Graefe's Arch Clin Exp Ophthalmol (1999)237:457±462 � Springer-Verlag 1999 C L I N I C A L I N V E S T I G A T I O N

Päivi PuskaEija VestiGoji TomitaKyoko IshidaChristina Raitta

Optic disc changes in normotensivepersons with unilateral exfoliation syndrome:a 3-year follow-up study

Received: 27 April 1998Revised version received: 23 July 1998Accepted: 21 September 1998

P. Puska ()) ´ E. Vesti ´ C. RaittaDepartment of Ophthalmology,Helsinki University Central Hospital,Haartmaninkatu 4DFIN-00029 HYKS, Helsinki, FinlandFax +358-9-471-5100

G. Tomita ´ K. IshidaDepartment of Ophthalmology,Gifu University School of Medicine,Gifu, Japan

Abstract l Background: If, at thetime of glaucoma diagnosis, the in-traocular pressure (IOP) is higher andthe initial field loss more advanced inglaucomatous eyes with than withoutexfoliation, the cause of the optic discdamage has been suggested to be thehigh IOP associated with the exfoli-ation syndrome (EXS). We decidedto investigate whether EXS alone,without the contributory effect ofmeasured raised IOP, is a risk factorfor optic nerve damage.l Methods: Twenty-two non-glauco-matous, normotensive persons withclinically unilateral EXS were exam-ined for IOP, visual fields (OctopusG1) and disc topography (Imagenet,

Topcon) and followed up for 3 years.l Results: At the start, the pairedexfoliative (E) and non-exfoliative(NE) eyes did not differ in IOP, disc,rim, or cup areas, or cup volumes.They differed in R/D (rim/disc) radi-us ratio in the inferior section of theoptic disc. During the follow-up pe-riod, the IOP increased in the E andthe NE eyes, and changes indicativeof nerve fiber loss were measured inboth eyes. In those (n=14) in whomthe IOP in the two eyes was equalthroughout the follow-up period, discchanges took place only in the E eye.l Conclusion: The exfoliative pro-cess in itself may be a risk factor foroptic disc changes.

Introduction

At the time of glaucoma diagnosis, the intraocular pres-sure (IOP) is higher, diurnal variation in IOP greater,and initial field loss more advanced in glaucomatous eyeswith than without exfoliation [16, 22, 28]. Furthermore,hypertensive eyes with exfoliation have been shown todevelop glaucoma more often than hypertensive eyeswithout it: 35% vs 18% in 9 years [24]. Thus, a highIOP associated with the EXS was earlier emphasized asthe cause of optic nerve damage. Recently, however, eyeswith EXS have been concluded to be damaged more eas-ily than eyes without exfoliation at equal IOP levels [5].Opinions differ about whether EXS alone, without thecontributory effect of raised IOP, is a risk factor for opticnerve head damage. LinnØr et al. [18] concluded that theexfoliative process was a risk factor for optic disc pallorafter examining persons with ocular hypertension whose

eyes did not differ in IOP or visual field tests, but did dif-fer in the occurrence of EXS. Davanger et al. [5] also con-cluded that EXS in itself may be a risk factor for opticnerve damage, independently of the IOP level, as the like-lihood of glaucomatous damage at equal IOP levels wasgreater in E than in NE eyes. Likewise, Ekström [7] rec-ognized exfoliation to be an independent risk factor forthe development of glaucoma; exfoliation increased thestandardized relative risk for glaucoma to 9.8-fold andeven intensified the risk of ocular hypertension from3.4-fold to 67-fold. When examining non-glaucomatouspersons with unilateral EXS, we found slight glaucoma-tous changes in optic disc configuration in the E eyescompared to the NE fellow eyes [29]. The optic discchanges seemed to depend on IOP, but we could not ruleout the effect of the exfoliative process itself. The aim ofthe present study was to follow optic disc configuration innon-glaucomatous, normotensive persons with unilateralEXS for 3 years, to find out whether EXS itself might

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cause glaucomatous changes in the optic nerve head. Spe-cial interest was focused on persons with unilateral EXSand equal IOPs in the paired eyes.

Materials and methods

In 1990, 66 non-glaucomatous subjects with unilateral EXS were ex-amined for IOPs, visual fields (VF), and optic disc topography.None of them had had previous intraocular operations or laser treat-ments or used ocular medication. Their refraction was between ±8Dand +8D. Those who, during the 3-year follow-up period, remainednon-glaucomatous and normotensive (IOP<22 mmHg) did not re-ceive any treatment. Subjects who had normal and reliable VFs inthe Octopus G1 program [8], who had had sharply focused andclearly imaged optic disc photographs, and who did not change toclinically detectable bilateral exfoliation were selected for the pres-ent study. Twenty-two persons (mean age 66.7�7.1 years, range 45±78 years) met these criteria.

Unilateral EXS was defined as the occurrence of biomicroscop-ically detectable exfoliation material on the anterior lens capsule orat the pupillary border in only one eye, the E eye, after pupillarydilatation with 10% phenylephrine hydrochloride. No biomicro-scopically detectable exfoliation was found in the contralateraleye (the NE eye). IOPs were measured with the Goldmann applana-tion tonometer during the study by the same examiner (P.P.). Thestudy IOP values were selected for calculations. Parallel IOP val-ues, measured during the follow-up time by private ophthalmolo-gists, were available for all these persons. Diurnal curves were mea-sured for 18/22 subjects in 1993. The IOP variation, measured at8 a.m., 12 a.m., and 3 p.m., was 0±5 mmHg (mean 2.3 mmHg)for the E eyes and 0±5 mmHg (mean 2.4 mmHg) for the NE eyes.All IOP readings in diurnal curves were normotensive, between 10and 21 mmHg in the E eyes and between 10 and 20 mmHg in theNE eyes.

The VF was defined as normal for the central 26 deg, accordingto the criteria of Caprioli [3], provided: (1) there were not three ormore adjacent points of ³5 bB loss each; (2) there were not twoor more adjacent points of ³10 dB loss each; and (3) there wasnot a difference of ³10 dB between two or more adjacent pointsacross the nasal horizontal meridian. The outer VF was defined asabnormal when there were two or more absolute defects on the nasalside. VFs measured with the Octopus G1 program were normal, ac-cording to Caprioli, in both eyes of 18/22 persons. Four persons in-cluded in the study showed false-positive test results due to cataract.The VF indices of the paired eyes did not differ in 1990 or in 1993.

Stereophotographs of the optic discs were obtained with theTRS-SS2 retinal camera (Topcon, Japan) with Ektachrome 100HC film. Topographic analysis of stereoscopic slides was performedwith the computerized three-dimensional image analysis systemTopcon Imagenet (Topcon TRS-S52) by one examiner (K.I.)masked to the clinical information. The optic cup was measured ata depth of 150 �m below the surface of the optic disc (retinal sur-face). Topographic parameters (disc area, cup area, rim area andcup volume) were then calculated as global parameters of the disc.As parameters for evaluating sectional differences in the optic discconfiguration, R/D (rim/disc) radius ratios were computed at inter-vals of 10 deg by the internal software of the instrument. Measure-ments for 12 imaginary sections at intervals of 30 deg, including thehorizontal and vertical axes (i.e. nasal, nasal-superior, superior-na-sal, superior, superior-temporal, temporal-superior, temporal, tem-poral-inferior, inferior-temporal, inferior, inferior-nasal and nasal-inferior) were used for analyses (Fig. 1).

A modification of Littmann©s method [19] adapted for use withthe Topcon fundus camera was used to correct the magnificationof the central fundus, taking into account the anterior corneal curva-ture, refraction and axial length.

The Wilcoxon sign rank test was used to compare the paired Eand NE eyes as well as to analyze changes over time. The Spearmancorrelation coefficient was calculated to analyze association be-tween the optic disc parameters and age or IOP.

All subjects gave their informed consent prior to their inclusionin the study. The study was performed in accordance with the ethicalstandards laid down in the 1964 Declaration of Helsinki.

Results

Disc topography was analyzed in the paired eyes of 22subjects with unilateral EXS. The data for the 14 subjectswith equal IOPs (IOP difference between the pairedeyes�1 mmHg, mean age 68.1�6.2 years) in the pairedeyes were also analyzed separately. In six subjects theIOP was ³2 mmHg higher in the E eye (mean age62.7�9.0 years), and in two subjects the IOP was³2 mmHg higher in the NE eye than in the contralateraleye. Because of the small number of subjects in thesetwo latter groups, only the results for the whole seriesand for the subjects with equal IOPs will be presentedhere.

The E eyes did not differ from their fellow NE eyes inrefraction (+1.77�1.56 D vs +1.70�1.15 D) or in axiallength (22.8�1.0 mm vs 22.9�0.8 mm).

Whole series

Interocular comparisons

IOP. The fellow E and NE eyes did not differ in IOP in1990 (16.0�2.4 vs 15.0�2.5 mmHg, range 12±21 vs 12±20 mmHg). Nor did they differ in IOP in 1993(16.7�2.1 vs. 15.5�2.3 mmHg, range 12±21 vs 13±20 mmHg).

Fig. 1 Rim-to-disc radius ratios were measured at the sections di-vided at intervals of 30 deg

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Papillary topography. The E and NE eyes did not differ indisc area (1.94�0.31 vs 2.01�0.36 mm2), rim area(1.46�0.23 vs 1.55�0.33 mm2), cup area (0.48�0.24 vs0.46�0.21 mm2) or cup volume (0.13�0.1 vs0.13�0.09 mm3) in 1990. Nor did they differ in these pa-rameters in 1993 (Table 1).

Optic disc configuration. The R/D radius ratio was signif-icantly smaller in the E eyes than in the NE eyes(0.52�0.13 vs 0.58�0.12, P<0.05) only in the inferiorsection in 1990. In 1993 the fellow eyes did not differin optic disc configuration (Table 2).

Changes over time

Exfoliative eyes. In the E eyes the IOP increased(16.0�2.4 mmHg vs 16.7�2.1 mmHg, P<0.001) and theR/D radius ratio in the temporal-inferior section decreased

(0.49�0.17 vs 0.43�0.14, P<0.05) during the follow-upperiod (Table 2).

Non-exfoliative eyes. During the follow-up period, therewere increases in IOP (15.0�2.5 mmHg vs15.5�2.3 mmHg, P<0.01), cup area (0.46�0.21 vs0.53�0.27 mm2, P<0.05) and cup volume (0.13�0.09 vs0.16�0.11 mm3, P<0.05) in the NE eyes. The decreasein rim area (1.55�0.33 vs 1.45�0.29 mm2, P<0.01) wassignificant (Table 1).

The decreases in the R/D radius ratio in the inferior(0.58�0.12 vs 0.53�0.13, P<0.05), the nasal-inferior(0.67�0.16 vs 0.62�0.16, P<0.05), and the nasal sections(0.67�0.17 vs 0.62�0.18, P<0.01) were also significantduring the follow-up period (Table 2).

Correlations. The initial IOP did not correlate with theoptic disc topography or the change in disc topographyin the E or in the NE eyes.

Table 1 Optic disc topographyin the non-exfoliative (NE) andthe exfoliative (E) eyes in 1990and 1993 (IOP intraocular pres-sure)

NE eyes E eyes

1990(mean � SD)

1993(mean � SD)

P(change)

1990(mean � SD)

1993(mean � SD)

P(change)

IOP (mmHg) 15.0 � 2.5 15.5 � 2.3 < 0.01 16.0 � 2.4 16.7 � 2.1 < 0.001

Papillary topographyDisc area (mm2) 2.01 � 0.36 2.00 � 0.35 ns 1.94 � 0.31 1.99 � 0.35 nsRim area (mm2) 1.55 � 0.33 1.45 � 0.29 < 0.01 1.46 � 0.23 1.46 � 0.28 nsCup area (mm2) 0.46 � 0.21 0.53 � 0.27 < 0.05 0.48 � 0.24 0.53 � 0.28 nsCup volume (mm3) 0.13 � 0.09 0.16 � 0.11 < 0.05 0.13 � 0.10 0.16 � 0.13 ns

Table 2 Optic disc configura-tion (rim/disc radius ratios) inthe non-exfoliative (NE) and theexfoliative (E) eyes in 1990 and1993

NE eyes E eyes

1990(mean � SD)

1993(mean � SD)

P(change)

1990(mean � SD)

1993(mean � SD)

P(change)

NasalInferior 0.67 � 0.16 0.62 � 0.16 < 0.05 0.68 � 0.14 0.65 � 0.14 nsNasal 0.67 � 0.17 0.62 � 0.18 < 0.01 0.70 � 0.16 0.60 � 0.16 nsSuperior 0.58 � 0.17 0.55 � 0.17 ns 0.62 � 0.19 0.57 � 0.16 ns

SuperiorNasal 0.49 � 0.14 0.48 � 0.16 ns 0.54 � 0.20 0.48 � 0.17 nsSuperior 0.46 � 0.12 0.46 � 0.13 ns 0.48 � 0.17 0.46 � 0.16 nsTemporal 0.48 � 0.11 0.45 � 0.14 ns 0.45 � 0.16 0.47 � 0.15 ns

TemporalSuperior 0.50 � 0.16 0.47 � 0.13 ns 0.46 � 0.16 0.48 � 0.17 nsTemporal 0.51 � 0.18 0.46 � 0.13 ns 0.48 � 0.18 0.44 � 0.16 nsInferior 0.54 � 0.18 0.49 � 0.15 ns 0.49 � 0.17 0.43 � 0.14 < 0.05

InferiorTemporal 0.54 � 0.13 0.49 � 0.13 ns 0.50 � 0.40 0.46 � 0.12 nsInferior 0.58 � 0.12* 0.53 � 0.13 < 0.05 0.52 � 0.13* 0.50 � 0.12 nsNasal 0.61 � 0.15 0.58 � 0.15 ns 0.59 � 0.14 0.58 � 0.13 ns

* P<0.05 (difference between NE and E eyes)

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Group with equal IOPs (n=14)

Interocular comparisons

The E eyes did not differ from their fellow NE eyes inIOP in 1990 (15.1�2.5 vs 15.1�2.5 mmHg, P NS) or in1993 (16.4�2.3 vs 16.2�2.3 mmHg, P NS). Nor did thefellow eyes differ in optic disc topography or in disc con-figuration in 1990 or in 1993 (Table 3).

Changes over time

Exfoliative eyes. During the follow-up period, the IOP in-creased significantly in the E eyes (15.1�2.5 vs16.4�2.3 mmHg, P<0.01).

In optic disc configuration, the decreases in the nasal-superior (0.68�0.15 vs 0.60�0.15, P<0.05) and the supe-rior-nasal R/D radius ratios (0.58�0.19 vs 0.49�0.16,P<0.05) were significant (Table 4).

Non-exfoliative eyes. During the follow-up period, theIOP increased significantly in the NE eyes (15.1�2.5 vs16.2�2.3 mmHg, P<0.05).

There were no significant changes in disc topographyor disc configuration in the NE eyes during the follow-up period (Tables 3 and 4).

Discussion

Non-glaucomatous, normotensive persons with unilateralEXS who did not convert to glaucoma, ocular hyperten-sion, or bilateral EXS were selected for this prospective3-year follow-up study to examine whether the exfoliativeprocess itself, without the contributory effect of raisedIOP, might cause optic nerve head damage. Special inter-est was focused on persons with unilateral EXS and equalIOPs during the study time.

The criterion for unilateral EXS was biomicroscopical-ly detectable exfoliation material on the lens capsule or at

Table 3 Optic disc topographyin 1990 and 1993 in a groupof eyes (n=14) with equal intra-ocular pressures (IOP) in thenon-exfoliative (NE) and theexfoliative (E) eyes

NE eyes E eyes

1990(mean � SD)

1993(mean � SD)

P(change)

1990(mean � SD)

1993(mean � SD)

P(change)

IOP (mmHg) 15.1 � 2.5 16.2 � 2.3 < 0.05 15.1 � 2.5 16.4 � 2.3 < 0.01

Papillary topographyDisc area (mm2) 2.10 � 0.40 2.10 � 0.38 ns 1.92 � 0.32 1.98 � 0.37 nsRim area (mm2) 1.62 � 0.40 1.55 � 0.31 ns 1.48 � 0.21 1.47 � 0.31 nsCup area (mm2) 0.47 � 0.21 0.52 � 0.27 ns 0.44 � 0.21 0.52 � 0.25 0.058Cup volume (mm3) 0.13 � 0.09 0.14 � 0.10 ns 0.11 � 0.08 0.15 � 0.10 0.058

Table 4 Optic disc configura-tion (rim/disc radius ratios) in1990 and 1993 in a group ofeyes (n=14) with similar intra-ocular pressure in the non-exfo-liative (NE) and the exfoliative(E) eyes

NE eyes E eyes

1990(mean � SD)

1993(mean � SD)

P(change)

1990(mean � SD)

1993(mean � SD)

P(change)

NasalInferior 0.68 � 0.18 0.65 � 0.19 ns 0.71 � 0.10 0.67 � 0.12 nsNasal 0.68 � 0.19 0.65 � 0.20 ns 0.74 � 0.11 0.69 � 0.13 nsSuperior 0.60 � 0.19 0.57 � 0.22 ns 0.68 � 0.15 0.60 � 0.15 < 0.05

SuperiorNasal 0.50 � 0.15 0.50 � 0.18 ns 0.58 � 0.19 0.49 � 0.16 < 0.05Superior 0.47 � 0.14 0.47 � 0.14 ns 0.49 � 0.15 0.45 � 0.14 nsTemporal 0.49 � 0.13 0.45 � 0.14 ns 0.46 � 0.15 0.46 � 0.14 ns

TemporalSuperior 0.49 � 0.18 0.45 � 0.11 ns 0.50 � 0.16 0.47 � 0.17 nsTemporal 0.50 � 0.20 0.47 � 0.11 ns 0.51 � 0.21 0.43 � 0.17 0.068Inferior 0.54 � 0.18 0.51 � 0.15 ns 0.49 � 0.20 0.42 � 0.14 0.069

InferiorTemporal 0.54 � 0.14 0.51 � 0.13 ns 0.49 � 0.16 0.44 � 0.12 0.078Inferior 0.58 � 0.13 0.56 � 0.15 ns 0.52 � 0.13 0.49 � 0.11 nsNasal 0.61 � 0.17 0.61 � 0.18 ns 0.60 � 0.12 0.60 � 0.12 ns

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the pupillary border; neither cycloscopy nor histologicalstudies were carried out. The possibility could not be ru-led out that some of the NE eyes represented a preclinicalstage of EXS, since cycloscopy has been shown to in-crease the diagnostic sensitivity [15, 21], and exfoliationmaterial has been identified electron-microscopically insome contralateral eyes that appeared clinically free ofEXS [13, 27]. Although recently it has been suggestedthat EXS is a bilateral disorder with asymmetric onset,in this series the subjects clinically remained unilaterallyaffected (as judged from the visibility of exfoliation ma-terial and also from pigment-related signs) during the fol-low-up time.

Only subjects with normal IOP values throughout the3-year follow-up period were selected for this study.The IOP variation in the E and the NE eyes was similar.However, unmeasured temporary pressure peaks, espe-cially in the E eyes, cannot be ruled out, as the E eyesmay show great variation in IOP in diurnal curves andpressure peaks outside office hours [16, 34].

Though the paired eyes remained normotensive, therewas a significant increase in IOP in both eyes. With re-gard to the E eyes this observation is in accordance withearlier follow-up studies [10, 14], but Aasved, in a studyon 8537 subjects, did not find any consistent alteration inIOP with increasing age either in eyes with or in thosewithout exfoliation. In his study, the appearance of exfo-liation was either accompanied or closely followed by anincrease in IOP, or the IOP remained unchanged [1].

As we have earlier shown, the optic disc size was thesame in the paired E and NE eyes [25, 29]. Though opticdiscs have been shown to be significantly smaller in glau-comatous or non-glaucomatous eyes with pseudoexfolia-tion than in those without it [2, 11, 32], this differencehas been concluded to be only moderate and, in view ofthe great overlap of the values, of marginal clinical signif-icance.

In this study, as in our previous studies, global disc pa-rameters did not differ between the paired eyes [25, 29].Global parameters have been shown to be less likely to re-veal early glaucomatous optic nerve head changes thanparameters representing localized changes [9, 29]. Earlier,when examining non-glaucomatous subjects with unilat-eral EXS, including persons with hypertensive IOP val-ues, we found slight changes in optic disc configurationin the inferior and the inferior-temporal sections of theE eyes. These changes seemed to be pressure-dependent[29]. In the present study, also, the R/D radius ratio inthe inferior section was significantly smaller in the E eyesthan in the fellow NE eyes in 1990, even though the eyeswere normotensive and did not differ in IOP. This may bean early sign of optic nerve head damage, as the lowerquadrant of the optic disc is known to be the area mostvulnerable to early glaucomatous optic disc changes [4,12], although diffuse enlargement of the cup is also com-mon in early glaucoma [23, 31].

In this study, in which the paired eyes differed only inthe presence of visible exfoliation material, changes indi-cative of nerve fiber loss occurred during the follow-upperiod in both eyes of the whole group. In the group inwhich the IOP was equal in the paired eyes, however, sig-nificant changes in optic disc topography took place onlyin the E eyes.

Aging alone may cause loss of optic nerve fibers [20].Airaksinen et al. [2] measured a rim area loss of0.0032 mm2 (0.23%) per year in normal subjects, and Tsaiet al. found a loss of 0.003 mm2 [30]. In the present study,the yearly loss of rim area was 0.024 mm2 (1.17%) for theNE eyes and 0.005 mm2 (0.43%) for the E eyes in thegroup with equal IOPs. In both E and NE eyes, the rimarea loss exceeded the values earlier measured for normaleyes. It seems unlikely that the slight, though significant,elevation of IOP during the follow-up period could be thecause of the optic nerve changes in these normotensivesubjects, unless there were marked undetected pressurepeaks.

It seems possible that the cause of the optic disc chang-es in the E eyes, in addition to aging, was the exfoliationprocess. This may be explained by the early vascularchanges found in EXS [13, 17, 26, 33] and by the fact thatexfoliation material has also been detected in the posteriorpart of the eye (walls of the short posterior ciliary arteriesand of the vortex veins as well as the optic nerve sheaths)[6, 27].

Significant disc changes in the clinically NE eyes ofthe whole series indicate changes caused by aging. Theyalso indicate that some of the NE eyes may actually havehad preclinical stages of EXS.

In this series, the disc changes took place in normoten-sive eyes. Thus, one component of disc damage in the ex-foliation glaucoma may be independent of IOP.

In clinical practice, more attention should be focusedon the fellow eyes of patients with clinically unilateralEXS with or without glaucoma. Slight changes in opticdisc configuration are to be expected in both eyes evenbefore hypertensive IOP values are measured. It is obvi-ous that the IOP rises from the base level and that opticdisc changes take place in both eyes of patients with clin-ically unilateral EXS even before the EXS becomes bilat-eral and before hypertensive IOP readings can be mea-sured in either eye.

Acknowledgements This study was supported by grants fromSilmäsäätiö (the Finnish Eye Foundation), Silmä-ja Kudos-pankkisäätiö (Finnish Eye and Tissue Bank Foundation) and PauloSäätiö (the Paulo Foundation).

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