A multivariate sensory model in glaucoma diagnosis

Share Embed


Descrição do Produto

A Multivariate Sensory Model in Glaucoma Diagnosis Peter Martus,1 Matthias Korth,2 FolkertHorn,2 Anselm Jiinemann2 Martin Wisse2 and Jost B. Jonas" evaluate whether the combination of two psychophysical and two electrophysiological procedures improves diagnostic validity compared with single procedures. METHODS. In a clinical study, 73 patients with glaucoma from the University Eye Hospital in Erlangen and 122 healthy control subjects from the university staff, ranging in age from 19 to 62 years, underwent measurement of temporal contrast sensitivity using a full-field flicker test, spatiotemporal contrast sensitivity, blue-on-yellow visual evoked potential (VEP), and a black-and-white, pattern-reversal electroretinogram. Diagnostic reference criteria included applanation tonometry, optic disc morphometry, and automated perimetry. Sensitivity was determined univariately with a fixed specificity of 80% and in a multivariate approach using logistic regression analysis. The classification rate was estimated using the leaving-one-out method. The correlation with intraocular pressure, visual field defects, and optic nerve defects was determined. PURPOSE. TO

Contrast sensitivity measurements and the blue-on-yellow pattern-onset VEP showed comparable sensitivity (85%, 84%, and 85%) with 80% specificity, and a pattern-reversal electroretinogram showed lower sensitivity (64%). The first three methods contributed independent information to a diagnostic score. This score improved sensitivity to 94%, with a specificity of 89%. All procedures moderately correlated with the neuroretinal rim area of the optic disc (r = 0.32- 0.46). The psychophysical tests showed a higher correlation with visualfielddefects (r > 0.5) than the electrophysiological tests (r < 0.3). RESULTS.

The multivariate approach substantially increased the diagnostic validity compared with single procedures. This was probably because the diagnostic procedures under investigation tested different aspects of visual function. (Invest Ophthalmol Vis Sci. 1998;39:1567-1574)

CONCLUSIONS.

T

he glaucomas are a heterogeneous group of progressive eye diseases. Diagnosis is based on optic disc damage and visual field defects. In many cases, an increased level of intraocular pressure GOP) is observed before other symptoms occur, but cases of ocular hypertensive patients who never suffer glaucomatous damage and cases of lowtension glaucoma show that increased IOP is neither a sufficient nor a necessary criterion for glaucoma. Because perimetric deficits can be considered as relatively late symptoms,1 numerous different sensory tests have been devised to find a more sensitive method of detecting glaucomatous damage before perimetric defects occur. Although rather good sensitivities for certain procedures have been claimed, none of them has become a generally accepted part of a standard repertoire of procedures to diagnose glaucomas. Part of the problem is the heterogeneity of the damage to visual function in patients with glaucoma. The use of only a single sensory test might not, therefore, be a useful device to achieve a high sensitivity in glaucoma diagnosis for all patients. In several studies, multivariate analyses have been used to discriminate between patients with glaucoma and healthy sub-

From the Departments of "Medical Statistics and Documentation and 2 Ophthalmology, University of Erlangen-Niirnberg, Germany. Supported by grants from the Deutsche Forschungsgemeinschaft (DFG Na 55/6 to 2). Submitted for publication February 11, 1997; revised February 13, 1998; accepted March 24, 1998. Proprietary interest category: N. Reprint requests: Peter Martus, Department of Medical Statistics and Documentation, University of Erlangen-Niirnberg, Waldstrafte 6, 91054 Erlangen, Germany. Investigative Ophthalmology & Visual Science, August 1998, Vol. 39, No. 9 Copyright © Association for Research in Vision and Ophthalmology

jects2 6 or to predict visual field loss in the future.7"9 Patients were classified according to history and systemic data,'^89 IOP, 389 morphometric data, 2 ' 4 ' 6 " 9 electrophysiological measurements,4'5 and early visualfieldloss.6 However, multivariate analyses using intrinsically different functional diagnostic procedures (excluding visual field data) have remained exceptional.5 In the Erlangen Glaucoma Study, among others, two psychophysical and two electrophysiological procedures have been considered. All procedures had been developed earlier and were standardized based on results found in previous patients. The two psychophysical tests under investigation were the temporal contrast sensitivity (TCS) and the spatiotemporal contrast sensitivity (STCS). The validity of both methods has been shown previously. 10 " The two electrophysiological procedures were the recording of the pattern electroretinogram (PERG) in response to a rapid pattern-reversal stimulus and the recording of the visual evoked potential (VEP) in response to the onset of a blue pattern presented on a strong yellow adaptation light (BY-VEP). The validity of the PERG and BY-VEP test as applied by us also has been shown previously.121^ The four procedures have been investigated in the same patients. This opened the possibility to prove whether the different procedures contain independent diagnostic information using a multivariate analysis. In this analysis, we constructed a diagnostic score and examined how the classification rates were improved by stepwise inclusion of the different procedures. We present the results of the multivariate analysis and illustrate the construction of the diagnostic score. 1567

1568

IOVS, August 1998, Vol. 39, No. 9

Martus et al.

TABLE 1. Subject Characteristics

Glaucoma (rc = 73; 28 men, 45 women) POAG (n = 53) LTG (n = 20) Control Subjects (n = 122; 70 men, 52 women)

Age (y)

IOP (mm Hg)

Neuroretinal Rim Area (mm 2 )

Mean Perimetric Defect (dB)

50.5 ± 9.7 [53; 21-62] 51.2 ± 9.6 [54; 21-62] 48.9 ± 10.0 [51; 27-62] 41.2 ± 11.5 [42; 19-62]

28.1 ± 10.8 [24; 16-75] 31.2 ± 11.2 [27; 21-75] 19.9 ± 14 [20; 16-21] 16.5 ± 30 [17; 10-21]

1.01 ± 0.44 [1.00; 0-2.16] 1.02 ± 0.46 [1.06; 0-2.16] 0.97 ± 0.38 [0.89; 0.40-2.09] 1.68 ± 0.31 [1.6; 1.12-2.79]

7.2 ± 4.9 [6.0; 1.45-25.45] 7.2 ± 5.2 [6.1; 1.45-25.45] 7.0 ± 4.0 [6.0; 1.60-15.70] 1.21 ± 1.18 [1.30; -1.50-4.00]

Values are mean ± SD, with median and minimum-maximum. Mann-Whitney test (53 with POAG, 20 with LTG); P < 0.0001. IOP, intraocular pressure; LTG, low tension glaucoma; POAG, primary open-angle glaucoma.

METHODS Patients and Control Subjects Patients with Glaucoma. Eyes (n = 119) from 73 patients with glaucoma (53 with primary open-angle glaucoma [POAG], IOP > 21 mm Hg; and 20 with low tension glaucoma [LTG], IOP < 21 mm Hg), 50.5 ± 9 7 years old (mean ± SD), were included in the study. Forty-five patients were women, and 28 were men. The diagnosis of LTG was based on at least two IOP measurements before initial medical therapy. There were no significant differences in age, neuroretinal rim area, and visual defect between the patients with POAG and those with LTG. The patients fulfilled the following criteria: optic disc damage (classification of Jonas,14 glaucomatous optic disc stages I-V) and pathologic cumulative perimetric defect curves (graphical display of ranked local defects compared with 95th and 99th percentiles of normal curves with identification of localized, diffuse, and broadly distributed visual field losses, Bebie15). For 27 patients, only one eye was included because there was no evidence of glaucoma for the fellow eye (21 eyes with a normal visual field and normal optic disc) or the diagnosis remained unclear (6 eyes). Sixty-four (88%) of the patients with glaucoma were treated with eye drops. When pilocarpine drops had been prescribed, administration was discontinued in the morning of the day on which visual function was tested. Other eye drops (beta blocker, clonidine) were continued (Table 1). Control Subjects. Eyes (n = 223) from 122 healthy subjects aged 41.2 ± 11.5 years were included in the study; 52 were women, 70 were men. They were recruited from the staff of the hospital and the university administration. The subjects had normal IOP ( >

A

130-

J>

i

kA

A

CO

120-

A

V

110-

v

v

^v

10090 -16

Discrimination

Y

Line A 73 Cases V 122 Controls

-12

-14

-10

-6

-4

-2

Diagnostic score containing STCS Diagnostic Score: 5.11-0.085*STCS

Discrimination Line

12

16

20

24

28

32

Diagnostic score containing STCS and BY-VEP

B

Diagnostic Score: -1.95 - 0.093'STCS + 0.21*BY-VEP

Discrimination Line •

73 glaucoma 122 controls

Diagnostic score containing STCS, BY-VEP and TCS C

Diagnostic Score: -0.012 - 0.02*STCS + 0.20 BY-VEP -13.1 'TCS

1. (A) Step 2 of the multivariate analysis. The inclusion of blue-on-yellow visual evoked potential (BY-VEP) increases the discrimination between patients with glaucoma and control subjects significantly compared with spatiotemporal contrast sensitivity (STCS) alone. (B) Step 3 of the multivariate analysis. The inclusion of temporal contrast sensitivity (TCS) increases the discrimination between patients with glaucoma and control subjects significantly compared with the score of STCS and BY-VEP. (C) Step 4 of the multivariate analysis. The inclusion of the pattern-reversal electroretinogram (PERG) does not improve discrimination between patients with glaucoma and control subjects after incorporation of additional knowledge from the TCS, the STCS, and BY-VEP tests.

FIGURE

Sensory Model in Glaucoma Diagnosis

10VS, August 1998, Vol. 39, No. 9

1,11,0-

k A A

.98,7-

15

#

V

CO _Q

o

v

^ V

A -

15

igl^ V i A

,6" ,5"

A

A

9

,3,2,1-

^

V

_

V V

V ^P_.

o,o-

1573

WWW



20 LTG

^

53 POWG

V 122 Controls 10

20

30

40

50

60

70

age [years] )) = -1.95-0.093*STCS+0.21*BY-VEP-13.0*TCS FIGURE 2. Final multivariate diagnostic model for discrimination between patients and control subjects for different ages. Spatiotemporal contrast sensitivity (STCS), blue-on-yellow visual evoked potential (BY-VEP), and temporal contrast sensitivity (TCS) are included. The best separation is for younger patients and control subjects.

rons seem to have thick axons and large cell bodies because they have higher conduction velocities than red- and greensensitive cells.3"'31 In our study, the univariate psychophysical procedures STCS and TCS, which are related to the M-cell pathway, showed the best discrimination between patients with glaucoma and control subjects. STCS showed the best separation (not significant compared with TCS and BY-VEP), which confirms the results of Aulhorn and Karmeyer'6, because the localized target of STCS was motivated by their analysis of the spatial pattern of early visual field loss. However, in the multivariate analysis the (probable) Ppathway- associated BY-VEP contributed the maximum additional information after including the most valid psychophysical procedure, STCS. Also, the noise perturbing TCS and STCS, namely, patient's compliance, should be highly correlated, whereas the noise of BY-VEP, namely, artifacts in signal processing, should be a rather independent entity. In the third step of our model, the selection procedure for TCS was preferred to that for PERG, which is consistent with the univariate analysis. Only a larger number of patients and control subjects could prove the question of whether the PERG might contain useful additional information for TCS, BY-VEP, and STCS. With 195 subjects, it is not sensible to prove or reject this hypothesis using a multivariate model. The result of our multivariate analysis was a weighted sum of different tests. The application of such a result in a clinical routine might be questionable. First, it is expensive to perform a battery of diagnostic tests in clinical routine. Second, our study only examined patients with early visualfieldloss. Third, clinicians usually prefer norm values for the different procedures and intuitively combine the information in a "normal versus pathologic result." However, the true clinical value of diagnostic procedures can only be assessed by the long-term follow-up of patients with an unknown disease status at the

point of examination. The final efficacy of inventing a diagnostic measure may be evaluated only in a study that takes into account the effects of therapy and that is dependent on the results of diagnostic measurements. In our study, we showed the increase in information achieved by using more than one diagnostic method and we gave an interpretation of this fact combining medical and methodological arguments. One has to keep in mind not only the difficulty of evaluating the "absolute" gain of diagnostic procedures in a cross-sectional study, but also the fact that the standard visual fields may lead to misclassifications and, therefore, to an underestimation of the sensitivity and the specificity of a new diagnostic measure.

References 1. Quigley HA, Addicks EM, Green RW. Optic nerve damage in human glaucoma: III, quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol. 1982; 100:135146. 2. Drance SM. Correlation between optic disc changes and visual field defects in chronic open angle glaucoma. Trans Am Acad Ophthalmol Oto-laryngol. 1976;81:224-226. 3. Drance SM, Schulzer M, Gordon RD, Sweeney VP. Use of discriminant analysis: II, identification of persons with glaucomatous visual field defects. Arch Ophthalmol. 1978;96:1571-1573. 4. Drance SM, Airaksinen PY, Price M, Schulzer M, Douglas GR, Tansley 13. The use of psychophysiological, structural, and electrodiagnostic parameters to identify glaucomatous damage. Graefe's Arch Clin Exp Ophthalmol. 1987;225:365-368. 5. Price MJ, Drance SM, Price M, Schulzer M, Douglas GR, Tansley B. The pattern electroretinogram and visual-evoked potential in glaucoma. Graefe's Arch Clin Exp Ophthalmol. 1988;226:542-547. 6. Caprioli J. Discrimination between normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 1992;33:153-159. 7. Susanna R, Drance SM. Use of discriminant analysis: I, prediction of visual field defects from features of the glaucoma disc. Arch Ophthalmol. 1978;96:1568-1570.

1574

Martus et al.

8. Hart WM, Yablonski M, Kass MA, Becker B. Multivariate analysis of the risk of glaucomatous visual field loss. Arch Ophthalmol. 1979; 97:1455-1458. 9. Drance SM, Schulzer M, Thomas B, Douglas GR. Multivariate analysis in glaucoma. Use of discriminant analysis in predicting glaucomatous visualfielddamage. Arch Ophthalmol. 1981;99:1019-1022. 10. Horn F, Martus P, Korth M. Comparison of temporal and spatiotemporal contrast-sensitivity tests in normal subjects and glaucoma patients. Ger J Ophthalmol. 1995;4:97-102. 11. Horn FK, Korth M, Martus P. Quick full-field flicker test in glaucoma diagnosis: correlations with perimetry and papillometry. / Glaucoma. 1994;3:206-21312. Korth M, Horn F, Storck B, Jonas J. The pattern-evoked electroretinogram (PERG): age-related alterations and changes in glaucoma. Graefe'sArch Clin Exp Ophthalmol. 1989;227:123-130. 13. Korth M, Nguyen NX, Jiinemann A, Martus P, Jonas JB. VEP test of the blue-sensitive pathway in glaucoma. Invest Ophthalmol Vis Sci. 1994;35:2599-26l0. 14. Jonas JB, Gusek GC, Naumann GOH. Optic disc morphometry in chronic primary open-angle glaucoma: I, morphometric intrapapillary characteristics. Graefe's Arch Clin Exp Ophthalmol. 1988; 226:522-530. 15. Bebie H, Flammer J, Bebie T. The cumulative defect curve: separation of local and diffuse components of visual field damage. Graefe'sArch Clin Exp Ophthalmol. 1989;227:9-12. 16. Aulhorn E, Karmeyer H. Frequency distribution in early glaucomatous visual field defects. Doc Ophthalmol Proc Series 14. 1976: 75-83. 17. Owsley C, Sekuler R, Siemsen D. Contrast sensitivity throughout adulthood. Vision Res. 23; 1983:689-699. 18. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York: Wiley; 1989:38-63. 19. Hand DJ. Discrimination and Classification. New York: Wiley; 1981:186-188.

IOVS, August 1998, Vol. 39, No. 9 20. Goldbaum MH, Sample PA, White H, et al. Interpretation of automated perimetry for glaucoma by neural network. Invest Ophthalmol Vis Sci. 1994;35:3362-3373. 21. Brigatti L, Hoffman D, Caprioli J. Neural networks to identify glaucoma with structural and functional measurements. Am J Ophthalmol. 1996;121:511-521. 22. Kaplan E, Shapley RM. The primate retina contains two types of ganglion cells, with high and low contrast sensitivity. Proc Natl Acad Sci USA. 1986;83:2755-2757. 23- Kaplan E, Lee BB, Shapley RM. New views of primate retinal function. In: Osborne N, Chader J, eds. Progress in Retinal Research. Oxford: Pergamon; 1990:273-336. 24. Quigley HA, Sanchez RM, Dunkelberger GR, L'Hernault NL, Baginski TA. Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci. 1987;28:913-920. 25. Quigley HA, Dunkelberger GR, Green WR. Chronic human glaucoma causing selectively greater loss of large optic nerve fibers. Ophthalmology. 1988;95:357-36326. Johnson CA. Selective versus nonselective losses in glaucoma. / Glaucoma (Suppl). 1994;3:S32-S44. 27. Lee BB, Pokorny J, Smith VC, Martin PR, Valberg A. Luminance and chromatic modulation sensitivity of macaque ganglion cells and human observers./ Opt Soc Am [A]. 1990;7:2223-2236. 28. Trick GL. Retinal potentials in patients with primary open-angle glaucoma: physiological evidence for temporal frequency tuning deficits. Invest Ophthalmol Vis Sci. 1985;26:1750-1758. 29. Korth M, Nguyen NX, Rix R, Sembritzki O. Interactions of spectral, spatial, and temporal mechanisms in the human pattern visual evoked potential. Vision Res. 1993:33:2397-2411. 30. Malpeli JG, Schiller P. Lack of blue OFF-center cells in the visual system of the monkey. Brain Res. 1978;l4l:385-38931. De Monasterio FM. Asymmetry of on- and off-pathways of bluesensitive cones of the retina of macaques. Brain Res. 1979;l66: 39-48.

Lihat lebih banyak...

Comentários

Copyright © 2017 DADOSPDF Inc.