Does Nocturnal Hypotension Play a Causal Role in Nonarteritic Anterior Ischemic Optic Neuropathy?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Does Nocturnal Hypotension Play a Causal Role in Nonarteritic Anterior Ischemic Optic Neuropathy? Dean M. Cestari, MD, Anthony Arnold Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute unilateral optic neuropathy in adults older than 50 years (1). Although NAION more commonly occurs in older patients with vascular risk factors, the precise cause of this condition remains unclear, which limits effective treatments. Exaggerated nocturnal hypotension has been proposed as a potential inciting event for NAION. Two experts discuss the possible role that nocturnal hypotension may play in this disorder. Pro: Nocturnal Hypotension is Causally Related to Nonarteritic Anterior Ischemic Optic Neuropathy: Dean M. Cestari, MD Evaluating the signs and symptoms of an optic neuropathy is the "bread and butter" of any neuro-ophthalmic practice, and these data guide the appropriate evaluation and treatment. Ischemic optic neuropathy (ION) is the term used to describe optic nerve injury from vascular insufficiency, and it is the most common acute optic neuropathy in older patients with an annual incidence estimated to be 2.3-10.2 cases per 100,000 persons aged 50 years or above (1-4). ION can be classified as anterior when disc edema is present or posterior when it is absent, the latter is presumably due to ischemia of the retrolaminar portion of the optic nerve. Anterior ischemic optic neuropathy (AION) and posterior ION can be further subdivided into arteritic (vasculitis usually from giant cell arteritis) or nonarteritic (not related to vasculitis) AION (NAION). Even although NAION is responsible for approximately 90% of ION cases, its exact cause remains unclear. There are many hypotheses regarding its underlying pathophysiology. One of the most widely held theories is that vascular insufficiency within the optic nerve head results in hypoperfusion and ischemia in patients with a small cup/ disc ratio, the so-called "disc-at-risk." The resulting optic neuropathy manifests clinically as acute, painless, monocular vision loss associated with optic disc edema. The exact location of the vasculopathy is unclear and some believe that it occurs at the short posterior ciliary arteries (SPCA) because blood flow through these arteries is Department of Ophthalmology (DMC), Mass Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; and UCLA Department of Ophthalmology (AA), Jules Stein Eye Institute, Los Angeles, California. The authors report no conflict of interest. Address correspondence to Dean M. Cestari, MD, Department of Ophthalmology, Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114; E-mail: Dean_Cestari@MEEI. HARVARD.EDU Cestari and Arnold: J Neuro-Ophthalmol 2016; 36: 329-333 believed to be reduced in patients with NAION (2,4-6). However, cases of NAION rarely have been studied histopathologically and none have demonstrated thrombosis of the SPCAs (6,7). Other reports have demonstrated inconsistent delays in choroidal filling in fluorescein angiography studies of patients with NAION, which suggests that the impaired perfusion may arise in the paraoptic tributaries of the SPCAs, distal to their split from the choroidal branches. These findings have led some to conclude that NAION may be in some cases due to generalized hypoperfusion and in others due to focal occlusion of the optic disc or laminar capillaries (8). In addition to a "disc-at-risk," almost all patients who develop NAION have at least 1 underlying vascular risk factor that may or may not be known at the time they lose vision (9). Whatever is the cause for impaired blood flow in the optic nerve vasculature, persistent hypoperfusion requires impairment in the normal autoregulatory mechanisms of the optic nerve head, and one hypothesis is that nocturnal systemic hypotension has a major role in the development of NAION (10). Normal blood pressure (BP) measurement varies among and within individuals, and on average, it is lower during the night (sleep) than during the day (waking hours) by approximately 10%-20%. In some patients with systemic hypertension, BP can decrease by more than 20%, whereas other patients may even have a rise in BP during the night in comparison with daytime BP (11). Hayreh et al (10) postulated that the relative hypotension that normally occurs with sleep may chronically impair optic disc circulation, especially in patients with systemic hypertension who may have impaired autoregulation of optic disc circulation. This effect may be exacerbated by aggressive antihypertensive therapy, especially if administered at night, by causing an exaggerated nocturnal drop in BP. 329 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point The idea that nocturnal systemic hypotension has a significant role in the development of NAION in certain susceptible subjects derives mostly from a study by Hayreh et al (10) that involved 24-hour ambulatory BP monitoring in 52 patients with NAION and compared the results with 19 patients with primary open-angle glaucoma (POAG) and 65 patients with normal tension glaucoma (NTG). The study showed that patients with NAION had a mean decrease in systolic BP of 25.3% and diastolic BP of 31.2%. Because no control group was included, it is not possible to know whether this represents an exaggerated drop in nocturnal BP. Generally, no differences were found in BP decreases among the 3 groups except for the 36% decrease in diastolic BP in the patients with NTG who was statistically significant compared with the decrease of 31.2% in the NAION group (P = 0.004). Moreover, nighttime BP recordings in patients with NAION with systemic hypertension taking oral antihypertensive therapy were significantly lower in patients believed to have progressive NAION with visual field deterioration. Similar findings were demonstrated by the same author in a larger study of 114 patients with NAION, 131 with NTG and 30 with POAG, which led him to conclude that nocturnal hypotension, in the presence of other vascular risk factors, may reduce the optic nerve head blood flow below a critical level that contributes to the development of NAION (12). The role of nocturnal hypotension is controversial. Landau et al (13) performed a similar study monitoring 24-hour BP in 24 patients with NAION and compared their results with 24 age- and medication-matched controls. There was no significant difference in the mean decreases of systolic and diastolic BP measured in the NAION group compared with that measured in controls. However, there was an average of 5-7 mm Hg lower daytime BP in patients with NAION compared with controls and the largest difference was observed in the morning, which suggests that patients with NAION have slower morning rise in BP when compared with normal controls. The conflicting results of these studies obscure the role of nocturnal hypotension in patients with NAION (9). However, because data on the natural history of this disease indicate us that some patients will have progression of their disease (14), Hayreh's data suggest that in a subset of patients, it is possible that exaggerated nocturnal dips of BP might explain this progression. Because there is no effective treatment and we cannot predict or prevent who will progress, physicians should consider monitoring nocturnal BP in their patients with NAION (24-hour BP measurements). If exaggerated nocturnal dips are observed, patients should be counseled about the theoretical risks of aggressive BP management and advised not to take their antihypertensive medications before bedtime to limit exaggerated nocturnal hypotension (12). These data will also help the neuroophthalmologist to effectively communicate with their patient's primary care physician about the potential role of BP management in patients with NAION. The 5-year risk of developing NAION in the fellow eye is approximately 15% (15) and the life-time risk is 30%- 40% (16). Hayreh et al (12) have stated that nocturnal hypotension may be the final insult in a multifactorial situation that leads to the development of NAION. If this is true, we could consider obtaining 24-hour BP recordings in our patients to try identify patients who are at highest risk to develop the disease in their fellow eye so that oral hypotensive medications can be properly managed to lower this risk. In addition, and perhaps more importantly, although the neuro-ophthalmologist is a subspecialist who focuses on evaluating neurogenic causes of vision loss, we should also attend to the systemic vascular risk factors of our patients. Most patients with NAION have at least 1 vascular risk factor that may or may not be known at the time of presentation (9), including systemic hypertension, that may increase their risk of myocardial infarction, stroke, and death. Interestingly, the absence of a nighttime dip in BP has been associated with poorer health outcomes, including increased mortality in one study (17). Furthermore, nocturnal hypertension is associated with end-organ damage and is a better indicator of disease than daytime BP readings (18). So even if 24-hour ambulatory BP monitoring does not affect the prognosis of visual loss in NAION, the additional knowledge that it can provide relating to BP patterns may lead to the initiation of treatment that prevents future vascular events, end-organ damage and, potentially, death. Con: Nocturnal Hypotension is Not Causally Related to Nonarteritic Anterior Ischemic Optic Neuropathy: Anthony Arnold, MD I agree with Dr. Cestari that the etiology of NAION remains unclear. Although there is evidence from fluorescein angiographic studies that optic disc perfusion is impaired (8), the precise location of the vasculopathy is unproven, and features predisposing or inciting the ischemic event lack clear substantiation. Suggested contributing factors have included the cupless, "crowded disc," lipohyalinosis of the disc microvas330 culature with decreased flow and impaired autoregulation, and the presence of nocturnal hypotension with associated impaired optic disc perfusion (2). The relation of nocturnal hypotension to NAION has been controversial, and the evidence remains inconclusive. The purported link of decreased systemic BP (and by implication, optic disc perfusion pressure) to the development Cestari and Arnold: J Neuro-Ophthalmol 2016; 36: 329-333 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point of optic disc ischemia is certainly reasonable, particularly in view of the clear association of severe hypotensive episodes with the development of optic disc infarcts. NAION after severe blood loss with anemia and hypotension, after GI bleed or cardiac surgery, is well documented, and the pathogenetic mechanism seems clear. To extrapolate from this condition to one in which an exaggerated physiologic drop in BP at night results in an inability to maintain adequate perfusion to the optic disc, however, is more difficult and the available data are not compelling. As noted by Dr. Cestari, in 1974, Hayreh (19) postulated that a drop in systemic BP at night might precipitate NAION, and that this could partially explain his observation that many patients first noted their visual loss on awakening. No accurate data existed at that time to support his theory, but the development of 24-hour ambulatory BP monitoring in the early 1990's allowed for the detailed study of this phenomenon. In 1994, Hayreh (12) proposed supportive evidence, not only for NAION but also for NTG and POAG. He suggested that a drop in BP might either be a precipitating event for NAION in patients predisposed to it by vasculopathic and other risk factors or that chronic relative hypotension may compromise optic disc circulation, particularly in patients with an exaggerated dip in BP or in patients with systemic hypertension, in whom optic disc circulation autoregulatory mechanisms are impaired. Twenty-four-hour ambulatory monitoring was performed in 52 subjects with NAION. There was a mean nocturnal decrease in systolic and diastolic BP of 25.3% and 31.2%, respectively. Similar monitoring was performed in 19 subjects with POAG and 65 subjects with NTG. Mean systolic BPs decreased at night 25.8% and 27.6%, respectively, with diastolic decrease 33.2% and 36.0%, respectively. In general, no significant differences in pressure decrease were observed among patients with NAION, NTG, and POAG. Hayreh interpreted these data to show that nocturnal hypotension plays a significant role in the development of NAION, but the data have significant limitations. No controls were monitored. The nocturnal drop in BP for all 3 groups was substantially larger than the reported figures for normotensive or hypertensive patients without ocular disease. A large meta-analysis of 24-hour ambulatory BP measurement revealed averages of 14% and 16% nocturnal drop in systolic and diastolic BP, respectively (20). However, techniques in measurement vary greatly, and without a control group, it is difficult to assess the significance of the absolute level of nocturnal decrease in BP. Hayreh et al measured peak daytime levels vs trough nighttime levels, whereas most investigators compared mean levels of BP day vs night. Moreover, the findings, if significant, would suggest with equal, if not greater, significance that nocturnal hypotension plays a pathogenetic role in the development of both NTG and POAG. Although a number of studies of ambulatory BP measurement in these diseases have been Cestari and Arnold: J Neuro-Ophthalmol 2016; 36: 329-333 performed, the role of nocturnal hypotension remains unproven. Graham et al (21) performed 24-hour ambulatory BP measurements in 38 subjects with NTG and 46 with POAG. Mean pressure levels demonstrated maximum nocturnal drop in systolic and diastolic BPs of 9.2%- 17.4%, not significantly different from control levels published in the literature, and much lower than Hayreh's measurements; there was no clear difference between patients with NTG and those with POAG. Although studies have found a correlation between progression of visual field defects in glaucoma and lower nocturnal BP (22), whether this relates to pathogenesis of NAION remains uncertain. Landau et al (13) performed 24-hour ambulatory BP monitoring in 24 subjects with NAION and 24 controls matched for age, disease, and medication. Mean decreases of 11% systolic and 18% diastolic were measured in NAION, compared with 13% and 18%, respectively in controls, showing no significant difference. These investigators concluded that nocturnal hypotension was not a cause of NAION, although there was some evidence that lower daytime mean BP was present in patients with NAION compared with controls. The contradicting results regarding the level of nocturnal "dip" in NAION and whether chronic or intermittent low systemic BP is a factor in etiology remain unresolved. A lively discussion between Drs. Hayreh and Landau was published in 1997 (23,24). In 1999, Hayreh published a continuation of his study with a larger number of subjects (10), but no additional features were presented to support his theory. In 1997, Hayreh et al (25) reported a detailed study of time of onset of visual loss in NAION. Of 544 episodes of visual loss in 635 patients with NAION collected over 20 years, "discovery" of visual loss was reported on awakening either from nighttime sleep or a daytime nap in 52%, and during the first "critical" use of vision in the morning in an additional 21.5%. The authors interpreted these data to show that the development of NAION was related to hypotension in approximately 73% of patients. In contrast, the results of the Ischemic Optic Neuropathy Decompression Trial (IONDT) documented that 174/418 (42%) of subjects described onset of visual loss within 2 hours of awakening in the morning, whereas 170/418 (41%) reported that it did not occur during the first 2 waking hours (26). Dr. Hayreh attributed the differences in the 2 studies to the focus of the interviewers in obtaining the information, suggesting that he was more specific and detailed in his discussions with subjects than the investigators in the IONDT. One could just as easily suggest that a broader base of interviewers might result in less biased results. Moreover, a portion (not detailed in the article) of the 52% of his cases reported on awakening followed not a nighttime prolonged sleep, but a nap of undetermined length. The relation of short-term sleep to the development of systemic hypotension is not established. If these cases may be discounted, it is possible that the percentage of patients noting visual loss on 331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point awakening from nocturnal sleep is similar to that reported in the IONDT and does not support a causal link. In summary, the theory that nocturnal hypotension is a significant contributor to the development of NAION is based on very limited data from a single series of studies and is not corroborated by others. Although isolated cases of severe systemic hypotension may result in ION, the normal or even mildly exaggerated nocturnal dip in BP seen in the general population has not been established as a cause in typical cases of NAION. Rebuttal: Dr. Cestari I completely agree with Dr. Arnold that the data pertaining to the role of nocturnal hypotension as a significant contributor to NAION is very limited because it comes from the same group of authors and has not been corroborated by others. However, because the pathogenesis of NAION is unknown and is likely to be multifactorial, I believe clinicians should evaluate every reasonable risk factor that might contribute to the development or progression of NAION, including nocturnal hypotension. Dr. Arnold and I seem to agree that multiple systemic and local factors, acting alone or in some combination, likely derange optic nerve head circulation, with some making the optic nerve head susceptible to ischemia, and others acting as the final insult. Hayreh's data, although imperfect, come from a series of prospective studies that suggest that systemic hypotension may play a role in what is likely to be a complex interaction of multiple risk factors that contribute to the development of NAION. Although I agree with Dr. Arnold that these studies are imperfect, prospective multicenter trials for NAION are challenging because of their relative rarity, and the time and expense of such studies. We are often guided by clinical observation, case reports, and prospective studies such as Hayreh's, and it is important to remember that despite their limitations, these studies often allow for important and valid insights and inferences that help us to properly evaluate and manage disease in our patients. The clinical development of NAION is likely to involve a myriad of unmodifiable risk factors including age, cup/ disc ratio and genetic predisposition. Therefore, it is important to identify every potential treatable risk factor, including nocturnal hypotension, even if its relative contribution to the development of NAION is small. Since ambulatory 24-hour BP monitoring is safe, relatively inexpensive and easy to obtain, clinicians should order it so that they can potentially decrease the likelihood that their patient's symptoms will worsen by appropriately treating their nocturnal BP fluctuations, if present. In conclusion, I agree with Dr. Arnold that there is a paucity of data in the literature regarding nocturnal hypotension in NAION, but I am reminded of Carl Sagan's quote that the "Absence of evidence is not evidence of absence!" Dr. Arnold's main argument is there is a lack of data supporting a causal role of nocturnal hypotension in the pathogenesis of NAION but I believe that there are enough data to support a possible role. Because we have no effective prophylaxis or treatment for NAION. I would evaluate all possible modifiable risk factors including 24-hour BP monitoring in your patients with NAION. Rebuttal: Dr. Arnold Dr. Cestari makes several important points, and I agree with most of them: 1) Persistent optic disc hypoperfusion probably requires impaired autoregulation of blood flow. This may be secondary to vasculopathic risk factors such as diabetes, hyperlipidemia, and hypertension, and patients with NAION should be evaluated for them; 2) systemic hypotension may contribute to optic disc hypoperfusion when it is severe enough to override the autoregulatory system. This certainly occurs in cases of severe hypotension secondary to blood loss in surgical procedures or gastrointestinal hemorrhage; 3) it makes theoretical sense that nocturnal hypotension, if severe enough, could be one factor that facilitates the cascade of events leading to optic disc ischemia. However, I do not see the evidence that this is the case in most patients with NAION. The study by Hayreh et al (10) performed without control subjects and by methods of data 332 analysis for nocturnal hypotension, which differ from most other investigators, does not allow interpretation as to whether the level of nocturnal dip in subjects studied differs significantly from normal controls. Moreover, the finding by Hayreh et al that patients using antihypertensive therapy and demonstrating lower nocturnal BP were at more risk for progressive NAION also is difficult to interpret from the data. Establishing "progression" in NAION and distinguishing it from "nonprogression" requires knowledge of the timing of visual field tests performed. Those patients tested early are more likely to demonstrate worsening of visual field than those tested later, after the event has stabilized. There are no other corroborating studies on NAION. Dr. Hayreh published an additional study in 1999 (10), adding an additional 64 subjects with NAION to the 50 from the previous study (8 of which were actually subjects Cestari and Arnold: J Neuro-Ophthalmol 2016; 36: 329-333 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point with idiopathic intracranial hypertension who demonstrated visual field loss!), but the methodology and the limitations noted above remained the same. The only other published study of this question (Dr. Landau's study (13) with controls) suggests no difference in nocturnal hypotension between patients with NAION and controls. Based on available data, I do not see the justification for physicians to monitor nocturnal BP in their patients with NAION. First, we have no data as to what would constitute a nocturnal dip level that increases risk, if such a level exists. Second, we have no evidence that modifying BP would have any beneficial effect in reducing risk of progression in the affected eye or risk of involvement of the fellow eye. Finally, there is the issue of resource management. Ambulatory 24-hour BP monitoring is a costly, personnel-intensive procedure. Without a stronger rationale, I do not believe that we can justify its routine use in patients with NAION. Conclusions: (Andrew G. Lee, MD, and Greg Van Stavern, MD) The specific etiology of NAION remains ill defined. As the experts note, this condition may represent a convergence of factors that finally reach a critical "tipping point", resulting in ischemia and irreversible injury to the optic nerve. Nocturnal hypotension is a tempting target for both etiology and treatment but the evidence remains unconvincing. Given the limitations of the studies cited, a randomized controlled study with a valid control group with ambulatory BP monitoring, and using standard measurement guidelines, may go a long way toward helping settle this issue. REFERENCES 1. Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT. Incidence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1997;123:103-107. 2. Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003;23:157-163. 3. Biousse V, Newman NJ. Ischemic optic neuropathies. N Engl J Med. 2015;372:2428-2436. 4. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy. Population-based study in the state of Missouri and Los Angeles County, California. J Neuroophthalmol. 1994;14:38-44. 5. Plange N, Kaup M, Weber A, Arend KO, Remky A. Retrobulbar haemodynamics and morphometric optic disc analysis in primary open-angle glaucoma. Br J Ophthalmol. 2006;90: 1501-1504. 6. Knox DL, Duke JR. Slowly progressive ischemic optic neuropathy. A clinicopathologic case report. Trans Am Acad Ophthalmol Otolaryngol. 1971;75:1065-1068. 7. Levin LA, Louhab A. Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114:488-491. 8. Arnold AC, Hepler RS. Fluorescein angiography in acute nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1994;117:222-230. 9. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond). 2015;29:65-79. 10. Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica. 1999;213:76-96. 11. Fagard RH. Dipping pattern of nocturnal blood pressure in patients with hypertension. Expert Rev Cardiovasc Ther. 2009;7:599-605. 12. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117:603-624. 13. Landau K, Winterkorn JM, Mailloux LU, Vetter W, Napolitano B. 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114:570-575. 14. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Cestari and Arnold: J Neuro-Ophthalmol 2016; 36: 329-333 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Decompression Trial. Arch Ophthalmol. 1996;114:1366- 1374. Newman NJ, Scherer R, Langenberg P, Kelman S, Feldon S, Kaufman D, Dickersin K. Ischemic Optic Neuropathy Decompression Trial Research Group. The fellow eye in NAION: Report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol. 2002;134:317-328. Beri M, Klugman MR, Kohler JA, Hayreh SS. Anterior ischemic optic neuropathy. VII. Incidence of bilaterality and various influencing factors. Ophthalmology. 1987;94:1020-1028. Minutolo R, Agarwal R, Borrelli S, Chiodini P, Bellizzi V, Nappi F, Cianciaruso B, Zamboli P, Conte G, Gabbai FB, De Nicola L. Prognostic role of ambulatory blood pressure measurement in patients with nondialysis chronic kidney disease. Arch Intern Med. 2011;171:1090-1098. Verdecchia P, Angeli F, Gattobigio R. Clinical usefulness of ambulatory blood pressure monitoring. J Am Soc Nephrol. 2004;15 (suppl 1):S30-S33. Hayreh SS. Anterior ischaemic optic neuropathy. I. Terminology and pathogenesis. Br J Ophthalmol. 1974;58:955-963. Staessen JA, Fagard RH, Lijnen PJ, Thijs L, Van Hoof R, Amery AK. Mean and range of the ambulatory pressure in normotensive subjects from a meta-analysis of 23 studies. Am J Cardiol. 1991;67:723-727. Graham SL, Drance SM, Wijsman K, Douglas GR, Mikelberg FS. Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. Ophthalmology. 1995;102: 61-69. Charlson ME, deMoraes CG, Link A, Wells MT, Harmon G, Peterson JC, Ritch R, Liebmann JM. Nocturnal systemic hypotension increases the risk of glaucoma progression. Ophthalmology. 2014;121:204-212. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nonarteritic anterior ischemic optic neuropathy: Role of nocturnal hypotension (letter). Arch Ophthalmol. 1997;115:942-943. Landau K, Winterkorn JMS, Napolitano B. Nonarteritic anterior ischemic optic neuropathy: Role of nocturnal hypotension (reply to letter). Arch Ophthalmol. 1997;115:943-945. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: Time of onset of visual loss. Am J Ophthalmol. 1997;124:641-647. IONDT Study Group. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic optic neuropathy decompression trial. Arch Ophthalmol. 1996;114:1366-1374. 333 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.