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Nonarteritic Anterior Ischemic Optic Neuropathy: Clinical Characteristics in Diabetic Patients Versus Nondiabetic Patients
Nonarteritic Anterior Ischemic Optic Neuropathy: Clinical Characteristics in Diabetic Patients Versus Nondiabetic Patients Sohan Singh Hayreh, MD, PhD,1 M. Bridget Zimmerman, PhD2 Objective: To investigate various aspects of nonarteritic anterior ischemic optic neuropathy (NA-AION) in patients with diabetes mellitus and to compare them with those in patients without diabetes mellitus. Design: Cohort study. Participants: A total of 655 consecutive patients (931 eyes) with NA-AION, first seen in the clinic from 1973 to 2000. Methods: At the first visit, all patients had a detailed ophthalmic and medical history and comprehensive ophthalmic evaluation, including color fundus photography and fluorescein fundus angiography. Visual evaluation was done by recording visual acuity with the Snellen visual acuity chart and visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow-up visit, except for fluorescein fundus angiography. Of this cohort, 528 eyes (345 patients) were treated with systemic corticosteroid therapy during the initial stage. Main Outcome Measures: Demographic and clinical differences between diabetic patients and nondiabetic patients with NA-AION. Results: Comparison of various clinical features of NA-AION in diabetic and nondiabetic patients showed no significant difference in age, but slightly more women than men (45% vs 38%; P ⫽ 0.078) were diabetic and had a higher prevalence of hypertension (P⬍0.0001), ischemic heart disease (P ⫽ 0.0001), transient ischemic attacks (P ⫽ 0.0003), and second eye involvement by NA-AION (P ⫽ 0.003). Initial visual acuity did not differ significantly between diabetic and nondiabetic patients; however, of those seen within 2 weeks of onset of NA-AION, diabetic patients had less severe visual field defect (P ⫽ 0.010). At 6 months from onset, there was no significant difference in visual acuity and visual field improvement between diabetic and nondiabetic patients. Time to optic disc edema resolution in NA-AION was (P ⫽ 0.003) longer in diabetic patients than in nondiabetic patients. The optic disc of diabetic patients usually has characteristic diagnostic dilated telangiectatic vessels during the early stages of NA-AION. Conclusions: Diabetic patients with NA-AION show several demographic and clinical differences from nondiabetic patients, which has led to controversy about its diagnosis and management. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:1818 –1825 © 2008 by the American Academy of Ophthalmology.
A voluminous amount of literature shows that diabetes mellitus is an important risk factor in the development of nonarteritic anterior ischemic optic neuropathy (NAAION);1–3 however, there is little information about the various characteristics of NA-AION in patients with diabetes mellitus and whether those differ in any way from those of nondiabetic patients. Moreover, NA-AION has been described in diabetic patients under different eponyms, the most common being “diabetic papillopathy.”4 –12 That has resulted in a good deal of confusion and controversy about the nature of optic neuropathy in diabetic patients, as well as the role of diabetes mellitus in NA-AION. The objective of the present study was to investigate various aspects of NA-AION in patients with diabetes mellitus and to compare them with those in patients without diabetes mellitus. The study population comprised a large
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
cohort of patients prospectively collected in the Ocular Vascular Clinic at the University of Iowa Hospitals and Clinics from 1973 to 2000.
Patients and Methods We have prospectively and systematically investigated various aspects of NA-AION in the Ocular Vascular Clinic at the Tertiary Care University of Iowa Hospitals and Clinics since 1973. The present study was a 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 various characteristics of NA-AION in patients with diabetes mellitus and how they differed, if at all, from NA-AION in patients without diabetes mellitus. The study consists of a cohort of 655 consecutive patients (931 eyes) who were first seen in the clinic from 1973 to 2000, and thereafter followed serially, and who ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.03.032
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus fulfilled the inclusion and exclusion criteria. The data were collected prospectively and systematically.
Criteria Required for Diagnosis of NA-AION and Inclusion in the Present Study The criteria included a history of sudden visual loss, usually discovered in the morning, and an absence of other ocular, systemic, or neurologic diseases that might influence or explain the patient’s visual symptoms; optic disc edema (ODE) at onset, documented in the Ocular Vascular Clinic and still present; observed spontaneous resolution of ODE; optic disc-related visual field defects in the eye; no neurologic, systemic, or ocular disorder that could be responsible for ODE and visual impairment; and no treatment for NA-AION before the evaluation. Patients with a follow-up of less than 2 months were included in the analysis of demographic variables and initial visual status but excluded from the follow-up analysis of visual outcome. The diagnosis of diabetes in this study was based on the following criteria: (a) Patients who were already on treatment for diabetes at the time of onset of NA-AION were considered to have a diabetes diagnosis; (b) In others, the diagnosis of diabetes was based solely on the evaluation and diagnosis by the internists at the University of Iowa Hospitals and Clinics or the local primary care physician of the patient. A patient was considered diabetic only if he or she had diabetes at the time when the NA-AION developed. If diabetes developed years later, that was not considered relevant to the development of NA-AION and the patient was not considered diabetic.
Exclusion Criteria Patients who had any retinal or optic nerve lesion or any other factor (e.g., cataract) that could have influenced the visual status were excluded. Patients with NA-AION with only background diabetic retinopathy were included, but all who had active neovascularization, vitreous hemorrhages, traction detachment, or other complications influencing the visual acuity or fields were excluded. Patients who had a diagnosis of glaucoma and visual field loss were excluded; however, those with elevated intraocular pressure with a documented normal field before the onset of NA-AION were included. Eyes with unreliable visual fields were excluded.
Studies Performed A detailed ophthalmic and medical history was obtained at the patient’s first visit to the 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; this included recording the best corrected visual acuity using the Snellen visual acuity chart, central visual field testing using the Amsler grid chart, visual fields with manual kinetic perimetry using the Goldmann perimeter (using I-2e, I-4e, and V-4e targets regularly), relative afferent pupillary defect, intraocular pressure using the Goldmann applanation tonometer, 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 or C-reactive protein, or suspicion of arteritic AION, a temporal artery biopsy was performed to rule out giant cell arteritis.13–15 At each follow-up visit, the same ophthalmic evaluation and stereoscopic color fundus photography were per-
formed, with the exception of fluorescein fundus angiography. 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.
Corticosteroid Therapy All patients were given a choice to be treated with systemic steroid therapy or to be followed without any treatment. The choice was entirely voluntary, that is, the treatment decision was based on a “patient choice” scheme, instead of the conventional randomization. Various aspects of corticosteroid therapy, treatment protocol, and safeguards against any potential bias in choice by the patient for treatment are discussed at length elsewhere.16,17 For treatment of diabetic patients with corticosteroid therapy, we initially discussed in detail the risks of treating diabetic patients with corticosteroid therapy with the Endocrinology Department of the University of Iowa Hospitals and Clinics because of its side effects; approval was granted, with the requirement that the patients be closely monitored by their internists for diabetes mellitus. Thus, when diabetic patients opted for the corticosteroid therapy, we first had a thorough discussion with their internists about monitoring the patient closely while on corticosteroid therapy, and the therapy was given only if the internists consented to do so (most did). If the internist did not feel comfortable with the treatment, we did not give corticosteroid therapy to that patient. Thus, the diabetic patients who decided to have corticosteroid therapy were managed jointly with their internists as long as they were receiving the therapy. Contrary to the highly prevalent impression, we have had no problems treating diabetic patients with corticosteroid therapy for more than 35 years with these precautions.
Follow-up Protocol for All Patients The patients who opted for corticosteroid therapy were followed approximately every 2 weeks as long as they were taking up to 40 mg prednisone daily, and at 3- to 4-week intervals after that until they finished the therapy. Patients who opted not to be treated were followed similarly. When necessary, they were seen more often in addition to this protocol. After that, they were followed at 3 months, 6 months, and then yearly; a few patients have been followed for as long as 33 years in the clinic.
Evaluations of Visual Acuity, Visual Field Defects, and Optic Disc Edema Evaluations of visual acuity, visual field defects, and ODE have been described in detail elsewhere.3 Each was evaluated separately in a masked fashion, that is, changes in visual acuity, visual fields, and ODE were evaluated independently of each other, so that the severity of one did not influence the evaluation of the other.3 Visual status evaluation and steps taken to reduce potential bias are discussed at length elsewhere.3 The method of grading the visual fields, examples of the various grades of visual fields, and their evaluation are also given in detail elsewhere.3,18 In eyes that developed recurrence of NA-AION, only the data on visual and other evaluations collected up to the last follow-up visit of the first episode were used, that is, before the onset of recurrence.
Statistical Methods Descriptive statistics (means, standard deviation, and percentages) were computed for the demographic, clinical variables, visual
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Ophthalmology Volume 115, Number 10, October 2008 acuity, and visual field defect at the initial visit. Changes in visual acuity and visual field defect were assessed from the initial visit to ODE resolution, from ODE resolution to 9 months after resolution, and for the overall follow-up at 3, 6, and 12 months from the initial visit. Because patient visits did not exactly fall at the specified time period for various logistic, seasonal, or geographic reasons, a ⫾6-week interval was used for the 3- and 6-month follow-ups and ⫾12 weeks for the 12-month follow-up. A change of at least 3 lines in the Snellen visual acuity chart was considered a significant change in either direction (i.e., improved or deteriorated), which is equivalent to a logarithm of the minimum angle of resolution (logMAR) change of at least 0.30. At these same intervals, change in visual field loss was also examined, with a difference in grade of at least 0.5 in either direction defined as improvement or deterioration. The percentages of improved and worse visual outcomes were calculated at each of these intervals. Only the eyes that had at least that length of follow-up for the specified interval were included in the computation. The changes were not carried over if the patient did not have follow-up for the later time period. These are reported separately for those first seen within 2 weeks of onset of visual loss and those first seen more than 2 weeks after visual loss. To compare the demographic and clinical variables between diabetic and nondiabetic patients, the Pearson chi-square test was used for the categoric variables and the 2-sample t test was used for the continuous variables. Visual acuity and visual field defect at the initial visit were compared between diabetic and nondiabetic patients using the Wilcoxon rank-sum test. The improvements in visual acuity (or visual field) from onset to ODE resolution, from ODE resolution to 9 months after ODE resolution, and at specified follow-up periods at 3 months, 6 months, and 1 year from onset of NA-AION were compared between diabetic and nondiabetic patients who had an initial visual acuity of 20/70 or worse (or moderate to severe initial visual field defect) and were first seen (or treated) within 2 weeks of NA-AION onset. This was done using repeatedmeasures logistic regression analysis fitted by the generalized estimating equations (GEE) method to account for the correlation of visual outcomes from the same eye over time, as well as between eyes from the same patient. The P values for comparing visual improvement in diabetic and nondiabetic patients at several time points have been adjusted using Bonferroni’s method to account for the number of tests performed.
Results This study comprised 655 patients with NA-AION (931 eyes) who were first seen between 1973 and 2000 (206 patients with diabetes and 449 patients without diabetes). The median duration of diabetes before onset of NA-AION was 8 years (interquartile range, 3–15 years). Of those with diabetes, 11% had juvenile diabetes. Table 1 gives a detailed comparison of the demographic and clinical characteristics of diabetic and nondiabetic patients. Time to involvement of the second eye was significantly shorter in diabetic than in nondiabetic patients (P ⫽ 0.003). There was also a greater prevalence of incipient NA-AION17 among diabetic patients compared with nondiabetic patients (P⬍0.0001); there was no significant difference in proportion that progressed to regular NA-AION between diabetic and nondiabetic patients (P ⫽ 0.18).17 Table 2 compares their initial visual acuity and visual field data. Comparison of the initial visual field defect in the eyes with NA-AION between patients with juvenile and adult-onset diabetes, first seen within 2 weeks of NA-AION onset, showed 73% of those with juvenile diabetes presented with mild to minimal visual field defect versus 40% in those with adult-onset diabetes (P ⫽ 0.013).
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This was similarly observed for initial visual acuity but was not statistically significant (P ⫽ 0.199; better than 20/40 visual acuity in 60% of those with juvenile diabetes and 45% of those with adult-onset diabetes).
Visual Acuity Improvement From Initial Visit to ODE Resolution. Of those who had initial visual acuity of 20/70 or worse and were first seen within 2 weeks of onset and not receiving corticosteroid therapy, there were at least 3 lines of improvement immediately after resolution of ODE in 26% (6/23) with diabetes and 19% (9/48) without diabetes (P⬎0.99). Among those who did have corticosteroid therapy, 47% (9/19) with diabetes and 43% (22/51) without diabetes had visual acuity improvement (P⬎0.99). Among those first seen more than 2 weeks from the onset of NA-AION, improvement was observed in 14% (3/21) of diabetic patients and 16% (5/31) of nondiabetic patients who were not treated with corticosteroid and in 25% (3/12) of diabetic patients and 31% (5/16) of nondiabetic patients who did receive corticosteroid therapy. From ODE Resolution to 9 Months after the Resolution. There was further improvement in visual acuity 9 months after ODE resolved in 21% (7/34) of diabetic patients and 26% (15/57) of nondiabetic patients without corticosteroid treatment (P ⫽ 0.70) and in 41% (7/17) of diabetic patients and 54% (30/56) of nondiabetic patients receiving corticosteroid treatment (both P⬎0.99). Overall Change at 3 Months, 6 Months, and 1 Year after the Initial Visit. Overall improvement in visual acuity among those first seen within 2 weeks of onset is presented in Table 3. At 6 months from onset, 33% (6/18) of nonsteroid-treated diabetic patients showed improvement and 46% (19/41) of nondiabetic patients showed improvement. Improvement in steroid-treated patients was 67% (12/18) among diabetic patients and 69% (34/49) among nondiabetic patients. In those first seen more than 2 weeks from onset, improvement at 6 months was 29% (5/17) for diabetic patients and 23% (5/22) for nondiabetic patients in nonsteroidtreated patients, and 63% (7/11) for diabetic patients and 57% (8/14) for nondiabetic patients in steroid-treated patients. There was no significant difference in visual acuity improvement between diabetic and nondiabetic patients (all P⬎0.99).
Visual Field Improvement From Initial Visit to ODE Resolution. Of those with moderate to severe visual field defect who were seen within 2 weeks of onset and not receiving corticosteroid therapy, there was improvement in visual field immediately after resolution of ODE in 18% (6/38) with diabetes and 21% (19/91) without diabetes (P⬎0.99). Among those who had corticosteroid therapy, visual field improvement was observed in 34% (10/29) with diabetes and 37% (56/153) without diabetes (P⬎0.99). Of those first seen more than 2 weeks after the onset of NA-AION, improvement was observed in 15% (4/26) of those with diabetes and 17% (10/60) of those without diabetes not treated with steroids and in 40% (10/25) of those with diabetes and 28% (13/47) of those without diabetes who were treated with steroids. From ODE Resolution to 9 Months after the Resolution. There was further improvement in visual field 9 months after ODE had resolved in 10% (5/50) of diabetic patients and 6% (6/106) of nondiabetic patients who were not receiving corticosteroid treatment (P ⫽ 0.39) and in 5% (23/42) of diabetic patients and 8%
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus Table 1. Demographic and Clinical Characteristics of Patients with Nonarteritic Anterior Ischemic Optic Neuropathy (n ⫽ 655 Patients, 931 Eyes) All Patients (n ⴝ 655 patients) 931 eyes
Variable Gender (male) Age (mean⫾SD) Involved eye Right eye Left eye Sequential bilateral involvement Time to involvement of second eye (y) Median (25th–75th percentile) Incipient NA-AION (eyes) On steroid therapy (eyes) Follow-up (of eyes) With follow-up ⱖ8 wk Median (25th–75th percentile)* Minimum to maximum* Other systemic conditions Hypertension Ischemic heart disease TIA/CVA Peripheral vascular disease Elevated cholesterol (⬎200) Smoked current/past Diabetic retinopathy Initial IOP (mean⫾SD)
With Diabetes (n ⴝ 206 patients) 306 eyes
No Diabetes (n ⴝ 449 patients) 625 eyes
392 (60%) 60.0⫾12.9
113 (55%) 60.0⫾13.1
279 (62%) 60.0⫾12.8
195 (30%) 184 (28%) 276 (42%)
55 (27%) 51 (25%) 100 (49%)
140 (31%) 133 (30%) 176 (39%)
8.2 (0.9–17.9) 60 (6%) 528 (57%)
6.9 (0.4–16.9) 40 (13%) 154 (50%)
9.1 (1.8–19.0) 20 (3%) 374 (60%)
772 (83%) 3.7 y (1.3–8.4) (2.1 mo–31.0 y)
241 (79%) 4.6 y (1.3–8.4) (2.3 mo–30.0 y)
531 (85%) 3.4 y (1.3–8.1) (2.1 mo–31.0 y)
258 (39%) 127 (19%) 52 (8%) 33 (5%) 290 (of n ⫽ 418) (69%) (n ⫽ 636 patients) 310 (49%) — (n ⫽ 911 eyes) 16.4⫾3.9
122 (59%) 58 (28%) 28 (14%) 14 (7%) 80 (of n ⫽ 116) (69%) (n ⫽ 198 patients) 97 (49%) 75 (36%) (n ⫽ 303 eyes) 16.7⫾3.5
136 (30%) 69 (15%) 24 (5%) 19 (4%) 210 (of n ⫽ 302) (70%) (n ⫽ 438 patients) 213 (49%) — (n ⫽ 608 eyes) 16.2⫾4.1
With Diabetes vs without Diabetes P Value 0.078 0.990
0.003 ⬍0.0001 0.051
⬍0.0001 0.0001 0.0003 0.164 0.910 0.933
0.036
CVA ⫽ cerebrovascular disorder; IOP ⫽ intraocular pressure; NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; SD ⫽ standard deviation; TIA ⫽ transient ischemic attack. *Of those with minimum follow-up of at least 8 weeks.
(13/156) of nondiabetic patients receiving corticosteroid treatment (both P⬎0.99). Overall Change at 3 Months, 6 Months, and 1 Year after the Initial Visit. Overall improvement in visual field among those first seen within 2 weeks of onset is presented in Table 4. At 6 months from onset, nonsteroid-treated patients showed improvement in 19% (6/31) of those with diabetes and 28%
(21/74) of those without diabetes. Improvement in corticosteroid-treated patients was 37% (10/27) among those with diabetes and 34% (14/41) of those without diabetes. In those first seen more than 2 weeks after onset, there was improvement at 6 months in 20% (4/20) of nonsteroid-treated diabetic patients and 21% (9/43) of nondiabetic patients, and 50% (12/24) of corticosteroid-treated diabetic patients and 29%
Table 2. Visual Acuity and Visual Field at Initial Visit* Initial Visit <2 wk from Onset (n ⴝ 562) Visual acuity† 20/15–20/20 20/25–20/30 20/40–20/60 20/70–20/100 20/200–20/400 Counting fingers or worse Visual field defect‡ Minimal Mild Moderate Marked Severe
With Diabetes
No Diabetes
(n ⫽ 177 eyes) 53 (30%) 30 (17%) 30 (17%) 22 (12%) 18 (10%) 24 (14%) (n ⫽ 174 eyes) 26 (15%) 49 (28%) 34 (20%) 41 (24%) 24 (14%)
(n ⫽ 385 eyes) 130 (34%) 71 (18%) 75 (19%) 30 (8%) 28 (7%) 51 (13%) (n ⫽ 382 eyes) 21 (6%) 104 (27%) 80 (21%) 122 (32%) 55 (14%)
P Value
0.170
0.010
Initial Visit >2 wk from Onset (n ⴝ 344) With Diabetes
No Diabetes
(n ⫽ 114 eyes) 23 (20%) 21 (18%) 22 (19%) 18 (16%) 16 (14%) 14 (12%) (n ⫽ 114 eyes) 11 (10%) 30 (26%) 17 (15%) 42 (37%) 14 (12%)
(n ⫽ 223 eyes) 56 (25%) 42 (19%) 45 (20%) 23 (10%) 26 (12%) 31 (14%) (n ⫽ 225 eyes) 5 (2%) 58 (26%) 43 (19%) 89 (40%) 30 (13%)
P Value
0.270
0.400
*A total of 25 eyes with onset date not known are not included. † Missing visual acuity in 7 eyes seen ⬎2 weeks. ‡ Missing field defect data in 6 eyes seen within 2 weeks and 5 eyes seen ⬎2 weeks.
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Ophthalmology Volume 115, Number 10, October 2008 Table 3. Visual Acuity Change from Initial Visit to 3 Months, 6 Months, and 1 Year in Patients with No Treatment and Patients Treated with Corticosteroid Therapy A. No Corticosteroid Therapy in Those Seen within 2 Weeks of Onset of Nonarteritic Anterior Ischemic Optic Neuropathy With Diabetes Time from First Visit/Initial Visual Acuity 3 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 6 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 1 y* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse
No Diabetes
No. (%) of Eyes n† (n ⫽ 64) 39 9 16 21 (n ⫽ 56) 34 9 13 18 (n ⫽ 54) 32 9 13 18
Improved
Worsened
1 (3%) 0 (0%) 2 (12%) 2 (10%)
6 (15%) 1 (11%) 0 (0%) 1 (5%)
1 (3%) 3 (33%) 5 (38%) 6 (33%)
3 (8%) 1 (11%) 3 (23%) 4 (22%)
1 (3%) 2 (22%) 5 (38%) 5 (28%)
4 (12%) 1 (11%) 3 (23%) 4 (22%)
No. (%) of Eyes n† (n ⫽ 130) 79 18 33 44 (n ⫽ 121) 75 15 31 41 (n ⫽ 112) 71 14 27 37
Improved
Worsened
2 (3%) 1 (6%) 8 (24%) 9 (20%)
4 (5%) 1 (6%) 1 (3%) 1 (2%)
2 (3%) 3 (20%) 16 (52%) 19 (46%)
6 (8%) 1 (7%) 4 (13%) 5 (12%)
4 (6%) 3 (21%) 15 (56%) 18 (49%)
5 (7%) 1 (7%) 4 (15%) 5 (14%)
B. Corticosteroid Therapy Started within 2 Weeks of Onset With Diabetes Time from First Visit/Initial Visual Acuity 3 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 6 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 1 y* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse
No Diabetes
No. (%) of Eyes †
n
(n ⫽ 56) 32 15 9 19 (n ⫽ 54) 31 15 8 18 (n ⫽ 49) 28 13 8 16
Improved
No. (%) of Eyes
Worsened
1 (1%) 4 (27%) 6 (67%) 10 (53%)
18 (14%) 0 (0%) 0 (0%) 0 (0%)
0 (0%) 6 (40%) 7 (88%) 12 (67%)
7 (23%) 0 (0%) 0 (0%) 0 (0%)
0 (0%) 6 (46%) 7 (88%) 11 (69%)
5 (18%) 0 (0%) 0 (0%) 0 (0%)
n
†
(n ⫽ 204) 129 40 35 51 (n ⫽ 190) 117 39 34 49 (n ⫽ 173) 107 35 31 45
Improved
Worsened
1 (1%) 10 (25%) 18 (51%) 23 (45%)
18 (14%) 1 (3%) 0 (0%) 1 (2%)
3 (3%) 16 (41%) 27 (79%) 34 (69%)
16 (14%) 2 (5%) 1 (3%) 2 (4%)
3 (3%) 16 (46%) 23 (74%) 31 (69%)
19 (18%) 2 (6%) 1 (3%) 2 (4%)
*⫾6 weeks for 3 and 6 months; ⫾12 weeks for 1 year. † n includes the eyes that have a follow-up for visual acuity of at least the lower limit specified.
(12/42) of nondiabetic patients. There was no significant difference in visual field improvement between diabetic and nondiabetic patients (all P⬎0.99).
betic patients and in 31% of nondiabetic patients (P ⫽ 0.36). For those receiving corticosteroid treatment, deterioration was observed in 26% (6/23) of diabetic patients and 35% (13/37) of nondiabetic patients (P ⫽ 0.62).
Visual Acuity and Visual Field Deterioration Overall deterioration in visual acuity at 1-year follow-up among those who presented with 20/100 or better vision, within 2 weeks of onset, with no corticosteroid treatment was 12% (5/41) in those with diabetes and 7% (6/85) in those without diabetes (P ⫽ 0.50). For those receiving corticosteroid therapy, deterioration at 1 year was observed in 12% (5/41) of those with diabetes and 15% (21/142) of those without diabetes (P ⫽ 0.48). Visual field deterioration at 1-year follow-up in those who presented with minimal to mild defect, within 2 weeks of onset, and who were not receiving corticosteroid treatment was observed in 19% (4/21) of dia-
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ODE Resolution In our previous study16 on the timing of ODE resolution in NA-AION for this same cohort, those with diabetes had a significantly longer duration to ODE resolution (P ⫽ 0.003) than nondiabetic patients. The median time to ODE resolution was 8.7 weeks (interquartile range, 6.4 –12.5 weeks) in diabetic patients and 7.6 weeks (interquartile range, 5.6 –10.9 weeks) in nondiabetic patients.
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus Table 4. Visual Field Change from Initial Visit to 3 Months, 6 Months, and 1 Year in Patients with No Treatment and Patients Treated with Corticosteroid Therapy A. No Corticosteroid Therapy in Those Seen within 2 Weeks of Onset of Nonarteritic Anterior Ischemic Optic Neuropathy With Diabetes Time from First Visit/Initial Visual Field Defect 3 mo* Minimal Mild Moderate to severe 6 mo* Minimal Mild Moderate to severe 1 y* Minimal Mild Moderate to severe
No Diabetes
No. (%) of Eyes n† (n ⫽ 61) 8 18 35 (n ⫽ 54) 8 15 31 (n ⫽ 49) 8 13 28
Improved
Worsened
— 2 (11%) 5 (14%)
0 (0%) 6 (33%) 8 (23%)
— 2 (13%) 6 (19%)
0 (0%) 4 (27%) 6 (19%)
— 2 (15%) 6 (21%)
0 (0%) 4 (31%) 7 (25%)
No. (%) of Eyes n† (n ⫽ 119) 4 35 80 (n ⫽ 112) 4 34 74 (n ⫽ 104) 3 33 68
Improved
Worsened
— 5 (14%) 8 (24%)
0 (0%) 11 (31%) 1 (3%)
— 5 (15%) 21 (28%)
0 (0%) 11 (32%) 10 (14%)
— 5 (15%) 20 (29%)
0 (0%) 11 (33%) 9 (13%)
B. Corticosteroid Therapy Started within 2 Weeks of Onset With Diabetes Time from First Visit/Initial Visual Field Defect 3 mo* Minimal Mild Moderate to severe 6 mo* Minimal Mild Moderate to severe 1 y* Minimal Mild Moderate to severe
No Diabetes
No. (%) of Eyes n
†
(n ⫽ 56) 6 21 29 (n ⫽ 54) 6 21 27 (n ⫽ 48) 5 18 25
Improved
Worsened
— 6 (29%) 10 (34%)
3 (50%) 5 (24%) 4 (14%)
— 6 (29%) 10 (37%)
3 (50%) 5 (24%) 5 (19%)
— 6 (33%) 9 (36%)
2 (40%) 4 (22%) 5 (20%)
No. (%) of Eyes n
†
(n ⫽ 199) 4 45 150 (n ⫽ 186) 3 41 142 (n ⫽ 167) 3 34 130
Improved
Worsened
— 14 (31%) 58 (39%)
4 (100%) 13 (29%) 23 (15%)
— 14 (34%) 57 (40%)
3 (100%) 12 (29%) 22 (15%)
— 12 (35%) 53 (41%)
3 (100%) 10 (29%) 23 (18%)
*⫾6 weeks for 3 and 6 months; ⫾12 weeks for 1 year. † n includes the eyes that have a follow-up for visual field of at least the lower limit specified.
Discussion Comparison of various aspects of NA-AION in diabetic and nondiabetic patients revealed interesting information. There was no significant difference in age (P ⫽ 0.990) between the 2 groups, and only slightly more diabetic patients were female. There was a higher prevalence of hypertension (P⬍0.0001), ischemic heart disease (P ⫽ 0.0001), and transient ischemic attacks (P ⫽ 0.0003) in diabetic patients than in nondiabetic patients (Table 1). Involvement of the second eye by NA-AION is more likely to occur sooner in diabetic patients than in nondiabetic patients (P ⫽ 0.003). Initial visual acuity did not differ significantly between diabetic and nondiabetic patients; however, in those seen within 2 weeks of the onset of NA-AION, diabetic patients had less severe visual field defect than nondiabetic patients (P ⫽ 0.010) (Table 2). Of nondiabetic patients, 60% of the eyes had corticosteroid treatment compared with 50% of the eyes in diabetic patients (P ⫽ 0.051). At 6 months from onset, there was no significant difference in visual acuity
improvement between diabetic and nondiabetic patients (P⬎0.99) (Table 3). Similarly, there was no significant difference in visual field improvement between diabetic and nondiabetic patients (P⬎0.99) (Table 4). In summary, the rate of visual acuity and visual field improvement did not differ significantly between diabetic and nondiabetic patients. In our study of the same cohort (i.e., combined group of both diabetic and nondiabetic patients) on assessment of visual acuity and visual field improvement with corticosteroid therapy,19 among those with initial visual acuity of 20/70 or worse (or moderate to severe visual field defect), the treated group showed a significantly greater improvement in visual acuity (P ⫽ 0.001) and visual field (P ⫽ 0.005) than the untreated group.19 The time from onset to resolution of ODE in NA-AION was significantly (P ⫽ 0.003) longer for diabetic patients than nondiabetic patients. At the initial visit, incipient NA-AION17 was present more frequently in diabetic than nondiabetic patients (P⬍0.0001). Of practical clinical importance is the difference in pattern of ODE and fundus findings in diabetic versus nondi-
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Ophthalmology Volume 115, Number 10, October 2008 abetic patients. Our studies on NA-AION since 1973 have shown that during the initial stages of NA-AION, the ODE is usually (although not always) associated with characteristic and diagnostic prominent, dilated, and frequently telangiectatic vessels over the disc, and more peripapillary retinal hemorrhages in diabetic patients of all ages than in nondiabetic patients (Figs 1A, C, and 2A, C).20,21 When the ODE resolves spontaneously, these prominent telangiectatic disc vessels and retinal hemorrhages also resolve spontaneously (Figs 1B, D, and 2B, D). This pattern of ODE and fundus changes in NA-AION in diabetic patients during the acute phase has confused the issue and often resulted in the following 2 types of misdiagnoses. 1. These findings have been mistaken for proliferative diabetic retinopathy associated with optic disc neovascularization and mistakenly treated with panretinal photocoagulation.20,21 Then the spontaneous resolution of optic disc and fundus changes have been attributed to the supposed “beneficial effect” of panretinal photocoagulation;20 in fact, panretinal photocoagulation is not indicated in this disease, because
Figure 1. Fundus photographs (A, B) of the right eye and (C, D) left eye, of a 19½-year-old white male juvenile with diabetes mellitus. (Reproduced with permission from Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72.) A, C, On first visit to the clinic: Fundus photographs (A) of the right eye and (C) left eye show massive ODE with marked telangiectatic vessels on the optic disc, many retinal hemorrhages, engorged retinal veins, and lipid deposits in the right macular region. Visual acuity was 20/25 in the right eye and 20/40 in the left eye, with enlargement of blind spot in both eyes. B, D, On resolution of ODE: Fundus photographs (B) of the right eye and (D) left eye show normal-looking optic discs, no abnormal vessels on the discs, and no retinal hemorrhages.
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Figure 2. Fundus photographs of both eyes of a 51-year-old woman with adult-onset diabetes mellitus. Bilateral NA-AION developed first in the right eye (A, B) and 8 months later in the left eye (C, D). A, C, On first visit to the clinic: Fundus photographs show massive ODE with marked telangiectatic vessels on the optic disc and many retinal hemorrhages. Visual acuity was 20/20 in the left eye and 20/15 in the right eye. Both eyes had inferior nasal visual field defect. B, D, On resolution of ODE: Fundus photographs show no ODE but mild temporal pallor, no abnormal vessels on optic disc, no retinal hemorrhages in the right eye (B), and a few resolving hemorrhages in the left eye (D).
it produces unnecessary extensive retinal damage and associated visual complications. 2. This pattern of ODE and fundus changes in NA-AION in diabetic patients has also often been misdiagnosed as a distinct clinical entity called “diabetic papillopathy” or “diabetic papillitis,”4 –12 causing confusion and controversy. The following 2 factors in diabetic patients are responsible for this controversy. (a) Incipient NAAION17 initially occurs more frequently in diabetic than nondiabetic patients. (b) Some diabetic patients with NA-AION or incipient NA-AION also concurrently have diabetic macular edema with poor visual acuity; this has added to the confusion. Diabetic macular edema, per se, does not produce any optic discrelated visual field defects. We have discussed at length elsewhere why “diabetic papillopathy” is actually NAAION in diabetic patients, and not a distinct clinical entity.16,17,20,22 Once one considers all these factors, it becomes apparent that the term “diabetic papillopathy” is not correct and confuses the issue. Our studies have shown that there is no difference in the optic disc morphology23 and fluorescein angiographic16 findings between diabetic and nondiabetic NA-AION eyes, except that, as discussed above, diabetic NA-AION eyes usually had telangiectatic vessels that leaked fluorescein during the acute phase of NA-AION (Figs 1 and 2). Among patients with NA-AION, there are several demographic and clinical differences between diabetic and non-
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus diabetic patients that have been the source of misunderstanding about the diagnosis and management of NA-AION in diabetes mellitus.
References 1. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1994;118:766 – 80. 2. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 1996;114:1366 –74. 3. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome. Ophthalmology 2008;115:298 –305. 4. Lubow M, Makley TA Jr. Pseudopapilledema of juvenile diabetes mellitus. Arch Ophthalmol 1971;85:417–22. 5. Appen RE, Chandra SR, Klein R, Myers FL. Diabetic papillopathy. Am J Ophthalmol 1980;90:203–9. 6. Barr CC, Glaser JS, Blankenship G. Acute disc swelling in juvenile diabetes: clinical profile and natural history of 12 cases. Arch Ophthalmol 1980;98:2185–92. 7. Algan M, Ziegler O, Drouin P. Optic neuropathy in diabetic subjects [in French]. Diabete Metab 1993;19:395–9. 8. Pavan PR, Aiello LM, Wafai Z, et al. Optic disc edema in juvenile-onset diabetes. Arch Ophthalmol 1980;98:2193–5. 9. Regillo CD, Brown GC, Savino PJ, et al. Diabetic papillopathy: patient characteristics and fundus findings. Arch Ophthalmol 1995;113:889 –95. 10. Inoue M, Tsukahara Y. Vascular optic neuropathy in diabetes mellitus. Jpn J Ophthalmol 1997;41:328 –31. 11. Ignat F, Baˇraˇscu D, Perovic I, Munteanu A. Optic nerve lesions in diabetes mellitus [in Romanian]. Oftalmologia 2002;54:39 – 43.
12. Vaphiades MS. The disk edema dilemma. Surv Ophthalmol 2002;47:183– 8. 13. Hayreh SS. Anterior ischaemic optic neuropathy: differentiation of arteritic from non-arteritic type and its management. Eye 1990;4:25– 41. 14. 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. 15. Hayreh SS, Zimmerman B. Management of giant cell arteritis. Our 27-year clinical study: new light on old controversies. Ophthalmologica 2003;217:239 –59. 16. Hayreh SS, Zimmerman MB. Optic disc edema in nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2007;245:1107–21. 17. Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72. 18. Hayreh SS. Posterior ischaemic optic neuropathy: clinical features, pathogenesis and management. Eye 2004;18:1188 – 206. 19. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol 2008 Apr 11 [Epub ahead of print]. 20. Hayreh SS, Zahoruk RM. Anterior ischemic optic neuropathy. VI. In juvenile diabetics. Ophthalmologica 1981;182: 13–28. 21. Hayreh SS. Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations, and management. Ophthalmol Clin North Am 1996;9:407– 42. 22. Hayreh SS. Diabetic papillopathy and nonarteritic anterior ischemic optic neuropathy. Surv Ophthalmol 2002;47: 600 –2. 23. 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.
Footnotes and Financial Disclosures Originally received: January 10, 2008. Final revision: March 23, 2008. Accepted: March 31, 2008. Available online: May 27, 2008.
Manuscript no. 2008 –59.
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, Bethesda, Maryland, 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 & Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1091. E-mail: [email protected].
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A voluminous amount of literature shows that diabetes mellitus is an important risk factor in the development of nonarteritic anterior ischemic optic neuropathy (NAAION);1–3 however, there is little information about the various characteristics of NA-AION in patients with diabetes mellitus and whether those differ in any way from those of nondiabetic patients. Moreover, NA-AION has been described in diabetic patients under different eponyms, the most common being “diabetic papillopathy.”4 –12 That has resulted in a good deal of confusion and controversy about the nature of optic neuropathy in diabetic patients, as well as the role of diabetes mellitus in NA-AION. The objective of the present study was to investigate various aspects of NA-AION in patients with diabetes mellitus and to compare them with those in patients without diabetes mellitus. The study population comprised a large
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
cohort of patients prospectively collected in the Ocular Vascular Clinic at the University of Iowa Hospitals and Clinics from 1973 to 2000.
Patients and Methods We have prospectively and systematically investigated various aspects of NA-AION in the Ocular Vascular Clinic at the Tertiary Care University of Iowa Hospitals and Clinics since 1973. The present study was a 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 various characteristics of NA-AION in patients with diabetes mellitus and how they differed, if at all, from NA-AION in patients without diabetes mellitus. The study consists of a cohort of 655 consecutive patients (931 eyes) who were first seen in the clinic from 1973 to 2000, and thereafter followed serially, and who ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.03.032
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus fulfilled the inclusion and exclusion criteria. The data were collected prospectively and systematically.
Criteria Required for Diagnosis of NA-AION and Inclusion in the Present Study The criteria included a history of sudden visual loss, usually discovered in the morning, and an absence of other ocular, systemic, or neurologic diseases that might influence or explain the patient’s visual symptoms; optic disc edema (ODE) at onset, documented in the Ocular Vascular Clinic and still present; observed spontaneous resolution of ODE; optic disc-related visual field defects in the eye; no neurologic, systemic, or ocular disorder that could be responsible for ODE and visual impairment; and no treatment for NA-AION before the evaluation. Patients with a follow-up of less than 2 months were included in the analysis of demographic variables and initial visual status but excluded from the follow-up analysis of visual outcome. The diagnosis of diabetes in this study was based on the following criteria: (a) Patients who were already on treatment for diabetes at the time of onset of NA-AION were considered to have a diabetes diagnosis; (b) In others, the diagnosis of diabetes was based solely on the evaluation and diagnosis by the internists at the University of Iowa Hospitals and Clinics or the local primary care physician of the patient. A patient was considered diabetic only if he or she had diabetes at the time when the NA-AION developed. If diabetes developed years later, that was not considered relevant to the development of NA-AION and the patient was not considered diabetic.
Exclusion Criteria Patients who had any retinal or optic nerve lesion or any other factor (e.g., cataract) that could have influenced the visual status were excluded. Patients with NA-AION with only background diabetic retinopathy were included, but all who had active neovascularization, vitreous hemorrhages, traction detachment, or other complications influencing the visual acuity or fields were excluded. Patients who had a diagnosis of glaucoma and visual field loss were excluded; however, those with elevated intraocular pressure with a documented normal field before the onset of NA-AION were included. Eyes with unreliable visual fields were excluded.
Studies Performed A detailed ophthalmic and medical history was obtained at the patient’s first visit to the 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; this included recording the best corrected visual acuity using the Snellen visual acuity chart, central visual field testing using the Amsler grid chart, visual fields with manual kinetic perimetry using the Goldmann perimeter (using I-2e, I-4e, and V-4e targets regularly), relative afferent pupillary defect, intraocular pressure using the Goldmann applanation tonometer, 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 or C-reactive protein, or suspicion of arteritic AION, a temporal artery biopsy was performed to rule out giant cell arteritis.13–15 At each follow-up visit, the same ophthalmic evaluation and stereoscopic color fundus photography were per-
formed, with the exception of fluorescein fundus angiography. 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.
Corticosteroid Therapy All patients were given a choice to be treated with systemic steroid therapy or to be followed without any treatment. The choice was entirely voluntary, that is, the treatment decision was based on a “patient choice” scheme, instead of the conventional randomization. Various aspects of corticosteroid therapy, treatment protocol, and safeguards against any potential bias in choice by the patient for treatment are discussed at length elsewhere.16,17 For treatment of diabetic patients with corticosteroid therapy, we initially discussed in detail the risks of treating diabetic patients with corticosteroid therapy with the Endocrinology Department of the University of Iowa Hospitals and Clinics because of its side effects; approval was granted, with the requirement that the patients be closely monitored by their internists for diabetes mellitus. Thus, when diabetic patients opted for the corticosteroid therapy, we first had a thorough discussion with their internists about monitoring the patient closely while on corticosteroid therapy, and the therapy was given only if the internists consented to do so (most did). If the internist did not feel comfortable with the treatment, we did not give corticosteroid therapy to that patient. Thus, the diabetic patients who decided to have corticosteroid therapy were managed jointly with their internists as long as they were receiving the therapy. Contrary to the highly prevalent impression, we have had no problems treating diabetic patients with corticosteroid therapy for more than 35 years with these precautions.
Follow-up Protocol for All Patients The patients who opted for corticosteroid therapy were followed approximately every 2 weeks as long as they were taking up to 40 mg prednisone daily, and at 3- to 4-week intervals after that until they finished the therapy. Patients who opted not to be treated were followed similarly. When necessary, they were seen more often in addition to this protocol. After that, they were followed at 3 months, 6 months, and then yearly; a few patients have been followed for as long as 33 years in the clinic.
Evaluations of Visual Acuity, Visual Field Defects, and Optic Disc Edema Evaluations of visual acuity, visual field defects, and ODE have been described in detail elsewhere.3 Each was evaluated separately in a masked fashion, that is, changes in visual acuity, visual fields, and ODE were evaluated independently of each other, so that the severity of one did not influence the evaluation of the other.3 Visual status evaluation and steps taken to reduce potential bias are discussed at length elsewhere.3 The method of grading the visual fields, examples of the various grades of visual fields, and their evaluation are also given in detail elsewhere.3,18 In eyes that developed recurrence of NA-AION, only the data on visual and other evaluations collected up to the last follow-up visit of the first episode were used, that is, before the onset of recurrence.
Statistical Methods Descriptive statistics (means, standard deviation, and percentages) were computed for the demographic, clinical variables, visual
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Ophthalmology Volume 115, Number 10, October 2008 acuity, and visual field defect at the initial visit. Changes in visual acuity and visual field defect were assessed from the initial visit to ODE resolution, from ODE resolution to 9 months after resolution, and for the overall follow-up at 3, 6, and 12 months from the initial visit. Because patient visits did not exactly fall at the specified time period for various logistic, seasonal, or geographic reasons, a ⫾6-week interval was used for the 3- and 6-month follow-ups and ⫾12 weeks for the 12-month follow-up. A change of at least 3 lines in the Snellen visual acuity chart was considered a significant change in either direction (i.e., improved or deteriorated), which is equivalent to a logarithm of the minimum angle of resolution (logMAR) change of at least 0.30. At these same intervals, change in visual field loss was also examined, with a difference in grade of at least 0.5 in either direction defined as improvement or deterioration. The percentages of improved and worse visual outcomes were calculated at each of these intervals. Only the eyes that had at least that length of follow-up for the specified interval were included in the computation. The changes were not carried over if the patient did not have follow-up for the later time period. These are reported separately for those first seen within 2 weeks of onset of visual loss and those first seen more than 2 weeks after visual loss. To compare the demographic and clinical variables between diabetic and nondiabetic patients, the Pearson chi-square test was used for the categoric variables and the 2-sample t test was used for the continuous variables. Visual acuity and visual field defect at the initial visit were compared between diabetic and nondiabetic patients using the Wilcoxon rank-sum test. The improvements in visual acuity (or visual field) from onset to ODE resolution, from ODE resolution to 9 months after ODE resolution, and at specified follow-up periods at 3 months, 6 months, and 1 year from onset of NA-AION were compared between diabetic and nondiabetic patients who had an initial visual acuity of 20/70 or worse (or moderate to severe initial visual field defect) and were first seen (or treated) within 2 weeks of NA-AION onset. This was done using repeatedmeasures logistic regression analysis fitted by the generalized estimating equations (GEE) method to account for the correlation of visual outcomes from the same eye over time, as well as between eyes from the same patient. The P values for comparing visual improvement in diabetic and nondiabetic patients at several time points have been adjusted using Bonferroni’s method to account for the number of tests performed.
Results This study comprised 655 patients with NA-AION (931 eyes) who were first seen between 1973 and 2000 (206 patients with diabetes and 449 patients without diabetes). The median duration of diabetes before onset of NA-AION was 8 years (interquartile range, 3–15 years). Of those with diabetes, 11% had juvenile diabetes. Table 1 gives a detailed comparison of the demographic and clinical characteristics of diabetic and nondiabetic patients. Time to involvement of the second eye was significantly shorter in diabetic than in nondiabetic patients (P ⫽ 0.003). There was also a greater prevalence of incipient NA-AION17 among diabetic patients compared with nondiabetic patients (P⬍0.0001); there was no significant difference in proportion that progressed to regular NA-AION between diabetic and nondiabetic patients (P ⫽ 0.18).17 Table 2 compares their initial visual acuity and visual field data. Comparison of the initial visual field defect in the eyes with NA-AION between patients with juvenile and adult-onset diabetes, first seen within 2 weeks of NA-AION onset, showed 73% of those with juvenile diabetes presented with mild to minimal visual field defect versus 40% in those with adult-onset diabetes (P ⫽ 0.013).
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This was similarly observed for initial visual acuity but was not statistically significant (P ⫽ 0.199; better than 20/40 visual acuity in 60% of those with juvenile diabetes and 45% of those with adult-onset diabetes).
Visual Acuity Improvement From Initial Visit to ODE Resolution. Of those who had initial visual acuity of 20/70 or worse and were first seen within 2 weeks of onset and not receiving corticosteroid therapy, there were at least 3 lines of improvement immediately after resolution of ODE in 26% (6/23) with diabetes and 19% (9/48) without diabetes (P⬎0.99). Among those who did have corticosteroid therapy, 47% (9/19) with diabetes and 43% (22/51) without diabetes had visual acuity improvement (P⬎0.99). Among those first seen more than 2 weeks from the onset of NA-AION, improvement was observed in 14% (3/21) of diabetic patients and 16% (5/31) of nondiabetic patients who were not treated with corticosteroid and in 25% (3/12) of diabetic patients and 31% (5/16) of nondiabetic patients who did receive corticosteroid therapy. From ODE Resolution to 9 Months after the Resolution. There was further improvement in visual acuity 9 months after ODE resolved in 21% (7/34) of diabetic patients and 26% (15/57) of nondiabetic patients without corticosteroid treatment (P ⫽ 0.70) and in 41% (7/17) of diabetic patients and 54% (30/56) of nondiabetic patients receiving corticosteroid treatment (both P⬎0.99). Overall Change at 3 Months, 6 Months, and 1 Year after the Initial Visit. Overall improvement in visual acuity among those first seen within 2 weeks of onset is presented in Table 3. At 6 months from onset, 33% (6/18) of nonsteroid-treated diabetic patients showed improvement and 46% (19/41) of nondiabetic patients showed improvement. Improvement in steroid-treated patients was 67% (12/18) among diabetic patients and 69% (34/49) among nondiabetic patients. In those first seen more than 2 weeks from onset, improvement at 6 months was 29% (5/17) for diabetic patients and 23% (5/22) for nondiabetic patients in nonsteroidtreated patients, and 63% (7/11) for diabetic patients and 57% (8/14) for nondiabetic patients in steroid-treated patients. There was no significant difference in visual acuity improvement between diabetic and nondiabetic patients (all P⬎0.99).
Visual Field Improvement From Initial Visit to ODE Resolution. Of those with moderate to severe visual field defect who were seen within 2 weeks of onset and not receiving corticosteroid therapy, there was improvement in visual field immediately after resolution of ODE in 18% (6/38) with diabetes and 21% (19/91) without diabetes (P⬎0.99). Among those who had corticosteroid therapy, visual field improvement was observed in 34% (10/29) with diabetes and 37% (56/153) without diabetes (P⬎0.99). Of those first seen more than 2 weeks after the onset of NA-AION, improvement was observed in 15% (4/26) of those with diabetes and 17% (10/60) of those without diabetes not treated with steroids and in 40% (10/25) of those with diabetes and 28% (13/47) of those without diabetes who were treated with steroids. From ODE Resolution to 9 Months after the Resolution. There was further improvement in visual field 9 months after ODE had resolved in 10% (5/50) of diabetic patients and 6% (6/106) of nondiabetic patients who were not receiving corticosteroid treatment (P ⫽ 0.39) and in 5% (23/42) of diabetic patients and 8%
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus Table 1. Demographic and Clinical Characteristics of Patients with Nonarteritic Anterior Ischemic Optic Neuropathy (n ⫽ 655 Patients, 931 Eyes) All Patients (n ⴝ 655 patients) 931 eyes
Variable Gender (male) Age (mean⫾SD) Involved eye Right eye Left eye Sequential bilateral involvement Time to involvement of second eye (y) Median (25th–75th percentile) Incipient NA-AION (eyes) On steroid therapy (eyes) Follow-up (of eyes) With follow-up ⱖ8 wk Median (25th–75th percentile)* Minimum to maximum* Other systemic conditions Hypertension Ischemic heart disease TIA/CVA Peripheral vascular disease Elevated cholesterol (⬎200) Smoked current/past Diabetic retinopathy Initial IOP (mean⫾SD)
With Diabetes (n ⴝ 206 patients) 306 eyes
No Diabetes (n ⴝ 449 patients) 625 eyes
392 (60%) 60.0⫾12.9
113 (55%) 60.0⫾13.1
279 (62%) 60.0⫾12.8
195 (30%) 184 (28%) 276 (42%)
55 (27%) 51 (25%) 100 (49%)
140 (31%) 133 (30%) 176 (39%)
8.2 (0.9–17.9) 60 (6%) 528 (57%)
6.9 (0.4–16.9) 40 (13%) 154 (50%)
9.1 (1.8–19.0) 20 (3%) 374 (60%)
772 (83%) 3.7 y (1.3–8.4) (2.1 mo–31.0 y)
241 (79%) 4.6 y (1.3–8.4) (2.3 mo–30.0 y)
531 (85%) 3.4 y (1.3–8.1) (2.1 mo–31.0 y)
258 (39%) 127 (19%) 52 (8%) 33 (5%) 290 (of n ⫽ 418) (69%) (n ⫽ 636 patients) 310 (49%) — (n ⫽ 911 eyes) 16.4⫾3.9
122 (59%) 58 (28%) 28 (14%) 14 (7%) 80 (of n ⫽ 116) (69%) (n ⫽ 198 patients) 97 (49%) 75 (36%) (n ⫽ 303 eyes) 16.7⫾3.5
136 (30%) 69 (15%) 24 (5%) 19 (4%) 210 (of n ⫽ 302) (70%) (n ⫽ 438 patients) 213 (49%) — (n ⫽ 608 eyes) 16.2⫾4.1
With Diabetes vs without Diabetes P Value 0.078 0.990
0.003 ⬍0.0001 0.051
⬍0.0001 0.0001 0.0003 0.164 0.910 0.933
0.036
CVA ⫽ cerebrovascular disorder; IOP ⫽ intraocular pressure; NA-AION ⫽ nonarteritic anterior ischemic optic neuropathy; SD ⫽ standard deviation; TIA ⫽ transient ischemic attack. *Of those with minimum follow-up of at least 8 weeks.
(13/156) of nondiabetic patients receiving corticosteroid treatment (both P⬎0.99). Overall Change at 3 Months, 6 Months, and 1 Year after the Initial Visit. Overall improvement in visual field among those first seen within 2 weeks of onset is presented in Table 4. At 6 months from onset, nonsteroid-treated patients showed improvement in 19% (6/31) of those with diabetes and 28%
(21/74) of those without diabetes. Improvement in corticosteroid-treated patients was 37% (10/27) among those with diabetes and 34% (14/41) of those without diabetes. In those first seen more than 2 weeks after onset, there was improvement at 6 months in 20% (4/20) of nonsteroid-treated diabetic patients and 21% (9/43) of nondiabetic patients, and 50% (12/24) of corticosteroid-treated diabetic patients and 29%
Table 2. Visual Acuity and Visual Field at Initial Visit* Initial Visit <2 wk from Onset (n ⴝ 562) Visual acuity† 20/15–20/20 20/25–20/30 20/40–20/60 20/70–20/100 20/200–20/400 Counting fingers or worse Visual field defect‡ Minimal Mild Moderate Marked Severe
With Diabetes
No Diabetes
(n ⫽ 177 eyes) 53 (30%) 30 (17%) 30 (17%) 22 (12%) 18 (10%) 24 (14%) (n ⫽ 174 eyes) 26 (15%) 49 (28%) 34 (20%) 41 (24%) 24 (14%)
(n ⫽ 385 eyes) 130 (34%) 71 (18%) 75 (19%) 30 (8%) 28 (7%) 51 (13%) (n ⫽ 382 eyes) 21 (6%) 104 (27%) 80 (21%) 122 (32%) 55 (14%)
P Value
0.170
0.010
Initial Visit >2 wk from Onset (n ⴝ 344) With Diabetes
No Diabetes
(n ⫽ 114 eyes) 23 (20%) 21 (18%) 22 (19%) 18 (16%) 16 (14%) 14 (12%) (n ⫽ 114 eyes) 11 (10%) 30 (26%) 17 (15%) 42 (37%) 14 (12%)
(n ⫽ 223 eyes) 56 (25%) 42 (19%) 45 (20%) 23 (10%) 26 (12%) 31 (14%) (n ⫽ 225 eyes) 5 (2%) 58 (26%) 43 (19%) 89 (40%) 30 (13%)
P Value
0.270
0.400
*A total of 25 eyes with onset date not known are not included. † Missing visual acuity in 7 eyes seen ⬎2 weeks. ‡ Missing field defect data in 6 eyes seen within 2 weeks and 5 eyes seen ⬎2 weeks.
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Ophthalmology Volume 115, Number 10, October 2008 Table 3. Visual Acuity Change from Initial Visit to 3 Months, 6 Months, and 1 Year in Patients with No Treatment and Patients Treated with Corticosteroid Therapy A. No Corticosteroid Therapy in Those Seen within 2 Weeks of Onset of Nonarteritic Anterior Ischemic Optic Neuropathy With Diabetes Time from First Visit/Initial Visual Acuity 3 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 6 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 1 y* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse
No Diabetes
No. (%) of Eyes n† (n ⫽ 64) 39 9 16 21 (n ⫽ 56) 34 9 13 18 (n ⫽ 54) 32 9 13 18
Improved
Worsened
1 (3%) 0 (0%) 2 (12%) 2 (10%)
6 (15%) 1 (11%) 0 (0%) 1 (5%)
1 (3%) 3 (33%) 5 (38%) 6 (33%)
3 (8%) 1 (11%) 3 (23%) 4 (22%)
1 (3%) 2 (22%) 5 (38%) 5 (28%)
4 (12%) 1 (11%) 3 (23%) 4 (22%)
No. (%) of Eyes n† (n ⫽ 130) 79 18 33 44 (n ⫽ 121) 75 15 31 41 (n ⫽ 112) 71 14 27 37
Improved
Worsened
2 (3%) 1 (6%) 8 (24%) 9 (20%)
4 (5%) 1 (6%) 1 (3%) 1 (2%)
2 (3%) 3 (20%) 16 (52%) 19 (46%)
6 (8%) 1 (7%) 4 (13%) 5 (12%)
4 (6%) 3 (21%) 15 (56%) 18 (49%)
5 (7%) 1 (7%) 4 (15%) 5 (14%)
B. Corticosteroid Therapy Started within 2 Weeks of Onset With Diabetes Time from First Visit/Initial Visual Acuity 3 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 6 mo* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse 1 y* 20/15–20/40 20/50–20/100 20/200 or worse 20/70 or worse
No Diabetes
No. (%) of Eyes †
n
(n ⫽ 56) 32 15 9 19 (n ⫽ 54) 31 15 8 18 (n ⫽ 49) 28 13 8 16
Improved
No. (%) of Eyes
Worsened
1 (1%) 4 (27%) 6 (67%) 10 (53%)
18 (14%) 0 (0%) 0 (0%) 0 (0%)
0 (0%) 6 (40%) 7 (88%) 12 (67%)
7 (23%) 0 (0%) 0 (0%) 0 (0%)
0 (0%) 6 (46%) 7 (88%) 11 (69%)
5 (18%) 0 (0%) 0 (0%) 0 (0%)
n
†
(n ⫽ 204) 129 40 35 51 (n ⫽ 190) 117 39 34 49 (n ⫽ 173) 107 35 31 45
Improved
Worsened
1 (1%) 10 (25%) 18 (51%) 23 (45%)
18 (14%) 1 (3%) 0 (0%) 1 (2%)
3 (3%) 16 (41%) 27 (79%) 34 (69%)
16 (14%) 2 (5%) 1 (3%) 2 (4%)
3 (3%) 16 (46%) 23 (74%) 31 (69%)
19 (18%) 2 (6%) 1 (3%) 2 (4%)
*⫾6 weeks for 3 and 6 months; ⫾12 weeks for 1 year. † n includes the eyes that have a follow-up for visual acuity of at least the lower limit specified.
(12/42) of nondiabetic patients. There was no significant difference in visual field improvement between diabetic and nondiabetic patients (all P⬎0.99).
betic patients and in 31% of nondiabetic patients (P ⫽ 0.36). For those receiving corticosteroid treatment, deterioration was observed in 26% (6/23) of diabetic patients and 35% (13/37) of nondiabetic patients (P ⫽ 0.62).
Visual Acuity and Visual Field Deterioration Overall deterioration in visual acuity at 1-year follow-up among those who presented with 20/100 or better vision, within 2 weeks of onset, with no corticosteroid treatment was 12% (5/41) in those with diabetes and 7% (6/85) in those without diabetes (P ⫽ 0.50). For those receiving corticosteroid therapy, deterioration at 1 year was observed in 12% (5/41) of those with diabetes and 15% (21/142) of those without diabetes (P ⫽ 0.48). Visual field deterioration at 1-year follow-up in those who presented with minimal to mild defect, within 2 weeks of onset, and who were not receiving corticosteroid treatment was observed in 19% (4/21) of dia-
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ODE Resolution In our previous study16 on the timing of ODE resolution in NA-AION for this same cohort, those with diabetes had a significantly longer duration to ODE resolution (P ⫽ 0.003) than nondiabetic patients. The median time to ODE resolution was 8.7 weeks (interquartile range, 6.4 –12.5 weeks) in diabetic patients and 7.6 weeks (interquartile range, 5.6 –10.9 weeks) in nondiabetic patients.
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus Table 4. Visual Field Change from Initial Visit to 3 Months, 6 Months, and 1 Year in Patients with No Treatment and Patients Treated with Corticosteroid Therapy A. No Corticosteroid Therapy in Those Seen within 2 Weeks of Onset of Nonarteritic Anterior Ischemic Optic Neuropathy With Diabetes Time from First Visit/Initial Visual Field Defect 3 mo* Minimal Mild Moderate to severe 6 mo* Minimal Mild Moderate to severe 1 y* Minimal Mild Moderate to severe
No Diabetes
No. (%) of Eyes n† (n ⫽ 61) 8 18 35 (n ⫽ 54) 8 15 31 (n ⫽ 49) 8 13 28
Improved
Worsened
— 2 (11%) 5 (14%)
0 (0%) 6 (33%) 8 (23%)
— 2 (13%) 6 (19%)
0 (0%) 4 (27%) 6 (19%)
— 2 (15%) 6 (21%)
0 (0%) 4 (31%) 7 (25%)
No. (%) of Eyes n† (n ⫽ 119) 4 35 80 (n ⫽ 112) 4 34 74 (n ⫽ 104) 3 33 68
Improved
Worsened
— 5 (14%) 8 (24%)
0 (0%) 11 (31%) 1 (3%)
— 5 (15%) 21 (28%)
0 (0%) 11 (32%) 10 (14%)
— 5 (15%) 20 (29%)
0 (0%) 11 (33%) 9 (13%)
B. Corticosteroid Therapy Started within 2 Weeks of Onset With Diabetes Time from First Visit/Initial Visual Field Defect 3 mo* Minimal Mild Moderate to severe 6 mo* Minimal Mild Moderate to severe 1 y* Minimal Mild Moderate to severe
No Diabetes
No. (%) of Eyes n
†
(n ⫽ 56) 6 21 29 (n ⫽ 54) 6 21 27 (n ⫽ 48) 5 18 25
Improved
Worsened
— 6 (29%) 10 (34%)
3 (50%) 5 (24%) 4 (14%)
— 6 (29%) 10 (37%)
3 (50%) 5 (24%) 5 (19%)
— 6 (33%) 9 (36%)
2 (40%) 4 (22%) 5 (20%)
No. (%) of Eyes n
†
(n ⫽ 199) 4 45 150 (n ⫽ 186) 3 41 142 (n ⫽ 167) 3 34 130
Improved
Worsened
— 14 (31%) 58 (39%)
4 (100%) 13 (29%) 23 (15%)
— 14 (34%) 57 (40%)
3 (100%) 12 (29%) 22 (15%)
— 12 (35%) 53 (41%)
3 (100%) 10 (29%) 23 (18%)
*⫾6 weeks for 3 and 6 months; ⫾12 weeks for 1 year. † n includes the eyes that have a follow-up for visual field of at least the lower limit specified.
Discussion Comparison of various aspects of NA-AION in diabetic and nondiabetic patients revealed interesting information. There was no significant difference in age (P ⫽ 0.990) between the 2 groups, and only slightly more diabetic patients were female. There was a higher prevalence of hypertension (P⬍0.0001), ischemic heart disease (P ⫽ 0.0001), and transient ischemic attacks (P ⫽ 0.0003) in diabetic patients than in nondiabetic patients (Table 1). Involvement of the second eye by NA-AION is more likely to occur sooner in diabetic patients than in nondiabetic patients (P ⫽ 0.003). Initial visual acuity did not differ significantly between diabetic and nondiabetic patients; however, in those seen within 2 weeks of the onset of NA-AION, diabetic patients had less severe visual field defect than nondiabetic patients (P ⫽ 0.010) (Table 2). Of nondiabetic patients, 60% of the eyes had corticosteroid treatment compared with 50% of the eyes in diabetic patients (P ⫽ 0.051). At 6 months from onset, there was no significant difference in visual acuity
improvement between diabetic and nondiabetic patients (P⬎0.99) (Table 3). Similarly, there was no significant difference in visual field improvement between diabetic and nondiabetic patients (P⬎0.99) (Table 4). In summary, the rate of visual acuity and visual field improvement did not differ significantly between diabetic and nondiabetic patients. In our study of the same cohort (i.e., combined group of both diabetic and nondiabetic patients) on assessment of visual acuity and visual field improvement with corticosteroid therapy,19 among those with initial visual acuity of 20/70 or worse (or moderate to severe visual field defect), the treated group showed a significantly greater improvement in visual acuity (P ⫽ 0.001) and visual field (P ⫽ 0.005) than the untreated group.19 The time from onset to resolution of ODE in NA-AION was significantly (P ⫽ 0.003) longer for diabetic patients than nondiabetic patients. At the initial visit, incipient NA-AION17 was present more frequently in diabetic than nondiabetic patients (P⬍0.0001). Of practical clinical importance is the difference in pattern of ODE and fundus findings in diabetic versus nondi-
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Ophthalmology Volume 115, Number 10, October 2008 abetic patients. Our studies on NA-AION since 1973 have shown that during the initial stages of NA-AION, the ODE is usually (although not always) associated with characteristic and diagnostic prominent, dilated, and frequently telangiectatic vessels over the disc, and more peripapillary retinal hemorrhages in diabetic patients of all ages than in nondiabetic patients (Figs 1A, C, and 2A, C).20,21 When the ODE resolves spontaneously, these prominent telangiectatic disc vessels and retinal hemorrhages also resolve spontaneously (Figs 1B, D, and 2B, D). This pattern of ODE and fundus changes in NA-AION in diabetic patients during the acute phase has confused the issue and often resulted in the following 2 types of misdiagnoses. 1. These findings have been mistaken for proliferative diabetic retinopathy associated with optic disc neovascularization and mistakenly treated with panretinal photocoagulation.20,21 Then the spontaneous resolution of optic disc and fundus changes have been attributed to the supposed “beneficial effect” of panretinal photocoagulation;20 in fact, panretinal photocoagulation is not indicated in this disease, because
Figure 1. Fundus photographs (A, B) of the right eye and (C, D) left eye, of a 19½-year-old white male juvenile with diabetes mellitus. (Reproduced with permission from Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72.) A, C, On first visit to the clinic: Fundus photographs (A) of the right eye and (C) left eye show massive ODE with marked telangiectatic vessels on the optic disc, many retinal hemorrhages, engorged retinal veins, and lipid deposits in the right macular region. Visual acuity was 20/25 in the right eye and 20/40 in the left eye, with enlargement of blind spot in both eyes. B, D, On resolution of ODE: Fundus photographs (B) of the right eye and (D) left eye show normal-looking optic discs, no abnormal vessels on the discs, and no retinal hemorrhages.
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Figure 2. Fundus photographs of both eyes of a 51-year-old woman with adult-onset diabetes mellitus. Bilateral NA-AION developed first in the right eye (A, B) and 8 months later in the left eye (C, D). A, C, On first visit to the clinic: Fundus photographs show massive ODE with marked telangiectatic vessels on the optic disc and many retinal hemorrhages. Visual acuity was 20/20 in the left eye and 20/15 in the right eye. Both eyes had inferior nasal visual field defect. B, D, On resolution of ODE: Fundus photographs show no ODE but mild temporal pallor, no abnormal vessels on optic disc, no retinal hemorrhages in the right eye (B), and a few resolving hemorrhages in the left eye (D).
it produces unnecessary extensive retinal damage and associated visual complications. 2. This pattern of ODE and fundus changes in NA-AION in diabetic patients has also often been misdiagnosed as a distinct clinical entity called “diabetic papillopathy” or “diabetic papillitis,”4 –12 causing confusion and controversy. The following 2 factors in diabetic patients are responsible for this controversy. (a) Incipient NAAION17 initially occurs more frequently in diabetic than nondiabetic patients. (b) Some diabetic patients with NA-AION or incipient NA-AION also concurrently have diabetic macular edema with poor visual acuity; this has added to the confusion. Diabetic macular edema, per se, does not produce any optic discrelated visual field defects. We have discussed at length elsewhere why “diabetic papillopathy” is actually NAAION in diabetic patients, and not a distinct clinical entity.16,17,20,22 Once one considers all these factors, it becomes apparent that the term “diabetic papillopathy” is not correct and confuses the issue. Our studies have shown that there is no difference in the optic disc morphology23 and fluorescein angiographic16 findings between diabetic and nondiabetic NA-AION eyes, except that, as discussed above, diabetic NA-AION eyes usually had telangiectatic vessels that leaked fluorescein during the acute phase of NA-AION (Figs 1 and 2). Among patients with NA-AION, there are several demographic and clinical differences between diabetic and non-
Hayreh and Zimmerman 䡠 NA-AION and Diabetes Mellitus diabetic patients that have been the source of misunderstanding about the diagnosis and management of NA-AION in diabetes mellitus.
References 1. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1994;118:766 – 80. 2. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 1996;114:1366 –74. 3. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome. Ophthalmology 2008;115:298 –305. 4. Lubow M, Makley TA Jr. Pseudopapilledema of juvenile diabetes mellitus. Arch Ophthalmol 1971;85:417–22. 5. Appen RE, Chandra SR, Klein R, Myers FL. Diabetic papillopathy. Am J Ophthalmol 1980;90:203–9. 6. Barr CC, Glaser JS, Blankenship G. Acute disc swelling in juvenile diabetes: clinical profile and natural history of 12 cases. Arch Ophthalmol 1980;98:2185–92. 7. Algan M, Ziegler O, Drouin P. Optic neuropathy in diabetic subjects [in French]. Diabete Metab 1993;19:395–9. 8. Pavan PR, Aiello LM, Wafai Z, et al. Optic disc edema in juvenile-onset diabetes. Arch Ophthalmol 1980;98:2193–5. 9. Regillo CD, Brown GC, Savino PJ, et al. Diabetic papillopathy: patient characteristics and fundus findings. Arch Ophthalmol 1995;113:889 –95. 10. Inoue M, Tsukahara Y. Vascular optic neuropathy in diabetes mellitus. Jpn J Ophthalmol 1997;41:328 –31. 11. Ignat F, Baˇraˇscu D, Perovic I, Munteanu A. Optic nerve lesions in diabetes mellitus [in Romanian]. Oftalmologia 2002;54:39 – 43.
12. Vaphiades MS. The disk edema dilemma. Surv Ophthalmol 2002;47:183– 8. 13. Hayreh SS. Anterior ischaemic optic neuropathy: differentiation of arteritic from non-arteritic type and its management. Eye 1990;4:25– 41. 14. 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. 15. Hayreh SS, Zimmerman B. Management of giant cell arteritis. Our 27-year clinical study: new light on old controversies. Ophthalmologica 2003;217:239 –59. 16. Hayreh SS, Zimmerman MB. Optic disc edema in nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2007;245:1107–21. 17. Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2007;114:1763–72. 18. Hayreh SS. Posterior ischaemic optic neuropathy: clinical features, pathogenesis and management. Eye 2004;18:1188 – 206. 19. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol 2008 Apr 11 [Epub ahead of print]. 20. Hayreh SS, Zahoruk RM. Anterior ischemic optic neuropathy. VI. In juvenile diabetics. Ophthalmologica 1981;182: 13–28. 21. Hayreh SS. Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations, and management. Ophthalmol Clin North Am 1996;9:407– 42. 22. Hayreh SS. Diabetic papillopathy and nonarteritic anterior ischemic optic neuropathy. Surv Ophthalmol 2002;47: 600 –2. 23. 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.
Footnotes and Financial Disclosures Originally received: January 10, 2008. Final revision: March 23, 2008. Accepted: March 31, 2008. Available online: May 27, 2008.
Manuscript no. 2008 –59.
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, Bethesda, Maryland, 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 & Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1091. E-mail: [email protected].
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