted to multiple modes of evaluation including a subjective score S D McLeod that ranks subtypes of fibrotic opacity, automated analysis of digitised photo- ...... graphs, and need for Nd:YAG laser capsulotomy.4 Hayashi and Hayashi7 Resolving nebulous data have argued that multiple methods are indeed required to adequately describe mprovements in techniques, instru- have specifically addressed the issue of these various features, and have sug- mentation, and intraocular lens the relative risk for posterior capsule gested that retroillumination photogra- Idesign appear to have been associated opacification associated with one piece phy is helpful in describing the area of with declining rates of posterior capsule acrylic compared with three piece acrylic involvement, but Scheimpflug photo- opacification following cataract sur- intraocular lenses, have failed to graphy can further provide a measure gery.1 While morbidity associated with demonstrate a significant difference in of density. Aslam and colleagues have posterior capsule opacification and its risk for posterior capsule opacity.2–4 As a contended, however, that Scheimpflug treatment, Nd:YAG laser capsulotomy, previous study by Wallin and collea- imaging is hampered by its restriction to is limited, progressive opacification gues5 supports the authors’ observations the examination of slit images and its affects quality of vision and visual of an increased risk associated with the analysis of back scattered rather than function, while capsulotomy requires one piece design, one must consider forward scattered light. Alternatively, this additional patient visits, consumes addi- explanations for these discrepancies, in group has suggested an analysis system tional surgical resources, and introduces so far as they may represent inconsis- that attempts to analyse the three dimen- the potential risks of cystoid macular tencies in study design or reporting. sional quality of capsular opacity (‘‘tex- oedema and retinal detachment. One must first ask if a negative study ture’’) through quantitation of measures Therefore, a better understanding of that fails to identify a difference in of entropy in the intensity histogram of the mechanisms of posterior capsule outcomes is based upon the evaluation digitised retroilluminated photographic opacification and its retardation would of relatively insensitive or unreliable images.8 While these provide more direct have obvious immediate benefits. parameters. This is a particular problem measures than capsulotomy rates, the Moreover, control of capsular optical in the evaluation of posterior capsule validity of their description of the complex and biomechanical characteristics fol- opacification. Laser capsulotomy repre- patterns and varying degrees of capsule lowing cataract extraction is essential if sents but a proxy for the process of opacity have yet to be broadly confirmed. dynamic accommodative intraocular opacification; it might be argued that it Another explanation for inconsistent lenses, which change in optical conjuga- is a perfectly reasonable measure to findings in studies of risks for capsule tion power in response to ciliary body study if our goal is to reduce the opacity would be that characteristics of motion translated via the zonules and additional burden that the procedure the populations under study might vary capsular bag, are to provide consistent places on patients and the medical significantly. For example, along with http://bjo.bmj.com/ and sustained performance. system but, in the event that opacifica- material properties and lens design, In addition to providing further evi- tion which fails to meet criteria for there is evidence that surgical techni- dence suggesting an increased risk for treatment induces some compromise of que, including factors such as the degree posterior capsule opacity associated visual function, there remains benefit to of capsulorhexis cover over the optic or with specific features of intraocular lens the reduction of these sub-interven- cortical clean up might influence the design independent of material, the tional threshold levels of capsule opa- course and pattern of subsequent cap- study presented by Mian and co-authors city. Moreover, the goal of capsule sule opacity.9 While Mian et al did not on October 2, 2021 by guest. Protected copyright. in this issue of the BJO (p 1453) control for reliable long term accommo- provide details of their management of supports the observation that we as yet dative intraocular lens function requires the relation between the capsulorhexis do not have a complete understanding an understanding of the mechanisms of edge and optic, or of cortical clean up, of all of the features that govern the posterior capsule fibrosis at an earlier Smith and colleagues,10 in a study of the behaviour of the capsular bag following stage than that associated with the need relation between capsule and lens edge cataract surgery; in this case, inability to for laser intervention. overlap found that incomplete anterior exercise control over this process capsule overlap, was associated with a resulted in laser capsulotomy in up to The problem of posterior capsular significant increase in capsule opacity, 7.5% of cases at 24 months. Moreover, opacification has not yet been con- and that this effect was indeed moder- the comprehensive review provided by quered ated by lens design. In order to compare the authors draws attention to incon- studies and refine our protocols, these sistency in the literature with regard to Aslam and colleagues6 have pre- factors must be controlled as best we can. its assessment of risk factors and stra- sented, in the BJO, a systematic analysis Significant advances have been made tegies for the development of posterior of strategies to evaluate posterior cap- in the design of intraocular lenses for capsule opacification after cataract sur- sule opacity and have pointed out that implantation after cataract surgery, and a gery. This, in turn, obfuscates research at present there is no entirely satisfac- wide range of options are now available directions for strategies to control the tory method of comprehensively quan- for patients and surgeons. However, the process of capsule opacification. tifying capsule opacity in vivo. In problem of posterior capsular opacifica- Well informed and sceptical readers addition to regional quantitation of the tion has not yet been conquered. It is will point out, as the authors acknowl- optical density of capsule opacity, typi- to be hoped that more sophisticated edge, that some previous studies, which cally scored subjectively or by analysis of methods of assessing and comparing the

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development of capsule opacity will help capsulotomy rates noted in an analysis of 5416 truncated hydrophobic acrylic intraocular lenses. Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from pseudophakic human eyes obtained post mortem. Am J Ophthalmol 2003;136:614–19. to guide research to this end. Ophthalmology 2001;108:18. 6 Aslam TM, Dhillon B, Werghi N, et al. Systems of Br J Ophthalmol 2005;89:1389–1390. 2 Bender L, Nimsgern C, Jose R, et al. Effect of 1- analysis of posterior capsule opacification. piece and 3-piece AcrySof intraocular lenses on Br J Ophthalmol 2002;86:1181–6. doi: 10.1136/bjo.2005.074310 the development of posterior capsule 7 Hayashi K, Hayashi H. Limitation of Scheimpflug opacification after cataract surgery. J Cataract videophotography system in quantifying posterior Correspondence to: Stephen D McLeod, MD, Refract Surg 2004;30:786–9. capsule opacification after intraocular lens University of California San Francisco, 3 Nejima R, Miyata K, Honbou M. A prospective, implantation. Am J Ophthalmol 2004;138:696. Department of Ophthalmology, and the Francis randomised comparison of single and three piece 8 Aslam TM, Patton N, Graham J. A freely I Proctor Foundation, San Francisco, San acrylic foldable intraocular lenses. Br J Ophthalmol accessible, evidence based, objective system of Francisco, CA 94143, USA; mcleods@vision. 2004;88:746–9. analysis of posterior capsular opacification; ucsf.edu 4 Sacu S, Findl O, Menapace R, et al. evidence for its validity and reliability. BMC Comparison of posterior capsule opacification Ophthalmol 2005;5:9. between the 1-piece and 3-piece Acrysof 9 Lane SS. Posterior capsule opacification and YAG REFERENCES intraocular lenses. Two year results of a capsulotomy. Am J Ophthalmol 2004;138:635–6. randomized trial. Ophthalmology 10 Smith SR, Daynes T, Hinckley M, et al. The effect 1 Apple DJ, Peng Q, Visessook, et al. Eradication of 2004;111:1840–6. of lens edge design versus anterior capsule posterior capsule opacification. Documentation of 5 Wallin TR, Hinkley M, Nilson C, et al. A clinical overlap on posterior capsule opacification. a marked decrease in Nd:YAG laser posterior comparison of single-piece and three piece Am J Ophthalmol 2004;138:521–6.

Tissue plasminogen activator chamber reaction and fibrin formation ...... was significantly reduced (p = 0.02 to 0.01) on days 1, 3, 7, and 14 after surgery and intracameral delivery of tPA. Tissue plasminogen activator therapy However, after 1–3 months of follow up, the difference between the two groups for the eye was statistically insignificant. Prophylactic use of tPA is akin to the R C Tripathi, B J Tripathi concept of using antibiotics preopera- tively or intraoperatively to prevent ...... postoperative infection of the eye. As clinicians, we have to weigh the possible Past, present, and future risks versus the benefits in deciding whether to pursue such an approach. he systemic (intravenous) adminis- Since fibrin clots can occur in several Because of the reactivity of ocular tration of genetically modified sites of the body, including the eye, the tissues and fibrinous exudation, espe- T(recombinant) tissue plasminogen notion was conceived that tPA therapy cially in children, and in view of the fact activator (tPA) for thrombolysis in could be effective for the rapid dissolu- that post-surgical intracameral admin- coronary arteries was approved by the tion of fibrin clots in the anterior istration of tPA in a child’s eye requires US Federal Drug Administration in chamber of the human eye,141213 as general anaesthesia or short seda- 1988. Since then, use of this approved well as for lysis of fibrin clots after tion,23 24 it may be reasonable to use drug has been extended to many non- vitrectomy14–17 and failed blebs after tPA prophylactically. The half life of tPA approved indications, especially in the glaucoma filtering surgery.1 18–20 in the blood circulation is short (about http://bjo.bmj.com/ eye.1 5 minutes).725 However, it is possible that in the closed cavity of the anterior Tissue plasminogen activator is a As clinicians, we have to weigh the naturally occurring serine protease pro- chamber of the eye, and with the low possible risks versus the benefits in duced by a variety of mammalian daily turnover of aqueous humour, tPA deciding whether to pursue the 1 tissues, especially endothelial cells. persists for several hours, which may Ocular tissues that contain tPA include prophylactic use of tPA justify intracameral delivery at the con-

the conjunctiva, cornea, trabecular clusion of surgery. We must also consider on October 2, 2021 by guest. Protected copyright. meshwork, lens, vitreous, and retina.1–3 In this issue of the BJO (p 1458), that paediatric patients who require In normal adult human eyes, the aqu- Siatiri and colleagues report the results surgical removal of congenital cataract eous humour contains a significant of a prospective, double masked rando- often have many other ocular and sys- amount of tPA that is some 30 times mised clinical trial in paediatric patients temic disorders and therefore warrant more than in plasma.4 The major enzy- to evaluate the efficacy of 20 mg tPA, careful individual evaluation before matic action of tPA is the conversion of administered intracamerally at the com- administration of prophylactic tPA. plasminogen (a zymogen) into plasmin, pletion of congenital cataract surgery, An amount of 25 mg or more of tPA an active serine protease that hydrolyses with the aim of preventing severe has been widely used intracamerally or fibrin. Compared to other fibrinolytic fibrinous effusion and its sequelae. The intravitreally.13–16 19 26–29 Based on extra- agents (for example, urokinase and rationale for this approach is based on polation of the therapeutic serum con- streptokinase), tPA has several advan- the frequent occurrence of fibrin exuda- centration of tPA achieved with tages: fibrin forms a ternary complex tion in paediatric patients, which may intravenous therapy for coronary throm- with tPA and plasminogen, which cause complications including delayed bolysis, we advocated that 10 mg would increases the rate of plasminogen acti- visual recovery, after an otherwise suc- be an equivalent and safe dose for vation several hundred-fold; in addition, cessful cataract surgery.21 22 The rando- intracameral administration.1 Several tPA serves to protect plasmin from misation in the study presumes that all reports in the literature support the antiplasmin inhibitors until complete patients would develop a fibrinous effectiveness of 10 mg tPA for rapid clot lysis is achieved.5–7 Even though reaction after the surgical procedure, (within minutes to a few hours) fibri- cost effective, urokinase and strepto- irrespective of tissue manipulation. The nolysis in the anterior chamber and kinase did not gain popularity because results show that compared to controls, some investigators even recommend a of their toxicity.8–11 the number of eyes that had anterior dose as low as 3 mg.12030–35 Indeed,

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untoward side effects such as intra- endothelium. Invest Ophthalmol Vis Sci cataract surgery in children. J Cataract Refract Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from 1987;28:1341–5. Surg 1999;25:357–62. ocular haemorrhage/rebleed/hyphaema, 3 Geanon JD, Tripathi BJ, Tripathi RC, et al. Tissue 24 Mehta JS, Adams GGW. Recombinant tissue especially after surgical trauma, as well plasminogen activator in avascular tissues of the plasminogen activator following paediatric as corneal and retinal toxicity, have eye: a quantitative study of its activity in the cataract surgery. Br J Ophthalmol 2000;84:983–6. been reported with the use of 25 mgor cornea, lens, and aqueous and vitreous humors of dog, calf, and monkey. Exp Eye Res 25 Rijken DC, Otter M, Kuiper J, et al. Receptor- 13 15–17 26 32 33 35–38 higher doses of tPA. 1987;44:55–63. mediated endocytosis of tissue-type plasminogen Although an optimal intracameral ther- 4 Tripathi RC, Park JK, Tripathi BJ, et al. Tissue activator (t-PA) by liver cells. Thromb Res Suppl 1990;10:63–71. apeutic or prophylactic dose of this very plasminogen activator in human aqueous humor and its possible therapeutic significance. 26 Wedrich A, Menapace R, Muhlbauer-Ries E. The potent drug has not been determined, Am J Ophthalmol 1988;106:719–22. use of recombinant tissue plasminogen activator 10 mg or less of TPA appears to achieve 5 Kwaan HC, Samama MM, Nguyen G. for intracameral fibrinolysis following cataract surgery. Int Ophthalmol, 1994–95, 18:277–80. the desired fibrinolytic action in the Fibrinolytic systems. In: Kwaan HC, Samama MM, eds. Clinical thrombosis. Boca Raton: CRC Press, 27 Wedrich A, Menapace R, Reis E, et al. anterior chamber with potentially mini- 1989:23–31. Intracameral tissue plasminogen activator to treat mal complications of rebleed and toxi- 6 Weitz JI, Stewart RJ, Fredenburgh JC. Mechanism severe fibrinous effusion after cataract surgery. 23 of action of plasminogen activators. Thromb J Cataract Refract Surg 1997; :873–7. city to the cornea and retina. 28 Georgiadis N, Bobiridis K, Halvatzis N, et al. Haemost 1999;82:974–82. Low-dose tissue plasminogen activator in the The topical application of tPA to 7 Collen D, Lijen HR. Tissue-type plasminogen management of anterior chamber fibrin dissolve fibrin clot in the anterior activator: a historical perspective and personal formation. J Cataract Refract Surg account. J Thromb Haemost 2004;2:541–6. chamber has been advocated by several 2003;29:729–32. investigators, although studies in 8 Forrester JV, Williamson J. Lytic therapy in 29 Erol N, Ozer A, Topbas S, et al. Treatment of vitreous haemorrhage. Trans Ophthalmol Soc UK human eyes and experimental animal intracameral fibrinous membranes with tissue 1974;94:583–6. plasminogen activator. Ophthalmic Surg Lasers models have produced equivocal 9 Bramsen T. The effect of urokinase on central Imaging 2003;34:451–6. results.39–42 Because of the large mole- corneal thickness and vitreous haemorrahge. Acta 30 Williams DF, Bennett SR, Abrams GW, et al. Low- Ophthalmol 1978;56:1006–12. cular size (68 kDa) of tPA, its penetra- dose intraocular tissue plasminogen activator for 10 Textorius O, Stenkula S. Toxic ocular effects of treatment of postvitrectomy fibrin formation. tion across the intact cornea may be two fibrinolytic drugs: an experimental Am J Ophthalmol 1990;109:606–7. limited.1 Transconjunctival or subcon- electroretinographic study on albino rabbits. Arch 31 Abrams GW, Murray TG, Boldt HC, et al. Tissue junctival, sub-Tenon’s capsule and Ophthalmol 1983;61:322–31. plasminogen activator (t-PA): determination of 11 Mindel JS. Special topics. Part 2: Drugs affecting clinical limits of efficacy for intracameral delivery. trans-scleral routes deserve considera- blood. In: Duane TD, ed. Biomedical foundations ARVO abstract. Invest Ophthalmol Vis Sci tion, especially if clinicians prefer to of ophthalmology Philadelphia, Harper and Row, 1991;32(suppl 4):1226. initiate tPA therapy postoperatively after 1991;41:1–26. 32 Starck T, Hopp L, Held KS, et al. Low-dose 12 Tripathi RC, Tripathi BJ, Park JK, et al. intraocular tissue plasminogen activator treatment paediatric or adult cataract surgery. Intracameral tissue plasminogen activator for for traumatic total hyphema, postcataract, and With this approach, the need for a short resolution of fibrin clots after glaucoma filtering penetrating keratoplasty fibrinous membranes. duration of general anaesthesia or seda- procedures. Am J Ophthalmol J Cataract Refract Surg 1995;21:219–24. 1991;111:247–28. 33 Lundy DC, Sidoti P, Winarko T, et al. Intracameral tion for intracameral injection especially 13 Snyder RW, Sherman MD, Allinson RW. tissue plasminogen activator after glaucoma in children, can be avoided and tPA Intracameral tissue plasminogen activator for surgery. Indications, effectiveness, and could be administered in the postopera- treatment of excessive fibrin response after complications. Ophthalmology penetrating keratoplasty. Am J Ophthalmol 1996;103:274–82. tive follow up period on an as needed 1990;109:483–4. 34 Heiligenhaus A, Steinmetz B, Lapuente R, et al. basis. This concept poses a challenge to 14 Williams GA, Lambrou FH, Jaffe GJ, et al. Recombinant tissue plasminogen activator in clinicians and the pharmaceutical Treatment of postvitrectomy fibrin formation with cases with fibrin formation after cataract surgery: intraocular tissue plasminogen activator. Arch a prospective randomised multicentre study. industry interested in developing novel Ophthalmol 1988;106:1055–8. Br J Ophthalmol 1998;82:810–15. methods for tPA drug delivery. 15 Jaffe GJ, Lewis H, Han DP, et al. Treatment of 35 Kim MH, Koo TH, Sah WJ, et al. Treatment of postvitrectomy fibrin pupillary block with tissue total hyphema with relatively low-dose tissue

Br J Ophthalmol 2005;89:1390–1391. plasminogen activator. Am J Ophthalmol plasminogen activator. Ophthalmic Surg Lasers http://bjo.bmj.com/ doi: 10.1136/bjo.2005.074401 1989;108:170–5. 1998;29:762–6. 16 Jaffe GJ, Abrams GW, Williams GA, et al. Tissue 36 Lambrou FH, Synder RW, Williams GA. Use of ...... plasminogen activator for postvitrectomy fibrin tissue plasminogen activator in experimental formation. Ophthalmology 1990;97:184–9. hypema. Arch Ophthalmol 1987;105:995–7. 37 Wollensak G, Meyer JH, Loffler KU, et al. Band- Authors’ affiliations 17 Dabbs CK, Aaberg TM, Aguilar HE, et al. like keratopathy after treatment of postoperative R C Tripathi, B J Tripathi, University of South Complications of tissue plasminogen activator fibrin reaction with tissue plasminogen activator. Carolina School of Medicine, Columbia, SC, therapy after vitrectomy for diabetes. Klin Monatsbl Augenheilkd 1996;209:43–6. Am J Ophthalmol 1990;110:354–60. USA 38 Chen SN, Yang TC, Ho CL, et al. Retinal toxicity of 18 Ortiz JR, Walker SD, McManus PE, et al. Filtering intravitreal tissue plasminogen activator: case on October 2, 2021 by guest. Protected copyright. bleb thrombolysis with tissue plasminogen Correspondenceto:ProfessorRameshCTripathi, report and literature review. Ophthalmology activator. Am J Ophthalmol 1988;106:624–65. 2003;110:704–8. Department of Ophthalmology, Vision Research 19 Baker ND, Lehman DM, Weber PA, et al. Tissue 39 Lim JI, Fiscella R, Tessler H, et al. Intraocular Laboratories, 6439 Garners Ferry Road, plasminogen activator treatment of failing penetration of topical tissue plasminogen Columbia, SC 29209, USA; glaucoma filtering surgery. ARVO Abstract. Invest activator. Arch Ophthalmol 1991;109:714–17. [email protected] Ophthalmol Vis Sci 1991;32(suppl 4):1122. 40 Lim JI, Maguire AM, John G, et al. Intraocular 20 Smith MF, Doyle JW. Use of tissue plasminogen tissue plasminogen activator concentrations after activator to revive blebs following intraocular subconjunctival delivery. Ophthalmology REFERENCES surgery. Arch Ophthalmol 2001;119:809–12. 1993;100:373–6. 21 Jameson NA, Good, WV, Hoyt CS. Inflammation 41 Cellini M, Baldi A, Possati GL. Topical treatment 1 Tripathi RC, Tripathi BJ, Bornstein S, et al. Use of after cataract surgery in children. Ophthalmic of postvitrectomy fibrin formation with tissue tissue plasminogen activator for rapid dissolution Surg Lasers 1992;23:99–102. plasminogen activator. Int Ophthalmol of fibrin and blood clots in the eye after surgery 22 Fallaha N, Lambert SR. Pediatric cataracts. 1994–95;18:351–3. for glaucoma and cataract in humans. Drug Dev Ophthalmol Clin N Am 2001;14:479–92. 42 Zwaan J, Latimer WB. Topical tissue plasminogen Res 1992;27:147–59. 23 Klais CM, Hattenbach LO, Steinkamp GW, et al. activator appears ineffective for the clearance of 2 Park JK, Tripathi RC, Tripathi BJ, et al. Tissue Intraocular recombinant tissue-plasminogen intraocular fibrin. Ophthalmic Surg Lasers plasminogen activator in the trabecular activator fibrinolysis of fibrin formation after 1998;29:476–83.

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DIABETES sensitivity loss in diabetes is probably Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from ...... linked to the abnormal function of the SW cones. Yamamoto et al15 16 demon- strated that the short wavelength (S) Detecting ocular-visual function cones were compromised selectively in adults with type 1 diabetes. These changes in diabetes changes were evident with or without evident retinal vasculopathy. A signifi- C A Westall cant (p,0.001) selective reduction in the amplitude of the short wavelength ...... cone response suggests a defect at the level of the S-cone photoreceptor. It is essential for the chosen biomarkers to assess accurately ocular Our group and others have found function as well as reproducible change deficits in the integrity of the SW or S- cone pathway in patients with type 1 n the 21st century we are nearing the Currently, there is a one in 300–500 diabetes, with no evidence of retinopa- time when treatment of ocular disease chance for a child developing type 1 thy, using the colour visual evoked 17 18 Iis becoming a reality. As such, the diabetes by 18–20 years of age.5–7 Of potentials (VEP). The SW VEP laten- ability to monitor disease progression these, 98% will show evidence of retinal cies (time to respond to blue-yellow and/or disease recovery is as important microvascular changes 15–20 years after stimulus) of those with diabetes are as the ability to detect disease related diagnosis.8 delayed when compared with those 17 ocular change. Minimising measure- Current treatments for diabetic reti- without diabetes. We investigated the ment variability is intrinsic to monitor- nopathy are based on the extent of the association between glucose control ing accurately any chosen ocular-visual retinal vasculopathy. The progression of (HbA1c) and colour vision in preteen biomarker that best represents disease vascular abnormality involves change (,12.9 years of age) children with type progression over time. This is the topic from background, to pre-proliferative, 1 diabetes using the colour VEP. Glucose of the paper by Gilmore and co-workers to proliferative disease over time. The control was well controlled and did not in this issue of BJO (p 1462). These Diabetic Retinopathy Study (DRS)9 and affect the S-cone pathway in this young authors have described the measure- the Early Treatment in Diabetic group of children with diabetes. ment variability of the short wavelength Retinopathy Study (ETDRS)10 set the However, pubertal status was associated (SW) automated perimetry (SWAP) in current standard of care. Treatment for significantly (p = 0.0114) and selectively patients with diabetes. SWAP has been proliferative retinopathy involves pan- with S-VEP latency: pubertal children used primarily to detect vision loss and retinal laser photocoagulation (PRP) with type 1 diabetes had delayed S-VEP to monitor progressive visual field loss used to ablate the peripheral retina latencies (mean S-VEP latency = in glaucoma.1 SWAP is more sensitive in and laser ablative therapy given when 144.3 ms) when compared with the detecting glaucomatous changes than high risk proliferative retinopathy devel- pre-pubertal children with type 1 dia- standard white on white (WW) perime- ops. betes (mean S-VEP latency = try.2 Gilmore and co-workers used the 134.8 ms).18 psychophysical frequency of seeing ana- An exciting development is the use of In the future, neuroprotective thera- lysis as a measure of within examina- the multifocal electroretinogram pies might conceivably delay onset tion variability, where the slope of the (mfERG) to study multiple small http://bjo.bmj.com/ frequency of seeing curve represents of proliferative retinal change in regions of the retina individually.19–27 threshold variability. Earlier Chauhan diabetes This enables precise mapping of the and co-workers3 integrated a psycho- neural retina. Multifocal ERG studies physical frequency of seeing paradigm But, what if the neuronal component of adults with diabetes demonstrate into WW automated perimetry testing. of the retina is compromised along with, clearly local deficits of retinal func- They found that in patients with glau- or even before, the earliest retinal tion.19–27 Significant delays in the first microvascular complications become order mfERG response, which is pre- coma and those with suspicion of on October 2, 2021 by guest. Protected copyright. glaucoma the variability in frequency apparent? This is an area receiving dominantly derived from bipolar cells,28 of seeing was not necessarily explained increasing attention and is the focus of were found.20 22 Importantly, Han et by the response threshold or threshold collaboration between the Hospital for al20 21 found localised functional deviation. Change in the slope of the Sick Children and St Michael’s Hospital abnormalities that predicted the site of frequency of seeing curve probably (Dr Shelley Boyd) in Toronto. Direct, new vasculopathy (microaneurysms or represents spontaneous change in non-invasive neuroretinal function test- leakage) observed 1 year later on clin- threshold. Gilmore and colleagues find ing of the human visual system demon- ical examination and confirmed by 50˚ the higher estimate of within examina- strates functional changes in the fundus photography. tion variability makes SWAP a less neuroretina of individuals with dia- Very recently, high frequency compo- valuable biomarker in monitoring pro- betes. Colour processing, in particular nents of mfERG recordings have been gression of certain ocular diseases. The the processing of short wavelength found to resemble oscillatory potentials increased sensitivity of SWAP has to be stimulus, is abnormal in diabetes.11–13 of the full field ERG. Wu and Sutter29 tempered with the higher within test Adults with type 1 diabetes show found that multifocal oscillatory poten- variability of SWAP over standard WW reduced blue-yellow colour vision dis- tials (mfOPs) were produced best by a perimetry. crimination before the onset of retino- flicker stimulus slowed by the insertion Diabetic retinopathy is the single pathy.14 The deficit in the short of dark stimulus frames. Bearse and most common cause of blindness in wavelength pathway was the focus of colleagues26 showed that the inner the developed world.4 The prevalence of the study by Gilmore and colleagues, retinal mfOP response, derived from diabetes is increasing and potential who tested frequency of seeing (FOS) the slow flash mfERG recording, was blindness is threatening a rapidly grow- areas of known decreased SW sensi- abnormal in patients with diabetes. In ing number of working age individuals. tivity. The importance of this SW addition response abnormalities were

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associated with the site of vascular 2 Sample PA, Bosworth CF, Blumenthal EZ, et al. in diabetes: relationship to systemic factors. Doc Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from leakage or haemorrhage. Visual function-specific perimetry for indirect Ophthalmol 1997;94:193–200. comparison of different ganglion cell populations 17 Crognale MA, Switkes E, Rabin J, et al. Because diabetes is generally consid- in glaucoma. Invest Ophthalmol Vis Sci Application of the spatiochromatic visual evoked ered a disease of the retinal blood 2000;41:1783–90. potential to detection of congenital and acquired vessels current treatment paradigms 3 Chauhan BC, Tompkins JD, LeBlanc RP, et al. color-vision deficiencies. J Opt Soc Am A Opt Characteristics of frequency-of-seeing curves in Image Sci Vis 1993;10:1818–25. are based on the extent of vascular normal subjects, patients with suspected 18 Elia YT, et al. Colour visual evoked potentials in damage and are typically given late in glaucoma, and patients with glaucoma. Invest children with type 1 diabetes: relationship to the disease, when significant end organ Ophthalmol Vis Sci 1993;34:3534–40. metabolic control. Invest Ophthalmol Vis Sci (in press). damage has already occurred. Perhaps 4 Ewing FM, Deary IJ, McCrimmon RJ, et al. Effect of acute hypoglycemia on visual information 19 Han Y, Bearse MA Jr, Schneck ME, et al. Towards the neuronal cells of the retina and processing in adults with type 1 diabetes mellitus. optimal filtering of ‘‘standard’’ multifocal visual pathways of the brain are Physiol Behav 1998;64:653–60. electroretinogram (mfERG) recordings: findings in normal and diabetic subjects. Br J Ophthalmol 5 Daneman D. Risk of developing diabetes. Novo damaged as well as retinal blood vessels 2004;88:543–50. Nordisk Canada: www.novonordisk.ca, 2001. in diabetes. In particular, our data show 20 Han Y, Bearse MA Jr, Schneck ME, et al. 6 Engelgau MM, Colagiuri S, Ramachandran A, Multifocal electroretinogram delays predict sites that abnormalities of the koniocellular et al. Prevention of type 2 diabetes: issues and of subsequent diabetic retinopathy. Invest pathway occur in adolescent children strategies for identifying persons far interventions. Ophthalmol Vis Sci 2004;45:948–54. with diabetes in the absence of obser- Diabetes Technol Ther 2004;6:874–82. 21 Han Y, Bearse MA Jr, Schneck ME, et al. vable changes in the retinal vasculature. 7 Daneman D. In: Hux J, Booth G, Slaughter P, Formulation and evaluation of a predictive model et al, eds. Diabetes in Ontario—an ICES practice to identify the sites of future diabetic retinopathy. In the future, neuroprotective therapies atlas. Toronto: Institute for Clinical Evaluative Invest Ophthalmol Vis Sci 2004;45:4106–12. might conceivably delay onset of pro- Sciences, 2003:219–30. 22 Fortune B, Schneck ME, Adams AJ. Multifocal liferative retinal change in diabetes. In 8 Klein R, Klein BE, Moss SE, et al. The Wisconsin electroretinogram delays reveal local retinal Epidemiologic Study of Diabetic Retinopathy. II. dysfunction in early diabetic retinopathy. Invest streptozotocin induced diabetic rats, Prevalence and risk of diabetic retinopathy when Ophthalmol Vis Sci 1999;40:2638–51. neurons and glial cells in the inner age at diagnosis is less than 30 years. Arch 23 Schneck ME, Bearse MA Jr, Han Y, et al. plexiform and nuclear layers of the Ophthalmol 1984;102:520–6. Comparison of mfERG waveform components 9 Diabetic Retinopathy Study Report No 5. and implicit time measurement techniques for retina undergo apoptosis early in the Photocoagulation treatment of proliferative 30 detecting functional change in early diabetic eye course of diabetes and actually precede diabetic retinopathy: relationship of adverse disease. Doc Ophthalmol 2004;108:223–30. the development of microvascular treatment effects to retinopathy severity. Dev 24 Palmowski AM, Sutter EE, Bearse MA Jr, et al. lesions.31 Ophthalmol 1981;2:248–61. Mapping of retinal function in diabetic 10 Early Treatment Diabetic Retinopathy Study retinopathy using the multifocal For studies investigating treatment Research Group. Fundus photographic risk electroretinogram. Invest Ophthalmol Vis Sci paradigms it is essential for the chosen factors for progression of diabetic retinopathy. 1997;38:2586–96. biomarkers to assess accurately ocular ETDRS report No 12. Ophthalmology 25 Bearse MA Jr, Han Y, Schneck ME, et al. Retinal function in normal and diabetic eyes mapped with function as well as reproducible change. 1991;98:823–33. 11 Bresnick GH, Condit RS, Palta M, et al. the slow flash multifocal electroretinogram. Invest Gilmore and colleagues have set an Association of hue discrimination loss and Ophthalmol Vis Sci 2004;45:296–304. excellent precedent in investigating diabetic retinopathy. Arch Ophthalmol 26 Bearse MA Jr, Han Y, Schneck ME, et al. Local variability in responses in paradigms 1985;103:1317–24. multifocal oscillatory potential abnormalities in 12 Kurtenbach A, Flogel W, Erb C. Anomaloscope diabetes and early diabetic retinopathy. Invest already shown to be sensitive. matches in patients with diabetes mellitus. Ophthalmol Vis Sci 2004;45:3259–65. 27 Kurtenbach A, Langrova H, Zrenner E. Multifocal Br J Ophthalmol 2005;89:1392–1393. Graefes Arch Clin Exp Ophthalmol 2002;240:79–84. oscillatory potentials in type 1 diabetes without doi: 10.1136/bjo.2005.073395 retinopathy. Invest Ophthalmol Vis Sci 13 Ong GL, Ripley LG, Newsom RS, et al. Screening 2000;41:3234–41. for sight-threatening diabetic retinopathy: Correspondence to: Dr Carol A Westall, 28 Hood DC, Frishman LJ, Saszik S, et al. Retinal comparison of fundus photography with Ophthalmology and Vision Sciences, The origins of the primate multifocal ERG: implications automated color contrast threshold test. University of Toronto and The Hospital for Sick for the human response. Invest Ophthalmol Vis Am J Ophthalmol 2004;137:445–52.

Children, Department of Ophthalmology and Sci 2002;43:1673–85. http://bjo.bmj.com/ 14 Hardy KJ, Lipton J, Scase MO, et al. Detection Vision Sciences, Toronto, M5G 1X8, Canada; 29 Wu S, Sutter EE. A topographic study of of colour vision abnormalities in uncomplicated [email protected] oscillatory potentials in man. Vis Neurosci type 1 diabetic patients with angiographically 1995;12:1013–25. normal retinas. Br J Ophthalmol 30 Barber AJ, Lieth E, Khin SA, et al. Neural 1992;76:461–4. REFERENCES apoptosis in the retina during experimental and 15 Yamamoto S, Kamiyama M, Nitta K, et al. human diabetes. Early onset and effect of insulin. 1 Hutchings N, Hosking SL, Wild JM, et al. Long- Selective reduction of the S cone J Clin Invest 1998;102:783–91. term fluctuation in short-wavelength automated electroretinogram in diabetes. Br J Ophthalmol 31 Rungger-Brandle E, Dosso AA, Leuenberger PM. perimetry in glaucoma suspects and glaucoma 1996;80:973–5. Glial reactivity, an early feature of diabetic

patients. Invest Ophthalmol Vis Sci 16 Yamamoto S, Takeuchi S, Kamiyama M. The retinopathy. Invest Ophthalmol Vis Sci on October 2, 2021 by guest. Protected copyright. 2001;42:2332–7. short wavelength-sensitive cone electroretinogram 2000;41:1971–80.

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Trypan blue intraocular pressure of 21 mm Hg or Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from ...... less was considered a successful outcome, whereas now intraocular pressures of 12 mm Hg are being sought and Trypan blue staining of antiproliferative achieved with surgery using the more potent antiproliferative agents. Over the agents for trabeculectomy surgery and past few years nearly all cases of trabeculectomy at Moorfields Eye bleb needling Hospital have been with mitomycin C (fig 2). W Franks It was soon recognised that the use of antiproliferative agents was associated ...... with cystic bleb formation.23 Cystic blebs lead to an uncomfortable eye, late Staining could be a useful tool in allowing comparison of the wound leaks, hypotony, and an effects of different antiproliferative agents increased risk of bleb related infections with potentially devastating conse- 24 25 ealey and Crowston, in the cases come to surgery because of fear of quences. If a small treatment area September issue of BJO,1 describe complications. Eye drops are the first is used subconjunctival fibrosis occurs Ha novel and ingenious study using line treatment of chronic open angle at the margins of the trabeculectomy trypan blue to stain antiproliferative glaucoma and the number of different bleb, confining drainage of aqueous agents used during trabeculectomy sur- types available leads to a myriad of humour to the treated area. The pres- gery and trabeculectomy bleb needling. possible combinations. The popularity sure of aqueous humour in this confined Trypan blue is commercially available as and variety of medical treatments were subconjunctival space causes thinning Vision Blue (Dorc, Zuidland, greatly increased by the introduction of of the overlying conjunctiva over time. Netherlands). It is widely used in prostaglandin agonist eye drops in the This led to the idea that cystic bleb formation would be less likely if per- cataract surgery to stain the anterior mid 1990s and have been associated operative treatments with antiprolifera- capsule, and in vitreoretinal surgery to with a halving of trabeculectomy tive agents were applied over a wide improve the visibility of preretinal mem- cases,16 17 although the number per- area of the upper fornix. This results in a branes and is therefore readily available formed at Moorfields Eye Hospital now greater area for aqueous humour drai- in most eye theatres. appears to have stabilised (fig 1). They describe a clinical safety and nage and reduced local tissue pressure. efficacy trial backed up by laboratory This necessitated a change in surgical based studies of colouring mitomycin C 700 technique from limbal to fornix based 26 27 or 5-fluorouracil with the vital dye 600 conjunctival flaps. The downside to trypan blue 0.1%. Addition of trypan 500 this change has been early bleb leaks blue in vitro had no effect on cell death 400 because the antiproliferative agent inhi- 300 bits healing of the anterior edge of the

rates in controls or on mitomycin C and Number 200 conjunctival flap. Surgeons learning 5-fluorouracil treated cells. In vivo, 100 there was no difference in outcome in 0 trabeculectomy surgery are doing fewer a series of eyes undergoing trabeculect- cases at a time when the technique has http://bjo.bmj.com/ omy surgery with trypan blue stained 1997 1998 1999 2000 2001 2002 2003 2004 become more demanding. By staining antiproliferative agent compared to con- Year the antiproliferative agent with trypan trols. This technique has the potential to blue it is clear, firstly, if an adequate be useful both in research to compare Figure 1 Number of trabeculectomy area has been treated and, secondly, any outcomes of surgery as well as in clinical operations at Moorfields Eye Hospital 1997– areas of inadvertent treatment are high- practice by enhancing safety in the use 2004. lighted. If the conjunctival edge is contaminated this will be visible and of antiproliferative agents and improv- on October 2, 2021 by guest. Protected copyright. ing surgical technique. The realisation that patients with give an indication if additional sutures Trabeculectomy is the surgical proce- progressive visual field loss need lower are needed to prevent wound leaks. dure of choice in most countries for target pressures,18 and that this can be Healey and Crowston found that by treatment of chronic open angle glau- difficult to achieve even with multiple using sponges pre-soaked with dyed coma. Since the first description in 1968 eye drops, means that trabeculectomy antiproliferative agent the treatment by Cairns2 the operation has survived surgery will continue to be an important area was larger than when the anti- challenges from procedures such as treatment to prevent blinding disease. proliferative agent was injected into dry laser trabeculoplasty,3 holmium laser In countries where the cost of drops is pre-placed sponges. This means that sclerostomy,4 artificial drainage prohibitively expensive and the supply surgeons will need to be careful to do devices5–7 and, more recently, deep uncertain, trabeculectomy is the only a thorough dissection of the subcon- sclerectomy89and viscocanalostomy.10 11 feasible sight saving treatment. junctival space before inserting sponges Some of the latter remain as lesser The most important refinement to as squeezing in wet sponges may cause weapons in the glaucoma surgery arma- trabeculectomy surgery has been the leakage. In particular, extra care will mentarium but none has stood the test use of antiproliferative agents to reduce need to be taken to prevent inadvertent of time to take trabeculectomy’s fore- postoperative subconjunctival fibrosis, treatment of the conjunctival edge by most place in the surgical management prevent bleb failure, and achieve better the dampened sponges and this will be of glaucoma. intraocular pressure control.19 20 easier to see if the antiproliferative Trabeculectomy is the most effective Evidence is accumulating that at lower agent is stained with trypan blue. treatment for glaucoma for reducing intraocular pressures visual field pro- Healey and Crowston also describe intraocular pressure and preventing gression is slowed or even arrested.21 22 the use of dyed 5-fluorouracil when visual field loss,12–15 but relatively few In the pre-antiproliferative era an needling failing trabeculectomy blebs.

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9 Sanchez E, Schnyder CC, Sickenberg M, et al. Br J Ophthalmol: first published as 10.1136/bjo.2005.076075 on 18 October 2005. Downloaded from 350 Deep sclerectomy: results with and without 1997 collagen implant. Int Ophthalmol 1998 1996–97;20:157–62. 300 1999 10 Stegmann R, Pienar A, Miller D. 2000 Viscocanalostomy for open-angle glaucoma in black African patients. J Cataract Refract Surg 250 2001 1999;25:316–22. 2002 11 Carassa RG, Bettin P, Fiori M, et al. 2003 Viscocanalostomy versus trabeculectomy in white 200 2004 adults affected by open-angle glaucoma: a 2- year randomised, controlled trial. Ophthalmology 2003;110:882–7. 12 Jay JL, Murray SB. Early trabeculectomy versus Numbers 150 conventional management in primary open angle glaucoma. Br J Ophthalmol 1988;72:881–9. 100 13 Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma. 50 Ophthalmology 1994;101:1651–6. 14 Migdal C, Hitchings R. Control of chronic simple glaucoma with primary medical, surgical and laser treatment. Trans Ophthalmol Soc UK 0 None 5-FU MMC 1986;105(Pt 6):653–6. 15 Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: Figure 2 Trabeculectomy and antiproliferative agents 1997–2004. 5-FU, 5-fluorouracil, MMC, the early manifest glaucoma trial. Arch mitomycin C. Ophthalmol 2003;121:48–56. 16 Bateman DN, Clark R, Azuara-Blanco A, et al. The effect of new topical treatments on Trypan blue staining can show both the to come. However, concern remains management of glaucoma in Scotland: an extent of the treatment area as the about potential complications. Healey examination of ophthalmological health care. Br J Ophthalmol 2002;86:551–4. antiproliferative agent is injected into and Crowston’s work will be of interest 17 Paikal D, Yu F, Coleman AL. Trends in glaucoma the subconjunctival space and, very to clinicians as it promises to make surgery incidence and reimbursement for importantly, can make penetration of surgery more predictable and to help in physician services in the Medicare population from 1995 to 1998. Ophthalmology the antiproliferative agent into the teaching safe surgical technique. It also 2002;109:1372–6. anterior chamber via the sclerostomy promises to be of use in developing 18 Jampel HD. Target pressure in glaucoma therapy. visible. It will make leakage back research protocols. Acta Ophthalmol Scand Supp 1997;224:43–4. 19 Parrish RK 2nd, Schiffman JC, Feuer WJ, et al. through the injection site into the tear Some caution is necessary however. The Fluorouracil Filtering Surgery Study Group. film more obvious and demonstrate Trypan blue is not yet licensed for this Prognosis and risk factors for early postoperative whether there is a risk of 5-fluorouracil application and, as the authors point wound leaks after trabeculectomy with and induced keratopathy. out, further in vitro studies of fibroblast without 5-fluorouracil. Am J Ophthalmol 2001;132:633–40. Comparing surgical outcomes contraction may be needed before such 20 Chen CW, Huang HT, Blair JS, et al. between centres in trials of new surgical approval is given. Trabeculectomy with simultaneous topical techniques in trabeculectomy surgery is application of mitomycin-C in refractory Br J Ophthalmol 2005;89:1394–1395. glaucoma. J Ocular Pharmacol 1990;6:175–82. problematic. Intraocular pressure low- doi: 10.1136/bjo.2005.076075 21 AGIS Investigators. The relationship between ering and visual field stability are control of intraocular pressure and visual field insufficient alone to assess success. The Correspondence to: Wendy Franks, Glaucoma deterioration. Am J Ophthalmol Service, Moorfields Eye Hospital, City Road, 2000;130:429–40. http://bjo.bmj.com/ comfort and appearance of the trabecu- London EC1V 2PD, UK; wendy.franks@ 22 Khaw PT. The More Flow (Moorfields/MRC UK lectomy bleb are also important out- moorfields.nhs.uk Study): a randomised prospective trial of comes for the patient. Clarke et al have intraoperative 5-fluorouracil versus placebo. Effect on long term pressure control and published a useful guide to bleb appear- REFERENCES glaucoma progression. Am Acad Ophthalmol ances to aid researchers in quantifying 2004:Abstract PAO 14. morphological outcomes of trabeculect- 1 Healey PR, Crowston JG. Trypan blue identifies 23 Franks WA, Hitchings RA. Complications of 5- 28 antimetabolite treatment area in trabeculectomy. fluorouracil after trabeculectomy. Eye 1991;5(Pt omy surgical technique. Br J Ophthalmol 2005;89:1152–6. 04):385–9. The surgeon chooses the concentra- 2 Cairns J. Trabeculectomy. Preliminary report of a 24 Higginbotham EJ, Stevens RK, Musch DC, et al. on October 2, 2021 by guest. Protected copyright. tion of mitomycin C but the area treated new method. Am J Ophthalmol 1968;66:673–9. Bleb-related endophthalmitis after trabeculectomy 3 Wise JB, Witter SL. Argon laser therapy for open- with mitomycin C. Ophthalmology is variable. Dyeing antiproliferative angle glaucoma. A pilot study. Arch Ophthalmol, 1996;103:650–6. agents with trypan blue may aid in 1979, 1997;2:319–22. 25 Edmunds B, Thompson JR, Salmon JF, et al. standardising treatment areas. This 4 Hoskins HD Jr, Iwach AG, Vassiliadis A, et al. The National Survey of Trabeculectomy. III. makes comparing outcomes of treating Subconjunctival THC:YAG laser thermal Early and late complications. Eye sclerostomy. Ophthalmology 1991;98:1394–9. 2002;16:297–303. series of patients difficult as the area 5 Molteno AC. New implant for drainage in 26 Rai PA, Bunce C, BartonK. Fornix versus limbus- and therefore the dosage of antiproli- glaucoma. Clinical trial. Br J Ophthalmol based conjunctival flap trabeculectomy and the ferative agent are not standardised. 1969;53:606–15. incidence of bleb-related infection. Invest 6 Coleman AL, Hill R, Wilson MR, et al. Initial Ophthalmol Vis Sci 2003;44:E abstract. Staining could be a useful tool in the clinical experience with the Ahmed glaucoma 27 Wells AP, Cordeiro MF, Bunce C, et al. Cystic future in developing protocols allowing Valve implant. 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