Parapapillary Atrophy and Retinal Vessel Diameter in Nonglaucomatous Optic Nerve Damage

Investigative Ophthalmology & Visual Science, Vol. 32, No. 11, October 1991 Copyright Association for Research in Vision and Ophthalmology Parapapillary Atrophy and Retinal Vessel Diameter in Nonglaucomatous Optic Nerve Damage Josr D. Jonas, Martin C. Fernandez, and Gottfried O. H. Naumann Parapapillary chorioretinal atrophy and decreased retinal vessel diameter occur in glaucomatous eyes. To evaluate the frequency and degree of these signs in nonglaucomatous optic neuropathy, the authors evaluated morphometrically and compared 47 patients with nonglaucomatous optic nerve atrophy from extraocular causes with 292 patients with primary open-angle glaucoma and 179 normal subjects. Eyes with anterior ischemic optic neuropathy were excluded. The parapapillary atrophy was differentiated into a central zone (beta) with sclera and large choroidal vessels visible by ophthalmoscopy and a peripheral zone (alpha) with irregular pigmentation. Both zones did not differ significantly in the eyes with nonglaucomatous optic neuropathy and the normal eyes. In the glaucomatous eyes, they were significantly larger and occurred more frequently. The retinal vessel diameter was significantly smaller in both groups with optic nerve atrophy than in the normal group. It was concluded that decreased retinal vessel diameters unspecifically suggest optic nerve atrophy. Evaluation of parapapillary chorioretinal atrophy can be helpful in differentiating nonglaucomatous from glaucomatous optic neuropathy. Invest Ophthalmol Vis Sci 32:2942-2947,1991 The abnormalities of parapapillary chorioretinal atrophy were reported to be more common and marked in eyes with glaucomatous optic nerve damage than in normal eyes or eyes with ocular hypertension. 1 " 19 Some authors described a spatial correlation between the location of the parapapillary chorioretinal atrophy and the most pronounced glaucomatous damage in the intrapapillary region of the optic disc and the most marked perimetric defect in the visual field. 816 In an indirect histomorphometric investigation, the parapapillary changes corresponded with irregular pigmentation or complete loss of retinal pigment epithelium cells and a decreased count of retinal photoreceptors. 19 Another feature of the parapapillary region, retinal vessel diameter, was found to be smaller in glaucomatous eyes compared with normal ones. 20 It is unclear whether the vessel diameter reduction was secondary to retinal ganglion cell loss or the primary event leading to ganglion cell death. From the Department of Ophthalmology and Eye Hospital, University Erlangen-Niirnberg, D-8520 Erlangen, Germany. Supported by Deutsche Forschungsgemeinschaft DFG Nau 55/ 6-1 /Jo. Submitted for publication: February 4, 1991; accepted May 30, 1991. Reprint requests: Dr. J. Jonas, University Eye Hospital, Schwabachanlage 6, D-8520 Erlangen, FRG. In this study, we considered to what degree parapapillary chorioretinal alterations and a reduction of the retinal vessel caliber occur in eyes with nonglaucomatous optic nerve atrophy. This might be helpful to differentiate eyes with glaucomatous and nonglaucomatous optic neuropathy and could provide hints for the pathogenesis. With these objectives in mind, we evaluated morphometrically and compared serial photographs of the optic discs of patients with nonglaucomatous and glaucomatous optic neuropathy and of normal subjects. Patients Materials and Methods Nonglaucomatous optic neuropathy (Figs. 1-4) was documented in 92 eyes (48 right eyes and 44 left eyes) of 23 men and 24 women with a mean age of 38.8 ± 15.7 years (mean ± standard deviation; range, 9-77 years) and a mean refractive error of -1.11 ± 2.41 diopters (range, -7.50-+2.0 diopters). Selection criteria were neuroophthalmologic diseases affecting the optic nerve directly, such as optic nerve gliomas, intracranial meningiomas, pituitary gland adenomas, and earlier inflammations of the optic nerve; visual field defects; a decreased visibility of the retinal nerve fiber bundles; normal intraocular pressure less than 22 mm Hg; and negative history of glaucoma. To pre- 2942

No. 11 NONGLAUCOMATOUS OPTIC NERVE DAMAGE / Jonos er ol 2943 vent influences of the ciliary circulation and the optic disc size, patients with nonarteritic or arteritic anterior ischemic optic neuropathy or optic disc drusen were excluded. The primary open-angle glaucoma group (Figs. 5-7) included 528 eyes (277 right eyes and 251 left eyes) of 292 patients (140 men and 152 women) with a mean age of 64.7 ± 12.4 years (range, 23-94 years) and an average refractive error of -0.62 ± 2.42 (range, -7.50-+7.00 diopters). Selection criteria were an open anterior chamber angle, intraocular pressure readings of at least 22 mm Hg, "idiopathic" origin of the elevated intraocular pressure, no other reason for optic nerve damage than glaucoma, glaucomatous changes in the intrapapillary region such as abnormal area and configuration of the neuroretinal rim, decreased visibility of the retinal nerve fiber bundles, and glaucomatous visual field loss. This included nasal steps of at least 10 and Bjerrum scotomata. The control group (Fig. 8) was composed of 290 normal optic nerve heads (138 right eyes and 152 left eyes) of 102 men and 77 women with a mean age of 49.0 ± 16.9 years (range, 7-82 years) and a mean refractive error of 0.09 ± 1.92 diopters (range, -7.25- +6.50 diopters). The subjects came to the eye clinic and hospital for refractometry and prescription of glasses, a checkup, or for treatment of diseases in the contralateral eyes not included in the study. These diseases, such as perforating corneal injuries and retinal detachments, did not affect the optic nerve primarily. Intraocular pressure in this group was less than 22 mg Hg. Some of the glaucoma patients and normal subjects had been examined in previous investigations, and others were included for the first time in a biomorphometric study of the optic disc. If both eyes of the same individual had been examined, only one randomly selected eye was taken for statistical analysis. High myopic subjects with a myopic refractive error of more than -8 diopters generally were excluded to avoid the altered characteristic of the optic disc morphology influencing the results. The patients with nonglaucomatous optic nerve atrophy were significantly younger than the normal subjects and the glaucoma patients. For this reason, two subgroups of the control and glaucoma group were formed. They were age matched with the patients with nonglaucomatous optic nerve damage (Table 1). Methods Fo^all eyes, 15 color stereo optic disc diapositives were taken using the Allen stereo separator and a telecentric fundus camera. For morphometric analysis, the slides were projected onto a screen, and the outline of the optic disc, peripapillary scleral ring, parapapillary chorioretinal atrophy, and inferior temporal and superior temporal retinal artery and vein at the optic disc border were plotted manually. The outer border of the optic disc was identical with the inner border of the parapapillary scleral ring. The parapapillary chorioretinal atrophy 15 was divided into a peripheral zone (Zone alpha), characterized by irregular hypopigmentation and hyperpigmentation, and a second zone (Zone beta), located close to the peripapillary scleral ring with sclera or denuded Bruch's membrane and large choroidal vessels visible by ophthalmoscopy (Figs. 5-7). The retinal vessel caliber was determined as the diameter of the superior temporal and inferior temporal retinal artery and vein at the optic disc border. To correct the ocular and camera magnification, Littmann's method was used after considering the anterior corneal curvature and the refractive error. 21-22 The nonparametric test Mann-Whitney test was used to analyze the significance of differences between the groups. Results The area and frequency of both zones of parapapillary chorioretinal atrophy taken separately or as a sum did not vary significantly between the normal eyes and the eyes with nonglaucomatous optic neuropathy matched or unmatched for age (P > 0.40, Table 1). Ophthalmoscopically, both zones were more detectable but not larger in the eyes with nonglaucomatous optic nerve atrophy than in the control group (Figs. 1-4, 8). In the glaucomatous eyes, Zones alpha and beta were significantly larger than in the normal eyes (P < 0.001 and P < 0.001, respectively) and the eyes with nonglaucomatous optic nerve damage (P < 0.007 and P < 0.001, respectively). Additionally, Zone beta occurred significantly more often in the glaucoma group than in the two other groups (P < 0.001, by chi-square test). The frequency of Zone alpha did not vary significantly among the three groups. The differences in the groups was significant after they had been matched for age (Table 1). Zone beta was smaller in the agematched glaucoma subgroup than in the total glaucoma group (Table 1). The reason for this was that the younger glaucoma patients in the age-matched glaucoma subgroup had less severe glaucomatous optic nerve damage (neuroretinal rim area, 1.18 ± 0.58 mm 2 ) than the patients of the total glaucoma group with a higher mean age (neuroretinal rim area, 0.98 ± 0.55 mm 2 ).

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No. 11 NONGLAUCOMATOUS OPTIC NERVE DAMAGE / Jonas er al 2945 Figs. 1-4. (Left to right, top to bottom) Optic discs with nonglaucomatous optic nerve atrophy due to extraocular reasons. White arrow heads: zone Alpha of the parapapillary chorioretinal atrophy; black arrow heads: peripapillary scleralring.note: marked decreased detectability of the retinal nerve fiber bundles; good visibility of zone Alpha; no zone Beta. Figs. 5-7. Optic disc with glaucomatous optic nerve atrophy. White arrow heads: zone Alpha of the parapapillary chorioretinal atrophy; white arrows: zone Beta; black arrow heads: peripapillary scleral ring. Note: marked decreased detectability of the retinal nervefiberbundles. Fig. 8. Normal optic disc. White arrow heads: zone Alpha of the parapapillary chorioretinal atrophy; black arrow heads: peripapillary scleral ring. Note: good detectability of the retinal nervefiberbundles. For calculating the sensitivity and specificity of the parapapillary chorioretinal atrophy to differentiate among the three groups examined, the parapapillary atrophy was considered to be abnormal if Zone alpha was larger than 0.71 mm 2 (mean plus one standard deviation in the control group) or if Zone beta was present. Using this arbitrary definition of an abnormal Zone alpha (beta), the eyes of 15.6% (18.4%) of the normal subjects, 39.7% (68.2%) of the glaucoma patients, and 8.9% (17.8%) of the patients with nonglaucomatous optic nerve atrophy were pathologic. We defined sensitivity as the ratio of the true-positive glaucoma diagnoses to the total number of glaucoma patients and specificity as the percentage of the truepositive diagnoses of nonglaucomatous optic nerve atrophy divided by the total count of patients with this disease. Using this terminology, Zones alpha and beta had a sensitivity of 39.7% and 68.2%, respectively, and a specificity of 91.1% and 82.2%, respectively, to differentiate between the eyes with glaucomatous and nonglaucomatous optic nerve damage. Because the normal subjects and the patients with nonglaucomatous optic nerve atrophy did not vary significantly in size and frequency of the two zones, the latter parameters did not have a sensitivity and specificity able to differentiate between these two groups. The retinal vessel diameter did not vary significantly between the eyes with glaucomatous and nonglaucomatous optic nerve atrophy (0.26 < P < 0.80). The vessel caliber was significantly smaller in the eyes with optic nerve damage than in the normal ones (P < 0.001, Table 1). An exception was the caliber of the inferior retinal vein. The area of the optic disc was not significantly different (P > 0.26) among the three groups. Discussion Parapapillary Chorioretinal Atrophy Morphologic differentiation of nonglaucomatous and glaucomatous optic nerve atrophy usually was based on intrapapillary features such as rim pallor and depth of the optic cup. In glaucomatous eyes, the neuroretinal rim characteristically shows a loss of area and a change of form with a secondary increase of cup area and cup-to-disc ratios. The same, however, was described for eyes with nonglaucomatous optic nerve damage. 23 " 28 Using the parameters "neuroretinal rim pallor" and "rim obliteration," it is difficult to differentiate between eyes with glaucomatous and nonglaucomatous optic nerve atrophy. 29 With exception of changes in the retinal nerve fiber layer, the parapapillary region has not been consid- Table 1. Papillomorphometric data (figures given in percent values indicate frequency) Group 1: patients with nonglaucomatous optic nerve atrophy (n = 47) Group 2: patients with primary open-angle glaucoma (POAG) (n = 292) Group 3: patients with POAG age-matched with group 1 (n = 32) Group 4: normal subjects (n = 179) Group 5: normal subjects age-matched with groups 1 and 3 (n = 103) Parapap. chorioretinal atrophy Zone alpha (mm 2 ) Zone beta (mm 2 ) Total (mm 2 ) 0.45 ± 0.27 (93%) 0.16 ±0.45 (17.8%) 0.61 ±0.48 0.62 ± 0.48 (87.3%) 0.78 ± 1.08(68.2%) 1.41 ± 1.13 0.68 ± 0.53 (93.8%) 0.48 ± 0.55 (75.0%) 1.12 ±0.66 0.41 ±0.30(82.1%) 0.17 ±0.56 (18.4%) 0.57 ± 0.65 0.37 ± 0.49 (82.5%) 0.15 ±0.54 (19.4%) 0.53 ± 0.59 Diameter retinal vessels (mm) Temporal superior artery Temporal inferior artery Temporal superior vein Temporal inferior vein 0.095 ±0.014 0.096 ±0.021 0.132 ±0.023 0.141 ±0.020 0.091 ±0.021 0.095 ± 0.022 0.130 ±0.027 0.132 ±0.027 0.085 ± 0.025 0.097 ± 0.024 0.132 ±0.025 0.126 ±0.033 2.61 ±0.54 0.110 ±0.022 0.114 ±0.023 0.143 ±0.032 0.145 ±0.028 0.109 ±0.022 0.115 ±0.025 0.143 ±0.035 0.146 ±0.030 Optic disc area (mm 2 ) 2.54 ± 0.40 2.66 ± 0.58 2.71 ±0.69 2.71 ±0.73

2946 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1991 Vol. 02 ered routinely. The chorioretinal atrophy in the parapapillary region of glaucomatous eyes can be interpreted as a precursor to halo glaucomatosus and therefore deserves attention in glaucomatous eyes. In this study, parapapillary chorioretinal abnormalities were found to occur less often and to be less marked in eyes with nonglaucomatous optic neuropathy than in glaucomatous eyes (Table 1). The differences were more pronounced for Zone beta with sclera or denuded Bruch's membrane and large choroidal vessels visible by ophthalmoscopy than for Zone alpha characterized by irregular pigmentation (Figs. 5-7). This shows that, in eyes with decreased visibility of retinal nerve fiber bundles and visual field defects, the presence of Zone beta or an unusually large Zone alpha suggest glaucomatous optic neuropathy; a normal appearance of the parapapillary region in respect to the chorioretinal atrophy is more likely to indicate the nonglaucomatous type of optic nerve atrophy. It must be remembered, however, that Zones alpha and beta were normal in 60.3% and 31.8% of the glaucomatous eyes, respectively, and abnormal in 8.9% and 17.8% of the eyes with nonglaucomatous optic nerve atrophy, respectively. This indicates that evaluation of the parapapillary chorioretinal atrophy may be helpful but not sufficient by itself to separate eyes with glaucomatous and nonglaucomatous optic nerve atrophy. Pathogenetically, we may infer that presence of the parapapillary chorioretinal atrophy in glaucoma does not depend entirely or at all on the nerve fiber loss, but that other factors may be responsible. One of these factors may be that the depth of the optic cup is more shallow in glaucoma eyes with marked parapapillary chorioretinal atrophy than in glaucomatous eyes with little or no parapapillary chorioretinal atrophy. 17 Retinal Vessel Diameter Retinal vessel diameter was significantly smaller in both groups with optic nerve atrophy than in the normal eyes (Table 1). This agrees with a previous morphologic study 30 and investigations of retinal blood flow. 31 It suggests that the decreased vessel caliber in glaucomatous eyes is not primary to the ganglion cell loss; it occurs secondarily as a consequence of a diminished retinal ganglion cell population. This indicates autoregulation of the retinal blood circulation. From a clinical point of view, in eyes with abnormally small retinal vessels, optic nerve atrophy should be excluded diagnostically. Key words: optic disc morphometry, optic nerve atrophy, parapapillary atrophy, retinal vessel caliber, glaucoma References 1. 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Heijl A and Samander C: Peripapillary atrophy and glaucomatous visual field defects. Doc Ophthalmol Proc Series 42:403, 1985. 9. Airaksinen PJ, Juvala PA, Tuulonen A, Alanko AI, Valkonen R, and Tuohino A: Change of parapapillary atrophy in glaucoma. In Glaucoma Update III, Krieglstein GK, editor. Berlin, Springer-Verlag, 1987, pp. 97-102. 10. Nevarez J, Rockwood EJ, and Anderson DR: The configuration of parapapillary tissue in unilateral glaucoma. Arch Ophthalmol 106:901, 1988. 11. Rockwood EJ and Anderson DR: Acquired parapapillary changes and progression in glaucoma. Graefes Arch Clin Exp Ophthalmol 226:510, 1988. 12. Buus DR and Anderson DR: Peripapillary crescents and halos in normal-tension glaucoma and ocular hypertension. Ophthalmology 96:16, 1989. 13. Kasner O, Feuer WJ, and Anderson DR: Possibly reduced prevalence of peripapillary crescents in ocular hypertension. Can J Ophthalmol 24:211, 1989. 14. Fantes FE and Anderson DR: Clinical histologic correlation of human peripapillary anatomy. Ophthalmology 96:20, 1989. 15. Jonas JB, Nhung XN, Gusek GC, and Naumann GOH: The parapapillary chorioretinal atrophy in normal and glaucoma eyes: I. Morphometric data. Invest Ophthalmol Vis Sci 30:908, 1989. 16. Jonas JB and Naumann GOH: Parapapillary chorioretinal atrophy in normal and glaucoma eyes: II. Correlations. Invest Ophthalmol Vis Sci 30:919, 1989. 17. Fernandez MC, Jonas JB, and Naumann GOH: Parapapillare chorioretinale Atrophie in Augen mit flacher glaukomatoser Papillenexkavation. Fortschr Ophthalmol 87:457, 1990. 18. Naumann GOH: Glaukome und Hypotonie-Syndrome. In Pathologie des Auges, Naumann GOH, editor. Berlin, Springer- Verlag, 1980, p. 792. 19. Jonas JB, Konigsreuther KA, and Naumann GOH: Histomorphometry of the parapapillary region in glaucomatous and normal human eyes. ARVO Abstracts. Invest Ophthalmol Vis Sci 31(Suppl):456, 1990. 20. Jonas JB, Nguyen XN, and Naumann GOH: Parapapillary retinal vessel diameter in normal and glaucoma eyes: I. Morphometric data. Invest Ophthalmol Vis Sci 30:1599, 1989. 21. Littmann H: Zur Bestimmung der wahren GroOe eines Objektes auf dem Hintergrund des lebenden Auges. Klin Monatsbl Augenheilkd 180:286, 1982.

No. 11 NONGLAUCOMATOUS OPTIC NERVE DAMAGE / Jonas er al 2947 22. Airaksinen PJ, Drance SM, and Schulzer M: Neuroretinal rim area in early glaucoma. Am J Ophthalmol 99:1, 1985. 23. Dalsgaard-Nielson E: Glaucoma-like cupping of the optic disc and its etiology. Acta Ophthalmol (Copenh) 15:151, 1937. 24. Blazar HA and Scheie HG: Pseudoglaucoma. Arch Ophthalmol 44:499, 1950. 25. Portney GL and Roth AM: Optic cupping caused by an intracranial aneurysm. Am J Ophthalmol 84:98, 1977. 26. Quigley HA and Anderson DR: Cupping of the optic disc in ischemic optic neuropathy. Trans Am Acad Ophthalmol Otolaryngol 83:755, 1977. 27. Radius RL and Maumenee AE: Optic atrophy and glaucomatous cupping. Am J Ophthalmol 85:145, 1978. 28. Trobe JD, Glaser JS, Cassady JC, Herschler J, and Anderson DR: Nonglaucomatous excavation of the optic disc. Arch Ophthalmol 98:1046, 1980. 29. Trobe JD, Glaser JS, and Cassady JC: Optic atrophy: Differential diagnosis by fundus observation alone. Arch Ophthalmol 98:1040, 1980. 30. Jonas JB, Nguyen NX, and Naumann GOH: Optic disc morphometry in "simple" optic nerve atrophy. Acta Ophthalmol 67:199, 1989. 31. Sebag J, Feke GT, Delori FC, and Weiter JJ: Anterior optic nerve blood flow in experimental optic atrophy. Invest Ophthalmol Vis Sci 26:1415, 1985.