Br J Ophthalmol 2004 Stanford 444 5

8/12/2019 Br J Ophthalmol 2004 Stanford 444 5

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Eccentric viewing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

What we dont know about eccentric viewingT W Raasch. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The link between central scotomas, Troxler fading, and preferredretinal locus

E very clinician who has worked withpatients with central scotomas hasobserved the difficulty those pati-ents experience. Not only have they lostthe ability to resolve fine detail, theyalso see nothing straight ahead. Theresulting behaviour, most commonlycalled eccentric viewing, typicallyinvolves the development of a pseudo-fovea, or a preferred retinal locus

(PRL). The use of a PRL is primarily aneye movement control issue: the indivi-dual must be able to place an object of interest on a particular fundus location.In addition to eye position control,however, successful use of an eccentriclocation must involve much more than just that. As Deruaz and colleagues havepointed out in this issue of BJO (p 461),higher level sensory processes are likelyto be involved.

These authors have made the observation that some patients alternatebetween two retinal locations whendeciphering a word. On further ques-

tioning, these patients reported that thedisplayed word was more distinctimmediately after an eye movement.That phenomenon is attributed to theTroxler effectthat is, the fading of anobject under stabilised conditions. Thisobservation prompted the authors toconduct a laboratory experiment withnormally sighted observers. This experi-ment is easy enough to replicate as a

demonstration. Such a demonstrationdoes seem to support the suggestionthat Troxler fading might be experi-enced by those with central scotomas.We do not know, however, whetherTroxler fading contributes to the devel-opment of multiple PRLs. As Deruaz et alsuggest, saccades and other eye move-ments that occur naturally, even with asingle PRL, probably prevent Troxler

fading.The efficient use of a PRL requires

careful eye movement control. It mustalso require a shift of ones attention tothat location in the visual field. Considera patient with two PRLs reading a fullpage of text. Words will fall on bothPRLs simultaneously much of the time.In order to make sense of what is being viewed, that patient must be able tofocus attention selectively on one or theother PRL. Without that ability, bothregions of text would be equally salient.

An area that remains relatively unex-plored is binocularity and PRLs. Most of

what is known about PRL use applies tomonocular viewing conditions. In anindividual with bilateral central scoto-mas, how is the input from the two eyesintegrated? Do PRLs tend to develop atcorresponding retinal locations? Does aPRL tend to develop at a location thatcorresponds to a scotomatous area inthe other eye? If PRLs develop in botheyes at non-corresponding locations,

what happens under binocular condi-tions? Can both PRLs at non-corre-sponding points be used in a readingtask? Can that person shift attentionbetween those PRLs? Can this personexperience confusion as the result of input from both PRLs? Is the inputfrom one eye simply suppressed? Wedo not know the answers to thosequestions.

Eccentric viewing training is part of many comprehensive visual rehabilita-tion programmes. One wonders whatshould be the goal of eccentric viewingtraining. Does one reinforce to thetrainee that the eccentric point iseccentric, preserving the normal oculo-centric direction? Or does one attemptto replace the non-functioning fovea with that eccentric point? That is,should the goal be to shift the oculo-centric direction to that eccentric point?If that is possible, it seems that wouldproduce the most effective and effortlesseccentric viewing behaviour possible. If the oculocentric direction shifts, how-ever, is it a binocular shift, or does theshift occur independently (and perhapsunequally) for both eyes?

How one learns to view objects in thepresence of a central scotoma is acomplex issue. We have learned a greatdeal about this problem, but there ismuch more that we do not know.Perhaps we will learn whether traininghelps patients develop skills they other- wise would not develop, what type of training might be most effective, and in which patients training will be mosteffective. The growing number of visually impaired individuals will bebetter served when we have betteranswers to these questions.

Br J Ophthalmol 2004;88 :443.doi: 10.1136/bjo.2003.034827

Authors affiliation. . . . . . . . . . . . . . . . . . . . . .

T W Raasch, College of Optometry, 320 W 10th Avenue, Columbus, OH, USA;[email protected]

Myopia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Myopia in AsiaP J Foster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

An unexploded bomb

In this issue of the BJO (p 538), Sawand colleagues show that, after exclu-sion of syndrome associated and reti-nopathy of prematurity (ROP) relatedmyopia, there was no identifiable link

between birth weight and refractiveerror in later childhood. Low birth weight has been linked to adultrisk of cardiovascular disease (CVD),hypertension, diabetes, and cancer.

The effects of low birth weight areincreased by slow infant growth andrapid weight gain in later childhood. 1

The so called Barker hypothesis sug-gests that antenatal factors may pro-gram physiology in later life. Theabsence of a clear association withrefractive error suggests the processcoordinating ocular dimensions doesnot fall under the control of a similarmechanism. Put simply, they showthat bigger children have bigger eyes,but not necessarily (after correctionfor other socioeconomic factors) higherlevels of myopia. However, it has beenshown that children who are bornsmall have small eyes, and that this

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trait is retained in adulthood. Fledeliusexamined 70 subjects with low birth weight (less than 2000 g) and 67 fullterm controls. The low birth weight-ocular size deficit remained an adultfeature, even in seemingly normal eyes.There was also a parallel, permanentlack of catch up in height, headcircumference, and other anthropo-metric factors. 2

What marks this paper as interest-ing is the analytical method used bythe investigators. Previous epidemiolo-gical studies of refractive error haveused refraction as the sole end point. 3 4

However, there is a growing recogni-tion that the risk factors for, and naturalhistory of, myopia and hypermetro-pia cannot be fully understood withoutrecourse to ocular biometry. 5 7 Theinclusion of biometric data in theanalysis has strengthened the authors abilities to examine the determinantsof refractive error in this study of 1413schoolchildren in Singapore. With the

recognition that that bigger peoplehave bigger eyes, without necessarilyhigher rates of myopia, the importanceof correcting for co-determinants of axial dimensions, such as height, canbe readily appreciated. 8 Similarly, inthe study of adult refractive error,changes in lens opacity are oftenaccompanied by changes in refractiveindex, further complicating the model-ling of risk factors. 9

The size of the problem may parallelthe rapid industrialisation and eco-nomic growth in China

The aetiology of myopia still excitesconsiderable debate. Comparison of prevalence data between Asia and the Westsuggests substantially higher rates of myopia in industrialised regions of east Asia. It is tempting to propose a geneticbasis for this observation. However, Sawand colleagues have also shown thatgreater reading exposure is associated with myopia in Singapore. 10 This, once

again, raises the chicken and egg debate of cause and effect, althoughthere is a broad consensus that near work is causally linked to myopia. 11

None the less, it is becoming moreplausible that myopia has a geneticpredisposition with environmental trig-gers, the interaction of which results inphenotypic plasticity. Studies of myopiagenetics have concentrated almostexclusively on high myopia, with incon-clusive results to date. Lower levels of myopia are likely to be an even morechallenging proposition. Common myopia probably has a complex genetic

mechanism for which Mendelian mod-els of disease will be inadequate. Myopia will probably become one of the mostfruitful areas of ophthalmology and visual science for the study of theinteraction of genetic and environmen-tal mechanisms in causation of disease.

The prevalence of myopia in east Asiaappears to be increasing at an alarmingrate. It seems likely that with the size of the problem will parallel the rapidindustrialisation and economic growthin China. If this issue is not tackledimmediately, we risk ignoring a tickingbomb.

Br J Ophthalmol 2004;88:443444.doi: 10.1136/bjo.2003.031476

Author s affiliation. . . . . . . . . . . . . . . . . . . . . .

P J Foster, Division of Epidemiology, Instituteof Ophthalmology, University College London,London EC1V 9EL, UK; [email protected]

REFERENCES1 Barker DJP, Eriksson JG, Forsen T, et al. Fetalorigins of adult disease: strength of effects and

biological basis. Int J Epidemiol 2002;31:12359.2 Fledelius HC. Ophthalmic changes from age of 10

to 18 years. A longitudinal study of sequels to low birth weight. IV. Ultrasound oculometry of vitreousand axial length. Acta Ophthalmol 1982;60:40311.

3 Katz J, Tielsch JM, Sommer A. Prevalence andrisk factors for refractive errors in an adult inner city population. Invest Ophthalmol Vis Sci 1997;38:33440.

4 Attebo K , Ivers RQ, Mitchell P. Refractive errors inan older population: the Blue Mountains EyeStudy. Ophthalmology 1999;106:106672.

5 Lin LL, Shih YF, Hsiao CK, et al. Epidemiologicstudy of the prevalence and severity of myopiaamong schoolchildren in Taiwan in 2000. J Formosa Med Assoc 2001;100:68491.

6 Zadnik K , Manny RE, Yu JA, et al. Ocular

component data in schoolchildren as a function of age and gender. Optom Vis Sci 2003;80:22636.7 Lo PI, Ho PC, Lau JT, et al. Relationship between

myopia and optical componentsa study amongChinese Hong Kong student population. Yan Ke Xue Bao 1996;12:1215.

8 Wong TY , Foster PJ, Johnson GJ, et al. Therelationship between ocular dimensions andrefraction with adult stature: the Tanjong Pagar Survey. Invest Ophthalmol Vis Sci 2001;42:1237 42.

9 Wong TY , Foster PJ, Ng TP, et al. Variations inocular biometry in an adult Chinese population inSingapore: The Tanjong Pagar Survey. Invest Ophthalmol Vis Sci 2001;42:7380.

10 Saw SM, Chua WH, Hong CY, et al. Nearwork inearly-onset myopia. Invest Ophthalmol Vis Sci 2002;43:3329.

11 Goss DA . Nearwork and myopia. Lancet 2000;356:14567.

Diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The pathogenesis of diabeticretinopathy M R Stanford. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sticky blood or sticky vessels, or both

There has been considerable interestin the past few years in the earlypathological events that lead to vascular occlusion in diabetic retinopa-thy. The finding of increased leucostasis(leucocytes attached to the endothelial wall) is a common pathological event inboth human disease 1 2 and in experi-mental models. 3 4 The heightened leu-cocyte/endothelial interaction inducedby hyperglycaemia occurs very early in

the diabetic process and, as a result,endothelial dysfunction and subsequentapoptosis occur. Although there issome reserve in terms of endothelialdivision and proliferation, this becomesexhausted with time, leading to theappearance of acellular capillary tubes,the pathological hallmark of disease. 5

These tubes do not support bloodflow and retinal ischaemia super- venes. Presumably there is pre-capillary

arteriolar thrombosis due to the loss of the anti-thrombogenic endothelial lin-ing, but pathological evidence for this isscant. 6 The question arises as to whetherthis process is mediated by changes inleucocytes (sticky blood), changes in theendothelial surface (sticky vessels), orboth.

Supporting the sticky blood hypo-thesis are the findings that leucocytes(particularly polymorphonuclear cells)are less deformable in diabetes, 7 thatthere is upregulation of integrins(ligands for vascular adhesion mole-cules) on their surface, 8 and that theyadhere more strongly to culturedendothelial cells in vitro in both staticassays and under conditions of flow. 9

Furthermore, in vivo treatment withanti-integrin monoclonal antibodiesexperimentally markedly reduces leu-costasis. 4 Recent work has shown thatthe glycosylating enzyme, core 2 GlcNActransferase, activity is upregulatedin leucocytes derived from diabetic

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patients and that this upregulationpositively correlates with the presenceof established retinopathy. This enzymecauses post-translational modificationsof the O-glycans on the cell membrane,some of which are molecules involved with endothelial interaction, and speci-fic blockade of the phosphorylation of this enzyme abrogated the heightenedleucocyte-endothelial interaction in

vitro.10 11

Support for abnormalities in theendothelium (sticky vessel) comes fromthe immunohistochemical demonstra-tion of increased adhesion moleculeexpression (particularly intercellularadhesion molecule-1, ICAM-1) on thecell surface in response to hypergly-caemia in both human 1 and experi-mental models, 3 and that the observedleucostasis in experimental modelscould be partially prevented by treat-ment with a monoclonal antibodyagainst ICAM-1. Moreover, ICAM-1knockout mice made diabetic do not

develop the expected retinal vascularchanges evident in their wild typecounterparts. 5 The cause of thisheightened expression is not knownbut may be from the action of endogen-ous vascular endothelial growth factor(VEGF) acting through a nitric oxidepathway since treatment with apta-mers to VEGF reduced retinal leu-costasis and blood-retinal barrierbreakdown in experimental models. 12 13

Abnormalities of both blood and vessel wall probably contribute tothe process of vaso-obliteration in

diabetesWhat occurs as a result of this

leucocyte-endothelial interaction is notcertain. Under normal physiologicalconditions, the interaction is necessaryto allow the immune system tosample the microvascular environment with the leucocyte rapidly returning tothe circulation if the correct sequentialexpression of adhesion molecules toallow firm tethering to the endothelialsurface is not found. In diabetes, thereduced deformability and increasedstickiness of the leucocyte may be

sufficient to physically block capillarytubes. 14 More likely is that the pro-longed interaction leads to endothelialdysfunction and apoptosis, eventually

leading to complete loss of the capillarylining. 15 16

One of the principal hypotheses on which the above scenario is based namely, that of increased adhesionmolecule expression in the diabeticretinal vasculature, is challenged in thisissue of the BJO . In a carefully per-formed immunohistochemical study of human specimens, Hughes et al (p 566)

show, in contrast with previous studies,that there is little difference in theexpression of ICAM-1 between normaland diabetic retinas. Furthermore, theirstudies also show diffuse ICAM-1 stain-ing of neural retina; this was increasedin the diabetic specimens and correlated with local breakdown of the blood-retinal barrier. The reason for the dis-parity in their results and those of previous studies is comprehensively dis-cussed and, although the diabetic his-tory of their specimens is not known,the evidence is sufficiently forceful toprompt a re-evaluation of the subject.

It seems likely that abnormalities of both blood and vessel wall contribute tothe process of vaso-obliteration in dia-betes although the relative importanceof either still remains to be determined.Further work examining the role of reactive oxygen species in the promotionof a prothrombotic phenotype in themicrovasculature and the contributionof leucocyte-platelet interactions tomicrothrombus formation needs to bedone. Understanding of the pathophy-siological basis of disease is fundamen-tal to the formulation of newtreatments. Already, considerable inter-

est has been shown in the use of anti-inflammatory drugs in the ameliorationof diabetic retinopathy 17 and earlyreports of the use of intravitreal steroidsare promising. Certainly, there is now anincreasing rationale for the use of specific protein kinase C inhibitors. 11 18 19

Current advances in knowledge of thepathology of the disease are likely tothrow up further candidates in the nearfuture.

Br J Ophthalmol 2004;88:444445.doi: 10.1136/bjo.2003.031443

Author s affiliation

. . . . . . . . . . . . . . . . . . . . . .

M R Stanford, Medical Eye Unit, St ThomassHospital, Lambeth Palace Road, London SE17EH, UK; [email protected]

REFERENCES1 McLeod DS, Lefer DJ, Merges C, et al. Enhanced

expression of intercellular adhesion molecule-1and p-selectin in the diabetic human retina andchoroid. Am J Pathol 1995;147 :64253.

2 Lutty GA , Cao J, McLeod DS. Relationship of polymorphonuclear leukocytes to capillary dropout in the human diabetic choroid. Am J Pathol 1997;151:707 14.

3 Miyamoto K , Khosrof S, Bursell S-E, et al.Prevention of leukostasis and vascular leakage instreptozotocin-induced diabetic retinopathy viaintercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci 1999;96:1083641.4 Canas-Barouch FC, Miyamoto K, Allport JR, et al.Integrin-mediated neutrophil adhesion and retinalleukostasis in diabetes. Invest Ophthalmol Vis Sci 2000;41:11538.

5 Adamis AP. Is diabetic retinopathy aninflammatory disease? Br J Ophthalmol 2002;86:3635.

6 Garner A . Histopathology of diabetic retinopathy in man. Eye 1993;7 :2503.

7 Miyamoto K , Ogura Y, Kenmochi S, et al. Role of leukocytes in diabetic microcirculatory disturbances. Microvasc Res 1997;54:438.

8 Rao KMK , Hatchell DL, Cohen HJ, et al. Alterationsin stimulus-induced integrin expression in peri-pheral blood neutrophils of patients with diabeticretinopathy. Am J Med Sci 1997;313:1317.

9 Morigi M, Angioletti S, Imberti B, et al. Leukocyte-endothelial interaction is augmented by highglucose concentrations and hyperglycaemia in aNF-kB-dependent fashion. J Clin Invest 1998;101:190515.

10 Chibber R, Ben-Mahmud BM, Coppini D, et al. Activity of the glycosylating enzyme, core 2GlcNAc (b 1,6) transferase, is higher inpolymorphonuclear leukocytes from diabeticpatients compared with age-matched controlsubjects. Diabetes 2000;49:172430.

11 Chibber R, Ben-Mahmud BM, Mann GE, et al.Protein kinase c b 2-dependent phosphorylation of core 2 GlcNAc-T promotes leukocyte-endothelialcell adhesion. Diabetes 2003;52:151927.

12 Joussen AM, Poulaki V, Qin W, et al. Retinal vascular endothelial growth factor inducesintercellular adhesion molecule 1 and endothelialnitric oxide synthase expression and initiatesearly diabetic retinal leukocyte adhesion in vivo. Am J Pathol 2002;160:5019.

13 Ishida S, Usui T, Yamashiro K, et al. VEGF164 isproinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003;44:215562.14 Schroder S, Palinki W, Schmid-Schonbein GW. Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabeticretinopathy. Am J Pathol 1991;139:81100.

15 Mizutani M, Kern TS, Lorenzi M. Accelerateddeath of retinal microvascular cells in human andexperimental diabetic retinopathy. J Clin Invest 1996;97 :288390.

16 Joussen AM, Murata T, Tsujikawa A, et al.Leukocyte-mediated endothelial cell injury anddeath in the diabetic retina. Am J Pathol 2001;158:147 52.

17 Joussen AM, Poulaki V, Mitsiades N, et al.Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-a suppression.Faseb J 2002;16:43840.

18 Nonaka A , Kiryu J, Tsujikawa A, et al. PKC-b Inhibitor (LY333531) attenuates leukocyteentrapment in retinal microcirculation of diabetic

rats. Invest Ophthalmol Vis Sci 2000;41:27026.19 Abiko T, Abiko A, Clermont AC, et al.Characterization of retinal leukostasis andhemodynamics in insulin resistance and diabetes.Diabetes 2003;52:82937.

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doi: 10.1136/bjo.2003.031443 2004 88: 444-445Br J Ophthalmol

M R Stanford The pathogenesis of diabetic retinopathy

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