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Recognizing Structural Damage to the Optic Nerve Head and Nerve Fiber Layer in Glaucoma
EDITORIAL Recognizing Structural Damage to the Optic Nerve Head and Nerve Fiber Layer in Glaucoma JOSEPH CAPRIOU, MD
T
HE DETECTION OF STRUCTURAL DAMAGE TO
the optic nerve head is central to the diagnosis of chronic glaucoma. Although characteristic optic nerve cupping, visual field loss, and increased intraocular pressure constitute a classic triad of findings, glaucomatous damage can be diagnosed in the absence of increased pressure or visual loss. Careful evaluation of the optic nerve head can usually identify early glaucomatous damage before automated static threshold perimetry demonstrates visual field defects. Increased cupping of the optic nerve head is a manifestation of retinal ganglion cell death and loss of ganglion cell axons from the optic nerve. This damage can also be recognized by careful examina tion of the retinal nerve fiber layer.1 Articles by Anton and associates2 and Eid and associates3 and, in this issue of THE JOURNAL, by Jonas and Griindler,4 reinforce three important concepts with respect to optic nerve head evaluation. First, careful assessment of the optic nerve head is often the most sensitive way to diagnose and monitor damage in the early stages of glaucoma. Second, careful spatial correlation between structural and functional damage can strengthen an otherwise uncertain diagnosis of early damage. Third, the recognition of patterns of optic nerve head damage and associated visual field loss can help identify subtypes of primary open-angle glaucoma.
Accepted for publication May 19, 1997. From the UCLA School of Medicine, Jules Stein Eye Institute, Los Angeles, California. Reprint requests to Joseph Caprioli, MD, UCLA School of Medicine, Jules Stein Eye Institute, 100 Stein Plaza, Box 957004, Los Angeles, CA 90095-7004; fax: (310) 206-7773; e-mail: [email protected]
516
The susceptibility to optic nerve damage from glaucoma varies greatly among individuals. One sixth to one half of all patients with glaucoma have an initial intraocular pressure reading of less than 21 mm Hg,5,6 whereas one tenth or less of those with elevated intraocular pressure have visual field loss from glauco ma.7,8 Measurements of intraocular pressure cannot See also pp. 455-472, 488-497, and 506-515.
be used to predict reliably which patients will suffer damage from glaucoma. Automated static threshold perimetry has provided sensitivity, standardization, and objectivity not otherwise routinely available in clinical practice, but the degree of fluctuation from test to test often confounds meaningful interpreta tion. It is not unusual for an individual test location in a depressed area of the visual field to fluctuate by 20 dB or more with repeated testing, even in highly reliable subjects.9,10 Corroboration of potentially sig nificant visual field changes with optic nerve appear ance is frequently the only way to differentiate pro gression from random fluctuation. Ample data support the concept that detectable structural damage to the optic nerve can be identified before measurable alterations in differential light sensitivity are found. The Collaborative Glaucoma Study found that a larger baseline cuprdisk ratio was significantly related to the subsequent development of visual field loss.11 Careful study of serial stereophotographs showed that progressive changes in optic nerve head structure were apparent in 10 of 12 eyes before the onset of glaucomatous visual field loss.12 Progres sive cupping generally preceded field loss in the
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER 1997
observations by Read and Spaeth of disk and field correlations in 460 glaucomatous eyes.13 A retrospec tive longitudinal study showed that disk cupping generally preceded visual field loss and that serial disk photographs were necessary for the earliest detection of optic nerve damage in ocular hypertension.14 In a prospective 5-year study of ocular hyperten sives, Odberg and Riise15 reported an increase in disk cupping in 19 of 46 eyes that maintained normal visual fields, whereas only one eye showed a field abnormality in the absence of discernible disk altera tion. Other studies have documented optic nerve abnormalities and defects of the retinal nerve fiber layer well in advance of the detection of visual field defects.16,17 An important caveat is that patients with small optic disks may demonstrate field loss before detectable cupping. In these patients, retinal nerve fibers crowd the optic nerve head so that significant loss of fibers can occur in the absence of recognizable cupping. Histologic examinations were used by Quigley and associates18 to estimate the number of nerve fibers in five optic nerves of normal subjects and in three optic nerves of glaucoma suspects with normal visual fields tested with the Goldmann perimeter. The mean number of axons in the normal control group was 964,000, with a 95% confidence interval of 827,000 to 1,100,000. The corresponding estimates of axon numbers for the three glaucoma suspects were 848,000, 808,000, and 577,000. Two of the latter estimates were smaller than the lower confidence boundary, and one value was only 60% of the normal average. This last case has been frequently and widely cited to suggest that as many as 40% of optic nerve fibers can be lost from a glaucomatous eye without a visual field abnormality. It is now generally appreciated that the develop ment of a reproducible glaucomatous visual field defect is characteristic of a patient with advanced, not early, disease. A published study19 provided evidence that the relative rate of measurable disk damage to field damage in glaucoma is quite high in early disease and decreases as the disease progresses, and conclud ed that careful evaluation of the optic nerve head and nerve fiber layer is important to detect early glauco matous damage but that in more advanced disease, perimetry provides a more robust measure of progres sive disease. The study by Jonas and Griindler4 in this VOL.124, No. 4
issue offers strong corroborative evidence. This work demonstrates that, in the early stages of chronic glaucoma, optic nerve head morphology is a more sensitive marker of damage and that in the later stages of disease, after visual field defects have become well established, perimetry is a more sensitive technique with which to monitor additional damage. Recent evidence suggests the preferential loss of larger retinal ganglion cells in early glaucoma;20'22 this observation has launched psychophysical studies to recognize early damage to the magnocellular path ways. Among these are included blue-on-yellow (or short-wavelength) automated perimetry and motiondetection perimetry.23 Early studies suggested that blue-on-yellow perimetry was more sensitive to early damage than white-on-white perimetry was.24 These early findings were subsequently confirmed.25,26 Fur thermore, blue-on-yellow perimetry has been shown to predict which patients are most likely to progress to white-on-white defects. It has also been demonstrated that progression rates are higher27,28 with blue-onyellow than with white-on-white perimetry. If the early work on selective ganglion cell loss holds up under additional scientific investigation and if appro priate psychophysical tests can be developed, then the temporal relation between visible structural damage and detectable functional damage could shift in favor of the functional measurements. Correlation of optic nerve and nerve fiber layer appearance with the location of visual field defects sharpens the physician's evaluation of patients with glaucoma. Clinical wisdom dictates that the absence of expected correlations between disk andfieldshould alert the examiner to diagnostic possibilities other than glaucoma. The anatomy of the nerve fiber layer and its retinotopic projections to the optic nerve head form the basis of the spatial relationships between structure and function in glaucoma. The arcuate arrangement of the axons and the presence of the median retinal raphe were described by the anato mists Michel and Dogiel in the latter part of the nineteenth century.29,30 Vogt31 correctly deduced the arrangement of nerve fibers in the retina when in 1913 he observed the nerve fiber layer ophthalmoscopically with the aid of red-free light. Observations about the correlation of optic nerve head abnormalities with patterns of visual field loss were summarized by Read and Spaeth more than 20
EDITORIAL
517
years ago.13 Examination of disk photographs can provide accurate predictions about the location of visual field defects in patients with glaucoma.32 Optic nerve axon counts in glaucomatous eyes showed that quadrants with the fewest axons correlated with regions of greatest visual field loss.18 Optic nerve damage in glaucomatous specimens, as predicted by clinical observation, was greatest at the superior and inferior poles. Measurements of the optic disk rim area and retinal nerve fiber layer height correlate quantitatively with measurements of visual function in glaucoma.33'36 Retinal nerve fiber layer abnormali ties and optic disk rim area also correlate with other psychophysical tests, such as flicker perimetry37 and high-pass resolution perimetry.38 A quantitative rela tion between the shape of the optic nerve head cup (measured with confocal laser ophthalmoscopy) and the amount of visual field loss has been demon strated.39 The work of Yamagishi and associates2 demonstrates a method of mapping optic nerve abnormalities in relation to visual field defects in glaucomatous patients with localized damage.3 Whereas these spatial correlations have been known for many years, the work provides a model for developing quantitative maps of structural-functional associations that could lead to better ways of substan tiating early localized damage. There has been speculation and debate about the presence of various patterns of visual field loss and optic nerve head appearance in possible subtypes of primary open-angle glaucoma. A recent report40 pre sented evidence for four distinct types of optic nerve head cupping in primary open-angle glaucoma. Per haps there are more. Eid and associates3 used scan ning laser ophthalmoscopy to revisit the debate about patterns of structural damage in normal-pressure primary open-angle glaucoma and higher-pressure primary open-angle glaucoma. For matched degrees of visual field loss, the patients with lower-pressure glaucoma had larger amounts of measurable optic nerve head cupping and greater inferior neuroretinal rim loss than did their counterparts with higherpressure glaucoma. These findings confirm the results of previous, less quantitative studies.41'43 The authors3 also suggest a subtle but entirely appropriate change in terminology for what have previously been termed low-tension glaucoma and high-tension glaucoma. The corresponding terms are low-tension primary 518
open-angle glaucoma and high-tension primary open-angle glaucoma. Although at first glance this may seem to be a trivial point, it emphasizes that these groups of patients exist along a continuum of disease and that neither group represents a pure, single, pathogenic entity. New techniques by which to recognize early struc tural alterations of the optic nerve head and nerve fiber layer have been introduced. Scanning confocal laser ophthalmoscopy exploits the advantages of the confocal principle to acquire tomographic-like image slices of the optic nerve head and nerve fiber layer to develop quantitative structural information. The reproducibility of this approach and its potential advan tages over other techniques have been described.44'47 New measures of optic nerve head shape have been introduced, and they correlate well with visual field loss.39,48 Scanning laser polarimetry makes use of the birefringent properties of the retinal nerve fiber layer. A property of the polarization state of an imaging laser, called retardation, is altered when it doublepasses through the nerve fiber layer. Retardation is pro portional to the thickness of the nerve fiber layer in hemisected monkey eyes49 and appears to correspond to the known architecture of the nerve fiber layer in normal and glaucomatous eyes. The measurements are reproducible and are higher in normal eyes than in glaucomatous eyes.50 These measurements also correlate with visual field loss in patients with glauco ma51 and are reduced in patients with ocular hyper tension compared with normal subjects.52 The infor mation obtained with this technique may be additive to that of ordinary nerve fiber layer photography.53 Nerve fiber layer thickness can also be measured with a new technique called optical coherence to mography, which uses light of low coherence to provide cross-sectional images of ocular tissues.54,55 The technique is analogous to axial mode ultrasound measurements. It appears to be reproducible56 and has been used to measure the nerve fiber layer thickness in normal and glaucomatous eyes.57 In a recent study, measurements of nerve fiber layer thickness were more diagnostic of field loss than were measurements of optic nerve head cupping or optic disk rim area.57 The importance of recognizing structural damage to the optic nerve head and nerve fiber layer in glaucoma cannot be overemphasized. Technologic developments may improve our ability to recognize
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER 1997
the very earliest evidence of damage, but widespread use should be preceded by further study. In the meantime, detailed evaluations of the optic nerve head and nerve fiber layer, preferably with the help of careful photography, will facilitate an early diagnosis of damage. Such an informed evaluation will alert the physician to the need for appropriate treatment of those patients with glaucomatous optic nerve damage. It may also help spare those who have no damage and those who are at little risk for damage the consider able morbidity of treatment.
REFERENCES 1. Quigley HA. Examination of the retinal nerve fiber layer in the recognition of early glaucoma damage. Trans Am Ophth Soc 1986;84:920-966. 2. Yamagishi N, Anton A, Sample PA, Zangwill L, Lopez A, Weinreb RN. Mapping structural damage of the optic disk to visual field defect in glaucoma. Am J Ophthalmol 1997; 123: 667-676. 3. Eid TE, Spaeth GL, Moster MR, Augsburger JJ. Quantitative differences between the optic nerve head and peripapillary retina in low-tension and high-tension primary open-angle glaucoma. Am J Ophthalmol. Forthcoming. 4. Jonas JB, Griindler AE. Correlation between mean visual field loss and morphometric optic disk variables in the openangle glaucomas. Am J Ophthalmol 1997;124:488-497. 5. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol 1983;118:166-191. 6. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open-angle glaucoma among black and white Americans: The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090-1095. 7. Hollows FC, Graham PA. Intraocular pressure, glaucoma, and glaucoma suspects in a denned population. Br J Ophthal mol 1966;50:570-586. 8. Bengtsson B. The prevalence of glaucoma. Br ] Ophthalmol 1981;65:46-49. 9. Werner EB, Petrig B, Krupin T, et al. Variability of automated visual fields in clinically stable glaucoma patients. Invest Ophthalmol Vis Sci 1989;30:1083-1089. 10. Boeglin RJ, Caprioli J, Zulauf M. Long-term fluctuation of the visual field in glaucoma. Am J Ophthalmol 1978;96: 2209-2211. 11. Armaly MF, Krueger DE, Maunder L, et al. Biostatistical analysis of the collaborative glaucoma study, I: summary report of the risk factors for glaucomatous visual field defects. Arch Ophthalmol 1980;98:2163-2171. 12. Sommer A, Pollack I, Maumenee AE. Optic disc parameters and onset of glaucomatous field loss, I: methods and progres sive changes in disc morphology. Arch Ophthalmol 1979; 9:1444-1448. 13. Read RM, Spaeth GL. The practical clinical appraisal of the optic disc in glaucoma: the natural history of cup progression and some specific disc-field correlations. Trans Am Acad Ophthalmol Otolaryngol 1974;78:255-274. VOL.124, No. 4
14- Pederson JE, Anderson DR. The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Oph thalmol 1980;98:490-495. 15. Odberg T, Riise D. Early diagnosis of glaucoma: the value of successive stereophotography of the optic disc. Acta Oph thalmol (Copenh) 1985;63:257-263. 16. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991;109:77-83. 17. Zeyen TG, Caprioli J. Progression of disc and field damage in early glaucoma. Arch Ophthalmol 1993;111:62-65. 18. Quigley HA, Addicks EM, Green WR. 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 Oph thalmol 1982;100:135-146. 19. Caprioli J. Clinical evaluation of the optic nerve in glaucoma. Trans Am Ophth Soc 1994;92:589-641. 20. Quigley HA, Sanchez RM, Dunkelberger GR, et al. Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci 1987;28:913-920. 21. Dandona L, Hendrickson A, Quigley HA. Selective effects of experimental glaucoma on axonal transport by retinal gangli on cells to the dorsal lateral geniculate nucleus. Invest Ophthalmol Vis Sci 1991;32:1593-1599. 22. Chaturvedi N, Hedley-Whyte ET, Dreyer EB. Lateral genicu late nucleus in glaucoma. Am J Ophthalmol 1993;116: 182-188. 23. Wall M, Jennisch CS, Munden PM. Motion perimetry identifies nerve fiber bundlelike defects in ocular hyperten sion. Arch Ophthalmol 1997;115:26-33. 24- Sample PA, Weinreb RN. Color perimetry for assessment of primary open-angle glaucoma. Invest Ophthalmol Vis Sci 1990;31:1869-1875. 25. Sample PA, Taylor JD, Martinez GA, Lusky M, Weinreb RH. Short-wavelength color visual fields in glaucoma suspects at risk. AmJ Ophthalmol 1993;115:225-233. 26. Johnson CA, Brandt JD, Khong AM, Adams AJ. Shortwavelength automated perimetry in low-, medium-, and high-risk ocular hypertensive eyes: initial baseline results. Arch Ophthalmol 1995;113:70-76. 27. Johnson CA, Adams AJ, Casson EJ, Brandt JD. Blue on yellow perimetry can predict the development of glaucoma tous visual field loss. Arch Ophthalmol 1993;111:645-650. 28. Johnson CA, Adams AJ, Casson EJ, Brandt JD. Progression of early glaucomatous visual field loss as detected by blue-onyellow and standard white-on-white automated perimetry. Arch Ophthalmol 1993;111:651-656. 29. Michel J. Uber die Asstrahlungweise der Opticusfasern in der menschlichen Retina: Beitrage zur Anatomie und Physiologie Als Festgabe. Leipzig: Carl Ludwig, 1874:56-63. 30. Dogiel AS. Uber die nervusen Elemente in der Retina des Menschen. Arch Mikr Anat (Bonn) 1891;38:317-344. 31. Vogt A. Die Nervenfaserstreifung der menschlichen Netzhaut mit besonderer Berucksichtigung der Differential diagnose gegeniiber patholgischen streilenfbrmigen Reflexen (praetinalen Faltelungen). Klin Monatsbl Augenheilkd 1917; 58:399-411. 32. Hitchings RA, Spaeth GL. The optic disc in glaucoma, II: correlation of the appearance of the optic disc with the visual field. Br J Ophthalmol 1977;61:107-113. 33. Airaksinen PJ, Drance SM, Douglas GR, et al. Neuroretinal rim areas and visual field indices in glaucoma. Am J Ophthalmol 1985;99:107-110.
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34. Balazsi AG, Drance SM, Schulzer M, et al. Neuroretinal rim area in suspected glaucoma and early chronic open-angle glaucoma: correlation with parameters of visual function. Arch Ophthalmol 1984;102:1011-1014. 35. Caprioli J, Miller JM. Correlation of structure and function in glaucoma: quantitative measurements of disc and field. Ophthalmology 1988;95:723-727. 36. Caprioli J. The contour of the juxtapapillary nerve fiber layer in glaucoma. Ophthalmology 1990;97:358-365. 37. Lachenmayr BJ, Airaksinen P], Drance SM, et al. Correla tion of retinal nerve fiber-layer loss, changes at the optic nerve head and various psychophysical criteria in glaucoma. Graefes Arch Clin Exp Ophthalmol 1991;229:133-138. 38. Airaksinen P], Tuulonen A, Valimaki ], et al. Retinal nerve fiber-layer abnormalities and high-pass resolution perimetry. Acta Ophthalmol (Copenh) 1990;68:687-689. 39. Brigatti L, Caprioli J. Correlation of visual field with scan ning confocal laser optic disc measurements in glaucoma. Arch Ophthalmol 1995;113:1191-1194. 40. Nicolela MT, Drance SM. Various glaucomatous optic nerve appearances: clinical correlations. Ophthalmology 1996;103: 640-649 41. Levene RZ. Low-tension glaucoma: a critical review and new material. Surv Ophthalmol 1980;24:621-664. 42. Caprioli ], Spaeth GL. Comparison of the optic nerve head in high- and low-tension glaucoma. Arch Ophthalmol 1985; 75:291-302. 43. Caprioli J, Spaeth GL. Comparison of visual field defects in the low-tension glaucomas with those in the high-tension glaucomas. Am J Ophthalmol 1984;97:730-737. 44. Dreher AW, Tso PC, Weinreb RN. Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser topographic scanner. Am J Ophthalmol 1991;111:221-229. 45. Chauhan BC, LeBlanc RI, McCormick TA, Rogers JB. Test-retest variability of topographic measurements with confocal scanning laser tomography in patients with glauco ma and control subjects. Am J Ophthalmol 1994;118:9-15. 46. Zangwill L, Shakiba S, Caprioli J, Weinreb RN. Agreement between clinicians and a confocal scanning laser ophthalmo scope in estimating cup/disk ratios. Am ] Ophthalmol 1995;119:415-421.
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47. Cioffi GA, Robin AL, Eastman RD, Perell HF, Sarfarazi FA, Kelman SE. Confocal laser scanning ophthalmoscope: the reproducibility of optic nerve head topographic measure ments with the confocal laser scanning ophthalmoscope. Ophthalmology 1993;100:57-62. 48. Uchida H, Brigatti L, Caprioli ]. Detection of structural damage from glaucoma with confocal laser image analysis. Invest Ophthalmol Vis Sci 1996;37:2393-2401. 49. Weinreb RN, Dreher AW, Coleman A, Quigley H, Shaw B, Reiter K. Histopathologic validation of Fourier-ellipsometry measurements of retinal nerve fiber-layer thickness. Arch Ophthalmol 1990;108:557-560. 50. Weinreb RN, Shakiba S. Scanning laser polarimetry to measure the nerve fiber layer of normal and glaucomatous eyes. Am ] Ophthalmol 1995;119:627-636. 51. Weinreb R, Shakiba S, Sample P, et al. Association between quantitative nerve fiber-layer measurement and visual field loss in glaucoma. Am ] Ophthlamol 1995;120:732-738. 52. Tjon-Fo-Sang M], De Vries ], Lemij HG. Measurement by nerve fiber analyzer of retinal nerve fiber-layer thickness in normal subjects and patients with ocular hypertension. Am ] Ophthalmol 1996;122:220-227. 53. Niessen AG, Van Den Berg TJ, Langerhorst CT, Greve EL. Retinal nerve fiber-layer assessment by scanning laser polar imetry and standardized photography. Am ] Ophthalmol 1996;121:484-493. 54. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995; 113:325-332. 55. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178-1181. 56. Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Repro ducibility of nerve fiber layer-thickness measurements using optical coherence tomography. Ophthalmology 1996;103: 1889-1898. 57. Schuman JS, Hee MR, Puliafito CA, et al. Quantification of nerve fiber layer-thickness in normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol 1995;113:586-596.
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER 1997
T
HE DETECTION OF STRUCTURAL DAMAGE TO
the optic nerve head is central to the diagnosis of chronic glaucoma. Although characteristic optic nerve cupping, visual field loss, and increased intraocular pressure constitute a classic triad of findings, glaucomatous damage can be diagnosed in the absence of increased pressure or visual loss. Careful evaluation of the optic nerve head can usually identify early glaucomatous damage before automated static threshold perimetry demonstrates visual field defects. Increased cupping of the optic nerve head is a manifestation of retinal ganglion cell death and loss of ganglion cell axons from the optic nerve. This damage can also be recognized by careful examina tion of the retinal nerve fiber layer.1 Articles by Anton and associates2 and Eid and associates3 and, in this issue of THE JOURNAL, by Jonas and Griindler,4 reinforce three important concepts with respect to optic nerve head evaluation. First, careful assessment of the optic nerve head is often the most sensitive way to diagnose and monitor damage in the early stages of glaucoma. Second, careful spatial correlation between structural and functional damage can strengthen an otherwise uncertain diagnosis of early damage. Third, the recognition of patterns of optic nerve head damage and associated visual field loss can help identify subtypes of primary open-angle glaucoma.
Accepted for publication May 19, 1997. From the UCLA School of Medicine, Jules Stein Eye Institute, Los Angeles, California. Reprint requests to Joseph Caprioli, MD, UCLA School of Medicine, Jules Stein Eye Institute, 100 Stein Plaza, Box 957004, Los Angeles, CA 90095-7004; fax: (310) 206-7773; e-mail: [email protected]
516
The susceptibility to optic nerve damage from glaucoma varies greatly among individuals. One sixth to one half of all patients with glaucoma have an initial intraocular pressure reading of less than 21 mm Hg,5,6 whereas one tenth or less of those with elevated intraocular pressure have visual field loss from glauco ma.7,8 Measurements of intraocular pressure cannot See also pp. 455-472, 488-497, and 506-515.
be used to predict reliably which patients will suffer damage from glaucoma. Automated static threshold perimetry has provided sensitivity, standardization, and objectivity not otherwise routinely available in clinical practice, but the degree of fluctuation from test to test often confounds meaningful interpreta tion. It is not unusual for an individual test location in a depressed area of the visual field to fluctuate by 20 dB or more with repeated testing, even in highly reliable subjects.9,10 Corroboration of potentially sig nificant visual field changes with optic nerve appear ance is frequently the only way to differentiate pro gression from random fluctuation. Ample data support the concept that detectable structural damage to the optic nerve can be identified before measurable alterations in differential light sensitivity are found. The Collaborative Glaucoma Study found that a larger baseline cuprdisk ratio was significantly related to the subsequent development of visual field loss.11 Careful study of serial stereophotographs showed that progressive changes in optic nerve head structure were apparent in 10 of 12 eyes before the onset of glaucomatous visual field loss.12 Progres sive cupping generally preceded field loss in the
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER 1997
observations by Read and Spaeth of disk and field correlations in 460 glaucomatous eyes.13 A retrospec tive longitudinal study showed that disk cupping generally preceded visual field loss and that serial disk photographs were necessary for the earliest detection of optic nerve damage in ocular hypertension.14 In a prospective 5-year study of ocular hyperten sives, Odberg and Riise15 reported an increase in disk cupping in 19 of 46 eyes that maintained normal visual fields, whereas only one eye showed a field abnormality in the absence of discernible disk altera tion. Other studies have documented optic nerve abnormalities and defects of the retinal nerve fiber layer well in advance of the detection of visual field defects.16,17 An important caveat is that patients with small optic disks may demonstrate field loss before detectable cupping. In these patients, retinal nerve fibers crowd the optic nerve head so that significant loss of fibers can occur in the absence of recognizable cupping. Histologic examinations were used by Quigley and associates18 to estimate the number of nerve fibers in five optic nerves of normal subjects and in three optic nerves of glaucoma suspects with normal visual fields tested with the Goldmann perimeter. The mean number of axons in the normal control group was 964,000, with a 95% confidence interval of 827,000 to 1,100,000. The corresponding estimates of axon numbers for the three glaucoma suspects were 848,000, 808,000, and 577,000. Two of the latter estimates were smaller than the lower confidence boundary, and one value was only 60% of the normal average. This last case has been frequently and widely cited to suggest that as many as 40% of optic nerve fibers can be lost from a glaucomatous eye without a visual field abnormality. It is now generally appreciated that the develop ment of a reproducible glaucomatous visual field defect is characteristic of a patient with advanced, not early, disease. A published study19 provided evidence that the relative rate of measurable disk damage to field damage in glaucoma is quite high in early disease and decreases as the disease progresses, and conclud ed that careful evaluation of the optic nerve head and nerve fiber layer is important to detect early glauco matous damage but that in more advanced disease, perimetry provides a more robust measure of progres sive disease. The study by Jonas and Griindler4 in this VOL.124, No. 4
issue offers strong corroborative evidence. This work demonstrates that, in the early stages of chronic glaucoma, optic nerve head morphology is a more sensitive marker of damage and that in the later stages of disease, after visual field defects have become well established, perimetry is a more sensitive technique with which to monitor additional damage. Recent evidence suggests the preferential loss of larger retinal ganglion cells in early glaucoma;20'22 this observation has launched psychophysical studies to recognize early damage to the magnocellular path ways. Among these are included blue-on-yellow (or short-wavelength) automated perimetry and motiondetection perimetry.23 Early studies suggested that blue-on-yellow perimetry was more sensitive to early damage than white-on-white perimetry was.24 These early findings were subsequently confirmed.25,26 Fur thermore, blue-on-yellow perimetry has been shown to predict which patients are most likely to progress to white-on-white defects. It has also been demonstrated that progression rates are higher27,28 with blue-onyellow than with white-on-white perimetry. If the early work on selective ganglion cell loss holds up under additional scientific investigation and if appro priate psychophysical tests can be developed, then the temporal relation between visible structural damage and detectable functional damage could shift in favor of the functional measurements. Correlation of optic nerve and nerve fiber layer appearance with the location of visual field defects sharpens the physician's evaluation of patients with glaucoma. Clinical wisdom dictates that the absence of expected correlations between disk andfieldshould alert the examiner to diagnostic possibilities other than glaucoma. The anatomy of the nerve fiber layer and its retinotopic projections to the optic nerve head form the basis of the spatial relationships between structure and function in glaucoma. The arcuate arrangement of the axons and the presence of the median retinal raphe were described by the anato mists Michel and Dogiel in the latter part of the nineteenth century.29,30 Vogt31 correctly deduced the arrangement of nerve fibers in the retina when in 1913 he observed the nerve fiber layer ophthalmoscopically with the aid of red-free light. Observations about the correlation of optic nerve head abnormalities with patterns of visual field loss were summarized by Read and Spaeth more than 20
EDITORIAL
517
years ago.13 Examination of disk photographs can provide accurate predictions about the location of visual field defects in patients with glaucoma.32 Optic nerve axon counts in glaucomatous eyes showed that quadrants with the fewest axons correlated with regions of greatest visual field loss.18 Optic nerve damage in glaucomatous specimens, as predicted by clinical observation, was greatest at the superior and inferior poles. Measurements of the optic disk rim area and retinal nerve fiber layer height correlate quantitatively with measurements of visual function in glaucoma.33'36 Retinal nerve fiber layer abnormali ties and optic disk rim area also correlate with other psychophysical tests, such as flicker perimetry37 and high-pass resolution perimetry.38 A quantitative rela tion between the shape of the optic nerve head cup (measured with confocal laser ophthalmoscopy) and the amount of visual field loss has been demon strated.39 The work of Yamagishi and associates2 demonstrates a method of mapping optic nerve abnormalities in relation to visual field defects in glaucomatous patients with localized damage.3 Whereas these spatial correlations have been known for many years, the work provides a model for developing quantitative maps of structural-functional associations that could lead to better ways of substan tiating early localized damage. There has been speculation and debate about the presence of various patterns of visual field loss and optic nerve head appearance in possible subtypes of primary open-angle glaucoma. A recent report40 pre sented evidence for four distinct types of optic nerve head cupping in primary open-angle glaucoma. Per haps there are more. Eid and associates3 used scan ning laser ophthalmoscopy to revisit the debate about patterns of structural damage in normal-pressure primary open-angle glaucoma and higher-pressure primary open-angle glaucoma. For matched degrees of visual field loss, the patients with lower-pressure glaucoma had larger amounts of measurable optic nerve head cupping and greater inferior neuroretinal rim loss than did their counterparts with higherpressure glaucoma. These findings confirm the results of previous, less quantitative studies.41'43 The authors3 also suggest a subtle but entirely appropriate change in terminology for what have previously been termed low-tension glaucoma and high-tension glaucoma. The corresponding terms are low-tension primary 518
open-angle glaucoma and high-tension primary open-angle glaucoma. Although at first glance this may seem to be a trivial point, it emphasizes that these groups of patients exist along a continuum of disease and that neither group represents a pure, single, pathogenic entity. New techniques by which to recognize early struc tural alterations of the optic nerve head and nerve fiber layer have been introduced. Scanning confocal laser ophthalmoscopy exploits the advantages of the confocal principle to acquire tomographic-like image slices of the optic nerve head and nerve fiber layer to develop quantitative structural information. The reproducibility of this approach and its potential advan tages over other techniques have been described.44'47 New measures of optic nerve head shape have been introduced, and they correlate well with visual field loss.39,48 Scanning laser polarimetry makes use of the birefringent properties of the retinal nerve fiber layer. A property of the polarization state of an imaging laser, called retardation, is altered when it doublepasses through the nerve fiber layer. Retardation is pro portional to the thickness of the nerve fiber layer in hemisected monkey eyes49 and appears to correspond to the known architecture of the nerve fiber layer in normal and glaucomatous eyes. The measurements are reproducible and are higher in normal eyes than in glaucomatous eyes.50 These measurements also correlate with visual field loss in patients with glauco ma51 and are reduced in patients with ocular hyper tension compared with normal subjects.52 The infor mation obtained with this technique may be additive to that of ordinary nerve fiber layer photography.53 Nerve fiber layer thickness can also be measured with a new technique called optical coherence to mography, which uses light of low coherence to provide cross-sectional images of ocular tissues.54,55 The technique is analogous to axial mode ultrasound measurements. It appears to be reproducible56 and has been used to measure the nerve fiber layer thickness in normal and glaucomatous eyes.57 In a recent study, measurements of nerve fiber layer thickness were more diagnostic of field loss than were measurements of optic nerve head cupping or optic disk rim area.57 The importance of recognizing structural damage to the optic nerve head and nerve fiber layer in glaucoma cannot be overemphasized. Technologic developments may improve our ability to recognize
AMERICAN JOURNAL OF OPHTHALMOLOGY
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the very earliest evidence of damage, but widespread use should be preceded by further study. In the meantime, detailed evaluations of the optic nerve head and nerve fiber layer, preferably with the help of careful photography, will facilitate an early diagnosis of damage. Such an informed evaluation will alert the physician to the need for appropriate treatment of those patients with glaucomatous optic nerve damage. It may also help spare those who have no damage and those who are at little risk for damage the consider able morbidity of treatment.
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