Unraveling the Enigma of Nonarteritic Anterior Ischemic Optic Neuropathy

Non-arteritic anterior ischemic optic neuropathy (NAON) is the second most common optic neuropathy in adults. Despite extensive study, the etiology of NAION is not definitively known. The best evidence suggests that NAION is caused by an infarction in the region of the optic nerve head (ONH), which is perfused by paraoptic short posterior ciliary arteries (sPCAs) and their branches. To examine the gaps in knowledge that defies our understanding of NAION, a historical review was performed both of anatomical investigations of the ONH and its relevant blood vessels and the evolution of clinical understanding of NAION. Notably, almost all of the in vitro vascular research was performed prior our current understanding of NAION, which has largely precluded a hypothesis-based laboratory approach to study the etiological conundrum of NAION. More recent investigative techniques, like fluorescein angiography, have provided valuable insight into vascular physiology, but such light-based techniques have not been able to image blood vessels located within or behind the dense connective tissue of the sclera and laminar cribrosa, sites that are likely culpable in NAION. The lingering gaps in knowledge clarify investigative paths that might be taken to uncover the pathogenesis of NAION and possibly glaucoma, the most common optic neuropathy for which evidence of a vascular pathology also exists.

Hoyt Lecture William 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 neuroophthalmology, Dr. Hoyt co-authored the 3rd edition of Clinical Neuro-Ophthalmology, 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 neuroophthalmologists on six continents. Unraveling the Enigma of Nonarteritic Anterior Ischemic Optic Neuropathy Joseph F. Rizzo III, MD Abstract: Non-arteritic anterior ischemic optic neuropathy (NAON) is the second most common optic neuropathy in adults. Despite extensive study, the etiology of NAION is not definitively known. The best evidence suggests that NAION is caused by an infarction in the region of the optic nerve head (ONH), which is perfused by paraoptic short posterior ciliary arteries (sPCAs) and their branches. To examine the gaps in knowledge that defies our understanding of NAION, a historical review was performed both of anatomical investigations of the ONH and its relevant blood vessels and the evolution of clinical understanding of NAION. Notably, almost all of the in vitro vascular research was performed prior our current understanding of NAION, which has largely precluded a hypothesis-based laboratory approach to study the etiological conundrum of NAION. More recent investigative techniques, like fluorescein angiography, have provided valuable insight into vascular physiology, but such light-based techniques have not been able to image blood vessels located within or behind the dense connective tissue of the sclera and laminar cribrosa, sites that are likely culpable in NAION. The lingering gaps in knowledge clarify investigative paths that might be taken to uncover the pathogenesis of NAION and possibly glaucoma, the most common optic neuropathy for which evidence of a vascular pathology also exists. Journal of Neuro-Ophthalmology 2019;39:529–544 doi: 10.1097/WNO.0000000000000870 © 2019 by North American Neuro-Ophthalmology Society Department of Ophthalmology, Harvard Medical School, and the Massachusetts Eye and Ear, Boston, Massachusetts. The author reports no conflicts of interest. Address correspondence to Joseph F. Rizzo, MD, Department of Ophthalmology, Harvard Medical School, and the Massachusetts Eye and Ear, 234, Charles Street, Boston, MA 02114; E-mail: [e-mail] Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 I traveled to visit with Dr. Hoyt twice during my residencies. I made my first visit because of his legend, but I made the second trip because I had experienced the influence of a consummate clinician who had utter command of the science and literature of neurovisual disorders. He welcomed me initially without knowing me, but he was generous with his time to discuss the cases that were being presented to him and my career plans. That time with Dr. Hoyt, though admittedly sparse, had a significant impact on how I approached my study of the field of neuro-ophthalmology which he helped to establish. Dr. Hoyt passed away just prior to giving this Hoyt lecture, but his teachings will live on in perpetuity, including his insightful observation that a small optic nerve cup might provide a clue to the pathogenesis of non-arteritic anterior ischemic optic neuropathy, which is the subject matter that I will address. BACKGROUND The etiology of nonarteritic anterior ischemic optic neuropathy (NAION), the second most common optic neuropathy (1,2), is not definitively known (3). The goal of this article is to critically review scientific and clinical milestones to define gaps in knowledge that could guide future investigations. A noteworthy generalization of this inquiry centers on 1966, the year of the first nuanced description of NAION: most vascular investigations of human optic nerve head (ONH) antedated this milestone, and few studies subsequently examined the penetrating and intraneural vessels likely responsible for NAION (Fig. 1). Improved insights of vascular 529 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 1. Timelines of historically significant publications of vascular (bottom) and clinical (top) research relevant to the understanding of nonarteritic anterior ischemic optic neuropathy (NAION). These timelines emphasize 2 important facts: 1) most of the relevant anatomical work was performed before the definitive descriptions of the clinical features of NAION; and 2) more recent vascular research has shifted to in vivo techniques, which heretofore have not been able to image blood vessels at or below the lamina cribrosa, which is the zone most likely relevant for NAION. perfusion of the ONH might inform our understanding of the etiology of NAION and of chronic open-angle glaucoma, which likewise might result from hypoperfusion of the ONH (4–9). THE EVOLVING RECOGNITION OF NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY In 1910, a thorough summary of optic nerve disease did not allude to a NAION-like disorder (Table 1) (10). In 1924, Uhthoff described 3 cases, with visual fields, of an arteriosclerotic affliction described as being entzündlichen (i.e., inflammatory) (11). Twenty-four years later, Kurz acknowledged several case reports and added 2 of his own thought to be similar to Uhthoff’s, but debatably one or both of his cases were likely caused by temporal arteritis (TA), which then was not readily distinguished from inflammatory optic neuropathies (12). To wit, in 1952 Carroll reported 240 cases of “optic neuritis” and categorized 5 patients as having TA, although “they had no evidence of” such; he also included 14 NAION-like cases of “arteriosclerosis of the vessels supplying the optic nerve” (13). In 1957, Francois et al described “pseudopapillitis vasculaires,” which they conjectured was caused by “sudden occlusion of the nourishing vessels of the juxta-bulbar region of the optic nerve in the context of either generalized arteriosclerosis or TA” (14). In 1958, Peters described 9 cases of “optic neuritis of arteriosclerotic origin.” In 1962, Francois et al (15) described 20 530 cases, some with funduscopic images, of arteriosclerotic optic nerve blindness, and {too generously (my interpretation is that many citations [Legrand et al (16); Williamson Noble (17)] did not conform to NAION)} cited another 18+ cases, concluding that “arteriosclerotic optic nerve blindness was not rare.” They discussed common features of arteriosclerotic and vasculitic disease, emphasized the importance of a temporal artery biopsy and assumed that both conditions were caused by occlusion of the controversial (see below) “central artery of the optic nerve.” By this juncture, blindness from arteritis had been recognized (18–20), but other than for Carroll (13), there was little mention of distinguishing inflammatory vs ischemic optic neuropathy, the profiles of which can overlap (21). Confusion worsened in 1961 when Lasco extended etiological considerations of “vascular affections of the optic nerve” beyond Francois’ by including trauma, systemic hemorrhage, tumor, and allergy, among others (22,23). In 1963 Wieser, without benefit of neuroimaging, enlightened the otherwise murky literature with cases of nontumorous Foster Kennedy syndrome caused by “successive apoplexia of the optic nerve” (24). Emerging Clarity The first English language description that parsed “ischemic optic neuropathy” from arteritic ischemia appeared in 1966 when G. Miller and Smith commented that some of their 11 cases were not consistent with “cranial arteritis” and had “certain features in common, or at least sufficiently similar as to resemble a clinical syndrome” (25). Those nonarteritic Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture TABLE 1. Evolution of NAION as a distinct clinical entity Year 1910 Author Weeks (10) 1924 Uhthoff (11) 1948 1952 Kurz (28) Carroll (13) 1957 Francois et al (14) 1961 Lasco (22) 1962 Francois et al (15) 1962 Wieser 1966 Miller and Smith (25) 1975 Boghen and Glaser (27) Description Broad differential of optic neuropathy, with prominent comment on “papillitis” Recognized “circulatory disturbances,” including “arteriosclerosis” of the CRA. Described 3 cases of an arteriosclerotic affliction causing optic nerve blindness, although described as being entzündlichen (i.e., inflammatory). Two cases 250 cases of “optic neuritis,” although 14 possibly “arteriosclerotic” “Pseudopapillitis vasculaires” caused by “sudden occlusion of nourishing vessels of the juxta-bulbar region of the optic nerve in the context of either generalized arteriosclerosis or temporal arteritis” Potpourri of 19 optic neuropathies presenting as early as 7 years of age His “observations illustrate the diversity of the clinical forms of “pseudopapillitis,” a term which “has the advantage of specifying both the location and etiology of lesion,” which were “always of vascular origin” 20 cases arteriosclerotic optic nerve blindness Described Foster Kennedy–like syndrome caused by “successive apoplexia of the optic nerve” 11 cases of acute optic nerve blindness were not consistent with “cranial arteritis” and had “certain features in common, or at least sufficiently similar as to resemble a clinical syndrome” 50 cases of ischemic optic neuropathy: 37 “idiopathic;” 13 arteritic Comment No recognition of NAION-like disorder “Nutrition to the disk principally from retinal vessels.augmented by arterial branches from the circle of Haller” “Etiology: Strong intravascular circulatory obstruction in vessels supplying ON and retina due to arteriosclerosis, without closure of vessels, as in thrombosis and embolism” One case possibly arteritic Classified optic neuropathies, but conflated retinal circulatory diseases Confusion of inflammatory vs. vascular optic neuropathies Confusion of arteritic vs. nonarteritic pathology Extended etiologies beyond Francois’ to include sudden or progressive blindness caused by trauma, hemorrhage, tumor, and allergy Improved understanding of distinction of arteritic vs. other optic neuropathies vs. CRAO, but relatively little attention to what later will be recognized to be NAION Cited another 18+ cases since his 1956 article, many of which (in my opinion) do not conform to NAION Achieved before modern neuroimaging 1st description of NAION in English Capsulized nonarteritic cases as manifesting later in life with ONH hemorrhage and pallor, commonly with altitudinal visual field loss Definitive distinction of NAION CRA, central retinal artery; CRAO, central retinal artery occlusion; NAION, nonarteritic anterior ischemic optic neuropathy; ON, optic nerve; ONH, optic nerve head. Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 531 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 2. Fundus photographs (left) and fluorescein angiograms (right) of patients with old (A) and acute (B) nonarteritic anterior ischemic optic neuropathy (NAION). The optic nerve appearance of the old attack shows sectoral pallor of the upper half of the optic nerve head (ONH: red oval), which corresponded to an inferior “altitudinal” visual field defect. The fluorescein angiogram (FA) shows relative hypoperfusion of the upper aspect of the ONH (red oval), which is a consequence of loss of neural substrate in this area. The ONH appearance of the acute attack (bottom row) shows ONH edema (red circle) and a penumbra of inner retinal swelling and subretinal edema (yellow oval). The FA shows relative darkness of the ONH (red circle) presumably due to hypoperfusion (that caused NAION); there also appears to be peripapillary choroidal hypoperfusion (yellow oval), but this zone essentially matches the peripapillary swelling on the fundus photograph. This example demonstrates how peripapillary swelling can block choroidal fluorescence and potentially lead to a spurious conclusion of hypoperfusion of the peripapillary choroid. cases, assumed to result from “small vessel disease,” occurred later in life, with painless, abrupt blindness, commonly with altitudinal infarction (Fig. 2) and fellow eye involvement years later. Their seminal, predigital era publication did not immediately impact the field, as the canonical neuroophthalmic textbook of that day published 3 years later (26) devoted 1/2 page to “ischemic papillitis” caused by “microembolization in small vessels, or, commonly, by a form of giant cell arteritis called cranial arteritis.” In 1974, Hayreh published the first book on the broad topic of “anterior ischemic optic neuropathy,” which did not always segregate arteritic vs nonarteritic features, and he offered a pathogenic mechanism by which the ONH is “much more susceptible to obliteration on a fall of perfusion pressure than the main choroid” (7). One year later, Bogen and Glaser more specifically addressed the nonarteritic disorder (by comparing 37 “idiopathic” with 13 arteritic cases) and commented that the pathophysiology of the former was “speculative” (27). Segmental ONH involvement, originally recognized by Kurz (28) and photographically documented by Francois et al (15), was mentioned but not emphasized, although later found to be diagnostically useful (29). 532 The body of clinical information on NAION was effectively summarized by Arnold in the 14th Hoyt lecture (30) and elsewhere (31–37). Toward my goal of exploring etiological factors, I dwell on certain features, including 1) strong tendency to nasal inferior (38) and altitudinal visual field loss (by Goldmann [21] and automated perimetry [39]) and retinal ganglion cell (RGC) attrition by optical coherence tomography (OCT) (40); 2) low (14%) percentage of cases ,50 years of age (41); 3) uncommon (,6.4%) second attack ipsilaterally (34,42); and 4) significant (20% over 5 years) risk of contralateral involvement (43,44). The slow evolution in defining NAION has confounded our understanding of its etiology. Given the strong evidence of ischemia, one approach to the etiologic conundrum is to reexplore the fund of knowledge about the relevant vasculature. VASCULAR STUDIES OF THE HUMAN OPTIC NERVE HEAD A pantheon of investigators has studied posterior ciliary arteries (PCAs), those vessels seemingly relevant for NAION. Vesalius, who performed his own dissections, Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 3. Historically significant images of the posterior ciliary arteries (PCAs) and smaller branches that supply the optic nerve head (ONH) in humans. Left: Gross dissection by Vesalius, the first anatomist to record PCAs, which are clearly evident alongside the optic nerve. This image, however, does not show insertion of vessels into the sclera near the ONH (i.e., short or paraoptic, PCAs). Next column to right: The next recorded image, from 1700, prepared by Wedel, shows generally similar findings. Next 2 columns to right: Later dissections by Haller, then Zinn, revealed more detail of orbital vasculature, including the short PCAs, especially in Zinn’s woodblock print, which he prepared using his notable artistic skills. This print also depicts the perineural anastomotic ring, thereafter known as the circle of Zinn–Haller (label q; yellow oval, with insert lower left), which, however, seems to lie outside of the sclera. Right: Vascular injection into the central retinal artery (CRA) by Leber clearly shows the CRA and vein, and PCAs and their branches entering the meninges and ONH. This image captures the density of arterioles in the region of the lamina cribrosa (purple brackets). which was not de rigueur, published the first images in 1543 (Fig. 3 and Table 2) (45). But, their function was shrouded by the prevailing misconception that different fluids traveled in arteries and veins, a fallacy not challenged until Harvey’s seminal publication on systemic circulation in 1628 (46). Haller and Zinn more clearly demonstrated retroorbital vasculature in 1754 and 1755, respectively (47,48), with Zinn’s image showing the perineural arterial anastomosis eponymously named the circle of Zinn and Haller (CZH). The order of names has varied historically. Although Haller published first, I adopted the primary position for Zinn because his image shows a perineural vascular structure (although seemingly extrascleral). Near the end of the 19th century, Wagenmann performed PCA occlusion studies to study retinal, not optic nerve, disease (49). In 1903, Leber published the first color images of vasculature around and within human ONH (made by injecting ophthalmic arteries). He confirmed existence of the CZH, recognized beams within the lamina cribrosa (LC), and vascular connections between the ONH and choroid, meninges, and central retinal artery (CRA) (50). The shear density of ONH vessels could have deluded early investigators into assuming the ONH was protected from ischemia. Increasingly more sophisticated technical methods enabled a more nuanced understanding of ONH perfusion. In the first quarter of the 20th century, vascular injection studies (using Prussian blue dye, then latex, and later plastic and silicone casts) provided greater definition of vascular patterns (50). The transition from compound to stereo microscopes in the mid-1950s enabled more detailed dissections and improved definition of smaller blood vessels. In 1954, Francois grappled with past inconsistencies and confirmed (with vascular injections in 34 specimens) a peripheral and “axial” (i.e., central) blood supply to the optic nerve, and distinctive supplies to peri-LC vs distal optic nerve (see below). He noted that his injections did Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 not image capillaries, which had been a limitation of most studies (51). He also generated controversy by affirmation of a “central optic nerve artery, a collateral of the ophthalmic artery,” originally proposed by Behr (52), which perhaps because of Hayreh’s firm rebuttals (53–57), he later recanted (58–60). Hayreh reported, however, as others had, frequent and often numerous (1–8) intraneural branches of the CRA (55–57,61). Hayreh’s (impressive) corpus began with his Masters’ thesis in 1958 (57), which was motivated by intrigue of Francois’ description of a “central artery of the optic nerve” (62). His insightful thesis was followed by voluminous work on orbital arteries (54), choroid (63), CRA (64), ophthalmic artery (65–68), and more relevant to NAION, PCAs (5,63,69–73). In 1974, Hayreh coined the term “anterior ischemic optic neuropathy” (74) and thus asserted the ischemic nature of the disorder. The eventual clarity that PCAs perfused the choroid (63,73) and ONH (42,54,71,75) in sectors was enabled by vascular occlusion studies (63,72,73,76) in combination with the first physiological imaging method—fluorescein angiography (FA) (71). Subsequent technical advancements, especially confocal OCT angiography, provided more subtle information (77), but these methods, like all optical methods including Doppler imaging (77) and laser speckle, have not been able to image the critical retro-LC vasculature. What Has Been Learned The human ONH is perfused across 4 zones primarily by branches of PCAs (Fig. 4 and Table 3) (47,48,50,70). Fluorescein angiographic studies by Hayreh and Zimmerman (38) and Arnold (78,79) demonstrated sectoral perfusion to the prelaminar region, which comports with common patterns of visual field loss in NAION (21,27,38). Slightly (5–6 mm) distal to the LC, the optic nerve is supplied only by centripetal arterioles (through branches of orbital, ophthalmic, and short PCAs (sPCAs) that straddle the 533 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture TABLE 2. Nonexhaustive overview of novel methods to study vasculature of human optic nerve head Year Investigator 1543 1700 1754 1755 1850 Vesalius (175) Wedel and Ruysch (176) Haller (48) Zinn (47) Helmholz (177) 1864 Schweigger (178) 1875 1890 1903 1935 1952 1954 Pagenstecher (179) Wagenmann (49) Leber (50) Behr (52) Bignell (180) Wybar (181) 1954 Francois and Neetens (51) 1955 Francois et al (182) 1956 1958 Blunt and Steele (183) Hayreh and Dass (61) 1967 1968 O’Day et al (184); Hayreh and Walker (185) Ernest and Potts (186,187) 1970 1972 1972 1973 1976 Anderson (188) Hayreh and Baines (63,72) Riva et al (189) Yuhasz et al (190) Lieberman et al (152) 1981 1990 2007 Briers and Fercher (191) Olver et al (80,81) Wang et al (192) Method Gross dissection; woodblock prints Gross dissection young eye; woodblock prints Gross dissection; woodblock prints Gross dissection; woodblock prints Developed direct ophthalmoscope, which provided in vivo views of the ONH that enabled insights into retinal vs optic nerve disease First microscopic sections of optic nerve found embolus in CRA of a “blinded eye” Serial sections of optic nerve Experimental vascular occlusion studies Optic nerve head histology, with colored drawing More detailed histological sections India ink vascular infusions, combined with histology Neoprene latex casts of posterior ciliary arteries, digestion with pepsin and trypsin, viewed with stereoscope Dissection down to arterioles using binocular microscope; neoprene latex casts* Microangiographic dyes (visualized smaller vessels not previously visible) Latex injections to image vasculature of optic nerve and chiasm Neoprene latex injection with tissue maceration; with and without Prussian blue injections of CRA for serial sections (10 mm); optic nerve studies followed Fluorescein angiography Cannulation of cat optic nerve to measure in situ pressures; neoprene casts and FA to study effect of elevated IOP on ONH perfusion in monkeys Silicone injections Experimental occlusion studies using FA Laser Doppler Video fluorescein angiography Thin serial sections; stains (including modified silver); magnified tracings; first 3D composites Laser speckle contrast imaging: Flowmetry Casts imaged with scanning laser ophthalmoscope OCT angiography N.B. The years cited are either the earliest published date, or a best estimate, for the technique. *Adapted from renal studies. CRA, central retinal artery; FA, fluorescein angiography; ONH, optic nerve head; OCT, optical coherence tomography. subarachnoid space) then ramify through the pia mater and enter the optic nerve through septae. Considerable variation exists (5,31,70,75). The CZH, which lies within the sclera at the level of the LC (47,48), is an anastomotic circle formed by branches of sPCAs that supply peripapillary choroid, LC region, and immediate retrolaminar zone (Fig. 5). There is considerable variability in the integrity and even presence of the CZH—Olver found an incomplete anastomosis in 23% of eyes (80), while Onda noted that 2 of 13 eyes lacked a CZH (81). Controversies linger about some details, including whether the peripapillary choroid contributes to prelaminar circulation (81–83) and whether anastomoses exist among 534 the various ONH perfusion zones (Fig. 4, Top row, right; Table 3) (76). Differences in semantics (31,70,83) and methods, especially comparisons of in vivo images like FA (70) to postmortem vascular infusion studies (which require injections under high pressure), may account for some differences in interpretations. ETIOLOGICAL HYPOTHESES Nonarteritic anterior ischemic optic neuropathy is a multifactorial disease, and the literature abounds with ideas on causation (31,84,85). The prevailing explanation, espoused initially by Hayreh (71,72,86), is that an inherent Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 4. Various depictions of perfusion patterns to the human optic nerve head (ONH). Top row, left: Colored rendition of the 4 perfusion zones (in shades of blue): Superficial retinal nerve-fiber layer; prelaminar; laminar cribrosa (LC); and retrolaminar. These regions are all supplied by branches of the paraoptic, short posterior ciliary arteries (sPCAs), except for a portion of the most superficial layer that receives additional branches from the central retinal artery. The LC is enclosed by green dashes. Top row, right: Artistic reconstruction map of vessels traced through serial 6-mm-thick sections stained for reticulin, which revealed a richly vascularized, highly anastomotic tissue (used with permission from Lieberman et al, 1976); this view differs from the perspective that the ONH perfusion is end-arterial and not sectoral. Middle row, left: Hypothetical site (labeled) of reduced perfusion within a sPCA just before branching into the eye; a plausible example of the perfusion defect from this site of vascular occlusion is shown on a fluorescein angiogram (FA), Middle row, right: with relative hypoperfusion of the ONH (within white arrows) and peripapillary zone (yellow oval), as in this case of giant cell arteritis. Bottom row, left: Hypothetical site of reduced perfusion within branches of a sPCA entering the sclera or leaving the circle of Zinn–Haller, which would plausibly produce on FA (courtesy of Dr. Anthony Arnold) relative hypoperfusion of a sector of the ONH (Bottom row, right: red arrows) but not of the peripapillary choroid. anatomical profile makes certain ONHs (i.e., “disc-at-risk”) susceptible to ischemia when nocturnal hypotension causes insufficient flow through sPCAs. Nuances of the disc-at-risk concept are discussed first. Disc-at-Risk Hayreh (87), in his study on pathogenesis of cupping, included data showing small cup:disc ratios of unaffected eyes of “NAION” patients, but he did not offer a mechanistic link. Eight years later, Hoyt initiated a repartee (88) by suggesting pathogenic relevance of a small cup, which energized a spate of reports. Lavin and Ellenberger (89) opined that ischemia caused “mechanical compression of optic nerve fibers within the scleral canal,” and thereafter, 4 studies confirmed small cups in NAION patients (90–93). Josef and Burde leveraged the earlier findings and perhaps recapitulated notions of a “choked” disc Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 (10) and structural vulnerability (as suggested by Sanders [94]) to conjure the “disc-at-risk” (95). In this scenario, ischemia induces swelling of axons, which become compressed by the rigid scleral canal. Burde hypothesized that ONHs with drusen are relatively spared from NAION, despite their disc-at-risk appearance, because of “progressive, insidious nerve-fiber bundle loss,” which decompresses the disc (96). The same suggestion plausibly could be made for neuronal attrition associated with glaucomatous cupping, which only uncommonly associates with NAION. Conversely, one might hypothesize that, given the (up to) 50% variation in optic nerve fibers among normals (97–99), individuals endowed with higher counts would have a greater risk of NAION. An examination of evidence relevant to the disc-at-risk paradigm offers insights into why certain ONHs might be vulnerable to NAION. Optic nerve head area is determined by the area of the scleral canal, whereas its tissue density is 535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture TABLE 3. General pattern of blood supply to human optic nerve head Optic Nerve Head Region Vascular Supply Surface nerve-fiber layer Arterioles derived from the CRA; temporal region may receive supply from prelaminar region supplied by PCAs Sectoral centripetal branches from peripapillary choroid Centripetal branches from short PCAs or branches from CZH (which is supplied from PCAs) Centripetal supply from pial plexus (supplied by recurrent branches from the CHZ, branches of the short PCAs, and peripapillary choroid) “Axial” (i.e. centrifugal) supply from branches of the CRA Prelaminar Laminar Retrolaminar N.B. Adapted primarily from Hayreh (31). Variations in these patterns exist, especially for the CZH and its branches. Controversies regarding this scheme linger, including the degree to which 1) the peripapillary choroid contributes to the prelaminar circulation (31,70,83); and 2) anastomoses exist across perfusion zones, as Lieberman et al (152) reported a continuous capillary network across the ONH. But Hayreh, who demonstrated sectoral perfusion from sPCAs to choroid and ONH (69,75,193), has argued that capillaries in vivo do not form a collateral circulation. CRA, central retinal artery; CZH, circle of Zinn and Haller; PCAs, posterior ciliary arteries; ONH, optic nerve head. determined primarily by axonal number (100). Larger optic ONHs, with their larger cups, have more neural bundles (and presumably nerve fibers) than smaller nerves (101,102), yet they are less vulnerable to NAION. So, how can these observations be reconciled? Perhaps the relevant parameter is not cup size, but packing density of axons. To this point, Jonas et al showed that nerve-fiber density per area (i.e., “crowding”) is greater in smaller ONHs (103), which supports the disc-at-risk concept. Nonetheless, curiosities remain. For instance, ONHs associated with NAION are only slightly smaller (,1 SD) than normal (101). And, the inexorable and significant agerelated loss of axons (99,103–107) does not confer protection from NAION by decompressing the ONH. Furthermore, OCT measurements of disc area do not support the small ONH/small cup paradigm (106–111). Finally, papilledema, which can cause marked axonal swelling within the scleral canal, only uncommonly causes ischemic optic neuropathy (112). Further inquiry into the disc-at-risk concept reveals a multifaceted matrix of potentially relevant factors. An alternative site of potential mechanical injury to axons is the LC, which is exposed to significant dynamic forces believed to be relevant in glaucoma (113). 3D analyses identified “profound” LC strain induced by high intraocular pressure (114–117), which might account for increased synthesis of rigid connective tissue in glaucomatous ONHs (118). This emerging concept is supported by earlier observations of decreased ONH compliance in glaucoma (119) and aging (120) and decreased axonal survival in ONH regions with reduced elastin (102). These factors could be relevant for NAION if swollen axons were strangled by a less pliant LC. Additional mechanical liabilities are revealed by Sibony’s OCT studies showing “seesaw” ONH motion in NAION (121). And, the increased risk of NAION with ONH drusen (122,123) might relate to similar dynamic forces (124). Demer demonstrated by MRI (125) and OCT (126) that ocular rotations distort the ONH and tether the globe on adduction (125,127). The complexity of biomechanical forces on the ONH is just emerging (114–116,128–130), and their potential relevance is reinforced by the increased risk of glaucoma associated with reduced cerebrospinal (128,131,132) (but not necessarily translaminar [133]) pressure. FIG. 5. Vascular structures of the human optic nerve head (ONH), including the circle of Zinn–Haller (CZH), demonstrated with microvascular corrosion casts imaged with scanning electron microscopy. A. Partial view of the anastomotic ring of the CZH (yellow arrows) formed by a posterior ciliary artery (PCA); one branch (red arrow) from the CZH enters the optic nerve (ON) as a pial artery (PA). Smaller branches (white arrows) enter the pia mater along the ON proper. B. Example of a complete CZH (yellow arrows) surrounding ONH (red circle). C. Example of an incomplete CZH (yellow arrows) surrounding part of the optic nerve had (red curved line) Images taken with permission from Cioffi and Van Buskirk, published in: The Glaucomas 1996. 536 Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture Vascular Factors Three studies (totaling 354 human optic nerves) found similar age-related vascular changes including 1) sclerosis of arteriolar walls in pia mater and optic nerve, 2) intimal thickening of PCAs, and 3) increased thickness of meninges and intraneural septae (through which centripetal arterioles travel) (35,104,134). Lindenberg et al (135) showed ischemic optic nerve damage associated with “excessively hyalinized,” “nearly obstructed” ciliary arteries. Age-related changes in PCA myogenic (i.e., autoregulatory) capacity (136), elastosis of small arteries (104), and thickening of fibrous septae (137) also could impair ONH blood flow. Demer also demonstrated that ocular rotations, which occur hundreds of thousands of times per day (138), compress the peripapillary choroid, potentially contributing to axonal loss in low tension glaucoma (126). And, OCT studies uncovered increased peripapillary choroidal thickness even in uninvolved eyes of NAION patients (110,111), which could increase vascular resistance, reduce ONH perfusion, and increase the risk of NAION (139). A similar finding occurs with sildenafil (140) or prolonged prone positioning (141) (as during sleep), both of which predispose to NAION. Evidence of the impact of biomechanical factors on the ONH is mounting. I agree with Girkin that “the morphology of the disc at risk in NAION may not be well understood and it is not simply a small ONH” (109). What Are Vulnerable Sites of Vascular Compromise? The challenge of uncovering an etiology for NAION is partially related to the lack of disease-mimicking (from an etiological standpoint) models, although some models have been valuable to study tissue responses to injury and to explore new therapies (142), and the dearth of pathological studies after NAION had been clinically defined (Fig. 1 and Table 4). One 3D reconstruction showed a 1.5-mm-long ONH infarct that did not correspond to a particular vascular distribution, leading the authors to conclude that “NAION is not a disease of large or small vessels but rather a compartment syndrome” (143). Hayreh valued this novel documentation of a centrally positioned infarct but disputed the interpretation (31). This case also was confounded by renal failure and hypercalcemia, which can contribute to an optic neuropathy (144,145). TABLE 4. Optic nerve histopathology in cases with clinical evidence of nonarteritic anterior ischemic optic neuropathy* Year Authors Optic Nerves Studied 1966 Cogan (169) 1 1971 Knox and Duke (172) 1 1985 Quigley et al (165) 4 2003 Tesser et al (143) 1 Comments Single case, without clinical information†, of a “well-defined” ONH infarct “Identifiable vessel changes are minimal” First ischemic optic nerve pathology without evident arteritis Atypical case: 55-year-old with slowly progressive visual loss; old luetic keratitis/numerous peripheral chorioretinal scars, suggestive of syphilis; diffuse arteriosclerosis; The authors state that “It is possible [...] blood supply to the optic nerve head,” which argues this case being NAION. Focal necrosis just posterior to cribriform plate Edema confined within tight space of ONH and sheathcompressed tissue No direct evidence of vascular occlusion, but specimens studied 3+ years after acute events Strong tendency for superior nerve to be infarcted Central half of the nerves were relatively preserved Serial sections, with 3D digital reconstruction of infarct 1.5-mm-long infarct in superior part of nerve, confined to boundaries of sclera and surrounding the CRA Consistent with “compartment syndrome;” infarct in watershed zone between pial supply and intraneural branches of CRA No obvious correlation between configuration of infarct and any single vascular territory *Made after the seminal clinical description of NAION (25). † Although lacking clinical detail, the author’s expertise and knowledge of this case support inclusion. CRA, central retinal artery; ONH, optic nerve head; NAION, nonarteritic anterior ischemic optic neuropathy. Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 6. Various images of the human optic nerve head (ONH) highlighting the Elschnig spur (ES). A. Light micrograph of the normally occurring, pointed fibrous scleral tissue surrounding the ONH (i.e., Elschnig spur); this promontory can distort soft tissues, as it does to retinal ganglion cell axons in this instance of papilledema (Taken with permission from Lindenberg et al, 1973). B. Light micrograph stained with the aldehyde fuchsin-Masson Goldner method, highlighting scleral collagen fibers (blue-green) of the ES (loosely outlined with yellow dashes). The most narrow aspect through which the optic nerve passes is across the edge of the circumferential spur (yellow asterisks) (CV, central retinal vein; EO, extraocular portion of optic nerve; Lam, laminar; OH, optic nerve head (Taken with permission from Oyama et al Archives of histology and Cytology, 2006). C. Composite illustration drawn to scale of vascular arrangements at the ONH, showing branches of short posterior ciliary arteries (sPCAs) coursing through ES (emphasized in darker blue tone and demarcated with white dashed lines to the right) to reach the ONH (inside black ovals). D. Histology with the modified silver reticulin stain showing branches of sPCAs (*) coursing through the sclera (S) at the level of the ES (demarcated by red hash marks). These vessels (highlighted in yellow and with the open arrowhead) enter the prelaminar region (Pre LC) and the more superficial nerve-fiber layer. E. A magnified view at the transition of the vessels from encasement by firm scleral tissue to softer tissue of the ONH, where they plausibly could be vulnerable to compression by swollen axons against the more rigid collagenous tissue of the ES (labeled “E”) C, D, and E taken with permission, and slightly modified, from Lieberman et al 1976. No study has revealed clear, causative vascular pathology, which supports Hayreh’s hypothesis that NAION is triggered by a dynamic factor—nocturnal systemic hypotension (146–148)—that causes blindness mostly during sleep (146), although this differs from our experience (21). Notwithstanding this one difference, undoubtedly a confluence of factors creates a fraught dynamic for ONH perfusion. Ultimately, these factors somehow disrupt flow at vulnerable locations to cause (often sectoral) infarction of the ONH. Plausible sites of vascular vulnerability include the following: Proximal Posterior Ciliary Artery NAION does not cause regional choroidal hypoperfusion (31,149) as seen with arteritic obstruction of proximal PCAs, thus this site can be exculpated. Distal Posterior Ciliary Artery Branch Reduced peripapillary choroidal and ONH flow on FA could signify disrupted flow of a distal PCA branch, perhaps exposing a “peripapillary watershed” region (150). But this 538 filling pattern, which can be seen in NAION, can be misconstrued because peripapillary edema can give the illusion of hypoperfusion (Fig. 2, Bottom row), although curiously nonischemic ONH edema does not (79). OCT angiography shows reduced peripapillary retinal capillary and choriocapillaris flow in NAION, but this was attributed to neural atrophy of chronic cases (139). Notwithstanding these considerations, Arnold’s study of 41 patients with acute NAION, which provides the most definitive assessment of ONH perfusion, showed delayed ONH filling “without consistent relation to adjacent peripapillary choroidal filling delay” (78). Given a study in monkeys that demonstrated a cuff of peripapillary choroidal hypoperfusion (smaller than that found by Hayreh using a quasisimilar method) (63,72,73) when PCAs were disrupted at the sclera, the lack of such finding in NAION suggests that sPCA flow is disrupted distal to scleral entry (151). However, the ONH hypoperfusion found by Arnold does not necessarily require that a vascular defect exist within the ONH proper. In fact, the challenge of accounting for the Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 7. Various in vitro images of optic nerve heads (ONHs), from the laboratories of Ian Sigal (top row, monkey) and Tatjana Jakobs (bottom row, mouse). A. 3D mapping of ONH blood vessels and connective tissue from serial sections imaged by polarized light microscopy (to provide quantitative information on collagen density [brightness] and orientation [color]), and fluorescence microscopy after DiI perfusion through arteries, which stains even small vessels. This coronal section, magnified to the right, shows individual vessels (red) and collagen beams of the lamina cribrosa (green). Yellow arrowhead shows a vessel within a beam, consistent with historical teaching, compared with a vessel that travels outside of a collagen beam (yellow arrow) where presumably it might be more susceptible to mechanical stress from elevated intraocular pressure. B. Perfusion of the central retinal artery (CRA), with reconstruction of serial, stacked sections of the laminar and immediate retrolaminar regions, with vasculature colored to show distinct watershed regions originating either from portions of the circle of Zinn–Haler or CRA. C. Arteries and veins labeled (i.e., “painted”) by systemic perfusion with DiI. Hundreds of individual images taken at a z-step size of 1.5 mm are volume reconstructed to show the entire arterial and venous tree, including the smaller vessels (background) which are from the deeper vascular plexus. D. Single cross section with immunohistochemical stain for smooth muscle actin (SMA: green), which is dense within the wall of the CRA but also quite evident in walls of small arterioles. SMA enables autoregulation. commonly observed altitudinal infarction in the capillary-rich ONH that lacks a corresponding vascular architecture (Fig. 3 right; 4 upper right; 5) weighs against an intra-axial nidus of vascular insufficiency. One potentially important exception to this assumption is compromise of the intra-axial, longitudinal arterial supply of the retrolaminar optic nerve (152), which could explain Tesser’s axial infarct (31,143). Thus, inherent variability of intra-axial (57,61,152) and PCA vasculature more generally, which Hayreh has emphasized (5), is another plausible risk factor for NAION, although not with any obvious relationship to the disc-at-risk concept. Dynamic factors related to intraocular pressure (see Sigal, below) also could potentially explain sectoral perfusion deficiency. But, perhaps with these exceptions, the general lack of peripapillary hypoperfusion would suggest that the vulnerability to PCA hypoperfusion in NAION might occur between the sclera and ONH, involving either direct penetrating branches to the ONH (see Elschnig spur, below) or branches into and out of the CZH. susceptibility to NAION. For instance, it has been observed that the CZH, when incomplete, can lack a superior branch (80), which might explain altitudinal infarction, and sometimes the CZH is supplied by only one sPCA (153,157,158). Unfortunately, the intrascleral CZH currently cannot be visualized in vivo, except (debatably [31]) in high myopia (154,157). Circle of Zinn–Haller The substantial variability in the existence (81,153), integrity (80,81,153–155), and shape and location (154,156) of the CZH provides an enticing mechanism to explain individual THE ENIGMA Rizzo: J Neuro-Ophthalmol 2019; 39: 529-544 Venous Etiology Venous insufficiency was hypothesized to cause an NAIONcompartment syndrome (159). In 1954, Francois observed no veins in the CZH (51), and others observed similar findings including only a single path of venous egress through the central retinal vein (53,81,150,160–162) (although perhaps with smaller centrifugal veins draining to the choroid and pia mater [152]), which could create precarious flow. In this regard, Girkin’s finding of peripapillary choroidal thickening could plausibly result from venous hypertension, which then could impede OHN perfusion (109,110). The enigma of NAION was posited from a clinical perspective (3), and the impressive history of investigation (Table 1) has not provided sufficient clarity. By whatever 539 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture mechanism(s), NAION is caused by hypoperfusion, then infarction, of the ONH. Interestingly, the etiology of the most common form of stroke—the “lacune”—defied researchers until Miller Fisher rigorously searched the course of penetrating vessels slide-by-slide, with thin (10 mm) serial sections, to discover stenotic and occluded vascular segments. But, an occlusive lesion may not be a necessary culprit at the complex and highly dynamic ONH region. An equipoise among myriad anatomical, physiological, biochemical, and biomechanical factors is required to maintain axonal health at the OHN (163,164). Static (i.e., small cup:disc ratio) and dynamic (e.g., low blood pressure) factors are widely believed to cause NAION. But, these factors do not readily explain why NAION affects only a small fraction of the population (1,2) or the strong tendencies for sectoral damage (29,165) and uniocular attack (43,44). Nonarteritic anterior ischemic optic neuropathy may represent a single phenotype of different pathologies prone to occur at the ONH. Sites where sPCA branches transition from softer into firmer tissue (i.e., sclera or dura mater) and then into the mobile ONH, which lies at the fulcrum of ocular rotation, could become tenuous and confer a risk of hypoperfusion within the ONH. Branches exiting at Elschnig’s spur (166,167) may be especially vulnerable to compression by swollen axons (Similarly, Lindenberg et al [168] suggested that with papilledema branches of sPCAs could be compressed against the “unyielding internal scleral ring”) (Fig. 6). Accrued age-related changes in these vessels may reduce the vascular reserve and impair autoregulation. Thus, a fraught confluence of inherent anatomy (especially of the CZH) and superimposed local susceptibility (influenced by static or dynamic factors) may pose a threat to axons at the ONH, with or without systemic hypotension. Our marginal understanding of potentially relevant factors, including challenges of maintaining intracellular homeostasis (164), beckons further study. GAPS IN KNOWLEDGE Few histopathological studies are available of NAION (Table 4) (143,165,169–172). Although age-associated vascular changes occur (35,134), pathology sufficient to explain NAION has not been uncovered. Clues may be obscured by 1) insufficient knowledge of complex ONH dynamics; 2) lack of extensive 3D characterization of relevant human vasculature; and 3) current inability of in vivo techniques to image retrolaminar vasculature in humans. The latter has created a technical blind spot of the dynamic interplay among factors, including autoregulation, that influence ONH blood flow, although recent advances in OCT-A methodology have enabled imaging of the immediate retrolaminar vessels in monkeys (personal communication, Brad Fortune; October 29, 2019). To paraphrase an aphorism attributed to Martin Rees (173), the lack of iden540 tified pathology does not exclude identifiable pathology. Thus, there is more work to be done to definitely establish the etiology of NAION. WHAT INVESTIGATIONS MIGHT IMPROVE THE UNDERSTANDING OF NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY Anatomical studies alone cannot unravel the complexity of the ONH. Future research must merge investigations of 1) 3D ONH vascular architecture with immunohistochemical characterization of adjacent neural and glial tissues; 2) in vivo biomechanical, pharmacological, and autoregulatory effects on blood flow; 3) in vivo retrolaminar imaging, and 4) RGC homeostasis. Tatjana Jakobs, Ian Sigal, and I have explored use of their methodologies to study the ONH. Their potentially relevant findings include Sigal’s demonstration in monkey ONH that 1) capillaries sometimes lie outside of septae (174) where they might be vulnerable to pressure, and 2) regional perfusion zones are influenced by intraocular pressure (unpublished observation); and Jakobs’ 3) use of a “painting” technique to visualize 3D vascular architecture without infusions, and 4) evidence in monkey ONH of significant smooth muscle actin, which enables autoregulation (Fig. 7). My synthesis of this remarkable history of discovery is based on significant accomplishments of others. 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