The 14th Hoyt Lecture: Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015

Hoyt Lecture Williams F. Hoyt, MD The North American Neuro-Ophthalmology Society, in conjunction with the American Academy of Ophthalmology, established the annual Hoyt Lecture in 2001 in honor of William Fletcher Hoyt, MD, whose contributions to neuro-ophthalmology have spanned seven decades. A fellow of Frank Walsh, MD, the grandfather of clinical neuro-ophthalmology, Dr. Hoyt co-authored the 3rd edition of Clinical NeuroOphthalmology, the "bible" of our specialty. A faculty member of the departments of Ophthalmology, Neurology and Neurosurgery at the University of California San Francisco since 1958, Dr. Hoyt is world-renowned as a clinician, scholar and educator. He has published more than 300 scientific contributions and has trained more than 100 fellows, many of whom are senior professors in their own right, training the next generations of neuro-ophthalmologists on six continents. The 14th Hoyt Lecture: Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015 Anthony C. Arnold, MD Abstract: Since the first English language description by Miller and Smith in 1966 of ischemic optic neuropathy as a distinct ophthalmic syndrome, a long series of studies has refined the clinical profile to what we consider to be accurate today. From the specifics of pathogenesis to the clinical appearance to the effect of therapy, the basic tenets of diagnosis and management have evolved over 5 decades. What we thought we knew about the following topics has changed: location of vasculopathy; incidence; age at onset; optic disc appearance; risk factors for development; natural history; rate of fellow eye involvement; ischemia as an all-or-none phenomenon; and treatment. A look back at these discoveries shows both how far we have come and how far we have to go in managing this disorder. Journal of Neuro-Ophthalmology 2016;36:208-215 doi: 10.1097/WNO.0000000000000395 © 2016 by North American Neuro-Ophthalmology Society W illiam F. Hoyt, MD, is widely known for 3 important contributions to the field of neuro-ophthalmology: his prodigious original research, his creation of a seminal textbook in the field, widely known to his many students as "The Book," and his training of more than 70 US and international fellows, many of whom went on to become academic and clinical leaders in the field. As an "academic grandson" of UCLA Department of Ophthalmology, Stein Eye Institute, Los Angeles, California. The authors report no conflicts of interest. Address correspondence to Anthony C. Arnold, MD, Stein Eye Institute, 100 Stein Plaza, Los Angeles, CA 90095; E-mail: arnolda@ jsei.ucla.edu 208 Dr. Hoyt, having received my training from one of his first fellows, Robert Hepler, MD, I am thankful for the opportunity to deliver the 14th Hoyt lecture in his honor, on a topic to which he contributed major insights. BACKGROUND Ischemic optic neuropathy was first described in the English medical literature in 1966 by Miller and Smith (1), but as is usually the case, the syndrome had been reported earlier, in the European literature, probably as early as 1924 by Uhthoff (2) as "entzunlichen sehnerven affektionen bei arteriosklerose," and more clearly and extensively as "pseudopapillites vasculaires," by Francois in 1957 (3) and 1962 (4). These early articles referred to the disorder as pseudoinflammation of the optic nerve head linked with vascular disease. Uhtoff reported 3 cases with severe arteriosclerosis, profound visual loss, visual field defects, optic disc edema and peripapillary flame hemorrhages, and poor visual recovery. Francois described 7 patients with "papillitis (oedema and later atrophy of the head of the optic nerve, perimetric defects of the fascicular type. which seem not due to inflammation. but to occlusion of the vascular supply.)." In their landmark report, Miller and Smith included 11 cases, 10 over the age of 50 years (range: 52-68 years) and 1 patient of 46 years. Their optic neuropathy appeared identical to that occurring in giant cell arteritis, but in which the diagnosis of giant cell arteritis could not be substantiated. The cases in which hypertension and diabetes were common, demonstrated acute, painless, altitudinal or arcuate visual field loss, pale optic disc edema with hemorrhages Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture which resolved in 3-4 weeks, a poor visual prognosis with little or no recovery, and no effective treatment. Since this report, a voluminous literature has developed around the topic, with clinical observations and research projects modifying our view of many of the original tenets of the disorder. The terminology also has evolved to the current nonarteritic anterior ischemic optic neuropathy (NAION) to distinguish it from arteritic anterior ischemic optic neuropathy (AAION) and those cases without disc edema, designated posterior ischemic optic neuropathy (PION). LOCATION OF THE VASCULOPATHY Francois (3,4) initially postulated that a central artery of the optic nerve supplied much of the anterior portion and was compromised in ischemic optic neuropathy. Early, separate reports by Eagling et al (5) and Hayreh (6) included fluorescein angiographic studies, concluding that impaired perfusion in the distribution of the short posterior ciliary arteries and the choroid were responsible for the syndrome. Most of the fluorescein angiographic studies at the time depicted cases of AAION rather than the nonarteritic form although in some reports, the distinction was not clearly made. These findings were consistent with impaired filling of both the optic disc and the peripapillary choroid (Fig. 1), indicating reduced blood flow in the short posterior ciliary arteries, proximal to their division into paraoptic and choroidal branches. Arnold and Hepler (7) subsequently performed detailed early filling fluorescein angiographic studies of the optic disc in NAION, confirming optic disc perfusion delay without consistent peripapillary choroidal perfusion delay (Fig. 2), FIG. 2. Fluorescein angiography in nonarteritic anterior ischemic optic neuropathy. Arteriovenous phase reveals poor filling of the optic disc (arrows) with normal filling of the peripapillary choroid at 18.4 seconds (Reproduced with permission from [8]). suggesting that the location of the vasculopathy is distal to the short posterior ciliary arteries, affecting either the paraoptic branches or their tributaries within the optic disc. In addition, Hayreh (6) and later Siatkowski and associates (9) demonstrated a marked delay in choroidal filling in patients with AAION. The lack of choroidal dilling delay provides a method for differentiation between the 2 forms of AION on the basis of fluorescein angiographic findings. INCIDENCE As late as the 1990's, no clear data on the incidence of NAION were available. It was generally thought to be relatively uncommon. In 1975, a comprehensive review by Boghen and Glaser (10) documented 37 cases were available for study over a 10-year period at a major academic center. In preparation for the clinical trial of optic nerve sheath decompression surgery for NAION (the Ischemic Optic Neuropathy Decompression Trial, IONDT), study investigators developed more accurate incidence figures, ranging from 2.3 to 10.2 cases per 100,000 US population (an estimated 6,000 new cases per year (11,12)). These figures established NAION as the most common acute optic neuropathy in patients over age 50 years of age. AGE AT ONSET FIG. 1. Fluorescein angiography in arteritic anterior ischemic optic neuropathy. Arteriovenous phase shows poor filling of both the optic disc and the peripapillary choroid at 30.5 seconds. Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 Early reports estimated an average age of 60 years for patients with NAION. While Rizzo and associates (13) addressed the "overlap" age of 40-50 years with NAION vs optic neuritis, most series and textbooks suggested that occurrence of NAION under the age of 50 years was rare. However, a number of publications have shown a significant prevalence of NAION in patients less than 50 years: Arnold 209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture (14), 52 of 491 sequential cases (10.5%); Deramo et al (15), 37 of 577 cases (6.4%); Preechawat et al (16), 169 of 727 cases (23.2%); and Arnold et al (8), 108 of 848 cases (12.7%), with 39 cases under the age of 40 and 18 under 35 years. The clinical features in these series generally did not differ significantly from those reported in older patients. However, Arnold et al (8) reported an increased frequency of chronic renal failure, migraine, and crowded optic discs in younger patients. OPTIC DISC APPEARANCE Francois' initial description of NAION indicated that "pallid edema" was present; Miller and Smith described "pallor and choking" of the nervehead. It has become apparent that NAION is characterized early in the course by hyperemic edema of the disc (Fig. 3), with pallor developing over several weeks as the edema resolves. This contrasts with the arteritic form (Fig. 4) in which pallor, often severe, is seen initially. There were no comments regarding fellow eye appearance in the initial studies, but separate documentation in a small series in 1974 by Hayreh (17) suggested that the fellow eyes in patients with NAION demonstrated a small cup-to-disc ratio. Dr. Hoyt later informally corroborated this finding in unpublished observations (18). A flurry of interest in this topic resulted in a series of studies in the 1980's confirming both small cup-disc ratio (19-21) and small optic disc diameter (22,23) in fellow eyes of patients with NAION, each postulating that the so-called "crowded disc" or "disc at risk" (18) (Fig. 5) predisposed to the development of the disorder. In 1984, Beck and associates (19) found cup-to-disc ratio of 0 in 37 of 51 fellow eyes in NAION cases, and following up this study in 1987 (24) found that the cup-disc ratio in NAION fellow eyes was significantly smaller than normal and AAION fellow eyes. The precise mechanism by which this structural configuration might predispose to NAION is speculative, but most theories invoke a compartment syndrome in the region of the lamina cribrosa. FIG. 3. In acute nonarteritic anterior ischemic optic neuropathy, there is diffuse optic disc edema without pallor (Reproduced with permission from [8]). FIG. 5. Fellow eye of a patient with NAION. Optic disc is small in diameter, with cup-disc ratio ,0.2 (Reproduced with permission from [8]). 210 FIG. 4. In acute arteritic anterior ischemic optic neuropathy, optic disc edema is diffuse and accompanied with marked pallor. RISK FACTORS Early studies associated common presumed vasculopathic risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and smoking with the development of NAION. Of these, diabetes has been implicated most consistently in well-designed studies. Another potential risk factor is that of nocturnal hypotension. Blood pressure during sleep typically drops by 10%-20% compared to waking hours. Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture Hayreh (25) has championed this possible pathophysiologic mechanism pointing out that impaired autoregulation of the optic disc circulation also may be a contributing factor. This hypothesis, while still controversial, offers an explanation as to why many individuals report onset of NAION upon awakening in the morning. Multiple additional factors have been studied, including hyperhomocysteinemia and prothrombotic risk factors (platelet polymorphisms, protein C and S abnormalities, antithrombin III, factor V Leiden, and antiphospholipid antibodies) (26-31). While associations have been made in limited series, there is still lack of consensus as to which, if any, of the factors is present consistently enough to implicate them in pathogenesis, and there is as yet no documentation that modification of any of them has a beneficial effect in reducing the risk of NAION. Two additional potential risk factors have received attention in recent years: obstructive sleep apnea (OSA) and the use of phosphodiesterase-5 inhibitors (PDE5i). OSA has been implicated in cardiovascular disease, with associated hypertension, elevation of c-reactive protein (CRP) levels, and increased risk of cardiac and cerebrovascular events. Several studies have linked this disorder to the development of NAION. Mojon and associates (32) reported 12 of 17 (71%) sequential cases of NAION diagnosed with OSA vs 3/17 (18%) of control subjects; Palombi et al (33) documented 24 of 27 (89%) without controls, whereas Bilgin et al (34) found 15 of 27 (56%) of NAION patients with obstructive sleep apnea vs. control group of 6 of 27 patients (22%). Despites these data, the precise mechanism by which OSA might relate to NAION remains unclear. A chronic or intermittent hypoxic state has been proposed, and although therapy to reverse this in OSA has been shown to reduce the risk for cardiovascular events, the benefit has not been documented for NAION; in fact, in a case series of 108 patients with NAION, there were 3 cases of NAION in patients with OSA on continuous positive airway pressure (CPAP) therapy (35). Regarding the use of PDE5 inhibitors, after several case reports documenting NAION developing in association with their use, Pomeranz and Bhavsar (36) summarized 14 such cases. Age at onset ranged from 50 to 69 years and all patients had at least 1 vasculopathic risk factor and "crowded discs." The events occurred within 36 hours taking the medication, consistent with the window of effect of the drug. Since that report, approximately 100 reported cases have been documented in the literature. The 2 most commonly proposed mechanisms of PDE5 inhibitors increasing the disc of NAION are: 1) exaggerated nocturnal hypotension with hypoperfusion of the optic nerve head and subsequent ischemia and infarct; 2) local optic nerve head vasodilation, which may have 2 effects: first, impaired autoregulation of the optic disc circulation and resultant inadequate maintenance of perfusion under varying conditions; second, compression of the venous system by the dilated arterioles, with a compartment syndrome within the laminar Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 region of a crowded optic disc and subsequent venous congestion and venous infarct (37). As a result of the data regarding the risk of NAION associated with PDE5i inhibitor use, the Federal Drug Administration (FDA) mandated that the involved pharmaceutical companies perform epidemiologic studies to assess risk. The first study, reported by Pfizer in 2015 (38), recruited 675 male subjects with NAION to obtain data on PDE5i exposure. Case crossover methodology was used to compare risk of NAION during 5 half-lives of the PDE5i used to a prior time frame without use, finding an increase by a factor of 2.15. The study estimated that weekly use of the drug would add an additional 3 NAION cases per 100,000 men annually. An additional study in 2015 (39) utilized claims database methodology to evaluate 1109 NAION cases, correlating the ICD-9 code 377.41 with a filled prescription for PDE5i (at both 30 days and 1 year before the event), comparing with matched controls. No statistically significant correlation was found between NAION and the use of PDE5i. Based on the results of these 2 studies, differing opinions remain regarding the link of PDE5i to NAION. NATURAL HISTORY Miller and Smith (1) reported a poor prognosis for visual recovery in their series, with most patients showing no improvement although the majority received systemic corticosteroids. Boghen and Glaser (10) suggested that the visual prognosis was poor, with visual acuity improving in only 2 of 37 (5.4%) patients. Other studies of visual prognosis have shown a more optimistic view. Arnold and Hepler (40) found spontaneous improvement of at least 3 lines of Snellen acuity in 24% of 27 patients at 3-months of follow-up. The Ischemic Optic Neuropathy Decompression Trial (IONDT) (41) documented improvement of at least 3 lines in 42.7% of 89 untreated patients at 6 months of follow-up. This previously unknown aspect of the clinical course subsequently has proved invaluable in assessing potential treatments for NAION, both within large clinical trials such as the IONDT and in many smaller pilot studies in which encouraging results in small numbers of patients must be kept in perspective. FELLOW EYE INVOLVEMENT The risk of fellow eye involvement in NAION was not quantified in initial reports. Miller and Smith (1) noted only that "both eyes are usually involved," but did not provide a time frame or frequency. Boghen and Glaser (10) documented 38% bilaterality in their series, with up to 22 years between events in the 2 eyes. A more structured analysis was performed by Beck and colleagues (42) as preliminary study for a possible clinical trial of aspirin prophylaxis for second eye involvement. They reviewed 431 patients, finding a 12%- 19% risk at 5 years. This was corroborated by the IONDT 211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 6. Optic disc edema preceding visual loss in NAION (preinfarct edema). A. Optic disc edema is present with a peripapillary hemorrhage. B. Fluorescein angiogram, arteriovenous phase reveals only segmental perfusion of the optic disc temporally (arrows) at 19.0 seconds (Reproduced with permission from [8]). follow-up study (43) in which 14.7% of subjects had documented fellow eye involvement at 5-year follow-up. However, in NAION patients under 50 years, there appears to be a worse prognosis for fellow eye involvement. Preechawat and associates (16) documented bilateral occurrence in 53 of 152 (35%) subjects, with a median follow-up of 12 months. Arnold et al (8) reported a second eye event in 46 of 108 (42.6%) of subjects, with a median follow-up of 6 months. This was compared to a control group of patients over age 50 in which 32 of 108 (29.6%) demonstrated bilaterality with the same follow-up period. Although the control group in this series had an unusually high rate, thought to be due to selection bias, the difference between groups remained statistically significant. These findings may prove relevant in the development of treatments or prophylaxis for NAION since the high rate of fellow eye involvement in a short time interval provides an opportunity to assess therapeutic effect in relatively short-term studies. SPECTRUM OF ISCHEMIA Early reports of optic disc ischemia focused on presumed infarction with irreversible axonal damage and visual loss. The concepts that optic disc ischemia may precede visual loss and may not necessarily lead to profound vision impairment were the results of studies by Hayreh (44,45). This was documented in 4 patients who presented with asymptomatic disc edema 2 weeks to 3 months prior to experiencing a decline in vision. Hayreh and Zahoruk (45) also showed that the visual decrease in NAION may be mild. In their report, 3 juvenile diabetics, they presented with mild visual field defects that subsequently resolved over weeks to months, as did the optic disc edema. These cases were consistent with other reports of "diabetic papillopathy" (46-48) and led to speculation of various mechanisms for the syndrome including diabetic metabolic dysfunction, local optic disc surface microvasculopathy, osmotic changes, and possible mild ischemia. Hayreh proposed a spectron of optic disc ischemia in NAION: the first group of preinfarct optic disc edema, the second (diabetic) group with reversible visual dysfunction and, finally, the typical NAION cases, with optic disc ischemia and irreversible optic nerve dysfunction. His hypotheses were supported by a number of subsequent publications (49-51), including those using fluorescein angiography (Figs. 6, 7). FIG. 7. Diabetic papillopathy. A. There is diffuse optic disc edema with prominent surface vascular dilation. B. Fluorescein angiogram, arteriovenous phase, shows poor optic disc filling (arrows) and very early leakage from adjacent surface vessels at 14.1 seconds (Reproduced with permission from [8]). 212 Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture TABLE 1. Treatment modalities used for nonarteritic anterior ischemic optic neuropathy Treatment Vasodilators Anticoagulants Diphenylhydantoin Oral corticosteroids Vasoconstrictors IOP lowering agents Optic nerve sheath fenestration Antiplatelet agents Hyperbaric oxygen therapy Dopamine agonists Topical neuroprotection Transvitreal radial optic neurotomy Lysis of vitreopapillary adhesions Intravitreal corticosteroids Intravitreal VEGF inhibitors Intravenous PGE1 LDL apheresis Intravitreal erythropoietin Intravenous corticosteroids Year (Reference) 1962 (4) 1967 (52) 1972 (53) 1974, 2008 (6,54) 1981 (55) 1981 (55) 1989 (56) 1996 (57) 1996 (58) 2000 (59) 2001 (60) 2003 (61) 2007 (62) 2007 (63) 2007, 2013 (64,65) 2008 (66) 2009 (67) 2011 (68) 2014 (69) IOP, intraocular pressure; LDL, low-density lipoprotein; PGE, prostaglandin E; VEGF, vascular endothelial growth factor. TREATMENT Early reports of NAION indicated no effective therapy. Since that time, a large number of modalities have been studied, none of which has demonstrated proven effectiveness (Table 1). In recent years, however, Bernstein (70) and other investigators have developed animal models of ischemic optic neuropathy in both rodents and primates, utilizing a photoablative technique on the inner surface of the disc to produce optic nerve ischemia. The ischemia mechanism differs from that presumed in human NAION in which injury to the perilaminar region of the nerve is the result of compromise of its more posterior blood supply. However, the models have allowed studies of the cell death mechanisms involved in optic disc ischemia, which may in the future be useful for identifying processes amenable to therapy (71). One compound directed at cell death processes is the synthetic siRNA QPI-1007 (Quark Pharmaceuticals). This antiapoptotic agent inhibits the expression of caspase 2 and has been well tolerated in human safety studies. A randomized double-masked, sham-controlled trial of intravitreal administration of this drug for subjects with acute NAION is scheduled for 2016-2019. CONCLUSION Our knowledge of NAION has grown tremendously in the intervening years since its first English language description in 1966. We now have a much clearer picture of the demographics, clinical features and natural history, but the Arnold: J Neuro-Ophthalmol 2016; 36: 208-215 specifics of pathogenesis, risk factors, and treatment remain elusive. Hopefully, new imaging techniques and study of animal models of this disorder will provide answers to these questions, but as of now, much remains to be discovered. REFERENCES 1. Miller GR, Smith JL. Ischemic optic neuropathy. Am J Ophthalmol. 1966;62:103-115. 2. Uhthoff W. Zu den entzundlichen Schnerven Affectionen bei arteriosklerose. Ber Zusammenkunft Dtsch Ophthalmol Ges. 1924;44:196-208. 3. Francois J, Verriest G, Baron A. Pseudo-papillites vasculaires. 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