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Preservation of Nerve Fiber Layer by Retinal Vessels in Glaucoma
Preservation of Nerve Fiber Layer by Retinal Vessels in Glaucoma Etsuo Chihara, MD, Yoshihito Honda, MD
T
he authors evaluated the correlation between various parameters and the local preservation of the retinal nerve fiber layer in 156 glaucomatous eyes. A vesselassociated preservation of the nerve fiber layer was observed in 45 of the 156 glaucomatous eyes. The presence of "straight" retinal vessels (either arterioles or large venules) and "tortuous" retinal vessels (large or small venules) inside of the scleral ring was correlated with the local preservation of the nerve fiber layer (P < 0.001 and P < 0.05, respectively). A local elevation of the floor of the cup was also correlated with the preservation of the nerve fiber layer (P < 0.01). However, no correlation existed between either the preservation of the nerve fiber layer and the type of glaucoma, sex or age of patient, tilting of the disc, cilioretinal vessel, vertical cup-to-disc ratiO, refractive error, disc size, distance between the disc and foveola, or the index of oval ness of the disc. These results suggest that retinal vessels in the disc Significantly influence the vulnerability of the nerve fibers to glaucomatous damage. Ophthalmology 1992; 99:208-214
The nerve fiber defect around the disc of glaucomatous eyes is not uniform but varies from patient to patient. In glaucomatous eyes, the nerve fiber layer at the superior and inferior poles of the disc is usually affected. Some explanations have been offered for this pattern of nerve damage. l -4 However, an early glaucomatous defect may not be confined to the superior or inferior poles of the disc. Furthermore, there may be other factors that could modify the local susceptibility of the nerve fiber layer to damage. By examination of many glaucomatous eyes, it is common to find that the nerve fiber layer shows a lesser Originally received: June 24, 1991. Revision accepted: September 3, 1991. From the Department of Ophthalmology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. Presented as a poster at the Association for Research in Vision and Ophthalmology Annual Meeting, Sarasota, April/May 1991. Supported by Grant-in-aid B02454403 for Scientific Research from the Ministry of Education, Science and Culture of Japan. The authors have no proprietary interest in the products or devices used in conducting this research. Reprint requests to Etsuo Chihara, MD, Department of Ophthalmology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan.
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or greater degree of damage in local areas. The optic discs are variable in shape. Thus, an uneven"distribution of the connective tissue, intercellular matrix, or vessels in the disc may either increase or decrease the local vulnerability of the nerve fiber layer to damage in specific areas of the disc. We had the clinical impression that the glaucomatous nerve fiber layer defects were frequently demarcated by retinal vessels. In some cases, the retinal nerve fiber layer or visual field was preserved in association with retinal vessels in the midst of a large defective area. This localized preservation of the nerve fiber layer may be associated with the presence of retinal vessels inside the scleral ring. In this study, we evaluated the correlation between the intrapapillary retinal vessels and the preservation of nerve fibers in glaucomatous eyes.
Materials and Methods In a prospective study, we examined 1 eye in each of 156 patients with glaucoma versus 122 control subjects. All patients were Asians who presented consecutively at the Glaucoma Service of the Department of Ophthalmology
Chihara and Honda . Preservation of Nerve Fiber Layer at the Medical School of Kyoto University. Of the glaucoma patients, 64 had normal-tension glaucoma and 92 had chronic high-tension glaucoma. The control subjects were healthy individuals who visited the department for routine ocular examination. Informed consent was obtained from each individual before examination of an eye. The left and right eyes were randomly selected for examination. All the glaucoma patients included in the study had clear media, retinal nerve fiber layer defects exceeding 30° in width, and a mean defect ofless than 17.5 decibels after a complete correction of the refractive error. The diagnosis of glaucoma was based on the following: an open angle, glaucomatous visual field defect, glaucomatous cupping ofthe optic disc, and no other possible cause for the nerve fiber loss such as trauma, diabetes mellitus, neuro-ophthalmologic disease, pigment dispersion, or congenital anomaly. An arcuate scotoma and nasal step were considered as glaucomatous field defects. Undermining of the cup, visualization of the laminar dots and diffuse or localized loss of the neural rim were considered as possible signs of glaucoma. Glaucomatous eyes with normal pressure (untreated pressure less than 22 mmHg) for at least 2 years were diagnosed with normal-tension glaucoma. Conversely, those eyes with a recorded high pressure (~26 mmHg) on 2 occasions during 1 month of follow-up were diagnosed with high-tension glaucoma. Optic disc parameters were measured and defined as follows: the optic disc area was measured by tracing the inner margin of the scleral ring with a computerized planimeter (Tamaya, Tokyo). An index of ovalness5 was defined as the ratio of the long to short optic disc axis. The distance between the disc and foveola was measured between the inner margin of the disc to the foveola. A tilted disc was defined as that showing a discrete difference between the nasal and temporal slope; with only the nasal slope of the cup being invisible beyond the protruding nerve tissue and contrasted visible temporal slope. Any intermediate cases were examined by a stereoscopic viewer (Stereo Viewer II, Asahi Kogaku, Tokyo). The configuration and local elevation of the bottom of the cup was examined by a stereoscopic viewer and a computerized disc analyzer (Imagenet, Topcon, Tokyo) as described previously.6 A localized elevation of the floor was defined as a tentorial elevation of the nerve tissue from the bottom or slope of the cup. This elevation had to be associated with the retinal vessels. Elevations of the floor that were not associated with the intrapapillary retinal vessels (e.g., the elevation of the floor at the area of the papillomacular bundle) were excluded from this evaluation. The long and short axes of the disc and cup were measured on a O.Ol-mm scale by a slide caliper (Digimatic Caliper 500, Mitutoyo, Tokyo). The cup-to-disc ratio was the ratio of the diameter of the long axis of the cup to that of the disc (the inside of the scleral ring). The axial length and corneal curvature were measured and the magnification of the measured values was corrected with Littmann's procedure. 7 The intrapapillary retinal vessels were defined as those found inside of the scleral ring and their diameter (measured by the above mentioned caliper and corrected for
magnification) was greater than 75 ~m. Those were classified as arterioles, venules, and cilioretinal vessels. The latter were not connected with the retinal vessels on a stereoscopic examination. The intrapapillary retinal arterioles or venules were categorized as being "straight," "tortuous," or "free." A "straight" vessel ran straight from the bottom of the cup to the neural rim or disc margin, and was independent of the localized depression and elevation on the surface of the cup. A "tortuous" vessel was tortuous or curved, and followed the undulation of the surface of the cup. A free vessel was separated from the surrounding nerve tissue and formed a vascular tree in the vitreous (cup). These intrapapillary retinal vessels were rated independently by two physicians using a stereoscopic viewer. Defects in the retinal nerve fiber layer were photographed on black and white film (ISO 100, Neopan SS, Fuji Film Co, Tokyo) under a red free light. As the green filter, we used the Wratan 58 (Kodak, Rochester, NY). Photographs were magnified fivefold. The optic disc was covered with black paper and the nerve fiber layer defect was assessed in a masked fashion. The preserved retinal nerve fiber layer was defined as follows: when striae of the nerve fiber layer were focally apparent in an area of diffuse and/or a large defect (an agreement was obtained between the two physicians) and retinal sensitivity in the preserved area exceeded that of the surrounding area by 5 decibels at 2 or more points, this was considered a preserved nerve fiber layer (Figs I and 2). The preserved nerve fiber layer conformed to the course of the arcuate bundle and showed striae where it crossed the small vessels; care was taken not to confuse it with the retinal reflexes which can be bright, discontinuous, nonstriated, and can change both in form and position with the shifting of the ophthalmoscopic beam. 8 The defective area had to be present on both sides of the preserved nerve fiber layer (Figs I and 2).
Statistical Methods Data were analyzed by the chi-square analysis, multivariate analysis-quantification II (available commercially from the Social Survey Research Information Co, Tokyo),9 and by discriminant analysis. 10 A correlation between the preserved nerve fiber layer and such discrete variables as the presence of a cilioretinal vessel, intrapapillary "straight" vessel, intrapapillary "tortuous" vessel, patient gender, type of glaucoma, and tilting of the disc was analyzed by chi-square analysis and by multivariate analysis-quantification II. Using the latter, a correlation between the preservation of the nerve fiber and each of the other parameters was evaluated and it was assumed that no interaction occurred with the other parameters. A similar analysis could be made with the "multiple regression model." The correlation between the preservation of the retinal nerve fiber layer and numerical parameters such as the age of patients, cup-to-disc ratio, refractive error, disc size, distance between the disc and foveola, and ratio of oval-
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Volume 99, Number 1, January 1992
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Figure 1. A, vessel-associated preservation of retinal nerve fiber layer (arrowhead) at temporal half of the disc (51-year-old man, -9.0 D, mean defect; -17.5 dB, normal tension glaucoma). The intrapapillary vessel (black arrowhead) and local elevation of the floor of the cup corresponded with preservation of the nerve fiber layer (white arrowhead and arrow, respectively). The "straight" arteriole and venule (black arrowhead), which corresponded to the inferior nerve fiber layer were 81 !lm and 91 !lm in diameter, respectively. B, fluorescein angiography of the same disc. There are intrapapillary retinal vessels, which corresponded with the preserved nerve fiber layer. A small arteriole (arrowhead) corresponded with local elevation of the floor. C, visual field defect (depression in decibels) by Octopus 500EZ (Interzeag). The retinal sensitivity at the preserved area (within the broken line) was better locally than that in the surrounding areas.
Results Of the 156 glaucomatous eyes examined, 49 showed a locally preserved retinal nerve fiber layer in a defective area. The location of the preserved nerve fiber layer corresponded with that of the intrapapillary retinal vessel in 45 of 49 eyes (Figs 1 and 2), while there was no correspondence in 4 other eyes (Fig 3). The patients' age, ver-
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Figure 2. A. preservation of retinal nerve fiber layer at superotemporal and inferotemporal sectors of the disc (arrowheads) in a 30-year-old man, (-2.0 D, mean defect -12.2 dB, primary open-angle glaucoma). Paired arrows indicate an area of nerve fiber layer defect. B. location of the intrapapillary retinal vessels, which corresponded with the preserved nerve fiber layer as depicted by fluorescein angiography. C. visual field defect (depression in decibels) by Octopus 500EZ (Interzeag). The retinal threshold at the inferonasal area (within the broken line) was better than the threshold at paracentral area or at midperiphery. The preserved nerve fiber layer at superior arcuate fiber (between two arrowheads in Figure 2A) corresponded to the preserved retinal sensitivity. Preservation of the retinal sensitivity at the superonasal visual field was less obvious.
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tical cup-to-disc ratio, refractive error, size of the disc, distance between the disc and foveola, and an index of ovalness in eyes with and without the vessel-associated preservation of the retinal nerve fiber layer of both patient groups are provided in Table 1. The correlation between these numerical parameters and the vessel-associated preservation of the nerve fiber layer was not significant by discriminant analysis (Table I). Sex, type of glaucoma,
tilting of the disc, and presence of a cilioretinal vessel did not correlate with the vessel-associated preservation of the nerve fiber layer (Table 2). A "straight" or "tortuous" vessel was correlated with the preservation of the nerve fiber layer; however, the correlation between the preservation and these vessels was not consistently seen. In 90 of the 156 glaucomatous eyes, "straight" retinal vessel(s) were found in a defective area of the retinal nerve fiber
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Figure 3. An example of nonvessel-associated preservation of retinal nerve fiber layer (arrows) in a diffuse atrophic area (paired arrow heads) (33year-old woman, -3.5 D, mean defect 16.8 dB, primary open-angle glaucoma). Stereoscopic examination of the cup showed that the floor of the cup in the superior half of the optic nerve head was less excavated than that in the inferior half. Small retinal arteriole in the preserved area (41 f.Lm in diameter; black arrowhead) was less than 75 f.Lm in diameter and was not analyzed statistically.
layer; 39 of these 90 eyes (43%) had a preserved retinal nerve fiber layer in the defective area (Fig 1). In contrast, only 6 of 66 (9%) glaucomatous eyes, which did not have a "straight" vessel in a defective area, had a preserved
nerve fiber layer. Thus, a "straight" vessel was linked significantly to the preservation of the nerve fiber layer (P < 0.001, chi-square = 21.75, Table 2). The "straight" vessel included only an arteriole or a large venule, but not a small venule. In 114 of the 156 glaucomatous eyes, "tortuous" intrapapillary retinal vessel(s) were found in a defective area of the retinal nerve fiber layer; 38 of these 114 eyes (33%) had a preserved nerve fiber layer in the defective area. Seven of the 42 eyes (17%), which did not have a "tortuous" vessel in a defective area, had preservation of the nerve fiber layer(P< 0.05, chi-square = 4.15, Table 2). The "tortuous" vessels were either large or small venules. In 19 eyes, the "straight" vessels coexisted with the "tortuous" vessels in a defective sector of the retinal nerve fiber layer. According to the partial correlation coefficient obtained with multivariate analysis-quantification II, a "straight" vessel (P < 0.001) was the parameter that correlated most closely with the preservation of the nerve fiber layer (Table 3). By stereoscopic examination of the cup, a local elevation of the floor corresponded with the preservation of the nerve fiber layer in 19 of the 45 (42%) eyes in which a vessel-associated preservation of the retinal nerve fiber layer was found. Of the 111 eyes that did not have a vesselassociated preservation of the nerve fiber layer, 22 (20%) had a local elevation of the floor of the cup in the defective area without any preservation of the nerve fiber layer. Thus, the local elevation of the floor was also correlated significantly with a preserved nerve fiber layer (P < 0.01, chi-square = 7.85) (Table 2). A correlation between the size of the vessels and preservation of nerve fiber layer was not apparent. Small vessels (caliber less than 100 ~m) may also participate in the preservation of the nerve fiber layer (Fig 1). In another study, a three-dimensional configuration of the cup was studied by a computer-assisted disc analyzer (Imagenet, Topcon, Tokyo). However, the computed optic disc analysis was not sufficiently precise to detect a slight elevation of the nerve tissue at the bottom of the cup.
Table 1. Characteristics of Eyes With (+) and Without (-) the Vessel-associated Preservation of the Retinal Nerve Fiber Layer (NFL) and Control Subjects
Parameter
Preserved NFL (+) (n = 45)
Age Cup-to-disc .ratio Refractive error (D) Disc size (mm2) Distance between disc and foveola (mm) Index of ovalness LDF
=
linear discriminant function; NS
50.6 0.79 -2.54 2.54
± 14.5 ± 0.12 ± 3.62 ± 0.54
=
LDF
F Value·
Control (n = 122)
± 13.5 ± 0.14 ± 3.79 ± 0.77
-0.02 1.61 -0.05 -0.28
1.55 NS 1.06 NS 0.60 NS 0.91 NS
51.3 0.26 -1.55 2.55
3.85 ± 0.40 1.11 ± 0.10
-0.44 0.67
0.70NS 0.10 NS
54.9 0.76 -1.78 2.60
3.79 ± 0.35 1.13 ± 0.10
not Significant by the discriminant analysis.
Mahalanovis generalized distance for the discriminant analysis • F > 5.29 corresponds to statistical Significance by P < 0.05.
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Preserved NFL(-) (n= 111)
=
0.214 .
± 15.4 ± 0.10 ± 1.91 ± 0.59
3.90 ± 0.41 1.10 ± 0.08
Chihara and Honda . Preservation of Nerve Fiber Layer Table 2. Correlation Between Various Parameters and Presence (+) or Absence (-) of the Vessel-associated Preservation of Nerve Fiber Layer (NFL) in 156 Glaucomatous Eyes
Parameter
Preservation of NFL (+) (n = 45)
Preservation ofNFL(-) (n = 111)
Gender Male (n = 76) Female (n = 80)
21/76 (28%) 24/80 (30%)
55/76 (72%) 56/80 (70%)
Type of Glaucoma High-tension glaucoma (n = 92) Normal-tension glaucoma (n = 64)
26/92 (28%) 19/64 (30%)
66/92 (72%) 45/64 (70%)
Tilted disc (+) (n = 23) (-) (n = 133)
4/23 (17%) 41/133 (31%)
19/23 (83%) 92/133 (69%)
Cilioretinal vessel (+) (n = 35) (-) (n = 121)
7/35 (20%) 38/121 (31%)
28/35 (80%) 83/121 (69%)
"Straight" vessel in the defective area (+) (n = 90) (-) (n = 66)
39/90 (43%)* 6/66 (9%)
51/90 (57%) 69/66 (91%)
"Tortuous" vessel in the defective area (+) (n = 114) (-) (n = 42)
38/114 (33%)t 7/42 (17%)
76/114 (67%) 35/42 (83%)
Local elevation of the floor (+) (n = 41) (-) (n = 115)
19/41 (46%)'1' 26/115 (23%)
22/41 (54%) 89/115 (77%)
• P < 0.001 by chi-square analysis.
t
P < 0.05, by chi-square analysis.
t P < 0.01, by chi-square analysis. Discussion
Levene ll reported a case in which the midtemporal area of the cup was preserved by a horizontally traversing retinal arteriole. The preservation of the cup in the midtemporal area and the local preservation of nerve fiber layer Table 3. Correlation between Vessel-associated Preservation of Nerve Fiber Layer and Other Parameters Studied by Partial Correlation Coefficient (Multivariate Analysis Quantification II) Parameter Gender Type of glaucoma Tilting of disc Cilioretinal vessel "Straight" vessel "Tortuous" vessel * P < 0.001.
Partial Correlation Coefficient
0.1246 0.0447 0.1806 0.1904 0.3603* 0.0254
in this study might be different in nature. The midtemporal area ofthe disc contained thicker connective tissue4 and a smaller pore size than that found in other quadrants. 12 As backward bowing of the lamina is suspected as an important trigger for nerve damage, 13,14 a resistance to the backward bowing at the midtemporal area may be correlated with the preservation of the papillomacular bundle in glaucoma. The local preservation of the nerve tissue in this study was associated with intrapapillary retinal vessels, which may be found at the superior temporal and inferior temporal sectors of the disc (Fig 2) and was different from the preservation of the papillomacular bundle. In some cases, superimposition of the intrapapillary retinal vessels on the basic elevation at the midtemporal sector may lead to a clearer preservation of nerve fibers at this place (Fig 1). There are some possible explanations for the correlation between the local preservation of the nerve fibers and the intrapapillary retinal vessels: (1) Rigidity of the vascular wall. Retinal vessels in the disc bridge a localized depression extending from the bottom of the cup to the neuroretinal rim; the underlying nerve tissue appears to be elevated by the vessels. When the nerve tissue is lifted
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by the vessels, the distortion of the lamina cribrosa may be relieved. Since the rigidity of the arteriolar wall exceeds that of the venule, this explanation is supported by the finding that "straight" vessels are more closely correlated with nerve tissue preservation than are "tortuous" vessels. (2) There may be a participation by the dense glial tissue or extracellular matrix surrounding the vessel. l5 ,16 Glial tissue or extracellular matrix richly surround the vessels and may prevent distortion of laminar tissue by the intraocular pressure. Alternatively they may provide a bed for the capillary network, and may participate in high oxygen tension at the place. The vessel size may not be a factor, because small vessels may have a large amount of glial tissue or extracellular matrix. (3) The preservation of nerve tissue might be primary, and might lead to secondary preservation of vessels in a defined region. If the vessels were preserved secondary to any preservation of nerve tissue, there should be no preference for "straight" vessels to be present in the preserved area. However, we did not make such an observation. (4) A high level of oxyhemoglobin in the arterioles may be another factor. In this study, the cilioretinal vessels did not correlate with any preservation of the nerve fiber layer. This result confirms another report that the cilioretinal artery, which has a high content of oxyhemoglobin, had no association with atypical visual field defect. I? The arterioles do not supply oxygen directly to the adjacent tissues. However, the results of oxygen mapping of the optic disc showed that there are areas next to the arteriole or choroid which had a high oxygen tension (Pournaras, unpublished data, presented at the ARVO Annual Meeting, 1991). These areas may be associated with nerve fiber preservation. Further studies will be required to elucidate the relationship between the local preservation of the nerve fiber layer and oxygen tension in the optic nerve head. There are some factors such as tilting,18 size of the disc,19 and diabetes mellitus20 that may also modify the pattern of nerve fiber loss in glaucoma. The results of our study suggest that, in the presence of intrapapillary vessels, there is less glaucoma-associated damage, which could help to explain variable nerve fiber loss in glaucoma.
References 1. Hayreh SS. Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. Br J Opthalmol 1969; 53:721-48. 2. Goldmann H, Block P. On the possibility to connect quantitatively ocular hypertension and damage to the optic nerve. Albrecht von Graefes Arch Klin Exp Ophthalmol 1971; 183: 232-43.
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3. Maumenee AE. Causes of optic nerve damage in glaucoma. . Robert N. Shaffer Lecture. Ophthalmology 1983; 90:74152. 4. Quigley HA, Addicks EM. Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol 1981; 99: 137-43. 5. Tomlinson A, Phillips CI. Ovalness of the optic cup and disc in the normal eye. Br J Ophthalmol 1974; 58:543-7. 6. Chihara E, Honda Y. Topographic changes in the optic disc in eyes with cotton-wool spots and primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 1991; 229: 13-18. 7. Littmann H. Zur Bestimmung der wahren Gro/3e eines Objektes auf dem Hintergrund eines lebenden Auges. Klin Monatsbl Augenheilkd 1988; 192:66-7. 8. Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol 1973; 12:814-29. 9. Hayashi C. On the quantification of qualitative data from the mathematico-statistical point of view. Ann Inst Statist Math 1950; 2:35-47. 10. Jennrich RI. Stepwise discriminant analysis. In: Enstein K, Ralston A, Wilf HS, eds. Statistical Methods for Digital Computers. New York: John Wiley, 1977; chap 4,5. 11. Levene RZ. Unusual optic discs in primary open-angle glaucoma. Ann Ophthalmol 1982; 14:617-20. 12. Ogden TE, Duggan J, Danley K, et al. Morphometry of nerve fiber bundle pores in the optic nerve head of the human. Exp Eye Res 1988; 46:559-68. 13. Levy NS, Crapps EE, Bonney RC. Displacement of the optic nerve head. Response to acute intraocular pressure elevation in primate eyes. Arch Ophthalmol1981; 99:2166-74. 14. Quigley HA, Hohman RM, Addicks EM, et al. Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 1983; 95:67391. 15. Hernandez MR, Igoe F, Neufeld AH. Extracellular matrix of the human optic nerve head. Am J Ophthalmol 1986; 102: 139-48. 16. Morrison JC, L'Hernault NL, Jerdan JA, Quigley HA. Ultrastructurallocation of extracellular matrix components in the optic nerve head. Arch Ophthalmol 1989; 107:123-9. 17. Lindenmuth KA, Skuta GL, Musch DC, Bueche M. Significance of cilioretinal arteries in primary open angle glaucoma. Arch Ophthalmol 1988; 106:1691-3. 18. Chihara E, Sawada A. Atypical nerve fiber layer defects in high myopes with high-tension glaucoma. Arch Ophthalmol 1990; 108:228-32. 19. Chihara E, Honda Y. Multiple retinal nerve fiber layer de,fects in glaucoma. Graefes Arch Clin Exp Ophthalmol [In Press]. 20. Zeiter JH, Shin DH, Baek NH. Visual field defects in diabetic patients with primary open-angle glaucoma. Am J Ophthalmol 1991; 111:581-4.
T
he authors evaluated the correlation between various parameters and the local preservation of the retinal nerve fiber layer in 156 glaucomatous eyes. A vesselassociated preservation of the nerve fiber layer was observed in 45 of the 156 glaucomatous eyes. The presence of "straight" retinal vessels (either arterioles or large venules) and "tortuous" retinal vessels (large or small venules) inside of the scleral ring was correlated with the local preservation of the nerve fiber layer (P < 0.001 and P < 0.05, respectively). A local elevation of the floor of the cup was also correlated with the preservation of the nerve fiber layer (P < 0.01). However, no correlation existed between either the preservation of the nerve fiber layer and the type of glaucoma, sex or age of patient, tilting of the disc, cilioretinal vessel, vertical cup-to-disc ratiO, refractive error, disc size, distance between the disc and foveola, or the index of oval ness of the disc. These results suggest that retinal vessels in the disc Significantly influence the vulnerability of the nerve fibers to glaucomatous damage. Ophthalmology 1992; 99:208-214
The nerve fiber defect around the disc of glaucomatous eyes is not uniform but varies from patient to patient. In glaucomatous eyes, the nerve fiber layer at the superior and inferior poles of the disc is usually affected. Some explanations have been offered for this pattern of nerve damage. l -4 However, an early glaucomatous defect may not be confined to the superior or inferior poles of the disc. Furthermore, there may be other factors that could modify the local susceptibility of the nerve fiber layer to damage. By examination of many glaucomatous eyes, it is common to find that the nerve fiber layer shows a lesser Originally received: June 24, 1991. Revision accepted: September 3, 1991. From the Department of Ophthalmology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. Presented as a poster at the Association for Research in Vision and Ophthalmology Annual Meeting, Sarasota, April/May 1991. Supported by Grant-in-aid B02454403 for Scientific Research from the Ministry of Education, Science and Culture of Japan. The authors have no proprietary interest in the products or devices used in conducting this research. Reprint requests to Etsuo Chihara, MD, Department of Ophthalmology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan.
208
or greater degree of damage in local areas. The optic discs are variable in shape. Thus, an uneven"distribution of the connective tissue, intercellular matrix, or vessels in the disc may either increase or decrease the local vulnerability of the nerve fiber layer to damage in specific areas of the disc. We had the clinical impression that the glaucomatous nerve fiber layer defects were frequently demarcated by retinal vessels. In some cases, the retinal nerve fiber layer or visual field was preserved in association with retinal vessels in the midst of a large defective area. This localized preservation of the nerve fiber layer may be associated with the presence of retinal vessels inside the scleral ring. In this study, we evaluated the correlation between the intrapapillary retinal vessels and the preservation of nerve fibers in glaucomatous eyes.
Materials and Methods In a prospective study, we examined 1 eye in each of 156 patients with glaucoma versus 122 control subjects. All patients were Asians who presented consecutively at the Glaucoma Service of the Department of Ophthalmology
Chihara and Honda . Preservation of Nerve Fiber Layer at the Medical School of Kyoto University. Of the glaucoma patients, 64 had normal-tension glaucoma and 92 had chronic high-tension glaucoma. The control subjects were healthy individuals who visited the department for routine ocular examination. Informed consent was obtained from each individual before examination of an eye. The left and right eyes were randomly selected for examination. All the glaucoma patients included in the study had clear media, retinal nerve fiber layer defects exceeding 30° in width, and a mean defect ofless than 17.5 decibels after a complete correction of the refractive error. The diagnosis of glaucoma was based on the following: an open angle, glaucomatous visual field defect, glaucomatous cupping ofthe optic disc, and no other possible cause for the nerve fiber loss such as trauma, diabetes mellitus, neuro-ophthalmologic disease, pigment dispersion, or congenital anomaly. An arcuate scotoma and nasal step were considered as glaucomatous field defects. Undermining of the cup, visualization of the laminar dots and diffuse or localized loss of the neural rim were considered as possible signs of glaucoma. Glaucomatous eyes with normal pressure (untreated pressure less than 22 mmHg) for at least 2 years were diagnosed with normal-tension glaucoma. Conversely, those eyes with a recorded high pressure (~26 mmHg) on 2 occasions during 1 month of follow-up were diagnosed with high-tension glaucoma. Optic disc parameters were measured and defined as follows: the optic disc area was measured by tracing the inner margin of the scleral ring with a computerized planimeter (Tamaya, Tokyo). An index of ovalness5 was defined as the ratio of the long to short optic disc axis. The distance between the disc and foveola was measured between the inner margin of the disc to the foveola. A tilted disc was defined as that showing a discrete difference between the nasal and temporal slope; with only the nasal slope of the cup being invisible beyond the protruding nerve tissue and contrasted visible temporal slope. Any intermediate cases were examined by a stereoscopic viewer (Stereo Viewer II, Asahi Kogaku, Tokyo). The configuration and local elevation of the bottom of the cup was examined by a stereoscopic viewer and a computerized disc analyzer (Imagenet, Topcon, Tokyo) as described previously.6 A localized elevation of the floor was defined as a tentorial elevation of the nerve tissue from the bottom or slope of the cup. This elevation had to be associated with the retinal vessels. Elevations of the floor that were not associated with the intrapapillary retinal vessels (e.g., the elevation of the floor at the area of the papillomacular bundle) were excluded from this evaluation. The long and short axes of the disc and cup were measured on a O.Ol-mm scale by a slide caliper (Digimatic Caliper 500, Mitutoyo, Tokyo). The cup-to-disc ratio was the ratio of the diameter of the long axis of the cup to that of the disc (the inside of the scleral ring). The axial length and corneal curvature were measured and the magnification of the measured values was corrected with Littmann's procedure. 7 The intrapapillary retinal vessels were defined as those found inside of the scleral ring and their diameter (measured by the above mentioned caliper and corrected for
magnification) was greater than 75 ~m. Those were classified as arterioles, venules, and cilioretinal vessels. The latter were not connected with the retinal vessels on a stereoscopic examination. The intrapapillary retinal arterioles or venules were categorized as being "straight," "tortuous," or "free." A "straight" vessel ran straight from the bottom of the cup to the neural rim or disc margin, and was independent of the localized depression and elevation on the surface of the cup. A "tortuous" vessel was tortuous or curved, and followed the undulation of the surface of the cup. A free vessel was separated from the surrounding nerve tissue and formed a vascular tree in the vitreous (cup). These intrapapillary retinal vessels were rated independently by two physicians using a stereoscopic viewer. Defects in the retinal nerve fiber layer were photographed on black and white film (ISO 100, Neopan SS, Fuji Film Co, Tokyo) under a red free light. As the green filter, we used the Wratan 58 (Kodak, Rochester, NY). Photographs were magnified fivefold. The optic disc was covered with black paper and the nerve fiber layer defect was assessed in a masked fashion. The preserved retinal nerve fiber layer was defined as follows: when striae of the nerve fiber layer were focally apparent in an area of diffuse and/or a large defect (an agreement was obtained between the two physicians) and retinal sensitivity in the preserved area exceeded that of the surrounding area by 5 decibels at 2 or more points, this was considered a preserved nerve fiber layer (Figs I and 2). The preserved nerve fiber layer conformed to the course of the arcuate bundle and showed striae where it crossed the small vessels; care was taken not to confuse it with the retinal reflexes which can be bright, discontinuous, nonstriated, and can change both in form and position with the shifting of the ophthalmoscopic beam. 8 The defective area had to be present on both sides of the preserved nerve fiber layer (Figs I and 2).
Statistical Methods Data were analyzed by the chi-square analysis, multivariate analysis-quantification II (available commercially from the Social Survey Research Information Co, Tokyo),9 and by discriminant analysis. 10 A correlation between the preserved nerve fiber layer and such discrete variables as the presence of a cilioretinal vessel, intrapapillary "straight" vessel, intrapapillary "tortuous" vessel, patient gender, type of glaucoma, and tilting of the disc was analyzed by chi-square analysis and by multivariate analysis-quantification II. Using the latter, a correlation between the preservation of the nerve fiber and each of the other parameters was evaluated and it was assumed that no interaction occurred with the other parameters. A similar analysis could be made with the "multiple regression model." The correlation between the preservation of the retinal nerve fiber layer and numerical parameters such as the age of patients, cup-to-disc ratio, refractive error, disc size, distance between the disc and foveola, and ratio of oval-
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Volume 99, Number 1, January 1992
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ness was analyzed with discriminant analysis. The SQuare ofthe Mahalanovis' generalized distance indicated a statistical distance between two groups (eyes with preservation [+] and without preservation [-]), and an index to determine whether the parameters selected were adequate for study. The significance of the correlation was determined by the F-value. A level of P < 0.05 was accepted as statistically significant.
210
Figure 1. A, vessel-associated preservation of retinal nerve fiber layer (arrowhead) at temporal half of the disc (51-year-old man, -9.0 D, mean defect; -17.5 dB, normal tension glaucoma). The intrapapillary vessel (black arrowhead) and local elevation of the floor of the cup corresponded with preservation of the nerve fiber layer (white arrowhead and arrow, respectively). The "straight" arteriole and venule (black arrowhead), which corresponded to the inferior nerve fiber layer were 81 !lm and 91 !lm in diameter, respectively. B, fluorescein angiography of the same disc. There are intrapapillary retinal vessels, which corresponded with the preserved nerve fiber layer. A small arteriole (arrowhead) corresponded with local elevation of the floor. C, visual field defect (depression in decibels) by Octopus 500EZ (Interzeag). The retinal sensitivity at the preserved area (within the broken line) was better locally than that in the surrounding areas.
Results Of the 156 glaucomatous eyes examined, 49 showed a locally preserved retinal nerve fiber layer in a defective area. The location of the preserved nerve fiber layer corresponded with that of the intrapapillary retinal vessel in 45 of 49 eyes (Figs 1 and 2), while there was no correspondence in 4 other eyes (Fig 3). The patients' age, ver-
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Figure 2. A. preservation of retinal nerve fiber layer at superotemporal and inferotemporal sectors of the disc (arrowheads) in a 30-year-old man, (-2.0 D, mean defect -12.2 dB, primary open-angle glaucoma). Paired arrows indicate an area of nerve fiber layer defect. B. location of the intrapapillary retinal vessels, which corresponded with the preserved nerve fiber layer as depicted by fluorescein angiography. C. visual field defect (depression in decibels) by Octopus 500EZ (Interzeag). The retinal threshold at the inferonasal area (within the broken line) was better than the threshold at paracentral area or at midperiphery. The preserved nerve fiber layer at superior arcuate fiber (between two arrowheads in Figure 2A) corresponded to the preserved retinal sensitivity. Preservation of the retinal sensitivity at the superonasal visual field was less obvious.
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tical cup-to-disc ratio, refractive error, size of the disc, distance between the disc and foveola, and an index of ovalness in eyes with and without the vessel-associated preservation of the retinal nerve fiber layer of both patient groups are provided in Table 1. The correlation between these numerical parameters and the vessel-associated preservation of the nerve fiber layer was not significant by discriminant analysis (Table I). Sex, type of glaucoma,
tilting of the disc, and presence of a cilioretinal vessel did not correlate with the vessel-associated preservation of the nerve fiber layer (Table 2). A "straight" or "tortuous" vessel was correlated with the preservation of the nerve fiber layer; however, the correlation between the preservation and these vessels was not consistently seen. In 90 of the 156 glaucomatous eyes, "straight" retinal vessel(s) were found in a defective area of the retinal nerve fiber
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Volume 99, Number 2, February 1992
Figure 3. An example of nonvessel-associated preservation of retinal nerve fiber layer (arrows) in a diffuse atrophic area (paired arrow heads) (33year-old woman, -3.5 D, mean defect 16.8 dB, primary open-angle glaucoma). Stereoscopic examination of the cup showed that the floor of the cup in the superior half of the optic nerve head was less excavated than that in the inferior half. Small retinal arteriole in the preserved area (41 f.Lm in diameter; black arrowhead) was less than 75 f.Lm in diameter and was not analyzed statistically.
layer; 39 of these 90 eyes (43%) had a preserved retinal nerve fiber layer in the defective area (Fig 1). In contrast, only 6 of 66 (9%) glaucomatous eyes, which did not have a "straight" vessel in a defective area, had a preserved
nerve fiber layer. Thus, a "straight" vessel was linked significantly to the preservation of the nerve fiber layer (P < 0.001, chi-square = 21.75, Table 2). The "straight" vessel included only an arteriole or a large venule, but not a small venule. In 114 of the 156 glaucomatous eyes, "tortuous" intrapapillary retinal vessel(s) were found in a defective area of the retinal nerve fiber layer; 38 of these 114 eyes (33%) had a preserved nerve fiber layer in the defective area. Seven of the 42 eyes (17%), which did not have a "tortuous" vessel in a defective area, had preservation of the nerve fiber layer(P< 0.05, chi-square = 4.15, Table 2). The "tortuous" vessels were either large or small venules. In 19 eyes, the "straight" vessels coexisted with the "tortuous" vessels in a defective sector of the retinal nerve fiber layer. According to the partial correlation coefficient obtained with multivariate analysis-quantification II, a "straight" vessel (P < 0.001) was the parameter that correlated most closely with the preservation of the nerve fiber layer (Table 3). By stereoscopic examination of the cup, a local elevation of the floor corresponded with the preservation of the nerve fiber layer in 19 of the 45 (42%) eyes in which a vessel-associated preservation of the retinal nerve fiber layer was found. Of the 111 eyes that did not have a vesselassociated preservation of the nerve fiber layer, 22 (20%) had a local elevation of the floor of the cup in the defective area without any preservation of the nerve fiber layer. Thus, the local elevation of the floor was also correlated significantly with a preserved nerve fiber layer (P < 0.01, chi-square = 7.85) (Table 2). A correlation between the size of the vessels and preservation of nerve fiber layer was not apparent. Small vessels (caliber less than 100 ~m) may also participate in the preservation of the nerve fiber layer (Fig 1). In another study, a three-dimensional configuration of the cup was studied by a computer-assisted disc analyzer (Imagenet, Topcon, Tokyo). However, the computed optic disc analysis was not sufficiently precise to detect a slight elevation of the nerve tissue at the bottom of the cup.
Table 1. Characteristics of Eyes With (+) and Without (-) the Vessel-associated Preservation of the Retinal Nerve Fiber Layer (NFL) and Control Subjects
Parameter
Preserved NFL (+) (n = 45)
Age Cup-to-disc .ratio Refractive error (D) Disc size (mm2) Distance between disc and foveola (mm) Index of ovalness LDF
=
linear discriminant function; NS
50.6 0.79 -2.54 2.54
± 14.5 ± 0.12 ± 3.62 ± 0.54
=
LDF
F Value·
Control (n = 122)
± 13.5 ± 0.14 ± 3.79 ± 0.77
-0.02 1.61 -0.05 -0.28
1.55 NS 1.06 NS 0.60 NS 0.91 NS
51.3 0.26 -1.55 2.55
3.85 ± 0.40 1.11 ± 0.10
-0.44 0.67
0.70NS 0.10 NS
54.9 0.76 -1.78 2.60
3.79 ± 0.35 1.13 ± 0.10
not Significant by the discriminant analysis.
Mahalanovis generalized distance for the discriminant analysis • F > 5.29 corresponds to statistical Significance by P < 0.05.
212
Preserved NFL(-) (n= 111)
=
0.214 .
± 15.4 ± 0.10 ± 1.91 ± 0.59
3.90 ± 0.41 1.10 ± 0.08
Chihara and Honda . Preservation of Nerve Fiber Layer Table 2. Correlation Between Various Parameters and Presence (+) or Absence (-) of the Vessel-associated Preservation of Nerve Fiber Layer (NFL) in 156 Glaucomatous Eyes
Parameter
Preservation of NFL (+) (n = 45)
Preservation ofNFL(-) (n = 111)
Gender Male (n = 76) Female (n = 80)
21/76 (28%) 24/80 (30%)
55/76 (72%) 56/80 (70%)
Type of Glaucoma High-tension glaucoma (n = 92) Normal-tension glaucoma (n = 64)
26/92 (28%) 19/64 (30%)
66/92 (72%) 45/64 (70%)
Tilted disc (+) (n = 23) (-) (n = 133)
4/23 (17%) 41/133 (31%)
19/23 (83%) 92/133 (69%)
Cilioretinal vessel (+) (n = 35) (-) (n = 121)
7/35 (20%) 38/121 (31%)
28/35 (80%) 83/121 (69%)
"Straight" vessel in the defective area (+) (n = 90) (-) (n = 66)
39/90 (43%)* 6/66 (9%)
51/90 (57%) 69/66 (91%)
"Tortuous" vessel in the defective area (+) (n = 114) (-) (n = 42)
38/114 (33%)t 7/42 (17%)
76/114 (67%) 35/42 (83%)
Local elevation of the floor (+) (n = 41) (-) (n = 115)
19/41 (46%)'1' 26/115 (23%)
22/41 (54%) 89/115 (77%)
• P < 0.001 by chi-square analysis.
t
P < 0.05, by chi-square analysis.
t P < 0.01, by chi-square analysis. Discussion
Levene ll reported a case in which the midtemporal area of the cup was preserved by a horizontally traversing retinal arteriole. The preservation of the cup in the midtemporal area and the local preservation of nerve fiber layer Table 3. Correlation between Vessel-associated Preservation of Nerve Fiber Layer and Other Parameters Studied by Partial Correlation Coefficient (Multivariate Analysis Quantification II) Parameter Gender Type of glaucoma Tilting of disc Cilioretinal vessel "Straight" vessel "Tortuous" vessel * P < 0.001.
Partial Correlation Coefficient
0.1246 0.0447 0.1806 0.1904 0.3603* 0.0254
in this study might be different in nature. The midtemporal area ofthe disc contained thicker connective tissue4 and a smaller pore size than that found in other quadrants. 12 As backward bowing of the lamina is suspected as an important trigger for nerve damage, 13,14 a resistance to the backward bowing at the midtemporal area may be correlated with the preservation of the papillomacular bundle in glaucoma. The local preservation of the nerve tissue in this study was associated with intrapapillary retinal vessels, which may be found at the superior temporal and inferior temporal sectors of the disc (Fig 2) and was different from the preservation of the papillomacular bundle. In some cases, superimposition of the intrapapillary retinal vessels on the basic elevation at the midtemporal sector may lead to a clearer preservation of nerve fibers at this place (Fig 1). There are some possible explanations for the correlation between the local preservation of the nerve fibers and the intrapapillary retinal vessels: (1) Rigidity of the vascular wall. Retinal vessels in the disc bridge a localized depression extending from the bottom of the cup to the neuroretinal rim; the underlying nerve tissue appears to be elevated by the vessels. When the nerve tissue is lifted
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by the vessels, the distortion of the lamina cribrosa may be relieved. Since the rigidity of the arteriolar wall exceeds that of the venule, this explanation is supported by the finding that "straight" vessels are more closely correlated with nerve tissue preservation than are "tortuous" vessels. (2) There may be a participation by the dense glial tissue or extracellular matrix surrounding the vessel. l5 ,16 Glial tissue or extracellular matrix richly surround the vessels and may prevent distortion of laminar tissue by the intraocular pressure. Alternatively they may provide a bed for the capillary network, and may participate in high oxygen tension at the place. The vessel size may not be a factor, because small vessels may have a large amount of glial tissue or extracellular matrix. (3) The preservation of nerve tissue might be primary, and might lead to secondary preservation of vessels in a defined region. If the vessels were preserved secondary to any preservation of nerve tissue, there should be no preference for "straight" vessels to be present in the preserved area. However, we did not make such an observation. (4) A high level of oxyhemoglobin in the arterioles may be another factor. In this study, the cilioretinal vessels did not correlate with any preservation of the nerve fiber layer. This result confirms another report that the cilioretinal artery, which has a high content of oxyhemoglobin, had no association with atypical visual field defect. I? The arterioles do not supply oxygen directly to the adjacent tissues. However, the results of oxygen mapping of the optic disc showed that there are areas next to the arteriole or choroid which had a high oxygen tension (Pournaras, unpublished data, presented at the ARVO Annual Meeting, 1991). These areas may be associated with nerve fiber preservation. Further studies will be required to elucidate the relationship between the local preservation of the nerve fiber layer and oxygen tension in the optic nerve head. There are some factors such as tilting,18 size of the disc,19 and diabetes mellitus20 that may also modify the pattern of nerve fiber loss in glaucoma. The results of our study suggest that, in the presence of intrapapillary vessels, there is less glaucoma-associated damage, which could help to explain variable nerve fiber loss in glaucoma.
References 1. Hayreh SS. Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. Br J Opthalmol 1969; 53:721-48. 2. Goldmann H, Block P. On the possibility to connect quantitatively ocular hypertension and damage to the optic nerve. Albrecht von Graefes Arch Klin Exp Ophthalmol 1971; 183: 232-43.
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3. Maumenee AE. Causes of optic nerve damage in glaucoma. . Robert N. Shaffer Lecture. Ophthalmology 1983; 90:74152. 4. Quigley HA, Addicks EM. Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol 1981; 99: 137-43. 5. Tomlinson A, Phillips CI. Ovalness of the optic cup and disc in the normal eye. Br J Ophthalmol 1974; 58:543-7. 6. Chihara E, Honda Y. Topographic changes in the optic disc in eyes with cotton-wool spots and primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 1991; 229: 13-18. 7. Littmann H. Zur Bestimmung der wahren Gro/3e eines Objektes auf dem Hintergrund eines lebenden Auges. Klin Monatsbl Augenheilkd 1988; 192:66-7. 8. Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol 1973; 12:814-29. 9. Hayashi C. On the quantification of qualitative data from the mathematico-statistical point of view. Ann Inst Statist Math 1950; 2:35-47. 10. Jennrich RI. Stepwise discriminant analysis. In: Enstein K, Ralston A, Wilf HS, eds. Statistical Methods for Digital Computers. New York: John Wiley, 1977; chap 4,5. 11. Levene RZ. Unusual optic discs in primary open-angle glaucoma. Ann Ophthalmol 1982; 14:617-20. 12. Ogden TE, Duggan J, Danley K, et al. Morphometry of nerve fiber bundle pores in the optic nerve head of the human. Exp Eye Res 1988; 46:559-68. 13. Levy NS, Crapps EE, Bonney RC. Displacement of the optic nerve head. Response to acute intraocular pressure elevation in primate eyes. Arch Ophthalmol1981; 99:2166-74. 14. Quigley HA, Hohman RM, Addicks EM, et al. Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 1983; 95:67391. 15. Hernandez MR, Igoe F, Neufeld AH. Extracellular matrix of the human optic nerve head. Am J Ophthalmol 1986; 102: 139-48. 16. Morrison JC, L'Hernault NL, Jerdan JA, Quigley HA. Ultrastructurallocation of extracellular matrix components in the optic nerve head. Arch Ophthalmol 1989; 107:123-9. 17. Lindenmuth KA, Skuta GL, Musch DC, Bueche M. Significance of cilioretinal arteries in primary open angle glaucoma. Arch Ophthalmol 1988; 106:1691-3. 18. Chihara E, Sawada A. Atypical nerve fiber layer defects in high myopes with high-tension glaucoma. Arch Ophthalmol 1990; 108:228-32. 19. Chihara E, Honda Y. Multiple retinal nerve fiber layer de,fects in glaucoma. Graefes Arch Clin Exp Ophthalmol [In Press]. 20. Zeiter JH, Shin DH, Baek NH. Visual field defects in diabetic patients with primary open-angle glaucoma. Am J Ophthalmol 1991; 111:581-4.