Does Vitreopapillary Traction Cause Nonarteritic Anterior Ischemic Optic Neuropathy?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Does Vitreopapillary Traction Cause Nonarteritic Anterior Ischemic Optic Neuropathy? Cameron F. Parsa, MD, Zoë R. Williams, MD, Gregory P. Van Stavern, MD, Andrew G. Lee, MD Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute optic neuropathy in adults older than 50 years and a frequent cause of referral to neuro-ophthalmologists. Although there are data regarding natural history and visual outcomes, the precise mechanism of pathogenesis remains unclear and the diagnosis is still made primarily on clinical grounds. A variety of mechanisms have been postulated, with varying degrees of evidence. Here, 2 experts debate whether vitreopapillary traction plays a role in the development of NAION. Vitreopapillary Traction Causes Nonarteritic Anterior Ischemic Optic Neuropathy Cameron F. Parsa, MD As will be addressed, a more appropriate title for this commentary could have been “How abrupt vitreoperipapillary separation causes so-called NAION.” Early descriptions of this optic neuropathy by Francois (1), and by Miller and Smith (2) in the 1960s, were followed by those of Boghan and Glaser in 1975 (3), the first to clearly identify a form of anterior optic neuropathy distinct from that produced by papillitis or arteritis. Such differentiation was a clear step forward, necessary to elucidate an etiology. Boghan and Glaser were careful to stress that this neuropathy, far more common than the well-documented arteritic form, should be understood as idiopathic, without any reference to ischemia that they highlighted was merely speculative. In what has nonetheless since been termed NAION, attempts at demonstrating an ischemic etiology have proven unsuccessful (4–7). Simmons Lessell described NAION as an “enigma,” (7) whereas Joseph Rizzo in his recent Hoyt lecture stated “The slow evolution in defining NAION has confounded our understanding of its etiology (8).” Just as Boghen and Glaser had been so careful to specify and emphasize that notions of ischemia had previously only been assumed without evidence and hence called this entity “idiopathic optic neuropathy,”(3) Bill Hoyt wished also to Department of Ophthalmology (CFP), Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium; Faculty of Medicine (CFP), Sorbonne University, Paris, France; Department of Ophthalmology (ZRW), University of Rochester Medical Center, Rochester, New York; Department of Ophthalmology and Visual Sciences (GPV), Washington University in St. Louis School of Medicine, St Louis, Missouri; and Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston Texas. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St Louis, MO; E-mail: vanstaverng@ vision.wustl.edu 260 direct focus to the particular locus of this entity, the anterior prelaminar portion of the optic nerve (9–11). Unlike the arteritic ischemic form of anterior optic neuropathy, for which Sohan Singh Hayreh had so well documented subsequent development of increased disc cupping (in the genitive sense) (12), no eventual cupping of, or damage to the lamina cribrosa, sharing the same posterior ciliary blood supply with the anterior nerve, could be shown to occur in so-called NAION. Bill Hoyt had noticed, moreover, that those with this nonarteritic entity were prone to have discs with small cups, the “disc-at-risk” (9–11,13). Such discs possess firmer, more intimate vitreo-neuronal attachments (14,15), often overlooked because of their invisible nature. Initial thoughts enunciated in 1978, followed up with various articles, had regarded this vitreo-papillary interface as potentially affecting disc vasculature (16,17). Telltale signs of traumatic vitreopapillary separation were apparent, from characteristic peripapillary and intrapapillary hemorrhages due to capillary rupture to the later discernible focal sheathing of peripapillary area surface arterioles (1–3,18) that Bill Hoyt referred to as “fundal narrowing”(19). Such irregular, occasionally sausage-shaped narrowing of peripapillary blood vessels was notably absent in the arteritic and ischemic forms of optic neuropathy. As Bill Hoyt also reiterated, where is the evidence for ischemia in this so-called ischemic disease affecting only nerve anterior to, yet sparing, the lamina cribrosa (3,7,19)? Bleeding does not imply ischemia and neither angiographic nor histopathologic evidence has emerged to demonstrate vascular obstruction (7,19,20). Nor is there an increased incidence of cardiac or cerebrovascular events in patients so afflicted (3,7,21,22). After so many years of unsuccessful attempts to demonstrate a presumed ischemic source for the neural injury, it behooves one to question underlying assumptions. Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point To paraphrase Arthur Conan Doyle, when one has ruled out the impossible, what remains, however improbable, must be the truth (23). As David McLeod so well pointed out with respect to cotton-wool spots, whiteness, and swelling at the level of the optic disc is not indicative of ischemia, but of a blockage of axoplasmic flow (24). Axoplasmic blockage can be due to ischemia but also be caused by mechanical distortion and folding of axons. Occasionally, this can be produced by vitreopapillary traction (VPT) (25). As noted by Schepens, VPT can produce segmental disc swelling and surface vessel telangiectasia (18), signs now recognized as consistent with so-called “incipient (or threatened) NAION” (20,26–28). Such VPT need not be continuous and manifest with a “Vshaped” hyaloid face to the surface on optical coherence tomography (OCT) scans (29), but be merely intermittent, with traction related to body position, or portions of ocular saccades, best noted with dynamic B-scan ultrasonography. However, it has been more recently understood that extreme axoplasmic blockage leading to neuronal death can result from sudden, abrupt mechanical disruption of the internal viscoelastic microtubular cytoskeleton of axons, the mechanism now understood to produce traumatic brain injury (concussion or commotio cerebri) (30,31). Axons are capable of considerable stretch with slow, gradual, traction, but their viscoelastic microtubular cytoskeleton shall snap and break should there even be small, but sudden, abrupt movements exceeding threshold velocities (32). Such mechanical fractures become several fold more likely as the elasticity of the axonal cytoskeleton diminishes with age (33). Cytoskeletal rupture of retinal ganglion cells (ocular commotio) can occur with brisk vitreous separation during normal activities and ocular saccades (34,35) and should not be confused with persistent vitreous traction or tug. Owing to the effects of gravity, vitreoretinal separation begins often superiorly, with maximum kinetic energy attained by the time the superior peripapillary area is reached (where little protective inner limiting membrane separates vitreous from axons) (14,15,18). The speed of vitreous separation thereafter is often reduced by the braking effects of stronger papillary and central vitreovascular attachments (19,25). Forces diminished below age-dependent threshold levels for fracture of the axonal cytoskeleton will spare axons of the inferior disc and peripapillary area. Hence, in stark contrast to compressive disc phenomenon, segmental disc atrophy, with corresponding dense altitudinal visual field defects, can develop, whereas other portions are entirely spared without even manifesting dyschromotopsia (36). After decades of discussion and study (37), these arguments were carefully laid forth in a detailed exposé as an editorial piece in 2015 (19), citing case series of NAION where peripapillary vitreous separation had been ubiquitous (38,39), also providing additional confirmatory data (40). Engendering much debate, some believed the evidence to nonetheless be insufficient. How so? Once again, Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 because of deficiencies in the use of language and terminology, with brisk, fleeting, vitreous separation being conflated with static, persistent, vitreous traction, or tug with V-shaped hyaloid face. Well-meaning investigators were disappointed subsequently not to find OCT images revealing persistent traction (41,42). That partial (Stage 3) posterior vitreous detachment (PVD) in the peripapillary area devoid of internal limiting membrane (14,15) sufficed to cause internal axonal disruption, without requiring a total (Stage 4) separation from the papilla itself, had also not been appreciated (39,41,42). Some, relying on incomplete OCT imagery or clinical comments obtained retrospectively, believed to have documented total vitreous detachment that had already occurred before neuropathy, negating vitreous separation as causative (42). As Schepens and others had explained before, with others yet since, the visibility of vitreous condensations, including Weiss rings, does not necessarily indicate total PVD nor outer cortical layer separation of this multilayer, cisternal tissue (18,43– 47). Entirely overlooked was the evidence that either peripapillary or full papillary vitreous separation had occurred in the totality of cases (38–40,42), a far cry from that encountered in a normal population (48,49). Reports conflating continuous traction with momentary traction during abrupt separation, overlooking possibilities of partial vitreous attachment, and failing to recognize partial vitreous separation as sufficient (41,42) to provoke axonal cytoskeletal fracture, a result of imprecisions in language, once again led to inaccurate conclusions. As the great logicians and expositors of language, Bertrand Russell and Ludwig Wittgenstein brought to the fore in our understanding of analytic philosophy and science, we think in the language we use. “When I think in language there are not ‘meanings’ going through my mind in addition to the verbal expressions: the language itself is the vehicle of thought” (50). The misnomer used to describe such anterior optic neuropathy, “NAION,” itself serves not only to detract from more fruitful investigations but the explicit supposition of ischemia or “stroke” intimated to patients also stokes fears (51) that they may be at greater risk for cardiovascular events, contributing to their anxieties with diminished quality of life. Applying Occam’s razor to the wealth of accumulated data can yield some clarity. Hence, that diabetes has been linked to attacks in younger individuals (21,52) should not be assumed because of late developing and yet to manifest microvascular effects but associated with the precocious vitreous syneresis induced by fluctuations in osmotic pressure, precipitating earlier detachment (53). Because axonal elasticity is higher in younger patients, many do not develop visual loss (52) but have what has sometimes been referred to in the past as diabetic papillopathy (13,21). 261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Without postulating elusive nocturnal hypoperfusion of the optic papillae in attempts to explain a unilateral loss of vision noted after awakening (4–6), one can recognize vitreoretinal separation progressing during saccades of rapid eye movement sleep. This combined with the effect of gravity, when arising from a recumbent position and then ambulating, will put the weight of peripherally detached vitreous descending more abruptly on the papilla. Sectoral disruption of axon microtubule cytoskeletons with loss of birefringence should not be surprising (54) nor that circumferential peripapillary folds or wrinkles involving the nerve fiber layer alone could be immediately produced (as opposed to deeper, radial folds eventually developing with compressive neuropathies) (41). That these, on occasion, may be accompanied by macular separation (41,55), should be simple to envision by the mechanics of vitreous separation. As should capillary tearing leading to characteristic hemorrhages along with focal, “waistband” narrowing of larger vessels after reparative gliotic sheathing. Optic discs with smaller cups have firmer vitreoaxonal attachments (14,15). This places axons, notably in the older age group when they become less elastic, at greater risk for microtubular fracture from vitreous forces generated during spontaneous separation. Smaller discs also have more rigid, less deformable lamina (Laplace law) (56) subjecting the axons to more abrupt vitreous separation forces. Similar effect can also be produced in larger, otherwise less “risky” discs (including those with large excavations where no “crowding” or secondary axonal compression can be argued) (28,57) with forces that are greater. Hence, temporal associations noted with cataract surgery (58), laser-assisted in situ keratomileusis (LASIK) (59,60), forceful vitrectomy (61,62), or heightened g forces experienced by fighter pilots (63) are explained by their effects on vitreous syneresis and forcing of abrupt posterior separation in various axes. Temporal associations noted with the use of sildenafil and other phosphodiesterase inhibitors (64–66) can also be simply understood, not by paradoxical vascular effects but the very intended purpose of promoting the desired vigorous physical activity, adding kinetic to the potential energy of the vitreous body to stimulate an occasionally abrupt, although nonetheless impending, vitreous separation. Rather than permitting “NAION” to remain a riddle as a construct of language, we should move on to new terminology allowing appropriate analysis. Indicative of the exceptional features encountered, one proposal would be papillary, or peripapillary, vitreous detachment neuropathy, abbreviated to “PVD-N” (19,20). Appropriate attention can then be directed to determining appropriate interventions to reduce either potential step progression (3,19,67–72) in an affected eye or potential contralateral eye involvement. Should one note total vitreous detachment having already occurred with hence no further traumatic separation 262 possible, one could provide immediate reassurance to patients anxious to understand whether progression, or second eye involvement, might occur. Conversely, should vitreous attachments be present with substantial gel still within the hyaloid sac, interventions might be in order (68–72). Prospective studies determining the likelihood of same eye progression, or of second eye involvement, as a function of vitreous status would be of use. Persisting loads could be tackled either by release of hyaloid face attachments, or by emptying of sac contents, whether by photodisruptive, enzymatic, or mechanical means. Assessing the need for such interventions and the entanglement of various forces in an individual patient may not always be straightforward or definite. Determination of such physical uncertainty, rather literally, is where lies the rub. and future challenges. Con: Zoë R. Williams, MD The hypothesis that VPT is the underlying pathophysiology causing NAION is intriguing. The typical age range of presentation with PVD is similar to NAION making an association plausible (73); however, PVD is very common yet the incidence of NAION is only 2–10 per 100,000 (74,75), implying VPT cannot be the only factor. Natural history studies of NAION and the reported association of NAION with microvascular conditions, obstructive sleep apnea (OSA), and blood flow altering erectile dysfunction medications suggest VPT may not be a factor at all. Pathophysiology of posterior vitreous detachment Although the pathophysiology of NAION is not known, the pathophysiology of PVD is well-established and explains risk factors for early PVD. PVD occurs because of a combination of vitreous syneresis and decreased attachment between posterior vitreous cortex and the internal limiting membrane of the retina (75,76). The evolution of PVD has been described based on OCT studies as occurring in 4 stages: 1) vitreous cortex separation from the internal limiting membrane at the perifoveal retina with persistent vitreofoveal attachment, 2) macular PVD with no residual vitreofoveal attachment, 3) near complete PVD with residual vitreopapillary attachment, and 4) complete PVD (76,77). The process of PVD has been shown to evolve slowly over months to years until symptomatic vitreopapillary release occurs (76). Typically early stage PVD causes pathology in the macula, whereas late stage PVD causes pathology in the retinal periphery. This suggests significant shift in the tractional forces as vitreous syneresis progresses and macular adhesion releases. If VPT directly causes NAION, the mean age at onset of NAION (66 years old in the Ischemic Optic Neuropathy Decompression Trial [IONDT]) (78) might be anticipated to be older as the incidence of PVD increases with age (80). In an ultrasonography study of 404 patients without prior eye surgery, history of proliferative retinal disease, or Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point significant refractive error (.3 D), only 11% of patients aged 65–69 had a complete PVD vs 46% of patients aged 80–89 (80). Importantly, in patients aged 65%–69%, 72% still had a completely attached vitreous body (therefore no VPT), whereas the percentage dropped to 43% in patients aged 80–89 (80). Risk factors for early posterior vitreous detachment are not risk factors for early nonarteritic anterior ischemic optic neuropathy Multiple risk factors for early PVD have not been shown to be risk factors for early NAION. It is known that PVD occurs significantly earlier in patients with high myopia (76,80–82) and connective tissue disorders (Stickler syndrome and Marfan syndrome) (76), yet high myopia and connective tissue disorders have not been identified as risk factors for NAION in young patients. PVD has also been found to occur at a younger age in women (76,82); however, the IONDT found no gender difference in age at presentation with NAION (78). In summary, risk factors for early PVD have not been demonstrated as risk factors for NAION at young age, as would be anticipated if the pathophysiology overlapped. Furthermore, PVD has been shown to occur later in patients with diabetic retinopathy (implicating a more robust vitreomacular attachment), (83) yet an increased incidence of NAION has been reported in young diabetic patients in most studies (84–86). This is difficult to reconcile if VPT is causative of NAION. If VPT leads to NAION, then cases of iatrogenic NAION might be anticipated with some frequency after pars plana vitrectomy (PPV) with iatrogenically induced PVD. This is not apparent from the literature review. There are only 3 case reports in the literature of suspected NAION after PPV in which optic disc edema was noted on examination (occurring between postoperative day 5–34) (62,87). Visual symptomatology of vitreopapillary traction is not described by patients with nonarteritic anterior ischemic optic neuropathy VPT can be asymptomatic or present with phosphenes or transient visual obscuration in association with saccades (25,76). Examination findings include elevation of the optic disc sometimes accompanied by optic disc or peripapillary hemorrhage, but central acuity is preserved, and visual field testing is generally normal or close to normal with rare exception (25,76). Visual symptomatology reported with VPT is not typically reported by patients before presentation with NAION despite routine questioning about transient visual obscurations to differentiate NAION from arteritic ischemic optic neuropathy. In the IONDT, only 5% of eligible subjects reported initial intermittent vision loss (78). Purvin et al found 15% of their patients with Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 NAION and underlying optic disc drusen reported preceding transient obscurations of vision before NAION onset (88); however, transient obscurations of vision can occur with optic disc drusen alone. Evidence for ischemia in nonarteritic anterior ischemic optic neuropathy Histopathology Histopathologic studies of NAION do implicate an ischemic process although the exact localization is unknown (89). Knox et al studied 193 eyes meeting histopathologic criteria for diagnosis of ischemic optic neuropathy including identification of focal ischemic edema, cavernous degeneration, or localized atrophy of the optic nerve superiorly or inferiorly. Only 27 of their cases had clinical correlation with ophthalmologic examination and included cases of arteritic ischemic optic neuropathy due to giant cell arteritis, embolic infarcts, sepsis, ICA occlusion, mucormycosis, and malignancy with compressive lesions in addition to possible cases of posterior ischemic optic neuropathy in setting of massive blood loss (89). Two of the 27 cases described may have been due to posterior ischemic optic neuropathy in setting of blood loss and hypotension vs NAION. Both cases showed histopathologic evidence of edema. One demonstrated “ischemic edema” with “loss of cellularity” and “distension of nerve fiber bundles in retrolaminar region” and “distension of collagen lamellae of lamina cribosa” and had swollen macrophages termed “gitter cells” at the lesion margin and the other had “prelaminar cellular edema” with “a small retrolaminar infarct” (89). The remaining 25 cases which were described were not cases of NAION. In 3 cases with peripapillary hemorrhage and sudden vision loss, “cavernous degeneration” of the optic nerve was identified at least 4 weeks after vision loss, with “swelling of nerve bundles” with “loss of axons and myelin” forming distended “caverns” that compress adjacent nerve fibers. The study showed no discrete vascular occlusion and lends weight to the theory of a compartment syndrome causing progressive vision loss in ischemic optic neuropathy. The study also alludes to the concept of “luxury perfusion” previously proposed by J. Lawton Smith as an autoregulatory response to optic nerve ischemia with resultant segmental vasodilation enhancing optic disc perfusion in response to “axoplasmic flow stagnation” (90). Knox et al suggest “diagnosis of progressive ischemic edema should be considered when an eye with partial loss of vision has early (days) progression of vision and field loss and when ophthalmoscopy demonstrates hyperemic edema of the nerve head, particularly in a segment of the nerve that does not correspond to the original field defect” (89). Animal models of nonarteritic anterior ischemic optic neuropathy It has been suggested that the mild venous engorgement accompanying the hyperemic disc edema of NAION 263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point reflects “a compressive restriction of central retinal venous return” because of “a compartment syndrome initiated by ONH capillary dysregulation (rather than arterial occlusion)” (91). This led to the design of rodent and nonhuman primate NAION models using intravenous rose Bengal and low-intensity laser to produce superoxide radical–induced damage to the capillary endothelium with progressive optic nerve head edema (91,92). Evidence of a cytokinebased early inflammatory response was seen in both rodent and nonhuman primate models of NAION with loss of the blood–brain barrier at the lesion site (91). Fluorescein angiography studies Fluorescein angiography studies also support a role for ischemia in the pathophysiology of NAION. Delayed optic disc filling in the setting of disc edema from NAION with absence of delayed adjacent choroidal filling has been demonstrated supporting possible occlusion at the level of the paraoptic branches of the short posterior ciliary arteries (93). A filling delay of the prelaminar disc was not seen in other causes of disc edema suggesting vascular insufficiency is intrinsic to the pathophysiology of NAION rather than a secondary effect of disc edema (93). As noted previously, the intellection of “luxury perfusion” to explain segmental ONH vasodilation was proposed by J. Lawton Smith as an autoregulatory mechanism to increase optic disc perfusion in the setting of optic nerve ischemia (90). As proof of concept, a case series of 5 patients with NAION showing evidence of luxury perfusion on fluorescein angiography was reported by Friedland et al (95). MRI studies of nonarteritic anterior ischemic optic neuropathy show disruption of the blood– brain barrier There have are several MRI studies showing at least some patients with NAION demonstrate optic disc enhancement. The presence of contrast enhancement on MRI signifies a loss of the blood–brain barrier. Schreiber et al have shown in a hypertensive stroke-prone rat model that vascular endothelial dysfunction, and possible subsequent failure of autoregulation, leads to disruption of the blood–brain barrier (95). Yovel et al reported a case of NAION which showed contrast enhancement of the optic disc on fluid-attenuated inversion recovery image sequences. The authors proposed this may result from luxury perfusion as fluorescein angiography showed vasodilation in the region of the optic disc corresponding with the spared visual field (96). Subsequently, a relatively large retrospective study of adult subjects diagnosed with either optic neuritis or NAION who underwent MRI within 1 month of presentation with vision loss was performed by Adesina et al with the interpreting neuroradiologists masked as to patient diagnosis 264 (Adesina 2017). 83% of subjects underwent dedicated orbital imaging in addition to MRI of the brain (Adesina 2017). There were 72 eyes (62 subjects) clinically diagnosed with NAION and 32 eyes (27 subjects) diagnosed with optic neuritis (97). The study showed most (56%) of the NAION cases demonstrated no abnormal enhancement or diffusion restriction of the optic disc or nerve when imaged an average of 16 days after vision loss; however, postcontrast enhancement of the optic disc in the absence of focalrestricted diffusion of the optic disc was seen in 14 eyes and was 100% specific for NAION. The authors proposed the contrast enhancement of the disc in absence of diffusion restriction may reflect luxury perfusion; however, extrapolating from animal models, the enhancement may reflect vascular endothelial damage causing loss of the blood– brain barrier. Microvascular risk factors associated with nonarteritic anterior ischemic optic neuropathy The role of ischemia in the pathophysiology of NAION is supported by the association of NAION with microvascular risk factors including diabetes (78,84,93,98), hypertension (78,84), and hyperlipidemia (84,85), which may cause vascular insufficiency or autoregulatory dysfunction (99,100). Similarly, NAION can also occur in the setting of systemic hypotension, anemia, or massive blood loss. Hayreh proposed that loss of autoregulation at the level of the optic nerve head may occur in response to a variety of processes including aging, hypertension, diabetes mellitus, hypotension, hyperlipidemia, and vascular endothelial dysfunction (99,100). Although rare, 2%–6% of patients develop recurrent NAION in the same eye months to years later (78,84,100), whereas recurrent ONH ischemia is conceivable, a VPT mechanism would be difficult to reconcile as the presumption is once a stage 3 PVD is reached; the VPT is relatively constant with saccadic eye movements until there is abrupt vitreopapillary release and a complete PVD occurs with no further VPT. Obstructive sleep apnea associated with nonarteritic anterior ischemic optic neuropathy Another association with NAION which cannot be explained by VPT is OSA. A cohort study of 89 patients with NAION undergoing polysomnography showed 75% had OSA and noncompliance with CPAP in patients with severe OSA significantly increased the risk of contralateral eye involvement (hazard ratio of 5.5) (101). OSA has been shown to cause episodic desaturation and hypercapnia requiring heightened respiratory effort with resultant altered cardiovascular response including evidence of endothelial dysfunction (101). OSA may also cause acute blood pressure spikes and nocturnal hypoxia contributing to NAION (102). In the study by Aptel et al (101), nocturnal Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point hypotension was found to occur in only 5% of patients with NAION . Alternatively, the association of OSA with NAION could be explained if the primary pathophysiology in NAION were venous insufficiency (104). Levin and Danesh-Meyer propose “closure of tributary venules that receive blood from optic nerve capillaries” would result in venous congestion and secondary constriction of arterioles, which could also explain the phenomenon of incipient NAION without actual infarct. Whether it is a primarily venous or arterial etiology, a vascular mechanism in NAION seems highly likely given the significant association with OSA. Erectile dysfunction medication associated with nonarteritic anterior ischemic optic neuropathy There is a reported association of NAION with phosphodiesterase type 5 (PDE5) inhibitor use for erectile dysfunction, although causality remains controversial. The literature includes a highly suggestive case report documenting 5 medication rechallenges with development of transient unilateral inferior visual field loss within 2 hours of taking tadalafil on 4 separate occasions followed by permanent visual field loss with clinical evidence of NAION after the fifth trial of tadalafil (104). PDE5 inhibitors can cause systemic hypotension, but a mechanism of nitric oxide–induced failed autoregulation has also been proposed (100,102). Studies by Haefliger et al have shown nitric oxide induces relaxation of the capillary endothelium thereby modulating blood flow (100). It would be difficult to explain any association of NAION with PDE5 inhibitors based on a pathophysiology of mechanical VPT. Optic disc drusen/structural crowding of optic disc associated with nonarteritic anterior ischemic optic neuropathy Structural crowding of the optic disc is well-documented as a risk factor for NAION and has been proposed to contribute to ischemia-induced axoplasmic flow stasis by creating a compartment syndrome (84,102,106). There are numerous case reports of patients with optic disc drusen developing NAION at a young age (106,107). A retrospective study of 20 patients with optic disc drusen who developed NAION showed vision loss occurred at a mean age of 49 years (range 18–69 years old) (Purvin 2004). Half of the patients had microvascular risk factors (4 patients had hypertension, 4 patients had diabetes, 1 patient had hyperlipidemia, and 1 patient had a smoking history) (88). Although Parsa and Hoyt have asserted the association of NAION with a “disc at risk” may be due to tighter vitreopapillary adhesion (VPA) on cupless optic discs (19), this does not explain the earlier age of presentation with NAION in patients with optic disc drusen. On literature review, there are no reports of development of earlier vitreous syneresis, VPT, or PVD in patients with optic disc Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 drusen. In a multicenter retrospective study of 65 patients presenting with NAION by age 50 or younger, Hamann et al (108) showed 51% had underlying optic disc drusen identified with enhanced depth imaging OCT. Only 35% of patients with underlying optic disc drusen and a history of NAION also had microvascular risk factors leading the investigators to suggest optic disc drusen represents an independent risk factor for the development of NAION in young patients (108). Vitreopapillary traction: a plausible mechanism for nonarteritic anterior ischemic optic neuropathy? Parsa and Hoyt propose VPT may cause NAION by dynamic stretch injury with potential for “fracture of the axonal cytoskeleton and frank membrane disruption” (19). It is well known patients with VPT may develop signs of optic neuropathy including an afferent pupillary defect (25,76), but inferior altitudinal visual field defects are decidedly rare from VPT and quite common in NAION. Furthermore, asymptomatic optic disc elevation (socalled “incipient NAION”) does occur, and in most cases, there is not subsequent development of optic neuropathy (26,52). Parsa explains the resolution without optic neuropathy as due to “the vitreoglial attachments (being) insufficiently firm or the glial-axonal impulse generated during vitreous separation insufficiently high for axonal injury to occur” (20). The studies by Almog et al and Hayreh and Zimmerman did not include OCT evaluation, so it is not known whether any of their patients with asymptomatic optic disc edema actually had VPT which subsequently released. However, fluorescein angiography studies have shown there can be delayed optic disc filling in incipient NAION (105) suggesting “subclinical ischemia” inducing axoplasmic flow stasis. Furthermore, a 20% rate of subsequent recurrent optic disc edema with development of actual NAION was found after resolution of incipient NAION (26). This is higher than the rates of contralateral eye involvement of NAION (15%) (78) or recurrent NAION in the ipsilateral eye (up to 6%) (105) suggesting after incipient NAION resolves, there is increased susceptibility to further ischemic insult. Optical coherence tomography studies assessing for vitreopapillary traction Despite the widespread use of OCT in clinical evaluation of optic disc edema, there are almost no cases of documented VPT in NAION. Shen and MacIntosh report one case of acute NAION with symptomatic development of ipsilateral PVD 2 weeks later in association with worsening then subsequent improvement of the visual field defect (71). They acknowledge OCT was not performed at presentation to confirm vitreopapillary traction was present at the time of NAION onset. 265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point OCT studies specifically assessing the vitreopapillary interface of patients presenting with NAION have not shown evidence of a causal association between VPT and NAION (39,41,42). A prospective spectral domain OCT (SD-OCT) study of 60 eyes with acute NAION (evaluated within 15 days of vision loss) which included raster images through the ONH by Kupersmith et al (41) demonstrated absence of VPT in all eyes. Similarly Lee et al evaluated 26 consecutive acute NAION patients by OCT and found 65% had no vitreous attachment to the optic disc and 35% had VPA by description rather than VPT (39). They found similar VPA in 6 patients with glaucoma. Ultimately, to prove a lack of association between VPT and NAION, it would be important to assess for pre-existing PVD in patients presenting with acute NAION. A retrospective cohort study by Thompson et al assessed for the presence of VPT or PVD on SDOCT in 74 patients (80 eyes) presenting with acute NAION (within 2 weeks of vision loss) (42). The authors found a PVD was already present in 30% of eyes at NAION presentation, with one third of the PVDs previously documented (before onset of NAION). Vitreopapillary traction was not present by SD-OCT in any of the eyes. Only 5 eyes developed a PVD after NAION by the last follow-up, whereas 88% of patients without a PVD at NAION presentation did not develop one over the course of follow-up (median 10 weeks). Of the 5 eyes that developed a PVD during follow-up, only one PVD occurred before complete resolution of the optic disc edema at approximately 2 months after NAION presentation, whereas the other 4 PVDs occurred between 5 and 33 months after NAION presentation. This work seems to rather definitively refute a causal role for vitreopapillary traction in NAION. In the study by Modarres et al in which 16 patients with acute NAION (within 1 month of vision loss) underwent pars plana vitrectomy for presumed VPT, the authors reported an impressive 94% of their patients showed improvement in the visual acuity but, interestingly, only 1 patient had concurrent improvement of color vision and only 4 patients had improvement of their visual field defects (68). It is unclear why some of the patients whose visual acuity improved with surgery actually had worsening of their visual field defects and/or color vision, but this mismatch would not be expected with improvement of NAION. It is also unclear from the study design what proportion of patients had VPT vs VPA as previously questioned by Lee et al (39). It may be as Weng et al suggest that VPT optic neuropathy is a separate clinical entity from NAION (72). There are sufficient data in the literature to refute a causal role of VPT in the development of NAION. Given the inherent risks of cataract formation, iatrogenic retinal tears, and retinal detachment with pars plana vitrectomy, 266 prophylactic PPV should not be recommended to prevent fellow eye NAION as the evidence is not there. Rebuttal-Cameron F. Parsa, MD Many of the issues raised have been addressed in the preceding opening statement. Nonetheless, some points deserve focus. When, for example, indicating that “blood-flow altering erectile dysfunction medications” are potentially causative of an ischemic neuropathy, should one further specify that the blood flow altering properties of such drugs are to increase blood flow, not decrease it, an implied ischemic mechanism becomes less plausible. The term “vitreopapillary traction (VPT)” implies a relatively static and persistent vitreous tugging force, forming a taut, V-shaped configuration to the vitreopapillary hyaloid face, a relatively uncommon event. Neurons readily tolerate elongation from tension that is slowly applied, with axoplasmic flow only minimally impeded by distortion or folds of pathways (25,30,33) potentially improved with release and realignment as demonstrated by Sanjari and coworkers (38,68). Terminology such as VPT should not be confused with the discussed PVD (19,69), a dynamic, occasionally rapid, process of vitreous separation producing traction that may be only fleeting and abrupt. VPT is uncommon, but stage 3 or stage 4 PVD is frequent (48), while demonstrated to be ubiquitous in patients with so-called NAION (19,38,39). Vitreous separation alone is insufficient for producing such neuropathy; the speed of its separation (32) at the level of the papilla and the age-related loss of microtubule cytoskeletal elasticity producing axonal fragility (33) are the 2 other essential elements. When vitreous separation occurs at younger ages (e.g., those with connective tissue disorders, high myopes, etc), the still elastic axonal microtubules do not fracture and axoplasmic blockage and swelling does not ensue. Despite the capillary rupture with characteristic intrapapillary and peripapillary hemorrhages unique to vitreopapillary traction and separation (16,17), an epiphenomenon unsurprisingly identical to that seen in older individuals diagnosed with NAION (causing the occasional disrupted blood barrier also visible on MRI), neither ischemia nor axoplasmic swelling is observed. Older individuals with larger, centrally excavated discs are also protected. Vitreous attachments are strongest at the emergence of the central retinal vessels, yet vitreoaxonal attachments cannot develop over large excavations where no axons are present. Larger diameter discs also possess a further advantage; per Laplace law, their lamina cribosa is more deformable (56) and can displace forward during the moment of vitreous separation. The greater ability of lamina to advance and “yield” in response to abrupt anterior vitreous forces, as per Newton third law, Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point reduces the forces the axons contained within it are subjected to. There have been several reports noting parallels with, or codevelopment of, apparent NAION with vitrectomy (61,62,87). Such instances are not seemingly rare but often labeled and classified instead by what they actually represent, vitrectomy-induced optic neuropathy (109–111). Investigations support hyaloid face peeling from the papilla as the most likely cause. Histopathologic evidence has not emerged to show occlusion of vessels or injury corresponding to the territory of particular arteries (112,113). The report by Knox and colleagues (89) focused on changes associated with ischemic optic neuropathy, or ION, not so-called NAION (28). NAAION, abbreviated to NAION, sometimes truncated to AION or ION has led to confusion of findings. Laser application to blood vessels in any tissue in any animal can produce occlusion and ischemia. Such artificial models have not led to any advances in our understanding of the actual pathology in question; the correlations listed are not indicative of causation nor do they have a potential for this. A more fitting model could be to reproduce natural separation of vitreous at various speeds, noting not only the well-understood potential effects on the retina, but heretofore neglected consequences on the papilla and peripapillary area. Such experiments have not yet been performed. Angiography studies have sown much confusion. In Arnold and Hepler’s initial report (114), the authors were careful to state how delayed prelaminar filling could correlate equally well with vascular occlusion, as from increased impedance to blood flow from disc swelling. In a subsequent study including patients with papilledema and papillitis as controls (115), the authors concluded impedance was unlikely to be responsible for the differences in delayed perfusion. However, significant overlap of delayed perfusion times was present and the sample size relatively small. That a compensatory increase in papillary arterial perfusion occurs with papilledema had not been taken into account, while the extent of edema in patients with papillitis may not have been as great. Unlike pathologies engendering edema over the entire disc, the uneven sectoral nature of disc swelling in such NAION will not “force” a compensatory increase in arterial perfusion pressure. Another overlooked aspect in angiography studies has been that the control patients with papilledema and papillitis had not yet suffered neuronal loss; those diagnosed with symptomatic NAION had metabolic needs already diminished vis-à-vis controls. Akin to thinning of vessels noted in retinitis pigmentosa, sectors affected by neuropathy require less blood flow. Because straightforward light-scattering and blocking effects of intra-axonal swelling and hemorrhages also produce hypofluorescence (116), sectoral axonal swelling, as Parsa et al: J Neuro-Ophthalmol 2022; 42: 260-271 well as hemorrhages are clearly noted, why incriminate ischemia at all? The simplest explanation, after all, is usually the correct one. The hyperemia and differences from the pallor observed in arteritic ischemic neuropathy should serve as indicators that ischemia is not a predominant feature (28,70), as too the lack of correlation to changes in visual field or in neural tissue (114). Articles describing slight disc edema with telangiectatic vessels, notably veins, have been described as “incipient” or “threatened” NAION (26,52). These acquired surface telangiectasia may be so elevated to appear as “proud flesh” (90) and often spontaneously resolve. This points to surface tension produced by intermittent, or steady, vitreous forces, including aforementioned VPT, as responsible, rather than defects in vascular walls, or flow impedance alternating with increased perfusion, as implied by “luxury perfusion.” When a stage 3 PVD has developed with loss of vision, intermittent vitreous traction on the papilla may yet ensue with bodily or ocular movements, notably when substantial vitreous gel remains within the hyaloid sac to cause further axonal fracture and step-wise loss of vision, so-called “progressive” or “recurrent” NAION (67). Eventually, liquefied vitreous empties from the sac, which diminishes the potential force it may apply on remaining axonal attachments and vitrectomy may be unnecessary. It is conceivable, however, that limited patient activities could be prescribed until spontaneous emptying occurs or, alternatively, enzymatic or other means used to accelerate liquefaction (26). Further studies and observation would be of benefit. Given the fluctuations in choroidal thickness during OSA (117), the repeated compression and decompression of the vitreous body enhances its syneresis and separation. About the invoked possibility of ischemia to be venous based, rather than arterial, one recalls Lessell’s philosophy (7); if, after so many years of study, there remain notions at such variance with one another, it calls into question the validity of either. That optic disc drusen that occurs in small, crowded discs is certain. That a strong, although not exclusive association of nonarteritic neuropathy occurs in discs with small central cups is also clear. Smaller discs also have vitreopapillary attachments that tend to be stronger (15). Such correlations are not disputed. However, that a compartment syndrome could be responsible for the neuropathy is disproved by the fact that such pathology also occurs in excavated discs without predisposition for drusen formation (57,59). Such cases can notably be understood to occur where vitreopapillary attachments, despite being generally weaker in larger area discs, may be subject to greater forces than that of simple gravity (e.g., LASIK, vitrectomy, etc). An earlier age of presentation of vitreopapillary neuropathy in those who suffer from optic drusen can be 267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point explained by the fact that if and when vitreous separation does occur in such younger individuals, the otherwise resilient, elastic axons of youth that normally could accommodate such sudden, abrupt stretch no longer are capable of doing so, having already been compromised by longstanding compressive drusen rendering them fragile. The tight, small diameter discs also tend to be calcified and quite stiff, with unyielding lamina cribosa making vitreoaxonal forces and separation all the more abrupt and traumatic. Although it is often said that a image is worth a 1,000 words, OCT images, nonetheless, cannot do justice to demonstrate the transient, intermittent, forces produced by vitreous separation as could motion images, provided, for example, by B-scan ultrasonography. PVD and VPT are not interchangeable terms, and the effects produced by each differ. Although there is widespread acceptance of the diverse physical effects of vitreous detachment on the retina, there seem attempts to use static OCT imagery to refute the potentially traumatic effects of vitreous on the papilla. And yet it moves. Rebuttal: Does vitreopapillary traction cause nonarteritic anterior ischemic optic neuropathy? —Zoё R. Williams, MD It is erroneous to suggest because histologic studies have not demonstrated vascular occlusion in NAION; this constitutes proof of an alternate nonischemic etiology. Ischemia, defined as insufficient blood supply, does not imply there is vascular occlusion. Ischemia can also be due to vasoconstriction, capillary endothelial dysfunction, failed autoregulation of blood supply, arteriosclerosis, or impairment of venous return—all of which have been proposed as possible pathologic mechanisms underlying NAION. Interestingly, these pathologic mechanisms have been demonstrated in OSA—the systemic condition most strongly associated with NAION. The “hypoxia– reoxygenation” cycle in OSA produces reactive oxygen species causing vascular endothelial dysfunction as evidenced by elevated vascular endothelial growth factor and endothelin-1 in the serum (118). There is also evidence that OSA causes vascular changes in the retina. Untreated severe OSA causes progressive retinal arterial attenuation, whereas treatment with continuous positive airway pressure (CPAP) yields a mild reversal of the vascular changes as assessed at the 2-year follow-up (119). It has been hypothesized that “intermittent sympathetic surges” in OSA may cause transient hypertension which “can lead to arteriosclerosis and altered autoregulation of the optic nerve” increasing susceptibility to ischemia (118). 268 A vitreopapillary traction–induced optic neuropathy mechanism would not explain the high association of NAION with OSA and other microvascular risk factors, the association with optic disc drusen in the very young without vitreous syneresis nor the association with erectile dysfunction medication use. Young patients with NAION tend to have poorly controlled microvascular risk factors or underlying optic disc drusen. It has been argued that the occurrence of NAION in young patients with poorly controlled diabetes is actually because of “precocious vitreous syneresis” as described by Sebag (46); however, very young patients with optic disc drusen have also been reported to develop NAION. There is no known association of early development of vitreous syneresis, VPT, or PVD in patients with optic disc drusen. As many young patients with optic disc drusen who develop NAION do so in absence of microvascular risk factors, the presence of optic disc drusen has been proposed as an independent risk factor for NAION supporting a role for compartment syndrome–induced ischemia (120,121). The reported temporal association of NAION with the use of sildenafil has been explained as due to sildenafil “promoting desired vigorous physical activity”; however, there is no reported association between NAION and vigorous physical activity. Conversely, a vitreopapillary traction–induced optic neuropathy mechanism would not explain the low incidence of NAION after pars plana vitrectomy (iatrogenic PVD). Whether the presence of VPT, partial PVD, or complete PVD are correctly interpreted or documented in the reported cases of NAION should be answerable in the era of OCT. If doubt persists, a large prospective study could be designed to answer this question in standardized fashion. Hopefully, with refinement of high-resolution imaging systems of the microvasculature, accurate studies of vascular changes in acute NAION will soon be possible. Summary and conclusion—Drs. Van Stavern and Lee The exact mechanism and pathophysiology of NAION remain disputed and somewhat ill defined. Although VPT is an “outside the box” theory of causation for NAION, there are significant arguments against VPT as the sole cause of NAION. VPT-induced optic neuropathy has been described in the literature, and it is possible that this mechanism can account for some cases of presumed NAION. Future prospective work using OCT in NAION might shed further light on this interesting and controversial subject. 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