clinically detectable nerve fiber atrophy

8/10/2019 Clinically Detectable Nerve Fiber Atrophy

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ClinicallyDetectableNerve FiberAtrophyPrecedesthe OnsetofGlaucomatousField Loss

AlfredSommer,MD, MHSc;JoanneKatz,MS;HarryA.Quigley,MD;NeilR.Miller,MD;AlanL. Robin,MD; RonaldC. Richter,MD;KatheA.Witt,COMT

\s=b\Standardizedperimetryand nerve fi-ber layer and color fundus photographywere performed annually on 1344 eyeswith elevated intraocular pressures.In 83

eyes, glaucomatous field defects devel-oped that met rigid criteria on manualkinetic and suprathreshold static perim-etry. Individual nerve fiber layer photo-graphs werereadby two masked observ-ers. The more sensitive of the twoidentified nervefiberlayerdefectsin 88%ofreadable photographs atthe time fieldloss first occurred; 60% (6/10) of eyesalready had nerve fiber layer defects

6yearsbefore field loss. In

contrast, thenerve fiber layer was considered abnor-mal inonly11%(3/27) ofnormaleyesand26% (84/327) of hypertensiveeyes. Thelocation of nerve fiber layer and fielddefectsclosely corresponded, but nervefiberlayer loss was generally more wide-spread. Examiner experience and sever-ity of optic nerve damage influenced re-sults. Mild focal defects wer e mor e

readily recognizedthan more severe dif-fuse atrophy. Nerve fiber layer defectsexpanded with time, often by the devel-opment and coalescence of adjacent ar-easof damage.

(ArchOphthalmol. 1991;109:77-83)

"1 he definition and diagnosis of pri-mary openangle glaucoma remain

problematic. Intraocular pressure(IOP) is an important risk factor forglaucomabut notdefinitive evidenceofthe disease.13 At present, diagnosisgenerallyrequires evidence of typicalglaucomatous optic nerve atrophy inthe absenceofotherpotential causes.

Methods for reliably establishing

glaucomatous nerve

atrophy are lim

ited. These include functional disturbance, traditionallyidentifiedby typicalfieldabnormalities (eg, localized orasymmetricdepressionsin retinal sensitivity corresponding to the arcuate

distribution of nerve fiber bundles),and/or anatomical evidencesuggestiveofoptic nerve fiber loss (eg, large orvertically elongated cups, notching ofthe disc rim, or asymmetric cuppingbetween the two eyes). These approaches have theirshortcomings, notthe least of which is a delay untilsufficientdamage fordefinitivediagnosis has occurred. For example, fielddefects can be precededby significantloss of retinal ganglion cells.4 Mostanatomical measures are nonspecific,overlapping to a considerable degreewithfindingsinthe normalpopulation.In 1972, Hoyt and coworkers"" suggested that slitlike defects in the appearance of the nerve fiber layer(NFL) may represent early, clinicallydetectable manifestationsof glaucomatousdamage. In1977, we confirmed, inmasked readings, that NFL defectsare more frequentamongpatients withestablishedfield loss.7Subsequent reports confirmed the correlation between NFLabnormalities and psycho-physical disturbances, including fieldloss.8"10

Importantly, in a small number of

subjects photographed (suboptimally)for different purposes, we identifiedNFL defectsyearsbeforethe development ofreproducible field abnormalities on routine kinetic and supra-threshold static perimetry.7 Thissuggestedthat NFLassessmentmightidentify patients with progressiveglaucomatous neuropathy before theloss offibersrequired forthe developmentofreproduciblefield defects.

In 1981, we initiated a prospective,longitudinal study of normal individuals,subjectswithocularhypertension

(OH), and

patients with

glaucoma to

define the roleof NFL assessment inthe diagnosis ofglaucoma. An earlierreport from this study11 establishedthat NFL assessment identifies eyeswith established glaucomatous fieldloss with relatively high sensitivityand specificity. With further recruitment andfollow-up, we nowreportthetemporalrelationshipbetweenthe development of visual field defects andthe prior appearance of the NFL.These data confirm the value of NFLassessment as an early indicator ofglaucomatousopticneuropathy.

SUBJECTSAND METHODS

After a comprehensive baseline evaluation, subjects were reexamined annuallyfollowing a strictprotocol.11

Recruitment

Ocularhypertension was defined as IOPabove 21 mm Hg on at least two visitsbefore treatment and normal visual fieldtest results asdescribedbelow. These sub

jects wererecruited fromthe WilmerInstitute, the Johns Hopkins Medical Institutions, Baltimore, Md; the practices ofcollaboratingophthalmologists; among sub

jectsoriginallyenrolledin theCollaborativeGlaucomaStudy12;andamongpatientsidentified in the course of the Baltimore EyeSurvey.1'1 Ophthalmologists responsible fortheir routine care remained free to treateach patient as they thought was mostappropriate. Normal controls wererecruited from the same sources, from patients,visitors, and staff of The Johns HopkinsHospital, and from church groups and seniorcitizen'sassociations. Allcontrols werefree of a personal or family history ofglaucoma,elevated IOP, orthe useof IOP-lowering medication and they all had anIOP below 22 mm Hg and entirelynormalvisualfields on atleast two visits.

At baseline, all subjects provided in

formed consent and a detailed history andwere examinedby oneof the several investigators withsubspecialty trainingin glaucoma.Ocular status wasconfirmed fromthebaselineexamination a nd fromrecordsprovidedby past and currentophthalmologistsand copiesofallavailablevisualfields.

Visual Field Tests

The central 30of the visual field wastestedwithbestdistancecorrectionandthe

appropriateplussphere for age. From 1981through 1986, the central and peripheralvisual field was evaluatedby detailedperi-metrictechniquesfollowing a strictprotocolemploying detailed threshold-related, su-

prathresholdkinetic, and static stimuli on aGoldmannperimeterexamination.11The average examination required 20 to 30 minutes per eye and included at least fourisopters encircling 360 of the field, twoadditionalisopters limited to the nasal periphery, and literally hundreds of staticpresentations.

Beginning in 1986, routine follow-up examinations were performed on the HumphreyField Analyzer(Allergan-HumphreyInstruments, San Leandro, Calif)usingtheC-30-2 program. All data were transferredto a centralfile and analyzedby our cross-meridional, mirror-image technique usingspecially created software.14 All subjects

Accepted forpublicationAugust28, 1990.Fromthe DanaCenter forPreventiveOphthal-

mology of the Wilmer Eye Institute, and theSchool ofPublic Health, theJohnsHopkinsMedi-cal Institutions, Baltimore, Md.

Reprint requests to Wilmer 120, The JohnsHopkinsHospital, 6 00N WolfeSt, Baltimore, MD21205(Dr Sommer).

wnloaded From: http://archopht.jamanetwork.com/ by a UQ Library User on 10/24/2014


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Fig 1.Resultsin a48-year-oldwhite womanwith normalvisual fieldexaminationbyGoldmannperimetryand HumphreyC-30-2 in botheyesuntil 1988,when asmallparacentral scotomaconnecting to theblindspotdeveloped in therighteye.Top left, Nervefiberlayer(NFL) photograph from 1984 of the right eye. Theappearance isentirely normal,withbrightstriations,which crossthe first- and second-order vessels, blurring thewalledges. The maculopapularbundle is darkrelativetothe arcuate zonesabove andbelow.Bottomleft,CorrespondingGoldmannfield fromthe samevisit.Topcenter,Photograph of the sameeyefrom 1985reveals a subtly dark,wedge-shaped areawithinthe inferior arcuate zone, with

brighterNFLstriations oneitherside(arrows).Bottomcenter,CorrespondingHumphreythresholdfield fromthe samevisit.Topright,Sameeyephotographedin1987.The inferiordefecthasbecomedarkerand wider.Themaculopapularbundleisnow brighter and more obviouslystriated in comparison. Vesselswithin the areao fNFLatrophystandout in sharprelief(arrows).Aswathof thesuperiorarcuate zonehasalso becomeatrophie.Bottomright,CorrespondingHumphreythresholdfield fromthe samevisit.

meetinganyof our criteriaforfield loss10 orwithsuspiciousclustersofdepressionsidentified by STATPAC (Allergan-HumphreyInstruments, San Leandro)16,1' were recalled and reexamined on the Goldmannperimeter, which remained the final basisfor interpretation of field status. Subjectsunreliable to threshold testing18 were routinely examined on the Goldmann

instrument.A definite,typicalglaucomatousfield abnormality included one or more of the following defects onthe Goldmannperimeter,confirmed on at least two occasions (whentheGoldmann defect was congruentwith adefect first detected by threshold perimetry, asecond, confirmingGoldmannfieldstudy was not required): (1) aparacentralor arcuate scotoma (including arcuate elongation but notgeneralizedenlargement ofthe blind spot) at least 0.4 log units indepth;(2) nasal stepof atleast 10 inwidthpresent to at least twoisopters; and centraland/or temporal islands. As this reportdeals only with subjects until such time as

they first developed a field defect at theirannualexamination, allthe defects metthemildest of our criteria.

Photographs of the posterior pole weretakenthrough adilatedpupil with a Zeissfundus camera. Stereoscopic color photographs ofthe disc and peripapillary nervefiber layer (focused at the level of thesuperficial vessels) were recorded onKoda-chrome25 film. Aseriesoffivemonoscopic,red-free black and whitephotographs weretaken of each eye: onecentered onthe discand two of each arcuate zone. These wereinitially recorded on Kodak Plus X filmusing a narrow band-pass filter.18 In 1983,thisapproach was replacedby ourimprovedhigh-resolution technique employing ashort-pass filter and Kodak 2415 TechnicalPan film."0Red-freenegatives were printedon positive transparency Dupont COS-7film and the optic nerve head blocked outwithopaquemetallicink. Bothred-free a ndcolor transparencies were coded and independently evaluated by the same two observers as in our previous report.11 Red-

free and color transparencies werecirculated (and evaluated) independent ofone another. In evaluating the photographs, each observer was masked as topatientand diagnosis, allpreviousand subsequentphotographs, and the visualfields.

Nerve fiber layer assessment followed arigorouspattern meant toelicitall availableinformation rather than allow pattern rec

ognition ofparticularly striking abnormalities (such as a focal wedge defectadjacentto normal, bright retina) to obscure moresubtle and often more severe damage of adiffuse nature. The readers focused theirattention onboththebrightness and density of striations (axonal bundles) and theclarity with which vessels could be visualized. Normally, major retinal vessels liewithin the NFL. Thinning of the NFLresults in areduction inoverlyingstriationsand greater visibility of the vessel walls(Fig 1). Most information was obtainedfrom within 2 disc diameters of the opticnerve. Comparisons were made betweenthe superior and inferior hemispheres and



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Fig 2.Results in a35-year-oldwhite womanwithdiffuse inferior nervefiberlayer(NFL)lossintherightey e(top)involvingthe maculopapularbundle(1984). Normalleft eye(topcenter)isshownforcomparison.Bottom center, Goldmannfield of right eye from 1983 isshown. Bottom, Humphrey threshold fieldfrom 1987 isshown.

Fig 3.A51-year-oldwhite woman wasfirstseen in 1984with elevatedintraocular pressure in both eyes. An isolated inferior paracentral scotoma and small nasal step werealready present in the right eye. Within 2years, there wasgeneralized threshold depressionthroughoutmostoftheinferiorhemisphere. This nervefiber layer(NFL) photograph of the right eye in 1985 reveals anobvious inferiorwedgeadjacentto far morenormalNFL nearthe 6 o'clockposition.Lessobvious is thediffuse NFL loss over awide

area of the superior hemisphere (arrows).Thepatternfromtoptobottom(temporally) i sdark-light-dark-(lightagain), areversalof normal. Notehowcircumferentiallyoriented vesselsatthe7 to 8 o'clockposition"disappear"as they move from the area ofatrophy intothickerNFL,whosestriationsoverlie,therebymaskingthevesselwalls.

the corresponding hemispheres ofthe twoeyes. Thetemporal retina was scanned foralterations in its usual appearance. In thenormal eye, the brightest reflexes of theNFL come from the upper and lower disc

polar areas, where the NFL is thickest.Thetemporalretina (particularlythe maculopapular bundle) has thinner NFL and isthereforedarker. Thus, thenormal temporal pattern from above to below is brightreflexessuperiorly, darktoward the fovea,and bright again inferiorly. The bright-dark-bright transition is relatively smoothineyes without atrophy(Figs 1 and 2).21"24Alterations in this pattern, particularly diffuseatrophy, wereoftendetected as one orboth ofthe arcuate zonesbeing as dark asordarkerthanthe adjacentmaculopapularbundle(Figs 1, 3 , and4). Slitdefects,whicharecommonly narrowerthanthediameterofadjacent retinal venules and fail to fanoutfrom disc toperiphery, areof no diagnosticsignificance sincethey arefrequentlyencounteredin normal eyes.

To maintainmaskingin relationto previousand futurephotographs, the two readers never received more than one annualsetofred-freephotographsof a subject at atime. To maintain masking as to clinicaldiagnosis as well as toprovide a basis foridentifyingpotential "drift"in the readingsor in the photographic technique, photographs ofnormal control eyes and of eyeswithOHinwhichabnormalvisualfieldsha dnot yet developed, matched for the follow-upvisit, were evaluated atthe sametime.

As the study is still ongoing, the twoobservershave notyetreviewedall (orthe

same) photographs available at each oftheannualvisits, andpatientshaveoccasionallymissed one or morevisits. Thus, the numbers ofphotographs read by the two observers are rarely identical, and the number of subjects on whom there are datavaries from interval to interval. To maximize the utility of the available data, weemploy alife-tableapproach:where photographs areavailablea t a particular intervalin relation to the onset of field loss, the

subjectis included;wherethey are

not,the

subjectis excluded.

RESULTS

A totalof 1344 eyes withOH underwent baseline evaluation and at least1 year of follow-up. Because of theserial nature of enrollment, the number present at subsequent visits declines with the duration of follow-up(Table 1). One thousand twelve eyeswith OH remain under active investi

gation. Only 91 eyes (6.8%) belongedtopatientswhorefusedfurtherfollow-up.

Eyes WithVisualFieldConversion

Of thesubjectsinwhomfielddefectsdevelopedand who arethe basisof thisreport, 63% wereblack and 69% were60 years or older. Visual acuity was20/40(6/12) orbetterin 92%.

Reader A examined red-free photographs from213 visits. Twenty (9.4%)of the photographs were consideredtoo poor to interpret. Reader considered a similar proportion unreadable(15/214 [7.0%]). The oldest red-freephotographs, taken an average of 6

years before field conversion, were

most likely to be uninterpretable (Table 2). These had been obtainedbeforetheintroductionof ourhigh-resolutionphotographic technique.2"

As in ourpreviousstudy,11 uninterpretablephotographs were more likelyto have been fromoldersubjects (Table3). Atthe timeoffield conversion,none of the eyes ofsubjects youngerthan60yearsevaluatedby either reader wereconsidered toopoor toanalyze(noneof19eyes, reader A; none of 18eyes,reader B); in contrast, reader Awasunable to evaluate six of 46 eyes,

and reader B, five of 46 eyes fromsubjects over 60 yearsold.

Reader was twice as likely asreader A to call NFL photographsabnormalfrom eyes thatsufferedfieldloss(Table2). Reader consideredtheNFL abnormalin a majorityof eyes atevery visit (except one) before thedevelopmentof a field defect. Nearly90% ofeyes had anabnormal NFL atthe time of field conversion, the ratedeclininggradually(andsomewhat erratically) as the interval to field losslengthened. While the positivity rate



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Fig 4.A 38-year-old white man was firstseen in 1982withelevated intraocular pressure in both eyes. A superiornasal stepfirstdeveloped in the right eye in 1985, whichbecamedenserand larger in 1987.By 1989,this formed a sharply demarcated arcuatescotomasuperiorly.(This case was previously reported for other purposes.31) Top left,Nervefiberlayer(NFL) photographtaken in1983 shows a disc hemorrhage at the 8o'clock position in an area where the NFLotherwiseappearsnormal.Notethepreexisting,mild lossofNFLatthe7o'clockposition(arrows). Center left, The correspondingGoldmann field is relativelynormal.TheNFLphotographs from 1985 through 1989 wereidentical. Top right,The defect inthe inferiorNFL ha sdeepenedandexpandedsuperiorly(toward the area of the disc hemorrhage in1983)and interiorly(towardthe 6 o'clockpositionmeridian)(arrows).Themaculopapularbundle isclearlyspared. Centerand bottomright, Goldmann (1985) and Humphreythreshold(1987)fieldsreflectthedamage.

Table 1.

Number of Ocular

Hypertensive Eyes at EachFollow-up Examination

No. of

Follow-upExaminations

_

No. ofEyes

1 1176*2 935

3 699

4 53015 672

6 449

One hundred forty eyesmissedtheir first follow-up but were seen at least once at a later follow-up.

tRepresentstemporary interruption o f study fromhiatus in funding.

Table 2.NFLAssessment inEyes in Which FieldDefects SubsequentlyDeveloped*

No. of YearsBefore Onset of

Field Defect

Unreadable Abnormal

Reader A,No. (%)

Reader B,No. (%)

Reader A,No. (%)

Reader B,No. (%)

3/14(21.4) 3/13(23.1) 5/11 (45.5) 6/10(60.0)2/16(12.5) 1/21 (4.8) 2/14 (14.3) 15/20(75.0)0/21 (0.0) 1/20(5.0) 7/21 (33.3) 9/19(47.3)0/18 (0.0) 0/19(0.0) 10/18 (55.6) 16/19(84.2)3/21 (14.3) 2/21 (9.5) 8/18(44.4) 15/19(78.9)6/58(10.3) 3/57 (5.3) 19/52 (36.5) 33/54(61.1)6/65(9.2) 5/63(7.9) 27/59 (45.8) 51/58 (87.9)

* NFL indicates nerve fiber layer. Year 0 was year in which visual fielddefect first appeared.

of reader A was lower, it too wasreasonably steady over time, withroughly one third to one half of thereadingsbeingabnormal.

Readings by the two observersagreed onthe NFL status moreoftenthan not (Table 4). Atconversion,theydisagreed about NFL status in 22eyes, all of which reader read asabnormal.Those eyes thattheyagreedwere abnormal had the most severefield defects; those that they agreedwerenormal had the mildest field defects; andthoseaboutwhich they disagreedhad defectsbetween these twoextremes (Table 5). Eyes that theyboth considered normal had smaller

cups andwiderrimsthanthoseconsideredabnormalby one orboth observers. Neither race nor iriscolor, factorscommonly associated with fundus pigmentation and therefore the potentialvisibility ofthe NFL, consistently influencedthe likelihood that an eye wasconsideredabnormal

(datanot

given).Nerve fiber layer abnormalitieswere seemingly more extensive thanthe corresponding field loss. At conversion,visualfield loss(bykinetic an dsuprathreshold static perimetry) involved both hemifields in only 14.8%(reader A ) and 13.2% (reader B) of alleyes in which NFL defects were recorded. In contrast, NFL abnormalities werenotedin bothhemispheresof81.5%(reader A)and84.9%(readerB)of these same eyes (Table 6). Theproportion of eyes in which NFL abnormalities involvedbothhemisphereswas greaterforthethreevisitsendingwith conversion than forthe four precedingvisits.

In eyes with apparently localizedNFLdefects, there was a close correspondencebetween the location of thevisual field and the NFL abnormalities. Atconversion,field lossand NFLdefects werebothlimited to onehemispherein seven eyesreadbyreaderB,and in everyinstancethehemisphereswere in perfectcorrespondence. Over-



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Table 3.Mean Age NFLAssessmenta tTime of FieldLoss*

Mean (SD)Assessment Age, y No.

Reader ANormal 61 13 32

Abnormal 64 15 27

Cannotevaluate 73 10 6Reader

Normal 65 10 7

Abnormal 62 14 51Cannot evaluate 76 6 5

NFL indicates nerve fiber layer.

all, in 34 examinations by reader B,field loss and NFL defects were limited to asingle hemisphere; in 33 (97%)these werein perfectcorrespondence.ResultsforreaderA,who foundfewerNFL abnormalities, werelesswell correlated: overall, there was 69% correspondence (11/16).

Once an eye wasjudged to have anabnormal nerve fiberlayer it was likely to bejudgedabnormal atal l subsequentvisits(Table7).

Eyes Without VisualField ConversionThe rates atwhich the two readers

reported NFL abnormalities for normalcontrol eyes and control eyes withOH were similar tothose atthe baseline examination, published 6 yearsago.*Bothrates,ofbothreaders, weresubstantially below the rates for eyesthat subsequently suffered glaucomatousfield loss(Table8).

COMMENT

Hoyt and Newman5 suggested thatslit and wedge-shaped defects mightbe theearliestclinicalsignsofglaucomatousoptic nerve atrophy. We subsequently demonstrated that the vastmajority of subjects with glaucomatous field defectsalready had demonstrable NFLabnormalities,711 and thatin asmallsamplefolloweduplongitudinally, such abnormalitiesdeveloped ina majority atleast 3 to 5yearsbeforethe onsetof fieldloss.7Asidefrom oursubsequent preliminary report fromthe present study,

z

few reliable prospectivedata haveappearedexceptforthe small group ofsubjects with dischemorrhages describedby Airaksinenetal.26

Thepresentstudyconfirms our original conclusions of over a decade ago7:NFL assessment can help identify patientswho havealreadysufferedopticnerve damage and in whom it willprogress to definitive visualfield loss.The present, prospective study employed improved photographic techniques, definedcriteria for NFL damage, rigid masking of observers, and

Table 4.Agreement Between Readers onNFL Status*

No. of YearsBeforeOnset of

Field Defect

Reader A/Reader

abn/abn abn/nl Total Agreement100.0

64.7

20 49 77.6

60.0

Total examinations 68 48 56 172*

Excludes photographsexaminedby only one reader to date or that one or both readers considered too poorto interpret. NFL indicates nerve fiber layer; abn, abnormal; and nl, normal.

Table5.AgreementBetween Readers and Severity of Optic NerveDamage*

At Field

Conversion

Reader A/Reader

abn/abn

(n = 26)nl/abn

(n= 22)nl/nl

(n = 7)More severe

field loss,No. (%) 19 (73.1) 14 (63.6) 4 (57.1)

Field defect

in more than

1 hemisphere,No. (%) 4 (15.4) 2(9.1) 0 (0.0)

Horizontal

cup/disc,mean 2 SE

Reader A

Reader

0.62 0.12

0.60 0.08

0.63 0.060.67 0.06

0.40 0.180.37 0.23

Narrowestrim width,mean 2 SE

Reader A

Reader

0.15 0.06

0.16 0.05

0.13 0.05

0.14 0.05

0.27 0.13

0.32 0.12

Severe indicates more than a single defect (isolated paracentral scotoma or isolated nasalstep), eg, fullarcuate scotoma or worse; abn, abnormal; and nl, normal.

Table 6.Correspondence Between NFLand Visual FieldAbnormalities*

No. ofYears

BeforeOnset of

Field Defect

Hemispheres With NFL AbnormalitiesHemifields .-

With

Goldmann ,-Defects Sup

Reader A Reader

Inf Both Total Sup Inf Both Total

3-6 Sup 1 10 oInf 6 0 8 16

Both 0 6 (27.3%) 8 11 (23.9%)

Total 2 17 (77.2%) 22 6 31 (67.. 46

2-0

(includesconversion)

Sup 5 26 32 10 45 56io 12 30

Both 1 10(18.5%) 0 1 14 15 (14.9%)Total 7 45 (83.3%) 54 11 84(83.2%) 101

At conversion Sup 12 15 4 26 308 0 13 16

Both 1 4(14.8%) 0 1 6 7 (13.2%)

Total 4 22 (81.5%) 27 5 45 (84.! 53

*ln all instances, visual field defects are, bydefinition, those at the timeo ffield conversion. NFL indicatesnerve fiber layer; Sup, superior; and Inf, inferior.

far more subjects,who were reexam-inedannuallyfollowing a strictly monitoredprotocol.

Nerve fiber layer abnormalitieswere infrequent among normal controls and somewhat more frequent

among eyes withOH that had not yetshowndefinitefield loss. Theseresultsare almost identical to thosereportedfrom the baseline assessment," confirming our previous results and demonstrating little driftin eitherthepho-



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Table 7.Consistency of SubsequentNFL Interpretations Following an

Individual's EarliestAbnormal

Reading*

Interpretation ofSubsequent

NFLPhotographsReader

A

Reader

Normal 16 12Abnormal 31(66%) 82(87%)

Total 47 94*NFL indicates nerve fiber layer. Results are of

NFL readings atvisits following the first at which thesubject's NFL was considered abnormal. Table excludes unreadable photographs.The proportion subsequently read as abnormal was greater than expected by chance (reader A, P-C.06; reader B,P


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tonormalretina.23Rare cases began with seemingly

focal loss, oftenadjacent to anotchedrim. With time, focaldefects tended todeepen and expand by merging withnewlythinned, adjacent areas ofatrophy (Fig 1). In a few cases, adjacentfocal atrophy was preceded or accompanied by a disc hemorrhage (Fig 4).Given the

infrequent (annual) exami

nation, we maywell havemissedtransientdischemorrhagesinother cases.31Occasionally, a focalwedgedefect wasnotaccompaniedby functional disturbances orfurtherdamage,butthis wasuncommon.

Diffuse atrophywouldoftendeepenover time, with further loss of striations,darkeningof thefundus, increasing definition and clarity of second-order vessels and their walls, andreversal ofthe normaltemporal retinalpattern. Instead ofbeing the darkestzone, thenormally thinmaculopapularbundle became as bright as, orbrighter than, the adjacent retina(Figs 1 and 2). Ultimately, little ifanyNFL persists, such that asymmetrybetween superior and inferior hemispheresdisappears. One is left with adark,granular-appearingfundus sometimes displaying very fine, widelyspaced, faint striations (Figs 3 and 5)and bright-walled vessels that standoutin sharp relief, devoid of overlyingstriations(Figs 1 and 5). Eventually,allstriations arelost.

The evolution of NFL loss is best

appreciatedbeforethedevelopmentofsubstantialfield loss. Oncethisoccurs,the NFL has practically disappeared,at least to our recording techniques,making current methods of NFL assessment mostsuitableformonitoringearly loss andprogression.

A variety of image enhancement

techniques that alter the recorded im

age have been applied to improvingvisibilityofthe NFLandi tsabnormalities. None has been particularly successful at improvingrecognitionofdefects and distinguishing normal fromabnormal NFL. Quantifyingthe actualthickness of theNFL2' (or, as a surrogate, the neurosensory retina in itsentirety) offers greater promise.28 Inthe meanwhile, the clinician is bestadvised to learn to recognize normalNFL, first in healthy young eyes andlater in older individuals. Only thenshould oneattempttorecognizeabnor

malities corresponding to glaucomatous damage. Red-free photographsare extremelyhelpfulwhen first learning to evaluate the NFL and identifyabnormalities. They remain convenient, but less essential, once directvisualizationwith a bright, direct ophthalmoscope or slit lamp and contactlens hasbeenmastered.

We do not claim our patients wereentirely free of psychophysical evidenceofoptic nerve dysfunctionbeforemeeting our criteria for visual field

loss. Nodoubtother testsand criteriawould have suggested abnormalitiesearlier in the course of disease, butwith less reliability, consistency, andspecificitythan thisstudy'slong-standing criteria.29,30 Indeed, referring physicians had already elected to give asubstantial numberofsubjects therapy, because ofthe height ofthe IOP,size ofthe

cup, presence of NFL ab

normalities, or the appearance of minor but potentially valid defects inthreshold perimetry. If effective inslowing progression of optic nervedamage, suchtherapy would have delayed the onset offield loss and prolongedthe apparentdurationbetweenthe onset of NFL defects and subsequentfieldconversion.

Thepresenceof NFL defectsshouldalertthephysician tothe likelihood ofpastoptic nerve damage and the needfor careful, detailed examination andfollow-up. A normal-looking disc and

visual field offer only partial reassuranceandshouldbe scrutinizedregularly until one is certain thatthe patientis not suffering progressive damage.In other settings, an abnormal NFLmay be sufficient evidence for initiatingglaucomatherapy.

This study was supported by grants EY03605and RR04060 from the National Institutes ofHealth,Washington,DC.

We wish tothank Donna Gilbert, RachelScott,Patty Lenane, and FeleciaKeel, a nd allthose whoreferred patients to thisstudy.

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19. Miller NR, George TW. Monochromatic(red-free) photography an dophthalmoscopyof theperipapillary retinal nerve fiber layer. InvestOphthalmolVis Sci. 1978;17:1121-1124.

20. Sommer A,D'AnnaSA,KuesHA,GeorgeT.High-resolutionphotography of the retinal nervefiber layer.Am J Ophthalmol. 1983;96:535-539.

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nervefiber layerlossinmonkeyand humanglauco-ma.Trans AmOphthalmolSoc.1986;84:920-966.

24. Quigley HA, Addicks EM. Quantitativestudies of retinal nerve fiber layer defects. ArchOphthalmol.1982;100:807-814.

25. SommerA, MillerNR, QuigleyH, RobinA,KatzJ,BurkhardK. Assessmentof the nerve fiberlayer as a predictorofglaucoma. InvestOphthal-molVisSci. 1985;26(suppl):122.Abstract.

26. AiraksinenPJ,MustonenE,AlankoHI. Op-tic dischaemorrhagesprecederetinal nervefibrelayer defects in ocular hypertension.ActaOphthal-mol.1981;51:627-641.

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29. EngerC, SommerA. Automated thresholdperimetry beforeglaucomatous field loss in eyeswith ocularhypertension. InvestOphthalmol VisSci.1990;31(suppl):432.Abstract.

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31. Diehl DLC, Quigley HA, Miller NR, Som-mer A, Burney EN.Prevalenceandsignificanceofoptic disc hemorrhage in a longitudinal study ofglaucoma.ArchOphthalmol.1990;108:545-550.

clinically detectable nerve fiber atrophy

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