Discordance between structure and function in glaucoma: Possible anatomical explanations

Optometry (2009) 80, 487-501

Discordance between structure and function in glaucoma:Possible anatomical explanations

Jerome Sherman, O.D.,a Samantha Slotnick, O.D.,b and Juliana Boneta, O.D.a

aState University of New York, State College of Optometry, New York, New York; and bTerri Optics, Dobbs Ferry,New York.

KEYWORDSGlaucoma;Visual fields;Retinal nerve fiber

layer;GDx;Scanning laser

polarimetry;Structure–function

concordance;Structure–function

discordance

AbstractPURPOSE: The aim of this study was to analyze glaucomatous eyes that show discordance betweenstructure and function and hypothesize plausible anatomical explanations for discordance.METHODS: Fifty eyes from 50 consecutive subjects with glaucoma (which was diagnosed accordingto multicenter criteria) were studied. One eye from each subject was selected randomly for inclusion, count-erbalancing right eye (O.D.) and left eye (O.S.). By comparing the available structural information(from clinical disc assessment as well as GDx retinal nerve fiber layer [RNFL] measurements) tothe Swedish Interactive Threshold Algorithm (SITA) Standard 24-2 (SS24-2) visual field results, study eyeswere assigned to the following categories: (1) positive structure-function correlation, (2) structuralabnormalities with no functional deficits, and (3) functional abnormalities with no structural deficits.Structure and function also were compared on a statistical basis, utilizing the nerve fiber indicator (NFI)of the GDx and the mean deviation (MD) and pattern standard deviation (PSD) of SS24-2 visual fields.RESULTS: Forty-four eyes were classified in category 1, 5 eyes in category 2, and 1 eye in category 3. Scatterplots showing the relationship between the NFI and MD and between the NFI and PSD depict a positivecorrelation in the 44 category 1 eyes with R2 values of 0.465 and 0.322, respectively. The remaining 6 eyeswith discordant structural and functional findings were analyzed in detail.CONCLUSION: The majority (88%) of glaucoma cases show concordance between structural loss and func-tional deficits. The primary proposed explanations for discordance include (1) visual field sampling and testselection limitations (i.e., the SS24-2 samples only axons that are anatomically connected to photoreceptorsin the central retina, whereas the GDx samples virtually all axons) and (2) GDx measurement limitations inthe papillo-macula bundle (i.e., the GDx has difficulty differentiating the normally thin RNFL from the path-ologically even thinner RNFL). Tests of both structure and function are recommended in glaucoma suspectsand patients, as neither mode is capable of identifying all glaucomatous deficits. Due to the apparentdiagnostic benefit that the peripheral functional data may provide, we strongly recommend that futurestudies evaluating the structure–function relationship in glaucoma record peripheral (60-4) visual fieldsfor all subjects at the outset of the study.Optometry 2009;80:487-501

Glaucoma diagnosis and management most often relieson both structural and functional tests. A concordance

Corresponding author: Samantha Slotnick, O.D., 468 Broadway, Dobbs

Ferry, NY 10522.

E-mail: [email protected]

1529-1839/09/$ -see front matter � 2009 American Optometric Association.

doi:10.1016/j.optm.2008.12.011

between structure and function facilitates clinical diagnosisand management, whereas discordant findings of structureand function complicate the diagnosis and monitoring ofprogression once a diagnosis has been established. Thisstudy reports on the prevalence of concordance anddiscordance in a consecutive series of glaucoma subjects

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mailto:[email protected]

488 Optometry, Vol 80, No 9, September 2009

and attempts to find explanations for discordance when it isdocumented.

Methods

Fifty consecutively treated cases of glaucoma were analyzedto establish whether a trend could be identified in cases ofdiscordance between structure and function. The 50 subjects(20 men/30 women) ranged in age from 25 to 84 years(average age, 61.5 6 13.8) and were predominantly black(42 [84%]) with 6 white (12%) and 2 Hispanic (4%). Thesubjects were initially recruited for a multicenter study(Collection of Normative and Glaucoma Values with theGDxVCC [Variable Corneal Compensation] and GDxECC[Enhanced Corneal Compensation]) funded by Laser Diag-nostic Technologies and Carl Zeiss Meditec. Strict inclusionand exclusion criteria were established and utilized by allcenters involved (see Table 1). Among the inclusion criteriawas best-corrected visual acuity of at least 20/40 and hadbeen diagnosed with glaucoma; among the exclusion criteriawere the presence of diabetes, any retinal disorder, and inva-sive ocular surgery. The established multicenter criteria fordiagnosis of glaucoma were based on careful disc assessmentthat found hemorrhage, notching, rim thinning, excavation,local retinal nerve fiber layer (RNFL) injury, observed changein cup-to-disc ratio (C/D) from prior examinations, orasymmetry between the eyes of more than 0.2 C/D (assumingno difference in disc size). Most subjects had reproducibleglaucomatous-type visual field defects on the SS24-2 visualfield program, but those who did not have reproducible visualfields were additionally scrutinized by glaucoma specialists(external to the site of data acquisition) who were selectedby the funding agency. All available data were consideredby these specialists, including range of intraocular pressure(IOP), pachymetry, and any other visual field results.

Abnormalities of structure were defined as progressiveevidence of optic nerve head notching, rim thinning,excavation, local RNFL injury, observed change in C/Dfrom prior examinations, or asymmetry between the eyes ofmore than 0.2 C/D. In addition, a nerve fiber indicator(NFI) R35 was considered abnormal, consistent with thereport by Reus and Lemij.1

Abnormalities of function were defined as a SS24-2visual field with a cluster of 3 or more adjacent points onthe pattern deviation map at the P , 5% level with at least1 point at the P , 2% level in a pattern consistent withglaucomatous loss.

In all glaucoma subjects with a normal SS24-2, otherfields were obtained to further explore structure–functioncorrelation. A SITA Standard 60-4 visual field was used toassess the function from 30� to 60� from fixation in eachquadrant, and a SITA Standard 30-2 visual field was alsoobtained to fill the gap between the 24-2 and the 60-4 in thetemporal, superior, and inferior quadrants. A 10-2 was usedto better define central defects uncovered in the centralzone of the 24-2. Short wavelength automated perimetry(SWAP) and frequency doubling technology (FDT) were

also obtained but not in every case. Relevant supplementarydata are presented in the Discussion section.

Reliability of visual fields was assessed; fields thatexhibited (1) fixation losses greater than 30% of the time,(2) false-positive results greater than 20%, or (3) false-negative results exceeding 20% were not analyzed. (Thesereliability limits are consistent with Weber and Caprioli.2)One eye from each subject was selected randomly for inclu-sion, counterbalancing in the right eye (O.D.) and the lefteye (O.S.). If the randomly selected eye did not have glau-coma as established above, the other eye of this subject wasused. (This other eye must have had glaucoma for thesubject to be included in the study). All the subjects inthe study reported herein were from one site: The GlaucomaInstitute of the University Optometric Center, State Univer-sity of New York (SUNY) State College of Optometry.SUNY Institutional Review Board approval was obtained,and all subjects signed an informed consent document.

As part of the study, all subjects included had scanninglaser polarimetry with variable corneal compensation per-formed at least 3 times, utilizing the GDx (Carl Zeiss

Table 1 Eligibility criteria for subjects with glaucoma

Inclusion criteriaa) At least 18 years of ageb) Signature on the informed consent formc) Glaucoma as evidenced by optic discs that demonstrate

hemorrhage, notching, rim thinning, exudation; localRNFL injury; observed change in C/D from prior exami-nation; and/or asymmetry between the eyes of morethan 0.2 C/D (assuming no difference in disc size)

d) Best-corrected visual acuity of 20/40 or better in eacheye

e) Potential to complete the entire course of the study andcomply with appropriate instructions

Exclusion criteriaa) History of diabetes, leukemia, AIDS, uncontrolled

systemic hypertension, arteriosclerosis, dementia,or multiple sclerosis

b) Concomitant use of hydroxychloroquine or chloroquinec) Active ocular disease, except glaucomad) Previous retinal surgery (e.g., buckle, photocoagulation)

Table 2 Repeatability of GDx measures

SD , 1 SD , 2

No. ofeyes %

No. ofeyes %

TSNITaverage

Nonglaucomatous 20 50.0 34 85.0Glaucomatous 36 66.7 51 94.4

Superioraverage


Inferioraverage


Data from Slotnick et al.4

Sherman et al Clinical Research 489

Table 3 Summary statistics from both GDx VCC and Swedish Interactive Threshold Algorithm (SITA) Standard 24-2 visual fields for all50 subjects

GDx VCC SITA Std 24-2 VF

Case# EYE NFI TSNIT Ave Sup Ave Inf Ave TSNIT SD MD PSD Category

1 R 98 31 30 36 9 - 15.0 12.0 #1a2 L 59 35 50 36 15 - 10.0 7.0 #1a3 L 98 27 26 30 5 - 30.0 9.0 #1a4 R 48 40 52 41 18 - 3.0 6.0 #1a5 L 82 34 34 46 14 - 11.0 11.0 #1a6 R 56 41 49 46 17 - 1.2 2.4 #1c7 L 20 52 68 57 21 - 4.0 3.0 #1a8 L 39 51 51 71 22 1.0 1.5 #29 L 70 36 42 36 10 - 7.0 6.0 #1a

10 L 45 40 55 37 15 - 9.0 10.0 #1a11 R 82 35 43 34 12 - 2.6 5.0 #1a12 L 68 35 48 39 17 - 8.6 7.7 #1a13 L 37 47 49 65 22 - 1.4 2.3 #1c14 R 60 40 51 39 12 - 24.0 9.0 #1a15 R 90 32 35 31 5 - 10.0 9.5 #1a16 R 62 35 49 32 15 - 5.5 5.0 #1a17 L 81 37 42 41 12 - 6.0 4.0 #1a18 L 68 45 39 54 11 - 2.5 2.7 #1a19 L 47 40 44 47 13 - 3.0 7.0 #1a20 L 98 25 24 30 7 - 30.0 8.0 #1a21 R 59 42 55 29 13 - 12.0 14.0 #1a22 R 94 35 38 26 6 - 22.0 13.0 #1a23 R 53 39 39 55 18 - 3.7 5.0 #1a24 R 48 42 54 40 15 - 4.0 2.6 #1a25 L 55 40 47 45 11 - 2.14 2.0 #1b26 L 68 36 34 36 10 - 10.0 6.0 #1a27 L 36 47 52 60 23 0.0 2.0 #1c28 L 24 51 66 61 30 - 1.5 1.7 #1c29 L 51 45 50 59 19 - 1.3 1.54 #230 R 77 38 42 38 13 - 12.0 8.0 #1a31 R 86 29 34 33 11 - 30.0 7.0 #1a32 L 56 41 50 50 17 - 2.0 2.0 #1c33 L 38 45 53 47 20 - 5.4 4.9 #1a34 R 28 47 62 57 22 - 4.0 2.4 #335 R 73 34 41 36 10 - 1.36 1.9 #236 R 98 37 38 38 5 - 27.0 7.0 #1a37 R 48 40 55 41 15 - 4.5 4.0 #1a38 L 85 35 40 39 13 - 21.0 10.0 #1a39 L 47 47 62 38 17 - 3.4 2.0 #1b40 L 51 46 56 51 15 - 2.8 2.2 #1b41 L 53 42 43 56 19 - 0.95 1.86 #242 R 98 26 29 26 7 - 15.0 9.0 #1a43 R 64 38 50 36 12 - 15.0 8.0 #1a44 R 82 32 40 35 13 - 26.0 7.0 #1a45 R 59 41 45 45 10 - 0.38 2.0 #246 L 88 35 44 36 13 - 6.0 4.4 #1a47 R 43 47 55 50 13 - 6.3 1.0 #1b48 R 48 41 55 36 13 - 4.0 7.0 #1a49 R 58 39 48 47 16 - 1.2 2.75 #1b50 L 81 39 43 39 8 - 5.5 3.4 #1a

Note. Right or left eyes were assigned randomly and counterbalanced for the study. ‘‘Category’’ refers to the clinical classification of (1) positive structure-

function correlation, (2) structural abnormalities with no functional deficits, and (3) functional abnormalities with no structural deficits. Category 1 is sub-

classified with (a) both MD and PSD statistically significant, (b) either MD or PSD statistically significant, and (c) neither MD nor PSD statistically significant.


y = -0.286x + 8.889R2 = 0.465

-35

-30

-25

-20

-15

-10

-5

0

5100806040200

MD

NFI

NFI vs MD

#1a#1b#1c#2#3

NF

I =

35

MD = -2 dB

y = 0.089x + 0.178R2 = 0.322

02468

1012141618

100806040200

PS

D

NFI

NFI vs PSD

#1a#1b#1c#2#3

NF

I =

35

PSD = 2.5

Figure 1 Scatter plots of structure versus function. Overall structural integrity is represented with the NFI. The left plot utilizes SITA standard 24-2 MD as

an indicator of visual field deficit, whereas the right utilizes SS24-2 PSD. Each data point is labeled according to its clinical classification: 1, Positive struc-

ture–function correlation; 2, Structural abnormalities with no functional deficits; 3, Functional abnormalities with no structural deficits. Category 1 is sub-

classified with (a) both MD and PSD statistically significant, (b) either MD or PSD statistically significant, and (c) neither MD nor PSD statistically significant.

The trend lines reflect category 1 only.

Meditec, Inc., Dublin, California). Reproducibility of thesescans from these subjects has been reported previously.3,4

In a study that assessed the repeatability of the GDx on 3consecutive measures, the TSNIT average (which averagesthe RNFL thickness proceeding around the optic nerve headin a temporal-superior-nasal-inferior-temporal progression)was the most consistently repeatable measure, with 20 of40 nonglaucomatous eyes and 36 of 54 glaucomatous eyesvarying by less than one standard deviation; 34 of 40 non-glaucomatous eyes and 51 of 54 glaucomatous eyes variedby less than 2 standard deviations.4 Similar findings for theSuperior Average and Inferior Average analysis parametersare displayed in Table 2.

The current study included 24 right eyes and 26 left eyesfrom the 50 consecutive subjects.

By comparing the available structural information (fromclinical disc analysis as well as GDx RNFL measurements)to the SS24-2 visual field results, each of the eyes wasassigned to 1 of the 3 following categories: (1) positivestructure–function correlation, (2) structural abnormalitieswith no functional deficits, (3) functional abnormalitieswith no structural deficits.

Analysis

The clinical assessment and categorization was measuredagainst summary statistics provided by the GDx for struc-ture and SS24-2 visual fields for function. To ensuretemporal comparability, a SS24-2 visual field must havebeen performed within 6 months of the GDx study. Again,the visual field reliability was confirmed using the reliabil-ity criteria (listed in the Methods section above). In cases inwhich multiple visual fields were available, the most recentwithin 6 months of the GDx was selected for use.

The NFI was selected to represent structural integritybecause it is a mathematical construct incorporating datafrom the GDx output parameters as well as the deviation plot.Of all of the statistical output parameters, the NFI has the

greatest area under the receiver operating characteristic(ROC) curve, confirming its superior discriminatory ability.1

The NFI ranges from 2 to 98; values between 30 and 50 aresuspect, and values greater than 50 represent likely glauco-matous damage (per manufacturer’s operation manual).Other recent studies have also found that the NFI is a strongindicator of visual field damage.5-7

No single statistic has been shown to consistently andaccurately represent functional loss on SS24-2 visual fields.The mean deviation (MD) is a good measure of overallseverity,8 but in early cases, MD often does not reach statis-tical significance before pattern standard deviation (PSD) in-dicates a statistically significant focal loss. Thus in earlycases, PSD may carry greater clinical weight than MD. MDvalues range from approximately 14 to 230 dB, and valuesmore negative than 22 dB indicate statistically significantfunctional loss.9 Based on a review of these 50 cases (both

Figure 2 The primary site of nerve fiber layer damage is localized for

each discordant case with respect to the trajectory of the retinal nerve fi-

ber layer and the SS24-2 test pattern. Note that damage to the superior

pole and nasal aspect of the disc does not impact the retinal area tested

on a SS24-2 visual field examination. Case 35 (the outlier on the figure)

represents diffuse loss over the entire nerve fiber layer.


eyes), PSD appears to become statistically significant be-tween a value of 2 and 3 dB but rarely exceeds 15 dB.

Two structure–function scatter plots were generated, oneusing MD to indicate severity of the visual field deficit, and theother using PSD; both utilize the NFI to indicate the severity ofRNFL loss. In cases in which both the MD and PSD weregreater than 22 dB and 2.5 dB, respectively, the data point wasfully shaded. In cases in which either the MD or the PSD wasgreater than the cut-off values, the data point was partiallyshaded. In cases in which neither visual field criterion was met,the data point was left open. All data points were labeled byclinical classification (i.e., category #1, 2, or 3).

Results

Descriptive statistics for all 50 cases are listed in Table 3. TheMD and PSD are included for the visual field results as are theTSNIT Average, the Superior Average, the Inferior Average,the TSNIT standard deviation, and the NFI for the GDx results.

The 50 eyes were classified into 1 of the 3 correlationcategories based on clinical assessment as discussed in theMethods section. Forty-four eyes are classified in category1 (positive structure–function correlation), 5 eyes fall intocategory 2 (structural abnormalities with no functional defi-cits), and only 1 eye is classified in category 3 (functionalabnormalities with no structural deficits). Category 1 issubclassified by performance on SS24-2 to indicate eyes inwhich (a) MD and PSD are statistically significant, (b) eitherthe MD or PSD is statistically significant, and (c) neither MDnor PSD is statistically significant. (That is, a subject wouldfall into category 1c if a cluster of points was detected onclinical assessment of the SS24-2, but neither the MD nor PSDwere statistically significant.) Scatter plots illustratingthe relationship of structure and function depict a positivecorrelation in the 44 category 1 subjects, with an R2 of 0.465between the NFI and MD and with an R2 of 0.322 betweenthe NFI and PSD (see Figure 1). The 6 eyes with discordantstructural and functional findings were analyzed in detailand are addressed in the Discussion section.

Structural abnormalities with no correspondingfunctional deficits

A total of 5 eyes fall into this category. Two had anabnormal RNFL at the 12 o’clock position, 2 had superiornasal loss, and the last case had a diffuse RNFL reduction,the densest portion of which was located superior-nasally(see Figure 2). All 5 eyes had a normal SS24-2 field result.Various anatomic explanations exist for each of these 5eyes and are reviewed in the Discussion section.

Functional abnormalities with no correspondingstructural deficits

Only 1 case fell into this category, and the possible anatomicexplanation is covered in the Discussion section. SS24-2

visual fields showed a central defect confined to the superiorhemifield O.D., not extending beyond 14� from fixation. NoRNFL thinning is detected with the GDx TSNIT curve,parameter table, or the deviation map in either eye.

Discordant cases

Of interest are the ‘‘discordant cases’’ in which structuraldamage and functional loss do not correlate. Anatomicconsiderations often explain the difficulty in proving astatistically significant defect, whether it is the structurethat belies the function or vice versa. Figure 2 superimposesthe SS24-2 test pattern on the RNFL, demonstrating theincongruity between the standard functional assessmentand the existing structural components. The primary siteof nerve fiber layer damage in each discordant case is local-ized on this diagram with respect to the trajectory of theRNFL and the 24-2 test pattern. These cases serve as exam-ples in which objective evidence of structural defects maybe used to direct visual field testing beyond the central 24�.

Case 35 (with O.D. selected for study by randomiza-tion). A 61-year-old black man presented for routine care.Best-corrected visual acuity (VA) was 20/25 O.D. and 20/40O.S. A left relative afferent pupillary defect (RAPD) wasobserved. Goldmann tonometry was measured at 40 mmHgOU, and the angles were assessed as being open to the ciliarybody. Optic disc assessment found a 0.85 V/ 0.8 H C/D O.D.and a 0.95 V/ 0.9 H C/D O.S. with diffuse pallor. The patientwas treated with various topical agents and the IOPsdecreased into the teens. The first SS24-2 was near normalO.D., considered normal by the study criteria, but revealedan MD of 227 dB O.S. Repeat visual fields were again normalO.D. (glaucoma hemifield test [GHT] within normal limits,MD 21.36 dB and PSD of 1.9 dB, see Figure 3). The GDxrevealed profound loss OU with an NFI of 73 O.D. and98 O.S. (see Figure 4). All monocular TSNIT parameterswere flagged in red OU (P , 0.5%). The O.D. deviationmap shows diffuse loss that is densest superior-nasally.However, with no edge defect inferior-temporally on theSS24-2, no peripheral visual field testing was performed. Inthis case, the findings are dramatically discordant in the righteye. A possible explanation is discussed later.

Case 45 (with O.D. selected for study by randomiza-tion). A black woman first presented at age 48 in 1988with a family history of glaucoma. Best-corrected VAswere 20/20 O.D. and O.S. and remained so for the next 16years. C/D ratios were estimated at 0.3 OU by severalobservers in the late 1980s and early 1990s. She was lost tofollow-up for several years, and at the next examination,Goldmann IOPs had increased from the low 20s to 30mmHg OU. The discs were noted to have substantiallyincreased cupping with respect to repeated observationsmade about a decade earlier; at this time, they were judgedas 0.75 V/ 0.6 H with a superior notch in the right eye at 12o’clock and 0.65 V/ 0.55 H in the left eye without an


Figure 3 Case 35. SITA Standard 24-2 visual field remains normal O.D.

obvious notch. Visual fields were again obtained and foundto be normal on SS24-2. In the right eye, the GHT waswithin normal limits, the MD was 20.38 dB, and thePSD was 1.99 dB. One inferior edge point was flaggednear the vertical midline inferiorly. The GDx obtained 3months prior to this visual field above was abnormal OU.In the right eye, the TSNIT average and superior averagewere flagged in red (P , 0.5%). The NFI was 59 in theright eye and 48 in the left eye, both abnormal.

This case documents an increase in cupping OU over a10-year period with the obvious development of a superiornotch in the right eye and a corresponding, but not

statistically significant, field reduction in sensitivity atonly 1 point. The explanation of why such vertical notchingand corresponding RNFL loss can be present without a fieldloss on the SS24-2 is covered in the discussion below.

Case 41 (with O.S. selected for the study by randomiza-tion). A 41-year-old black woman presented with nosymptoms but a family history of glaucoma. Best-correctedVAs were 20/20 O.D. and O.S. Goldmann IOPs were 12mmHg O.D. and 13 mmHg O.S. Disc assessment found a0.25 round C/D in the right eye and a 0.35 round C/D in theleft eye. The ‘‘ISNT rule’’ appeared to be violated in the left


Figure 4 Case 35. The GDx showed profound loss OU, both superiorly and inferiorly, with an NFI of 73 O.D. and 98 O.S.

eye with the nasal rim tissue being thicker than the superiorrim tissue. In addition, the superior rim in the left eye wasclearly thinner than the superior rim tissue in the right eye.The RNFL appeared thinned superiorly in the left eye (seered-free photo in Figure 5). Pachymetry measured 550 mmO.D. and 555 mm O.S. A SS24-2 was essentially normal inboth eyes, and the GHT was classified as borderline O.S.(see Figure 6, left). The MD was 21.09 and the PSD was1.80 in the left eye, and neither was statistically significant.A GDx was obtained, and it showed 2 abnormal TSNITparameters O.S.: TSNIT average (P , 1%) and superioraverage (P , 0.5%). The deviation map showed a largezone of superior RNFL loss O.S. (see Figure 7). The NFI

was 53 (considered abnormal) O.S. Diurnal IOPs showeda range of 12-22 mmHg in both eyes, classified as abnormaland diagnostic of glaucoma.

Like case 45 above, this is the second eye of the studythat showed a superior RNFL loss with no statistically signif-icant field loss on the SS24-2. The probable anatomic expla-nation for these 2 cases is the same and is explored below.

Case 8 (with O.S. selected for study by randomization).A black woman initially presented at age 39 in 1987.A family history of glaucoma was limited to one grand-mother. Goldmann IOPs were 16 mmHg O.D. and 18mmHg O.S. at presentation and never measured higher over


the next 16 years. Best-corrected VAs were 20/20 O.D. andO.S. and remained at the same level throughout the follow-up. Records indicate obliquely inserted discs OU, withsome initial interobserver variability in disc assessmentwith C/Ds between 0.3 and 0.4 OU (early photos are notavailable). Recent disc assessment (after 11 years) showssubstantially increased cupping to 0.7 OU. Visual fieldswere tested on several occasions but fixation was neverideal. The SS24-2 of the left eye had a GHT labeled aswithin normal limits (but low patient reliability was noted,with 3/14 fixation losses, 2% false–positive errors, and 0%false–negative errors). The MD was 11.00 dB, and the PSDwas 1.50 dB. One GDx parameter is flagged as abnormal inthe study eye: the superior average (P , 2%). The left

Figure 5 Case 41. Red-free fundus photo O.S. shows marked RNFL drop-

out, superior-nasal to the optic nerve head.

deviation map showed a 1 disc diameter size of RNFLloss superior-nasal to the disc. This same abnormality wasfound on 3 consecutive scans. The explanation of the normalSS24-2 field is again based on anatomical considerations asexplained in the discussion below. The diagnosis of normal-tension glaucoma was based on the documented increase incupping in both eyes over more than a decade in the absenceof elevated IOP.

Case 29 (with O.S. selected for study by randomiza-tion). A black woman, first presented at the age of 42in 1998 with a previous diagnosis of glaucoma. GoldmannIOPs were 27 mmHg O.D. and 18 mmHg O.S. The angleswere open OU, and the C/Ds were noted to be 0.7 O.D.and 0.7 O.S. with rim thinning in the left eye at 4 to 5o’clock. At that time (1998), a SITA 30-2 was assessed ashaving mildly reduced overall sensitivity, left more sothan right. Several years later, the discs were reassessed ashaving C/Ds of 0.9 O.D. and 0.85 O.S., and both discswere noted to be quite large; poor compliance wasconsidered as an explanation for the progression. ASS24-2 visual field in 2004 was normal O.S., with aGHT within normal limits, an MD of 21.30 dB, and aPSD of 1.54. On the GDx, only the superior average wasflagged O.S. The NFI was 83 O.D. and 51 O.S., bothabnormal. This is a case of asymmetric glaucoma with thebetter (left) eye retaining a normal SS24-2 visual field andan abnormal GDx RNFL.

Case 34 (with O.D. selected for study by randomiza-tion). A black woman initially presented in 1994 at age46 and was already under treatment for glaucoma. Gold-mann tonometry measurement was 24 mmHg OU. Visualacuities were corrected to 20/20 in each eye and remained

Figure 6 Case 41. The 24-2 SITA standard was essentially normal O.S., with the GHT classified as borderline (left). In contrast, both the central 30-2 SWAP

(middle) and the 60-4 (right) showed inferior defects O.S. corresponding to the RNFL thinning noted with ophthalmoscopy (see Figure 5).


Figure 7 Case 41. The GDx showed 2 abnormal TSNIT parameters O.S.: TSNIT average (P , 1%) and superior average (P , 0.5%). The deviation map

showed a large zone of superior RNFL loss O.S., with an NFI of 53 O.S.

so for the 10-year follow-up. The initial disc assessmentfound 0.6 vertical C/D O.D. and 0.4 vertical C/D O.S. Full-threshold 30-2 visual fields, performed with the HumphreyField Analyzer, were consistently abnormal O.D. andborderline O.S. Over the next decade, disc assessmentshowed an increasing cup O.D. with vertical cup enlarge-ment. The highest IOPs documented over the decade whileunder therapeutic management were 28 mmHg O.D. and26 mmHg O.S., with most IOP readings in the high teensOU. Angles were always judged to be open, and pachy-metry was 554 mm O.D. and 553 mm O.S. Recent C/Dassessment found a modest increase in cupping O.D. to

0.7 V/ 0.4 H O.D. and 0.4 V/ 0.3 H O.S. The cupasymmetry may be in part caused by a larger disc sizeO.D. (see Figure 8). More recent SS24-2 visual fieldsshowed a central defect confined to the superior hemifieldO.D., not extending past 14� (see Figure 9, left). There isa general reduction in sensitivity, greater inferiorly, ob-served on the total deviation map, but the Pattern Deviationmap did not identify this as an inferior arcuate defect. NoRNFL thinning was detected with the GDx TSNIT param-eter table or the deviation map in either eye, and the sus-pected fibers of the inferior papillomacular bundle O.D.appear intact (see Figure 10). The NFI was 28 O.D. and


Figure 8 Case 34. Note the O.D. disc is significantly larger than the O.S. disc, accounting for some of the cup asymmetry.

20 O.S. Thus, it is possible to have moderate central func-tional loss respecting the horizontal meridian without de-tectable structural damage when the temporal aspect ofthe optic nerve head is involved. The probable explanationof this relates to the difficulty of measuring an abnormalRNFL in the papillomacular (PM) bundle as noted in thediscussion below.

Discussion

Justifiably, the relationship between structure and functionin glaucoma diagnosis has received increased attentionrecently by researchers and clinicians alike.10-16 Mostwould agree that select structure–function relationships(such as a classic superior and slightly temporal notchwith a corresponding inferior nasal arcuate scotoma) havebeen appreciated for decades. But the advent of new imag-ing devices (Heidelberg retina tomograph, GDx, optical co-herence tomography, retinal thickness analyzer) and novelfield tests (SWAP, FDT, Matrix) has led to increased em-phasis on structure–function concordance. Many well-documented investigations report that in glaucomatouseyes, structural changes often precede functional deficits.Several investigators have reported a considerable relation-ship between changes in the optic nerve head appearance orretinal nerve fiber layer and functional visual field loss(standard white on white perimetry).17-26 Some forms offunctional testing are more sensitive than standard auto-mated perimetry, enabling the detection of functional defi-cits concomitant with or before the identification ofstructural damage.27,28 Caprioli and Miller found signifi-cant correlations between the C/D and cup volume com-pared with the mean defect and loss of standard deviationvisual field indices.29 Lee et al. found a high correlation be-tween the rim volume (utilizing the HRT) and both the MDand corrected PSD. A strong correlation was noted betweenthe inferior and superior optic nerve head rim and its corre-sponding visual field hemifields.30 Quigley et al. report thatup to half of the retinal ganglion cells can be lost before avisual field defect as demonstrated on the Goldmann kinetic

perimeter.31 Quigley et al. have also quantified functionalloss corresponding to ganglion cell atrophy, reporting thata 20% ganglion cell loss was associated with a visual fielddefect of approximately 5 dB; a 40% cell loss was associ-ated with a 10-dB field deficit.32 Harweth et al. used an ex-perimental glaucoma primate model, in which they found a30% to 50% ganglion cell loss had to be present before avisual field defect was detected with standard perimetry,while SWAP was capable of identifying a functional deficitwith only 20% to 30% ganglion cell loss.33 This indicatedthat there is a weak relationship between ganglion cell lossand visual field sensitivity for early to moderate retinal gan-glion cell loss (up to 50% cell injury). In contrast, there is astrong, linear relationship between ganglion cell loss andvisual field sensitivity in loss of ganglion cells beyondthe 50% level.34 Tuulonen et al. found that conventional pe-rimetry may not always be able to detect functional deficits,concluding that high-resolution perimetry is necessary toreveal the earliest functional losses occurring within afew degrees of the fovea. This study conjectures that nor-mal optic discs and normal visual fields do not indicatethe absence of glaucomatous abnormality.35 In a longitudi-nal study of the structure/function relationship, Sommeret al. concluded that in 60% of the cases, retinal nerve fiberlayer deficits were present 6 years before the visual fieldloss developed.36 Subtle and statistically nonsignificantfindings on structure and function tests may emerge as clin-ically significant when correspondence or concordance canbe demonstrated. Indeed, if the databases are merged, con-cordant findings have the potential to increase to statisticalsignificance.37,38

The present study compares and contrasts structuralmeasurements of RNFL thickness as determined by theGDx and functional assessment as reflected by SS24-2visual fields. Because evidence of structural damage wasthe primary criterion required for study inclusion, structuraldeficits are expected in virtually all cases. There are anumber of possible explanations for structure–functiondiscordance using the GDx and SS24-2 visual fields. Thefollowing explanations draw upon the results of this studyas well as anatomic considerations.


Figure 9 Case 34. The left image shows a significant superior centro-cecal defect within the SITA standard 24-2 visual field. The right image, a central

10-2 visual field, verifies the density of this defect.

Discordance caused by method of measurement

The GDx indirectly measures RNFL thickness by birefrin-gence, but birefringence from other structures may also bemeasured inadvertently.39

Discordance caused by nonglaucomatous retinaldisorder

Arcuate-type field defects in a glaucoma patient or suspectmay be caused by another disorder that spares the RNFL.For example, certain retinal degenerations (affecting thephotoreceptors but not the ganglion cells), such as retinitispigmentosa, often result in an incomplete ring scotoma thatmimics a glaucomatous field loss.40

Discordance caused by visual field samplinglimitations

Because every axon within the RNFL traverses through theGDx measuring circle, the thickness of as many as 1.2million axons (or even more) may influence the result. Incontrast, visual fields using the 24-2 program sample onlythose axons that are anatomically connected or

‘‘neurologically wired’’ to those photoreceptors within thecentral retina (30� temporally and 24� in the remaining 3quadrants). Hence, the photoreceptors at 40� away from thefovea, e.g., are not stimulated during the test, and thefunction of their corresponding ganglion cells is notassessed. Although it is highly impractical to test eachlocation in the entire visual field (and thus stimulate allphotoreceptors and record subjective responses mediatedby all ganglion cells), the concordance of the GDx RNFLmeasurements with the entire visual field would arguablybe higher than what is found by limiting the field to thecentral 24�.

In case 45 (PC), visual fields were also obtained with theSITA Standard 30-2 program and the SITA 60-4. The singledepressed edge point found inferiorly on the SS24-2 O.D.was repeatable on the 30-2. In fact, there appeared to be anextension of this defect into the inferior peripheral fieldwith the 60-4.

In case 41 (TC), further testing included both a Central30-2 SWAP (see Figure 6, middle) and a SITA 60-4 visualfield (see Figure 6, right). Each of these tests showed infe-rior defects O.S. corresponding to the RNFL thinning notedwith ophthalmoscopy (see Figure 5).

Cases 45 and 41 (PC and TC, respectively) reflectdiscordance caused by insufficient sampling, where the


Figure 10 Case 34. The GDx depicts both eyes as structurally sound on all statistical parameters as well as deviation maps and RNFL Thickness maps.

structural damage localizing toward the superior pole of theoptic nerve head has resulted in more peripheral functionaldeficits, demonstrable on SITA 60-4 visual fields.

The SS24-2 program only tests 4 points temporal to theblind spot, with 2 points above and 2 below the horizontalmeridian. An RNFL loss on the GDx, which is, forexample, superior-nasal, should correspond to an inferior-temporal field deficit.12 But with only 2 correspondingpoints tested, the field loss may readily be missed. Perform-ing the 60-4 field (that presents stimuli from 30� to 60�

from fixation in each quadrant) sometimes yields betterstructure–function concordance in such cases.

In case 8 (DJ), peripheral threshold (60-4) fields wereobtained, identifying a profound inferior–temporal step:

Depth defects inferior to the temporal horizontal meridianwere 27, 29, and 29 dB below normal. In contrast, themirrored points above the horizontal meridian were eachlabeled ‘‘0,’’ i.e., within 4 dB of normal. This visual fielddefect was reproducible when tested for the second time.This case shows how RNFL loss on the nasal aspect of thedisc may well be missed on central SS24-2 visual fields:The functional deficit may localize farther in the peripheraltemporal visual field without being reflected immediatelytemporal to the optic nerve head. In this case, the superior-nasal RNFL loss does indeed correspond to the inferior-temporal peripheral field loss. Both findings are repeatable.

Loss of function as measured with white-on-white centralvisual fields may lag behind loss of structural RNFL


measurements10 because of redundancy of ganglion cells. Ina hypothetical case of glaucoma in which every other axon islost, the field would likely be normal. This represents theextreme of diffuse glaucoma without functional evidenceof focal glaucomatous loss. Efforts to reduce the functionalredundancy of ganglion cells with test protocols such asSWAP or FDT may reveal a functional deficit earlier thanwith white-on-white perimetry methods. Note that case 41(TC) did not show a functional defect on SS24-2 testing,but SWAP visual fields detected functional loss. Case 35(GW) represents the extreme case in which the RNFL lossis very severe, but because the loss is diffuse, the patientretains a full SS24-2 O.D., with a MD of 21.36, not reachingstatistical significance.

Discordance caused by test selection

Axons entering the optic nerve head at or close to the verticalmeridian, especially the axons deep within the RNFL, areanatomically connected to photoreceptors in the mid- and far-peripheral retina. Loss of these axonal bundles at the poles isdetectable with the GDx, but there may be no correspondingvisual field defect with the SS24-2 field program. Again, referto cases 45 and 41, wherein structural damage at the poles hasprojected into the mid- and far-peripheral retina.

Discordance caused by disease progressiontimeline

Glaucoma induces apoptosis (programmed cell death) inretinal ganglion cells.41 In this chronic and slowly progress-ive disease, ganglion cells become distressed, decreasingaxonal transport.41,42 Before the process of apoptosis iscomplete, it is conceivable that the axons eventually stopproducing action potentials, especially to threshold stimuli.These impaired ganglion cells may still have measurableaxons with the GDx. It follows that functional impairment(as measured with visual fields) is possible without struc-tural loss (as measured with the GDx) (see the scatterplot, Figure 1). Case 7 (see Table 3) has an NFI of 20,well within the normal range, but statistically significantfunctional loss with an MD of 24 dB and a PSD of 3 dB.These findings reflect functional loss that appears to exceedthe extent of structural damage. This case was diagnosedwith glaucoma OS on the basis of rim thinning at 4-5o’clock with a maximum IOP recorded at 38 mmHg and0.8 H/ 0.8 V cups. With both structural and functional dam-age, this patient was classified in Category 1. In this case,the GDx does not detect statistically significant RNFL dam-age with any of the output parameters. Only subtle focalRNFL loss is observed OS on the GDx deviation mapand RNFL thickness map, extending from the site of rimthinning. Perhaps this case illustrates this concept of func-tional deficits exceeding what would be predicted on thebasis of structural observations.

Discordance caused by measurement limitations

Neuro-ophthalmology textbooks note that the RNFL isthickest at the superior and inferior poles of the disc border,where it measures about 200 mm, but is only about one tenthas thick in the temporal and nasal zones.43 GDx findings areindirect measurements of the RNFL based on its property ofbirefringence. Birefringence measurements, when mathe-matically converted into RNFL thickness, virtually never ex-ceed 100 mm superiorly and inferiorly and are rarely greaterthan 30 mm nasally and temporally. Furthermore, noise in thesystem appears to contribute to a 20-mm baseline birefrin-gence measurement because even subjects with NLP,chalk-white discs, an amaurotic pupil, and a flat VEP willmeasure about 20 mm in each quadrant.44 Because theRNFL is only one tenth as thick nasally and temporally asit is superiorly and inferiorly, the GDx database has great dif-ficulty in differentiating the normally thin RNFL from thepathologically even thinner RNFL because the measure-ments in the nasal and temporal zones are so close to the noiselevel in the system. Detecting a reduced RNFL both superi-orly and inferiorly, well above the noise level, is far simpler.Although the GDx results include superior average and infe-rior average parameters, similar parameters of the nasal andtemporal zone are not even listed, because previous studiesusing regression analyses have not found these to be helpfulin diagnosis.44

Case 35 (GW) shows dense arcuate loss O.S. in the 10-2visual field, superiorly greater than inferiorly, with thesuperior loss extending to fixation. Although an RNFLdepression is anticipated at the corresponding papillomac-ular bundle, the GDx does not detect such damage, evenin the case of a severe papillomacular bundle infarct (seeFigure 4, temporal aspect of OS TSNIT curve falls withinconfidence interval).

Case 34 (MF) shows a central superior arcuate defectO.D. on the SS24-2 visual field. A central 10-2 visual fieldcorroborated the defect noted on the SS24-2, extending inan arcuate pattern through the superior central hemifield,densest superiorly, and respecting the horizontal meridian(see Figure 9, right). Again, no defect is detected on theGDx in the corresponding inferior temporal zone.

These cases highlight the difficulty in proving statisticalsignificance in the papillomacular region of rim tissue,because of (1) too large a range of normal values, (2) toosmall a change between normal and abnormal, or (3) acombination of these factors, limiting the ability of thedevice to declare statistical significance.

Visual fields of the central 10� to 15� reflect the activity ofthe papillo-macular bundle. Although there are a dispropor-tionately large number of axons within the PM bundle, theseaxons are very thin, and even the sum of all the axons in thePM bundle still result in a PM bundle that is only one tenth thethickness of the RNFL at the vertical poles. (In an analysis ofmore than 1,000 GDx scans, the PM bundle was neverflagged on the deviation map as being abnormally thin [based


on unpublished data; to our knowledge, such a finding hasnot been published]). It follows that glaucomatous field losslimited to the center of the SS24-2 (and the 10-2) can bepresent without a corresponding and measurable RNFL losswith the GDx. Again, cases 34 and 35 depict how suchlimitations in measurement can lend false security to theclinician when clearly functional tests reveal a frank deficit.

Summary

The majority of cases showed concordance between struc-ture and function (88%). Five of the 6 discordant eyes hadstructural abnormalities without functional abnormalities,whereas only 1 had functional abnormalities withoutstructural abnormalities. Finding cases of structural lossprior to functional deficits is perhaps not surprising if weconsider the results of a long-term study showing thatabnormal GDx RNFL results predict the eventual develop-ment of repeatable glaucomatous field defects in a group ofglaucoma suspects.10 Our single case of abnormal functionin the presence of normal structure appears to be predictedbased on the anatomy of the papillo-macular bundle as dis-cussed above. Visual fields are likely better at documentingabnormalities in the PM bundle than are GDx nerve fiberlayer measurements. Four of the 5 discordant cases of struc-tural abnormalities with no functional abnormalities are ex-plainable on the basis of visual field sampling limitations asdiscussed above. The remaining case shows diffuse glauco-matous loss. Because of redundancy of ganglion cells andtheir axons, there appears to be an adequate supply of func-tioning axons to yield a normal SS24-2 result in spite of anapparent profound RNFL loss.

Our results suggest that both structure and functionshould be assessed in glaucoma suspects because neitheridentifies all cases of glaucomatous deficits. Because of theapparent diagnostic benefit that the peripheral and macularfunctional data may provide, we strongly recommend thatfuture studies evaluating the structure–function relationshipin glaucoma record peripheral (60-4) visual fields andcentral (10-2) visual fields on all subjects at the outset ofthe study. When structure and function agree, as in mostcases in this study, the power of the association could leadto an earlier diagnosis and more successful intervention.

Acknowledgements

The data used in this study were generated from a multicentergrant funded by Laser Diagnostic Technologies (San Diego,California) and by Carl Zeiss Meditec (Dublin, California).Juliana Boneta, O.D., was paid through the grants as aresearch analyst of the SUNY Research Foundation.Jerome Sherman, O.D., has lectured for both LDT andCZM. Samantha Slotnick, O.D., has had no financial in-volvement with either company. Michelle Battaglia, ElenaLaskova, and Evan Lieberman assisted in the data collectionand manuscript preparation.

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Documents

Discordance between structure and function in glaucoma: Possible anatomical explanations