- Email: [email protected]
Disc Ratio
Nonarteritic Anterior Ischemic Optic Neuropathy: Refractive Error and Its Relationship to Cup/Disc Ratio Sohan Singh Hayreh, MD, PhD,1 M. Bridget Zimmerman, PhD2 Objective: To investigate refractive error in eyes with nonarteritic anterior ischemic optic neuropathy (NA-AION) and its relationship to cup/disc (C/D) ratio. Design: Cohort study. Participants: A total of 608 consecutive patients with NA-AION. Methods: At first visit, all patients had a comprehensive ophthalmic evaluation, including recording bestcorrected visual acuity, visual fields, anterior segment examination, ophthalmoscopy, and fluorescein fundus angiography. Morphometric measurement of C/D ratio was performed in 65 fellow normal eyes in patients with unilateral NA-AION. Refraction was converted into spherical equivalent for data analysis. The data were analyzed using Pearson correlation, Mantel-Haenszel chi-square test, Cochran-Mantel-Haenszel test, chi-square goodness-of-fit test, and segmented linear regression. Main Outcome Measures: Refractive error in NA-AION eyes and any association between refractive error and C/D ratio. Results: Mean age of patients with NA-AION was 60.9 (standard deviation [SD] ⫽ 12.6; range 20.5–95.2) years. Median time from onset to refraction was 2 weeks (interquartile range 1–5 weeks). There was a significant association between spherical equivalent and age (P⬍0.0001). Comparison of refraction in patients with NAAION who were aged ⱖ50 years with that of an age-matched general population in the Framingham study cohort showed no significant difference between the 2 groups (P ⫽ 0.289). Comparison with the age-matched US population from the 1999 –2000 National Health and Nutrition Examination Survey showed a higher proportion of NA-AION eyes with spherical equivalent from ⫺0.5 to 0.5 diopters and a smaller proportion with ⫺3 to ⬍⫺0.5 and ⬎0.5 to ⫹3 diopters (P⬍0.001). For horizontal C/D ratio, a higher degree of myopia and higher degree of hyperopia were significantly associated with a larger C/D ratio (P⬍0.021). A similar pattern was seen for vertical C/D ratio in hyperopia (P ⫽ 0.057) but not in myopia (P ⫽ 0.428). Conclusions: There was a significant association between spherical equivalent refraction and age (P⬍0.0001). C/D ratio in persons with NA-AION is significantly smaller than that seen in the general population. Morphometric study in patients with NA-AION showed that a higher degree of myopia and higher degree of hyperopia are significantly associated with a larger C/D ratio. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:2275–2281 © 2008 by the American Academy of Ophthalmology.
In 1974, Hayreh1 reported that 7 of 10 eyes with nonarteritic anterior ischemic optic neuropathy (NA-AION) had no optic disc cup, and the remainder had only a small cup. Absence of an optic disc cup or only a small cup in NA-AION has since been confirmed by several large studies.2 The study by Tomlinson and Phillips3 showed that the more hypermetropic the eye the smaller the cup in relation to the whole disc, and conversely the more myopic an eye the larger the cup in relation to the whole disc. This raised the intriguing issue of whether eyes that develop NA-AION have refractive error different from that of the general population. Beck et al,2 in a study of 126 NA-AION and 122 control eyes, found more than ⫹1.0 diopter hypermetropia in 25% of the NA-AION group compared with only 6.5% of the control group. Katz and Spencer,4 on comparison of 50 patients with NA-AION with an agematched control group, concluded that patients with NA© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
AION are more hypermetropic. Philips et al5 compared 37 eyes with NA-AION with 74 eyes of a sex- and agematched control group and found that mild hypermetropia was more frequent in the NA-AION group. Mansour et al,6 in a study of 9 NA-AION eyes and 26 control eyes, found no difference in refractive error between the 2 groups. In view of these conflicting results, we decided to investigate a cohort of 609 consecutive patients with NA-AION, who fulfilled our inclusion and exclusion criteria, to ascertain whether they had refractive error different from that of the general population and whether there is any association between refractive error and cup/disc (C/D) ratio.
Materials and Methods We have prospectively investigated various aspects of NA-AION systematically in the Ocular Vascular Clinic at the Tertiary Care ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.08.007
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Ophthalmology Volume 115, Number 12, December 2008 University of Iowa Hospitals and Clinics since 1973. The present study was part of the prospective study on NA-AION funded by the National Institutes of Health (R01 grant) and approved by the institutional review board. In the present study, we investigated the refractive error and C/D ratio in eyes with NA-AION and whether that differed from the general population. The study consists of a cohort of 608 consecutive patients (608 eyes), first seen in our clinic from 1973 to 2000, who fulfilled our inclusion and exclusion criteria for this study. The data were collected prospectively and systematically.
Criteria Required for Diagnosis of NA-AION The criteria required for a diagnosis of NA-AION were as follows: (1) A history of sudden visual loss, usually discovered in the morning, must have been reported and there must be no other ocular, systemic, or neurologic diseases that might influence or explain the patient’s visual symptoms. (2) Optic disc edema at onset must have been documented in the Ocular Vascular Clinic and must still be present for inclusion in this study. (3) Spontaneous resolution of optic disc edema was observed. (4) The eye had optic disc-related visual field defects. (5) There was no neurologic, systemic, or ocular disorder that could be responsible for optic disc edema and visual impairment. (6) All eyes must have information on best-corrected phakic refraction. (7) Only eyes with NA-AION, or in cases with bilateral NA-AION, only the most recently involved eye, were included, that is, only 1 eye per patient.
Exclusion Criteria Exclusion criteria were as follows: (1) retinal or optic nerve lesion or any other factor (e.g., cataract, intraocular lens implant or aphakia) that may influence the visual status or refraction; (2) NA-AION with proliferative diabetic retinopathy with active neovascularization, vitreous hemorrhages, traction detachment, or other complications influencing the visual acuity or fields; (3) glaucoma; and (4) aphakia or contact lens.
Studies Performed A detailed ophthalmic and medical history was obtained at the patient’s first visit to our clinic (by SSH); in the medical history, we elicited a detailed history of all previous or current systemic diseases, particularly of arterial hypertension, diabetes mellitus, ischemic heart disease, strokes, transient ischemic attacks, carotid artery disease, and hyperlipidemia. A comprehensive ophthalmic evaluation was performed at that time (by SSH); this included recording of best-corrected visual acuity using Snellen visual acuity chart, central visual field testing using Amsler grid chart, visual fields with manual kinetic perimetry with Goldmann perimeter (using I-2e, I-4e, and V-4e targets regularly), relative afferent pupillary defect, intraocular pressure, slit-lamp examination of the anterior segment, lens and vitreous, direct and indirect ophthalmoscopy, stereoscopic color fundus photography, and, in acute cases, stereoscopic fluorescein fundus angiography. When giant cell arteritis was suspected on the basis of systemic symptoms, elevated erythrocyte sedimentation rate, and/or C-reactive protein, or arteritic AION was suspected, a temporal artery biopsy was performed to rule out giant cell arteritis.7–9 At each follow-up visit, the same ophthalmic evaluation and stereoscopic color fundus photography were done, except that fluorescein fundus angiography was not performed. At the initial visit, a detailed systemic evaluation was performed by a cardiologist, an internist, or the patient’s local physician. Where indicated, other systemic or neurologic investigations were done to rule out any systemic or neurologic cause of visual loss.
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Refraction data evaluated in this study were based on the findings at only the initial visit with NA-AION to our clinic. The refractive error was read from the distance glasses of the patient, which provided the best visual acuity, or the refraction done in the clinic. Patients without glasses and no refractive error in the distance in our study were considered emmetropic. Refractive error was converted to spherical equivalent for data analysis. Spherical equivalent of refraction is equal to (⫾sphere) ⫹ ½ (⫾cylinder). For comparison of spherical equivalent refraction of our study group with that in the general population, we used the data from the Framingham Eye Study cohort10 (in 5197 eyes of persons aged 52– 85 years) and the visual examination in 1999 –2000 National Health and Nutrition Examination Survey (NHANES)11 (4094 eyes in persons aged ⱖ20 years). Protocols for evaluation of refractive error used in those 2 studies were different, resulting in different findings (see below). Our protocol for refraction evaluation was identical to that used in the Framingham Eye Study cohort.10
Morphometric Measurement of C/D Ratio Morphometric measurement of C/D ratio was performed in the normal fellow optic discs of 65 randomly picked patients with unilateral NA-AION in the present study. The morphometric measurements were performed by the team of Professor Jost Jonas (Department of Ophthalmology, Ruprecht-Karls-University Heidelberg, Mannheim, Germany) on the fundus photographs taken at Iowa City. Optic disc photographs were taken in both eyes of all patients with NA-AION at their initial visit. The disc slides were projected on a scale of 1 to 15. The outlines of the optic cup and optic disc were plotted on paper and morphometrically analyzed. The optic cup was defined on the basis of contour and not of pallor. The border of the optic disc was identical to the inner side of the peripapillary scleral ring. Because the magnification of the optic disc photographs varied according to the fundus camera used, and keratometric readings had not been obtained for all eyes included in the study, the optic disc measurements were expressed in relative size units.
Statistical Analysis Refraction data were evaluated from only the findings at the initial visit. In patients in whom both eyes were involved, the refraction data of the eye whose onset was closest to the initial visit were used. There were 19 patients who reported the same onset time for both eyes. Of these patients, 6 had the same spherical equivalent in both eyes. For the remaining 13 patients, the eye with the worse refraction (i.e., highest absolute spherical equivalent value) was used (10 within 0.50 diopter difference and 3 between 0.8 and 1.25 diopter difference). The association of spherical equivalent refraction of eyes with NA-AION with age was examined by Pearson correlation coefficient and Mantel-Haenszel chi-square test. The Cochran-MantelHaenszel test was used to compare the spherical equivalent between male and female patients, controlling for age. To determine whether the distribution of spherical equivalent in eyes with NAAION differs from that of the general population, refraction data reported in the Framingham study10 and 1999 –2000 NHANES Vision Examination11 were used for comparison. This was done by dividing spherical equivalent into the intervals reported in the Framingham study10 for age groups 50 to 64 years, 65 to 74 years, and ⬎75 years, and comparing NA-AION and Framingham refraction data using the Mantel-Haenszel chi-square test based on the ranked ordered intervals. For comparison with spherical equiv-
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy Table 1. Distribution of Spherical Equivalent by Age* in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy Age (y)
n
<ⴚ6.0
ⴚ6 to ⴚ3.1
ⴚ3 to ⴚ0.1
0
ⴙ0.1 to ⴙ3.0
ⴙ3.1 to ⴙ5.0
>ⴙ5.0
20–49 50–64 65–74 ⬎75
106 263 170 69
6 (5.7%) 3 (1.1%) 0 (0.0%) 0 (0.0%)
6 (5.7%) 5 (1.9%) 5 (2.9%) 1 (1.4%)
20 (18.9%) 51 (19.4%) 18 (10.6%) 11 (15.9%)
52 (49.1%) 72 (27.4%) 35 (20.6%) 13 (18.8%)
18 (17.0%) 112 (42.6%) 85 (50.0%) 35 (50.7%)
2 (1.9%) 13 (4.9%) 17 (10.0%) 3 (4.4%)
2 (1.9%) 7 (2.7%) 10 (5.9%) 6 (8.7%)
Refractive error classification, The following classification was used in this study:12 Emmetropia ⫽ no refractive error. Myopia: high myopia ⫽ ⬍ ⫺6.0 diopters; medium myopia ⫽ ⫺6 to ⫺3.1 diopters; low myopia ⫽ ⫺3 to ⫺0.1 diopters. Hyperopia: low hyperopia ⫽ ⫹0.1 to ⫹3.0 diopters; medium hyperopia ⫽ ⫹3.1 to 5 diopters; high hyperopia ⫽ ⬎ ⫹5.0 diopters. *There is a significant association between spherical equivalent and age (Mantel-Haenszel chi-square P⬍0.0001).
alent in the NHANES study,11 the chi-square goodness-of-fit test was used.
Results Refractive Error Refraction data came from 608 eyes (608 patients) with NAAION: 308 right eyes (51%) and 300 left eyes (49%). The study comprised 358 male (59%) and 250 female (41%) patients, with a mean age of 60.9 years (standard deviation [SD] ⫽12.6; range 20.5–95.2). The mean age was 61.1 (14.1) years for female patients and 60.7 (11.5) years for male patients. Seventy-one percent of patients were aged between 50 and 74 years, 11% of patients were aged ⱖ75 years, and 17% were aged ⬍50 years. The median time from the onset to the date of refraction was 2 weeks (interquartile range 1–5 weeks). Table 1 shows the distribution of spherical equivalent refraction in NA-AION eyes by age, with the intervals for spherical equivalent corresponding to high myopia (greater than ⫺6.0 diopters), medium myopia (⫺6 to ⫺3.1 diopters), low myopia (⫺3 to ⫺0.1 diopters), emmetropia (no refractive error), low hyperopia (⫹0.1 to ⫹3.0 diopters), medium hyperopia (⫹3.1–5 diopters), and high hyperopia (greater than ⫹5.0 diopters).12 There is a significant association between spherical equivalent refraction and age (P⬍0.0001); the prevalence of emmetropia decreases with age, and the prevalence of hyperopia increases with age. The distribution of spherical equivalent did not differ significantly
between male and female patients (P ⫽ 0.994), with the difference between male and female patients in the myopia, emmetropia, and hyperopia categories ranging from 0.1% to 3%. A similar result was seen after controlling for age (P ⫽ 0.976). Comparison of refraction spherical equivalent of patients with NA-AION who were aged ⱖ50 years with the age-matched Framingham study10 showed no significant difference between the 2 groups (P ⫽ 0.289). The differences between NA-AION and the Framingham study were 0.1% to 3.2% for myopia, 0.7% to 8.1% for emmetropia, and 0.2% to 10.8% for hyperopia (Table 2). Comparison with the age-matched United States’ general population from the 1999 –2000 NHANES Vision Examination11 showed a higher proportion of NA-AION eyes with spherical equivalent between ⫺0.5 and 0.5 diopters, and a smaller proportion with ⫺3 to ⬍⫺0.5 diopters and ⬎0.5 to ⫹3 diopters (P⬍0.001; Table 3).
C/D Ratio In the 65 fellow normal eyes of patients with unilateral NA-AION, morphometric study of the optic disc showed a vertical C/D ratio of ⬍0.15 in 37% and ⬍0.25 in 75% (mean 0.199 [SD 0.093]; range 0.04 – 0.46) and a horizontal C/D ratio of ⬍0.15 in 31% and ⬍0.25 in 82% (mean horizontal C/D ratio 0.194 [SD 0.090]; range 0.08 – 0.6). Figure 1 shows the morphometric findings of the horizontal and vertical C/D ratio in the 65 eyes plotted against the spherical equivalent. For the horizontal C/D ratio, a higher degree of myopia and higher degree of hyperopia were significantly associated with larger C/D ratio (P ⫽ 0.021 for myopia and P ⫽ 0.004 for hyperopia; Fig 1A). A similar pattern was seen for
Table 2. Comparison of Spherical Equivalent in Nonarteritic Anterior Ischemic Optic Neuropathy with Framingham Study10 by Age‡ Age 50–64 y*
Age 65–74 y
Age >75 y
Spherical Equivalent
NA-AION (n ⫽ 263)
Framingham† (n ⫽ 2739)
NA-AION (n ⫽ 170)
Framingham† (n ⫽ 1692)
NA-AION (n ⫽ 69)
Framingham† (n ⫽ 766)
⬍⫺4.0 ⫺4.0 to ⫺2.1 ⫺2.0 to ⫺0.1 0 ⫹0.1 to ⫹2.0 ⫹2.1 to ⫹4.0 ⬎⫹4.0
5 (1.9%) 10 (3.8%) 44 (16.7%) 72 (27.4%) 95 (36.1%) 27 (10.3%) 10 (3.8%)
75 (2.7%) 98 (3.6%) 370 (13.5%) 771 (28.1%) 1001 (36.5%) 323 (11.8%) 101 (3.6%)
3 (1.8%) 4 (2.4%) 16 (9.4%) 35 (20.6%) 67 (39.4%) 31 (18.2%) 14 (8.2%)
30 (1.8%) 68 (4.0%) 143 (8.5%) 294 (17.4%) 640 (37.8%) 432 (25.5%) 85 (5.0%)
0 (0%) 2 (2.9%) 10 (14.5%) 13 (18.8%) 28 (40.6%) 9 (13.0%) 7 (10.1%)
20 (2.6%) 14 (1.8%) 94 (12.3%) 82 (10.7%) 291 (38.0%) 183 (23.9%) 82 (10.6%)
NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy. *Includes age 50 – 64 years in NA-AION, with a minimum age of 52 years in the Framingham study. † From Table 8.6 of the Framingham Eye Study.10 ‡ No significant difference in spherical equivalent of patients with NA-AION compared with Framingham Study (Cochran-Mantel-Haenszel controlling for age P ⫽ 0.289). Comparison at each age category: P ⫽ 0.416 for 50 – 64 years; P ⫽ 0.572 for 65–74 years; and P ⫽ 0.465 for ⬎75 years.
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Ophthalmology Volume 115, Number 12, December 2008 Table 3. Comparison of Spherical Equivalent in Nonarteritic Anterior Ischemic Optic Neuropathy with the U.S. Population from National Health and Nutrition Examination Survey 1999 –2000 Vision Examination,11 by Age Age 20–49 y Spherical Equivalent
NA-AION (n ⫽ 106)
⬍⫺3.0 4 (10.3%) ⫺3.0 to ⬍⫺0.5 5 (12.8%) ⫺0.5 to ⫹0.5 26 (66.7%) ⬎⫹0.5 to ⫹3.0 2 (5.1%) ⬎⫹3.0 2 (5.1%) P ⫽ 0.001
NHANES* (n ⫽ 2152)
Age 50–64 y NA-AION (n ⫽ 263)
16.3% (14.1, 18.6) 8 (11.9%) 27.0% (22.7, 31.3) 6 (9.0%) 43.1% (40.4, 45.8) 47 (70.2%) 11.8% (9.5, 14.2) 4 (6.0%) 1.7% (1.1, 2.3) 2 (3.0%) P⬍0.0001
Age 65–74 y
NHANES* (n ⫽ 902)
NA-AION (n ⫽ 170)
NHANES* (n ⫽ 595)
Age >75 y NA-AION (n ⫽ 69)
NHANES* (n ⫽ 445)
10.6% (7.7, 13.6) 4 (2.7%) 3.7% (1.6, 5.8) 5 (2.4%) 5.7% (2.0, 9.4) 26.4% (23.6, 29.1) 18 (12.2%) 18.2% (13.6, 22.8) 12 (5.7%) 28.3% (23.5, 33.2) 21.5% (17.7, 25.3) 92 (62.2%) 18.4% (14.1, 22.8) 115 (54.3%) 12.7% (7.7, 17.7) 37.4% (33.5, 41.3) 27 (18.2%) 49.1% (43.1, 55.2) 56 (26.4%) 43.8% (37.7, 49.8) 4.0% (2.1, 6.0) 7 (4.7%) 10.5% (7.8, 13.2) 24 (11.3%) 9.6% (6.8, 12.3) P⬍0.0001 P ⫽ 0.0006
NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; NHANES ⫽ National Health and Nutrition Examination Survey. *Weighted estimate of prevalence with 95% confidence limits.
vertical C/D ratio in hyperopia (P ⫽ 0.057) but not in myopia (P ⫽ 0.428) (Fig 1B).
control groups, but their sample size was small; it is possible that with a larger sample size their findings might have been different.
Discussion
C/D Ratio
Refractive Error
It is unfortunate that great stress has been placed on the importance of a small or absent cup (the so-called disc at risk) in NA-AION,13–15 leading to the impression in the ophthalmic community that a small or absent cup is actually the primary factor in the development of the disease. We have met persons without any visual symptom who have been alarmed by ophthalmologists telling them that they were at risk of developing NA-AION simply because they have no cup or a small cup. It is important to place this subject in proper perspective; to do that one has to look at the overall pattern of C/D ratio in the normal general population versus that in patients with NA-AION.
Our study in patients with NA-AION showed a significant (P⬍0.0001) association between age and refractive error, with the prevalence of emmetropia decreasing with age and the prevalence of hyperopia increasing with age, but no difference between male and female patients. We found no significant difference in spherical equivalent refraction in eyes with NA-AION compared with that of an age-matched general population in the Framingham Eye Study cohort10 (Table 2). However, comparison with the age-matched US population from the 1999 –2000 NHANES Vision Examination11 showed a higher proportion of NA-AION eyes with a spherical equivalent between ⫺0.5 and 0.5 diopters, and a smaller proportion with ⫺3 to ⬍⫺0.5 diopters and ⬎0.5 to ⫹3 diopters (P⬍0.001, Table 3). The disparity in the findings between the Framingham Eye Study cohort10 and the NHANES study11 is due to the difference in the protocols of refraction evaluation between the 2 studies. Our protocol for refraction was identical to that used in the Framingham Eye Study cohort.10 Refraction findings in our study (in 608 eyes), as well as comparison of our findings with those in the Framingham Eye Study cohort10 (in 5197 eyes; Table 2) and the NHANES study11 (in 4094 eyes; Table 3), contradict the findings of 3 previous studies based on 1262, 50,4 and 375 eyes, all suggesting that patients with NA-AION are more hypermetropic than the control group. Of the 3 previous studies, the study by Beck et al2 had the largest number of eyes (i.e., 126 eyes with NA-AION). In that study, the mean age was 62.1 years in the NA-AION group and 36.8 years in the control group; that marked age difference accounts for the finding of more hypermetropia in the NA-AION group than in the control group (see above). This is further supported by the fact that there was no difference in refraction between NA-AION and arteritic AION eyes in the study by Beck et al, because those groups were almost similar in age. The other 2 studies4,5 had age-matched
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C/D Ratio in the Normal General Population Information about the C/D ratio in persons without NAAION is provided by 4 general population-based studies (Table 4).2,10,16,17 The Framingham Eye Study,10 in a survey of a general population without any visual symptom, evaluated the C/D ratio in 5054 eyes of persons of all ages on ophthalmoscopy. The mean horizontal C/D ratio was 0.250 (SD 0.159), and the mean vertical C/D ratio was 0.255 (SD 0.166). There was no evidence that C/D ratio changes significantly with age. The Rotterdam Study,16 based on a general population study of 5114 subjects aged ⱖ55 years, showed a mean vertical C/D ratio of 0.49 (SD, 0.14) and a mean horizontal C/D ratio of 0.40 (SD, 0.14) using a stereoscopic image analyzer. It showed no association of cup area, vertical C/D ratio, and horizontal C/D ratio with age, refractive error, or height.16 In another investigation,17 this Rotterdam Study group evaluated vertical C/D ratio in 5143 subjects aged ⱖ55 years by 2 methods: ophthalmoscopic and semiautomated. That study showed a mean ophthalmoscopic vertical C/D ratio 0.30 (standard error, 0.0021; range, 0.00 – 1.00) compared with a semiautomated measured vertical C/D ratio of 0.49 (standard error, 0.0019; range, 0.04 –
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy In our current morphometric study in 65 normal fellow eyes, the vertical C/D ratio was ⬍0.15 in 37% and ⬍0.25 in 75% (mean, 0.199 [SD, 0.093]), and the horizontal C/D ratio was ⬍0.15 in 31% and ⬍0.25 in 82% (mean, 0.194 [SD, 0.090]) (Fig 1; Table 4). In our previous ophthalmoscopic study2 in 126 normal fellow eyes, the C/D ratio was ⬍0.15 in 48% and ⬍0.25 in 71% (mean, 0.16⫾0.15) (Table 4).
Comparison of C/D Ratio in Patients with NA-AION Versus Normal Control Population Table 4 summarizes the data. This shows that the C/D ratio in persons with NA-AION is smaller than that of the normal control population. The methods used to evaluate the C/D ratio have been different in different studies, resulting in different C/D ratios. However, the magnitude of the difference between the control eyes and the NA-AION eyes suggests that this difference cannot be attributed solely to the different methods used to estimate the C/D ratio in various studies. As discussed previously, the semiautomated methods for measurement of the C/D ratio (used in the Rotterdam Study16 and our current study) give a larger ratio than the ophthalmoscopically measured ratio.17
The Role of an Absent or Small Cup in the Pathogenesis of Development of NA-AION
Figure 1. Plots of correlations between the C/D ratios and spherical equivalent refraction in diopters. (A) Plot of horizontal C/D ratio against spherical equivalent refraction in diopters. (B) Plot of vertical C/D ratio against spherical equivalent refraction in diopters. C/D ⫽ cup/disk ratio. NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy.
0.86). This showed that semiautomated measurement of the vertical C/D ratio is larger than the ophthalmoscopically measured ratio. According to the authors, the reason for this discrepancy between the 2 methods is the use of different criteria for defining the cup and possibly the disc. The authors concluded that currently “there is no gold standard for assessment of the VCDR (vertical C/D ratio).”17 Beck et al,2 in a study of 122 eyes of persons without NA-AION, showed that 12% had no cup, 8% had a C/D ratio from 0.05 to 0.149, and 19% had a C/D ratio from 0.15 to 0.249.
C/D Ratio in Patients with NA-AION Because the C/D ratio is almost always the same in both eyes in normal persons, we have carried out 2 types of studies in the normal fellow eyes of patients with unilateral NA-AION.
We have discussed this subject in detail elsewhere.2 Briefly, in the multifactorial scenario of the pathogenesis of NAAION, one has to consider the role of the following 2 factors relevant to C/D ratio. The size of the physiologic cup is determined primarily by the size of the scleral canal embryologically.18 With a small scleral canal and associated small opening in the Bruch’s membrane in the region of the optic disc, there is a small cup or no cup. As shown above, the C/D ratio in persons with NA-AION is smaller than that seen in general population (Table 4). This means the optic discs of patients with NA-AION tend to have smaller openings in their Bruch’s membrane and scleral canal than the general population, resulting in crowding of the optic nerve fibers as they pass through the restricted space in the optic disc and lamina cribrosa. Axoplasmic flow stasis has a variety of causes, for example, ischemia and hypoxia,19 which result in swollen axons. Axoplasmic flow stasis has been shown to be responsible for optic disc edema in ischemic optic neuropathy.20 We believe the sequence of events in the development of NA-AION is as follows. Initially, optic nerve head ischemia/hypoxia causes axoplasmic flow stasis. When there is no cup or only a small cup, the swollen axons are crowded in a restricted space in the optic disc. In that case, the swollen axons can expand only by compressing the surrounding tissues. The tissues that are most vulnerable to compression in this case are capillaries and other fine vessels lying among the nerve fibers. Thus, swollen axons in restricted space within the optic disc produce secondary vascular changes.21 It has been shown that asymptomatic optic disc edema is the earliest sign of NA-AION.22,23 It has also been demonstrated that nocturnal arterial hypotension
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Ophthalmology Volume 115, Number 12, December 2008 Table 4. Comparison of Cup/Disc Ratio in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy Versus the Normal Control Group Normal Control or with NA-AION
Study Group Framingham Eye Study
10
No. of Eyes Examined
Method Used to Evaluate C/D Ratio
Control
5054
Ophthalmoscopy
Rotterdam Study16 Rotterdam Study17 Beck et al2
Control Control Control
5114 5143 122
Stereoscopic image analyzer Ophthalmoscopy Ophthalmoscopy
Beck et al2
NA-AION
126
Our current study
NA-AION
65
Ophthalmoscopy Morphometric
C/D Ratio Mean horizontal C/D ratio 0.250⫾0.159; mean vertical C/D ratio 0.255⫾0.166. Mean 0.49⫾0.14 Mean 0.30 (standard error 0.0021) ⬍ 0.15 in 20%; ⬍0.25 in 39% (mean 0.3⫾0.19) ⬍0.15 in 48%; ⬍0.25 in 71% (mean 0.16⫾0.15) ⬍0.15 in 37% and ⬍0.25 in 75% (mean 0.199⫾0.093)
C/D ⫽ cup/disc ratio; NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; ⫾ ⫽ SD.
precipitates the development of NA-AION.24 Thus, the available evidence indicates that the sequence of events in the development of NA-AION is as follows: subclinical ischemia (hypoxia) of the optic nerve head ¡ axoplasmic flow stasis in the optic nerve fibers ¡ axonal swelling ¡ asymptomatic optic disc edema22 (incipient NA-AION23) ¡ compression of the intervening capillaries by swollen axons in a crowded disc ¡ setting up a vicious cycle, that is, the greater the compression of capillaries, the greater the blood flow compromise, the greater the axoplasmic flow stasis and the more axonal swelling. Because compression of the optic disc capillaries compromises their blood flow, a decrease in blood pressure must further derange their blood flow. Therefore, in this situation, a decrease in perfusion pressure in the optic disc capillaries because of nocturnal arterial hypotension results in marked ischemia and precipitates visual loss (symptomatic NA-AION), which is usually discovered on waking up in the morning.24 From this sequence of events, it is evident that in the multifactorial scenario of pathogenesis of NA-AION, contrary to the prevalent impression, an absent or small cup is simply a secondary contributing factor, once the process of NA-AION has started, and not a primary factor.2,23,25
Relationship Between Refractive Error and C/D Ratio Tomlinson and Phillips3 stated that the more hypermetropic the eye, the smaller the C/D ratio, and conversely the more myopic an eye, the larger the C/D ratio. The Rotterdam Study,16 in contrast, showed no association of C/D ratio with refractive error in the general population. That was also true in our previous study.2 Our current morphometric study in fellow normal eyes of patients with unilateral NA-AION showed that for horizontal C/D ratio, a higher degree of myopia and higher degree of hyperopia were both significantly associated with a larger C/D ratio (P ⫽ 0.021 for myopia and P ⫽ 0.004 for hyperopia; Fig 1A). A similar pattern was seen for the vertical C/D ratio in hyperopia (P ⫽ 0.057) but not in myopia (P ⫽ 0.428) (Fig 1B). Thus, none of the studies based on much larger populations support the conclusion of Tomlinson and Phillips.3
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The main findings of this study are as follows: There is a significant (P⬍0.0001) association between spherical equivalent refraction and age, with the prevalence of emmetropia decreasing with age and the prevalence of hyperopia increasing. Studies in the general population16 and in patients with NA-AION2 show no association between refractive error and C/D ratio. Our morphometric study in patients with NA-AION showed that a higher degree of myopia and a higher degree of hyperopia are significantly associated with larger C/D ratio. These findings contradict a previous study3 showing that the more hypermetropic the eye, the smaller the C/D ratio. The C/D ratio in persons with NA-AION is smaller compared with that in the general population (Table 4). As discussed previously, contrary to the prevalent impression, an absent or small cup is simply a secondary contributing factor in the development of NAAION, once the process of NA-AION has started, and not a primary factor.2,23,25 Acknowledgments. We thank Dr. Mark Wilkinson, for expert advice about refraction, and Professor Jost Jonas, for help with the morphometric evaluation of C/D ratio in our study.
References 1. Hayreh SS. Pathogenesis of cupping of the optic disc. Br J Ophthalmol 1974;58:863–76. 2. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503– 8. 3. Tomlinson A, Phillips CI. Ratio of optic cup to optic disc in relation to axial length of eyeball and refraction. Br J Ophthalmol 1969;53:765– 8. 4. Katz B, Spencer WH. Hyperopia as a risk factor for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116:754 – 8. 5. Philips B, Dralands L, Missotten L. Non-arteritic anterior ischemic optic neuropathy and refraction. Bull Soc Belge Ophtalmol 1995;259:183–7. 6. Mansour AM, Shoch D, Logani S. Optic disk size in ischemic optic neuropathy. Am J Ophthalmol 1988;106:587–9. 7. Hayreh SS. Anterior ischaemic optic neuropathy: differentiation of arteritic from non-arteritic type and its management. Eye 1990;4:25– 41.
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy 8. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123:285–96. 9. Hayreh SS, Zimmerman B. Management of giant cell arteritis: our 27-year clinical study: new light on old controversies. Ophthalmologica 2003;217:239 –59. 10. Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study Monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973–1975. Surv Ophthalmol 1980;24 (suppl):335– 610. 11. National Center for Health Statistics. National Health and Nutrition Examination Survey, 1999 –2000, Vision Exam. Available at: http://www.cdc.gov/nchs/about/major/nhanes/ exam99_00.htm. Accessed April 9, 2008. 12. Borish IM. Clinical Refraction. 3rd ed. vol 1. Chicago, IL: Professional Press; 1970:90, 116. 13. Burde RM. Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116: 759 – 64. 14. Wang MY, Sadun F, Levin LB, et al. Occurrence of familial nonarteritic anterior ischemic optic neuropathy in a case series. J Neuroophthalmol 1999;19:144 –7. 15. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafilassociated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002;109:584 –7. 16. Ramrattan RS, Wolfs RC, Jonas JB, et al. Determinants of
17.
18.
19. 20.
21. 22. 23. 24.
25.
optic disc characteristics in a general population: the Rotterdam Study. Ophthalmology 1999;106:1588 –96. Wolfs RC, Ramrattan RS, Hofman A, de Jong PT. Cup-to-disc ratio: ophthalmoscopy versus automated measurement in a general population: the Rotterdam Study. Ophthalmology 1999;106:1597– 601. Duke-Elder S, Cook C. Normal and abnormal development. Part 1. Embryology. In: Duke-Elder S, ed. System of Ophthalmology. Vol III. Normal and abnormal development. Part 1. St. Louis, MO: Mosby, 1963:109 –10. Hayreh SS. Fluids in the anterior part of the optic nerve in health and disease. Surv Ophthalmol 1978;23:1–25. McLeod D, Marshall J, Kohner EM. Role of axoplasmic transport in the pathophysiology of ischaemic disc swelling. Br J Ophthalmol 1980;64:247– 61. Hayreh SS. Optic disc edema in raised intracranial pressure. V. Pathogenesis. Arch Ophthalmol 1977;95:1553– 65. Hayreh SS. Anterior ischemic optic neuropathy. V. Optic disc edema an early sign. Arch Ophthalmol 1981;99:1030 – 40. Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol 1997;124:641–7. Hayreh SS, Zimmerman MB. Optic disc edema in nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2007;245:1107–21.
Footnotes and Financial Disclosures Originally received: May 16, 2008. Final revision: August 5, 2008. Accepted: August 6, 2008.
Manuscript no. 2008-594.
1
Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa City, Iowa. 2
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa.
Financial Disclosure(s): The authors have no conflict of interest. Supported by grant EY-1151 from the National Institutes of Health, and in part by unrestricted grant from Research to Prevent Blindness, Inc., New York. Correspondence: Sohan Singh Hayreh, MD, PhD, Department of Ophthalmology and Visual Sciences, University Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1091. E-mail: [email protected].
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In 1974, Hayreh1 reported that 7 of 10 eyes with nonarteritic anterior ischemic optic neuropathy (NA-AION) had no optic disc cup, and the remainder had only a small cup. Absence of an optic disc cup or only a small cup in NA-AION has since been confirmed by several large studies.2 The study by Tomlinson and Phillips3 showed that the more hypermetropic the eye the smaller the cup in relation to the whole disc, and conversely the more myopic an eye the larger the cup in relation to the whole disc. This raised the intriguing issue of whether eyes that develop NA-AION have refractive error different from that of the general population. Beck et al,2 in a study of 126 NA-AION and 122 control eyes, found more than ⫹1.0 diopter hypermetropia in 25% of the NA-AION group compared with only 6.5% of the control group. Katz and Spencer,4 on comparison of 50 patients with NA-AION with an agematched control group, concluded that patients with NA© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
AION are more hypermetropic. Philips et al5 compared 37 eyes with NA-AION with 74 eyes of a sex- and agematched control group and found that mild hypermetropia was more frequent in the NA-AION group. Mansour et al,6 in a study of 9 NA-AION eyes and 26 control eyes, found no difference in refractive error between the 2 groups. In view of these conflicting results, we decided to investigate a cohort of 609 consecutive patients with NA-AION, who fulfilled our inclusion and exclusion criteria, to ascertain whether they had refractive error different from that of the general population and whether there is any association between refractive error and cup/disc (C/D) ratio.
Materials and Methods We have prospectively investigated various aspects of NA-AION systematically in the Ocular Vascular Clinic at the Tertiary Care ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.08.007
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Ophthalmology Volume 115, Number 12, December 2008 University of Iowa Hospitals and Clinics since 1973. The present study was part of the prospective study on NA-AION funded by the National Institutes of Health (R01 grant) and approved by the institutional review board. In the present study, we investigated the refractive error and C/D ratio in eyes with NA-AION and whether that differed from the general population. The study consists of a cohort of 608 consecutive patients (608 eyes), first seen in our clinic from 1973 to 2000, who fulfilled our inclusion and exclusion criteria for this study. The data were collected prospectively and systematically.
Criteria Required for Diagnosis of NA-AION The criteria required for a diagnosis of NA-AION were as follows: (1) A history of sudden visual loss, usually discovered in the morning, must have been reported and there must be no other ocular, systemic, or neurologic diseases that might influence or explain the patient’s visual symptoms. (2) Optic disc edema at onset must have been documented in the Ocular Vascular Clinic and must still be present for inclusion in this study. (3) Spontaneous resolution of optic disc edema was observed. (4) The eye had optic disc-related visual field defects. (5) There was no neurologic, systemic, or ocular disorder that could be responsible for optic disc edema and visual impairment. (6) All eyes must have information on best-corrected phakic refraction. (7) Only eyes with NA-AION, or in cases with bilateral NA-AION, only the most recently involved eye, were included, that is, only 1 eye per patient.
Exclusion Criteria Exclusion criteria were as follows: (1) retinal or optic nerve lesion or any other factor (e.g., cataract, intraocular lens implant or aphakia) that may influence the visual status or refraction; (2) NA-AION with proliferative diabetic retinopathy with active neovascularization, vitreous hemorrhages, traction detachment, or other complications influencing the visual acuity or fields; (3) glaucoma; and (4) aphakia or contact lens.
Studies Performed A detailed ophthalmic and medical history was obtained at the patient’s first visit to our clinic (by SSH); in the medical history, we elicited a detailed history of all previous or current systemic diseases, particularly of arterial hypertension, diabetes mellitus, ischemic heart disease, strokes, transient ischemic attacks, carotid artery disease, and hyperlipidemia. A comprehensive ophthalmic evaluation was performed at that time (by SSH); this included recording of best-corrected visual acuity using Snellen visual acuity chart, central visual field testing using Amsler grid chart, visual fields with manual kinetic perimetry with Goldmann perimeter (using I-2e, I-4e, and V-4e targets regularly), relative afferent pupillary defect, intraocular pressure, slit-lamp examination of the anterior segment, lens and vitreous, direct and indirect ophthalmoscopy, stereoscopic color fundus photography, and, in acute cases, stereoscopic fluorescein fundus angiography. When giant cell arteritis was suspected on the basis of systemic symptoms, elevated erythrocyte sedimentation rate, and/or C-reactive protein, or arteritic AION was suspected, a temporal artery biopsy was performed to rule out giant cell arteritis.7–9 At each follow-up visit, the same ophthalmic evaluation and stereoscopic color fundus photography were done, except that fluorescein fundus angiography was not performed. At the initial visit, a detailed systemic evaluation was performed by a cardiologist, an internist, or the patient’s local physician. Where indicated, other systemic or neurologic investigations were done to rule out any systemic or neurologic cause of visual loss.
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Refraction data evaluated in this study were based on the findings at only the initial visit with NA-AION to our clinic. The refractive error was read from the distance glasses of the patient, which provided the best visual acuity, or the refraction done in the clinic. Patients without glasses and no refractive error in the distance in our study were considered emmetropic. Refractive error was converted to spherical equivalent for data analysis. Spherical equivalent of refraction is equal to (⫾sphere) ⫹ ½ (⫾cylinder). For comparison of spherical equivalent refraction of our study group with that in the general population, we used the data from the Framingham Eye Study cohort10 (in 5197 eyes of persons aged 52– 85 years) and the visual examination in 1999 –2000 National Health and Nutrition Examination Survey (NHANES)11 (4094 eyes in persons aged ⱖ20 years). Protocols for evaluation of refractive error used in those 2 studies were different, resulting in different findings (see below). Our protocol for refraction evaluation was identical to that used in the Framingham Eye Study cohort.10
Morphometric Measurement of C/D Ratio Morphometric measurement of C/D ratio was performed in the normal fellow optic discs of 65 randomly picked patients with unilateral NA-AION in the present study. The morphometric measurements were performed by the team of Professor Jost Jonas (Department of Ophthalmology, Ruprecht-Karls-University Heidelberg, Mannheim, Germany) on the fundus photographs taken at Iowa City. Optic disc photographs were taken in both eyes of all patients with NA-AION at their initial visit. The disc slides were projected on a scale of 1 to 15. The outlines of the optic cup and optic disc were plotted on paper and morphometrically analyzed. The optic cup was defined on the basis of contour and not of pallor. The border of the optic disc was identical to the inner side of the peripapillary scleral ring. Because the magnification of the optic disc photographs varied according to the fundus camera used, and keratometric readings had not been obtained for all eyes included in the study, the optic disc measurements were expressed in relative size units.
Statistical Analysis Refraction data were evaluated from only the findings at the initial visit. In patients in whom both eyes were involved, the refraction data of the eye whose onset was closest to the initial visit were used. There were 19 patients who reported the same onset time for both eyes. Of these patients, 6 had the same spherical equivalent in both eyes. For the remaining 13 patients, the eye with the worse refraction (i.e., highest absolute spherical equivalent value) was used (10 within 0.50 diopter difference and 3 between 0.8 and 1.25 diopter difference). The association of spherical equivalent refraction of eyes with NA-AION with age was examined by Pearson correlation coefficient and Mantel-Haenszel chi-square test. The Cochran-MantelHaenszel test was used to compare the spherical equivalent between male and female patients, controlling for age. To determine whether the distribution of spherical equivalent in eyes with NAAION differs from that of the general population, refraction data reported in the Framingham study10 and 1999 –2000 NHANES Vision Examination11 were used for comparison. This was done by dividing spherical equivalent into the intervals reported in the Framingham study10 for age groups 50 to 64 years, 65 to 74 years, and ⬎75 years, and comparing NA-AION and Framingham refraction data using the Mantel-Haenszel chi-square test based on the ranked ordered intervals. For comparison with spherical equiv-
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy Table 1. Distribution of Spherical Equivalent by Age* in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy Age (y)
n
<ⴚ6.0
ⴚ6 to ⴚ3.1
ⴚ3 to ⴚ0.1
0
ⴙ0.1 to ⴙ3.0
ⴙ3.1 to ⴙ5.0
>ⴙ5.0
20–49 50–64 65–74 ⬎75
106 263 170 69
6 (5.7%) 3 (1.1%) 0 (0.0%) 0 (0.0%)
6 (5.7%) 5 (1.9%) 5 (2.9%) 1 (1.4%)
20 (18.9%) 51 (19.4%) 18 (10.6%) 11 (15.9%)
52 (49.1%) 72 (27.4%) 35 (20.6%) 13 (18.8%)
18 (17.0%) 112 (42.6%) 85 (50.0%) 35 (50.7%)
2 (1.9%) 13 (4.9%) 17 (10.0%) 3 (4.4%)
2 (1.9%) 7 (2.7%) 10 (5.9%) 6 (8.7%)
Refractive error classification, The following classification was used in this study:12 Emmetropia ⫽ no refractive error. Myopia: high myopia ⫽ ⬍ ⫺6.0 diopters; medium myopia ⫽ ⫺6 to ⫺3.1 diopters; low myopia ⫽ ⫺3 to ⫺0.1 diopters. Hyperopia: low hyperopia ⫽ ⫹0.1 to ⫹3.0 diopters; medium hyperopia ⫽ ⫹3.1 to 5 diopters; high hyperopia ⫽ ⬎ ⫹5.0 diopters. *There is a significant association between spherical equivalent and age (Mantel-Haenszel chi-square P⬍0.0001).
alent in the NHANES study,11 the chi-square goodness-of-fit test was used.
Results Refractive Error Refraction data came from 608 eyes (608 patients) with NAAION: 308 right eyes (51%) and 300 left eyes (49%). The study comprised 358 male (59%) and 250 female (41%) patients, with a mean age of 60.9 years (standard deviation [SD] ⫽12.6; range 20.5–95.2). The mean age was 61.1 (14.1) years for female patients and 60.7 (11.5) years for male patients. Seventy-one percent of patients were aged between 50 and 74 years, 11% of patients were aged ⱖ75 years, and 17% were aged ⬍50 years. The median time from the onset to the date of refraction was 2 weeks (interquartile range 1–5 weeks). Table 1 shows the distribution of spherical equivalent refraction in NA-AION eyes by age, with the intervals for spherical equivalent corresponding to high myopia (greater than ⫺6.0 diopters), medium myopia (⫺6 to ⫺3.1 diopters), low myopia (⫺3 to ⫺0.1 diopters), emmetropia (no refractive error), low hyperopia (⫹0.1 to ⫹3.0 diopters), medium hyperopia (⫹3.1–5 diopters), and high hyperopia (greater than ⫹5.0 diopters).12 There is a significant association between spherical equivalent refraction and age (P⬍0.0001); the prevalence of emmetropia decreases with age, and the prevalence of hyperopia increases with age. The distribution of spherical equivalent did not differ significantly
between male and female patients (P ⫽ 0.994), with the difference between male and female patients in the myopia, emmetropia, and hyperopia categories ranging from 0.1% to 3%. A similar result was seen after controlling for age (P ⫽ 0.976). Comparison of refraction spherical equivalent of patients with NA-AION who were aged ⱖ50 years with the age-matched Framingham study10 showed no significant difference between the 2 groups (P ⫽ 0.289). The differences between NA-AION and the Framingham study were 0.1% to 3.2% for myopia, 0.7% to 8.1% for emmetropia, and 0.2% to 10.8% for hyperopia (Table 2). Comparison with the age-matched United States’ general population from the 1999 –2000 NHANES Vision Examination11 showed a higher proportion of NA-AION eyes with spherical equivalent between ⫺0.5 and 0.5 diopters, and a smaller proportion with ⫺3 to ⬍⫺0.5 diopters and ⬎0.5 to ⫹3 diopters (P⬍0.001; Table 3).
C/D Ratio In the 65 fellow normal eyes of patients with unilateral NA-AION, morphometric study of the optic disc showed a vertical C/D ratio of ⬍0.15 in 37% and ⬍0.25 in 75% (mean 0.199 [SD 0.093]; range 0.04 – 0.46) and a horizontal C/D ratio of ⬍0.15 in 31% and ⬍0.25 in 82% (mean horizontal C/D ratio 0.194 [SD 0.090]; range 0.08 – 0.6). Figure 1 shows the morphometric findings of the horizontal and vertical C/D ratio in the 65 eyes plotted against the spherical equivalent. For the horizontal C/D ratio, a higher degree of myopia and higher degree of hyperopia were significantly associated with larger C/D ratio (P ⫽ 0.021 for myopia and P ⫽ 0.004 for hyperopia; Fig 1A). A similar pattern was seen for
Table 2. Comparison of Spherical Equivalent in Nonarteritic Anterior Ischemic Optic Neuropathy with Framingham Study10 by Age‡ Age 50–64 y*
Age 65–74 y
Age >75 y
Spherical Equivalent
NA-AION (n ⫽ 263)
Framingham† (n ⫽ 2739)
NA-AION (n ⫽ 170)
Framingham† (n ⫽ 1692)
NA-AION (n ⫽ 69)
Framingham† (n ⫽ 766)
⬍⫺4.0 ⫺4.0 to ⫺2.1 ⫺2.0 to ⫺0.1 0 ⫹0.1 to ⫹2.0 ⫹2.1 to ⫹4.0 ⬎⫹4.0
5 (1.9%) 10 (3.8%) 44 (16.7%) 72 (27.4%) 95 (36.1%) 27 (10.3%) 10 (3.8%)
75 (2.7%) 98 (3.6%) 370 (13.5%) 771 (28.1%) 1001 (36.5%) 323 (11.8%) 101 (3.6%)
3 (1.8%) 4 (2.4%) 16 (9.4%) 35 (20.6%) 67 (39.4%) 31 (18.2%) 14 (8.2%)
30 (1.8%) 68 (4.0%) 143 (8.5%) 294 (17.4%) 640 (37.8%) 432 (25.5%) 85 (5.0%)
0 (0%) 2 (2.9%) 10 (14.5%) 13 (18.8%) 28 (40.6%) 9 (13.0%) 7 (10.1%)
20 (2.6%) 14 (1.8%) 94 (12.3%) 82 (10.7%) 291 (38.0%) 183 (23.9%) 82 (10.6%)
NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy. *Includes age 50 – 64 years in NA-AION, with a minimum age of 52 years in the Framingham study. † From Table 8.6 of the Framingham Eye Study.10 ‡ No significant difference in spherical equivalent of patients with NA-AION compared with Framingham Study (Cochran-Mantel-Haenszel controlling for age P ⫽ 0.289). Comparison at each age category: P ⫽ 0.416 for 50 – 64 years; P ⫽ 0.572 for 65–74 years; and P ⫽ 0.465 for ⬎75 years.
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Ophthalmology Volume 115, Number 12, December 2008 Table 3. Comparison of Spherical Equivalent in Nonarteritic Anterior Ischemic Optic Neuropathy with the U.S. Population from National Health and Nutrition Examination Survey 1999 –2000 Vision Examination,11 by Age Age 20–49 y Spherical Equivalent
NA-AION (n ⫽ 106)
⬍⫺3.0 4 (10.3%) ⫺3.0 to ⬍⫺0.5 5 (12.8%) ⫺0.5 to ⫹0.5 26 (66.7%) ⬎⫹0.5 to ⫹3.0 2 (5.1%) ⬎⫹3.0 2 (5.1%) P ⫽ 0.001
NHANES* (n ⫽ 2152)
Age 50–64 y NA-AION (n ⫽ 263)
16.3% (14.1, 18.6) 8 (11.9%) 27.0% (22.7, 31.3) 6 (9.0%) 43.1% (40.4, 45.8) 47 (70.2%) 11.8% (9.5, 14.2) 4 (6.0%) 1.7% (1.1, 2.3) 2 (3.0%) P⬍0.0001
Age 65–74 y
NHANES* (n ⫽ 902)
NA-AION (n ⫽ 170)
NHANES* (n ⫽ 595)
Age >75 y NA-AION (n ⫽ 69)
NHANES* (n ⫽ 445)
10.6% (7.7, 13.6) 4 (2.7%) 3.7% (1.6, 5.8) 5 (2.4%) 5.7% (2.0, 9.4) 26.4% (23.6, 29.1) 18 (12.2%) 18.2% (13.6, 22.8) 12 (5.7%) 28.3% (23.5, 33.2) 21.5% (17.7, 25.3) 92 (62.2%) 18.4% (14.1, 22.8) 115 (54.3%) 12.7% (7.7, 17.7) 37.4% (33.5, 41.3) 27 (18.2%) 49.1% (43.1, 55.2) 56 (26.4%) 43.8% (37.7, 49.8) 4.0% (2.1, 6.0) 7 (4.7%) 10.5% (7.8, 13.2) 24 (11.3%) 9.6% (6.8, 12.3) P⬍0.0001 P ⫽ 0.0006
NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; NHANES ⫽ National Health and Nutrition Examination Survey. *Weighted estimate of prevalence with 95% confidence limits.
vertical C/D ratio in hyperopia (P ⫽ 0.057) but not in myopia (P ⫽ 0.428) (Fig 1B).
control groups, but their sample size was small; it is possible that with a larger sample size their findings might have been different.
Discussion
C/D Ratio
Refractive Error
It is unfortunate that great stress has been placed on the importance of a small or absent cup (the so-called disc at risk) in NA-AION,13–15 leading to the impression in the ophthalmic community that a small or absent cup is actually the primary factor in the development of the disease. We have met persons without any visual symptom who have been alarmed by ophthalmologists telling them that they were at risk of developing NA-AION simply because they have no cup or a small cup. It is important to place this subject in proper perspective; to do that one has to look at the overall pattern of C/D ratio in the normal general population versus that in patients with NA-AION.
Our study in patients with NA-AION showed a significant (P⬍0.0001) association between age and refractive error, with the prevalence of emmetropia decreasing with age and the prevalence of hyperopia increasing with age, but no difference between male and female patients. We found no significant difference in spherical equivalent refraction in eyes with NA-AION compared with that of an age-matched general population in the Framingham Eye Study cohort10 (Table 2). However, comparison with the age-matched US population from the 1999 –2000 NHANES Vision Examination11 showed a higher proportion of NA-AION eyes with a spherical equivalent between ⫺0.5 and 0.5 diopters, and a smaller proportion with ⫺3 to ⬍⫺0.5 diopters and ⬎0.5 to ⫹3 diopters (P⬍0.001, Table 3). The disparity in the findings between the Framingham Eye Study cohort10 and the NHANES study11 is due to the difference in the protocols of refraction evaluation between the 2 studies. Our protocol for refraction was identical to that used in the Framingham Eye Study cohort.10 Refraction findings in our study (in 608 eyes), as well as comparison of our findings with those in the Framingham Eye Study cohort10 (in 5197 eyes; Table 2) and the NHANES study11 (in 4094 eyes; Table 3), contradict the findings of 3 previous studies based on 1262, 50,4 and 375 eyes, all suggesting that patients with NA-AION are more hypermetropic than the control group. Of the 3 previous studies, the study by Beck et al2 had the largest number of eyes (i.e., 126 eyes with NA-AION). In that study, the mean age was 62.1 years in the NA-AION group and 36.8 years in the control group; that marked age difference accounts for the finding of more hypermetropia in the NA-AION group than in the control group (see above). This is further supported by the fact that there was no difference in refraction between NA-AION and arteritic AION eyes in the study by Beck et al, because those groups were almost similar in age. The other 2 studies4,5 had age-matched
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C/D Ratio in the Normal General Population Information about the C/D ratio in persons without NAAION is provided by 4 general population-based studies (Table 4).2,10,16,17 The Framingham Eye Study,10 in a survey of a general population without any visual symptom, evaluated the C/D ratio in 5054 eyes of persons of all ages on ophthalmoscopy. The mean horizontal C/D ratio was 0.250 (SD 0.159), and the mean vertical C/D ratio was 0.255 (SD 0.166). There was no evidence that C/D ratio changes significantly with age. The Rotterdam Study,16 based on a general population study of 5114 subjects aged ⱖ55 years, showed a mean vertical C/D ratio of 0.49 (SD, 0.14) and a mean horizontal C/D ratio of 0.40 (SD, 0.14) using a stereoscopic image analyzer. It showed no association of cup area, vertical C/D ratio, and horizontal C/D ratio with age, refractive error, or height.16 In another investigation,17 this Rotterdam Study group evaluated vertical C/D ratio in 5143 subjects aged ⱖ55 years by 2 methods: ophthalmoscopic and semiautomated. That study showed a mean ophthalmoscopic vertical C/D ratio 0.30 (standard error, 0.0021; range, 0.00 – 1.00) compared with a semiautomated measured vertical C/D ratio of 0.49 (standard error, 0.0019; range, 0.04 –
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy In our current morphometric study in 65 normal fellow eyes, the vertical C/D ratio was ⬍0.15 in 37% and ⬍0.25 in 75% (mean, 0.199 [SD, 0.093]), and the horizontal C/D ratio was ⬍0.15 in 31% and ⬍0.25 in 82% (mean, 0.194 [SD, 0.090]) (Fig 1; Table 4). In our previous ophthalmoscopic study2 in 126 normal fellow eyes, the C/D ratio was ⬍0.15 in 48% and ⬍0.25 in 71% (mean, 0.16⫾0.15) (Table 4).
Comparison of C/D Ratio in Patients with NA-AION Versus Normal Control Population Table 4 summarizes the data. This shows that the C/D ratio in persons with NA-AION is smaller than that of the normal control population. The methods used to evaluate the C/D ratio have been different in different studies, resulting in different C/D ratios. However, the magnitude of the difference between the control eyes and the NA-AION eyes suggests that this difference cannot be attributed solely to the different methods used to estimate the C/D ratio in various studies. As discussed previously, the semiautomated methods for measurement of the C/D ratio (used in the Rotterdam Study16 and our current study) give a larger ratio than the ophthalmoscopically measured ratio.17
The Role of an Absent or Small Cup in the Pathogenesis of Development of NA-AION
Figure 1. Plots of correlations between the C/D ratios and spherical equivalent refraction in diopters. (A) Plot of horizontal C/D ratio against spherical equivalent refraction in diopters. (B) Plot of vertical C/D ratio against spherical equivalent refraction in diopters. C/D ⫽ cup/disk ratio. NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy.
0.86). This showed that semiautomated measurement of the vertical C/D ratio is larger than the ophthalmoscopically measured ratio. According to the authors, the reason for this discrepancy between the 2 methods is the use of different criteria for defining the cup and possibly the disc. The authors concluded that currently “there is no gold standard for assessment of the VCDR (vertical C/D ratio).”17 Beck et al,2 in a study of 122 eyes of persons without NA-AION, showed that 12% had no cup, 8% had a C/D ratio from 0.05 to 0.149, and 19% had a C/D ratio from 0.15 to 0.249.
C/D Ratio in Patients with NA-AION Because the C/D ratio is almost always the same in both eyes in normal persons, we have carried out 2 types of studies in the normal fellow eyes of patients with unilateral NA-AION.
We have discussed this subject in detail elsewhere.2 Briefly, in the multifactorial scenario of the pathogenesis of NAAION, one has to consider the role of the following 2 factors relevant to C/D ratio. The size of the physiologic cup is determined primarily by the size of the scleral canal embryologically.18 With a small scleral canal and associated small opening in the Bruch’s membrane in the region of the optic disc, there is a small cup or no cup. As shown above, the C/D ratio in persons with NA-AION is smaller than that seen in general population (Table 4). This means the optic discs of patients with NA-AION tend to have smaller openings in their Bruch’s membrane and scleral canal than the general population, resulting in crowding of the optic nerve fibers as they pass through the restricted space in the optic disc and lamina cribrosa. Axoplasmic flow stasis has a variety of causes, for example, ischemia and hypoxia,19 which result in swollen axons. Axoplasmic flow stasis has been shown to be responsible for optic disc edema in ischemic optic neuropathy.20 We believe the sequence of events in the development of NA-AION is as follows. Initially, optic nerve head ischemia/hypoxia causes axoplasmic flow stasis. When there is no cup or only a small cup, the swollen axons are crowded in a restricted space in the optic disc. In that case, the swollen axons can expand only by compressing the surrounding tissues. The tissues that are most vulnerable to compression in this case are capillaries and other fine vessels lying among the nerve fibers. Thus, swollen axons in restricted space within the optic disc produce secondary vascular changes.21 It has been shown that asymptomatic optic disc edema is the earliest sign of NA-AION.22,23 It has also been demonstrated that nocturnal arterial hypotension
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Ophthalmology Volume 115, Number 12, December 2008 Table 4. Comparison of Cup/Disc Ratio in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy Versus the Normal Control Group Normal Control or with NA-AION
Study Group Framingham Eye Study
10
No. of Eyes Examined
Method Used to Evaluate C/D Ratio
Control
5054
Ophthalmoscopy
Rotterdam Study16 Rotterdam Study17 Beck et al2
Control Control Control
5114 5143 122
Stereoscopic image analyzer Ophthalmoscopy Ophthalmoscopy
Beck et al2
NA-AION
126
Our current study
NA-AION
65
Ophthalmoscopy Morphometric
C/D Ratio Mean horizontal C/D ratio 0.250⫾0.159; mean vertical C/D ratio 0.255⫾0.166. Mean 0.49⫾0.14 Mean 0.30 (standard error 0.0021) ⬍ 0.15 in 20%; ⬍0.25 in 39% (mean 0.3⫾0.19) ⬍0.15 in 48%; ⬍0.25 in 71% (mean 0.16⫾0.15) ⬍0.15 in 37% and ⬍0.25 in 75% (mean 0.199⫾0.093)
C/D ⫽ cup/disc ratio; NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; ⫾ ⫽ SD.
precipitates the development of NA-AION.24 Thus, the available evidence indicates that the sequence of events in the development of NA-AION is as follows: subclinical ischemia (hypoxia) of the optic nerve head ¡ axoplasmic flow stasis in the optic nerve fibers ¡ axonal swelling ¡ asymptomatic optic disc edema22 (incipient NA-AION23) ¡ compression of the intervening capillaries by swollen axons in a crowded disc ¡ setting up a vicious cycle, that is, the greater the compression of capillaries, the greater the blood flow compromise, the greater the axoplasmic flow stasis and the more axonal swelling. Because compression of the optic disc capillaries compromises their blood flow, a decrease in blood pressure must further derange their blood flow. Therefore, in this situation, a decrease in perfusion pressure in the optic disc capillaries because of nocturnal arterial hypotension results in marked ischemia and precipitates visual loss (symptomatic NA-AION), which is usually discovered on waking up in the morning.24 From this sequence of events, it is evident that in the multifactorial scenario of pathogenesis of NA-AION, contrary to the prevalent impression, an absent or small cup is simply a secondary contributing factor, once the process of NA-AION has started, and not a primary factor.2,23,25
Relationship Between Refractive Error and C/D Ratio Tomlinson and Phillips3 stated that the more hypermetropic the eye, the smaller the C/D ratio, and conversely the more myopic an eye, the larger the C/D ratio. The Rotterdam Study,16 in contrast, showed no association of C/D ratio with refractive error in the general population. That was also true in our previous study.2 Our current morphometric study in fellow normal eyes of patients with unilateral NA-AION showed that for horizontal C/D ratio, a higher degree of myopia and higher degree of hyperopia were both significantly associated with a larger C/D ratio (P ⫽ 0.021 for myopia and P ⫽ 0.004 for hyperopia; Fig 1A). A similar pattern was seen for the vertical C/D ratio in hyperopia (P ⫽ 0.057) but not in myopia (P ⫽ 0.428) (Fig 1B). Thus, none of the studies based on much larger populations support the conclusion of Tomlinson and Phillips.3
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The main findings of this study are as follows: There is a significant (P⬍0.0001) association between spherical equivalent refraction and age, with the prevalence of emmetropia decreasing with age and the prevalence of hyperopia increasing. Studies in the general population16 and in patients with NA-AION2 show no association between refractive error and C/D ratio. Our morphometric study in patients with NA-AION showed that a higher degree of myopia and a higher degree of hyperopia are significantly associated with larger C/D ratio. These findings contradict a previous study3 showing that the more hypermetropic the eye, the smaller the C/D ratio. The C/D ratio in persons with NA-AION is smaller compared with that in the general population (Table 4). As discussed previously, contrary to the prevalent impression, an absent or small cup is simply a secondary contributing factor in the development of NAAION, once the process of NA-AION has started, and not a primary factor.2,23,25 Acknowledgments. We thank Dr. Mark Wilkinson, for expert advice about refraction, and Professor Jost Jonas, for help with the morphometric evaluation of C/D ratio in our study.
References 1. Hayreh SS. Pathogenesis of cupping of the optic disc. Br J Ophthalmol 1974;58:863–76. 2. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503– 8. 3. Tomlinson A, Phillips CI. Ratio of optic cup to optic disc in relation to axial length of eyeball and refraction. Br J Ophthalmol 1969;53:765– 8. 4. Katz B, Spencer WH. Hyperopia as a risk factor for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116:754 – 8. 5. Philips B, Dralands L, Missotten L. Non-arteritic anterior ischemic optic neuropathy and refraction. Bull Soc Belge Ophtalmol 1995;259:183–7. 6. Mansour AM, Shoch D, Logani S. Optic disk size in ischemic optic neuropathy. Am J Ophthalmol 1988;106:587–9. 7. Hayreh SS. Anterior ischaemic optic neuropathy: differentiation of arteritic from non-arteritic type and its management. Eye 1990;4:25– 41.
Hayreh and Zimmerman 䡠 Nonarteritic Anterior Ischemic Optic Neuropathy 8. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123:285–96. 9. Hayreh SS, Zimmerman B. Management of giant cell arteritis: our 27-year clinical study: new light on old controversies. Ophthalmologica 2003;217:239 –59. 10. Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study Monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973–1975. Surv Ophthalmol 1980;24 (suppl):335– 610. 11. National Center for Health Statistics. National Health and Nutrition Examination Survey, 1999 –2000, Vision Exam. Available at: http://www.cdc.gov/nchs/about/major/nhanes/ exam99_00.htm. Accessed April 9, 2008. 12. Borish IM. Clinical Refraction. 3rd ed. vol 1. Chicago, IL: Professional Press; 1970:90, 116. 13. Burde RM. Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116: 759 – 64. 14. Wang MY, Sadun F, Levin LB, et al. Occurrence of familial nonarteritic anterior ischemic optic neuropathy in a case series. J Neuroophthalmol 1999;19:144 –7. 15. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafilassociated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002;109:584 –7. 16. Ramrattan RS, Wolfs RC, Jonas JB, et al. Determinants of
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optic disc characteristics in a general population: the Rotterdam Study. Ophthalmology 1999;106:1588 –96. Wolfs RC, Ramrattan RS, Hofman A, de Jong PT. Cup-to-disc ratio: ophthalmoscopy versus automated measurement in a general population: the Rotterdam Study. Ophthalmology 1999;106:1597– 601. Duke-Elder S, Cook C. Normal and abnormal development. Part 1. Embryology. In: Duke-Elder S, ed. System of Ophthalmology. Vol III. Normal and abnormal development. Part 1. St. Louis, MO: Mosby, 1963:109 –10. Hayreh SS. Fluids in the anterior part of the optic nerve in health and disease. Surv Ophthalmol 1978;23:1–25. McLeod D, Marshall J, Kohner EM. Role of axoplasmic transport in the pathophysiology of ischaemic disc swelling. Br J Ophthalmol 1980;64:247– 61. Hayreh SS. Optic disc edema in raised intracranial pressure. V. Pathogenesis. Arch Ophthalmol 1977;95:1553– 65. Hayreh SS. Anterior ischemic optic neuropathy. V. Optic disc edema an early sign. Arch Ophthalmol 1981;99:1030 – 40. Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol 1997;124:641–7. Hayreh SS, Zimmerman MB. Optic disc edema in nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2007;245:1107–21.
Footnotes and Financial Disclosures Originally received: May 16, 2008. Final revision: August 5, 2008. Accepted: August 6, 2008.
Manuscript no. 2008-594.
1
Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa City, Iowa. 2
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa.
Financial Disclosure(s): The authors have no conflict of interest. Supported by grant EY-1151 from the National Institutes of Health, and in part by unrestricted grant from Research to Prevent Blindness, Inc., New York. Correspondence: Sohan Singh Hayreh, MD, PhD, Department of Ophthalmology and Visual Sciences, University Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1091. E-mail: [email protected].
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