Peripapillary Hyper-reflective Ovoid Mass-like Structure (PHOMS): An Optical Coherence Tomography Marker of Axoplasmic Stasis in the Optic Nerve Head

With the development and widespread adoption of spectral-domain optical coherence tomography (OCT), peri- papillary hyper-reflective ovoid mass-like structures (PHOMS) have become a frequent OCT finding in neuro-ophthalmic practice. Although originally assumed to represent a form of buried optic disc drusen (ODD), PHOMS differ from ODD in many important ways. The histopathological underpinnings of PHOMS are now becoming more clearly understood

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD Peripapillary Hyper-reflective Ovoid Mass-like Structure (PHOMS): An Optical Coherence Tomography Marker of Axoplasmic Stasis in the Optic Nerve Head J. Alexander Fraser, MD, Patrick A. Sibony, MD, Axel Petzold, MD, PhD, Caroline Thaung, MB, ChB, DPhil, Steffen Hamann, MD, PhD, for the ODDS Consortium Background: With the development and widespread adoption of spectral-domain optical coherence tomography (OCT), peripapillary hyper-reflective ovoid mass-like structures (PHOMS) have become a frequent OCT finding in neuro-ophthalmic practice. Although originally assumed to represent a form of buried optic disc drusen (ODD), PHOMS differ from ODD in many important ways. The histopathological underpinnings of PHOMS are now becoming more clearly understood. Evidence acquisition: Review of literature. Results: PHOMS can be broadly classified as disk edema– associated PHOMS, ODD-associated PHOMS, or anomalous disk–associated PHOMS. PHOMS are seen in many conditions, including papilledema, nonarteritic anterior ischemic optic neuropathy, central retinal vein occlusion, acute demyelinating optic neuritis, ODD, and tilted disks (myopic obliquely inserted disks) and in many cases resolve along with the underlying condition. The histopathological study of these Department of Clinical Neurological Sciences and Department of Ophthalmology (JAF), Western University, London, Canada; Department of Ophthalmology (PAS), State University of New York at Stony Brook, Stony Brook, New York; Moorfields Eye Hospital (AP), London, United Kingdom; Department of Neurology (AP), Amsterdam Neuroscience, VUmc MS Center Amsterdam and Dutch Expertise Centre for Neuro-ophthalmology, VU University Medical Centre, Amsterdam, The Netherlands; Institute of Neurology (AP), University College London, London, United Kingdom; Department of Eye Pathology (CT), UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital (CT), London, United Kingdom; and Department of Ophthalmology (SH), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jneuro-ophthalmology.com). Members of ODDS Consortium investigators are listed in appendix section. Address correspondence to J. Alexander Fraser, MD, Department of Clinical Neurological Sciences and Department of Ophthalmology, Western University, Room B7-104, London Health Sciences Centre, University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada; E-mail: [e-mail] Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 diverse entities reveals the common feature of a bulge of optic nerve fibers herniating centrifugally over Bruch membrane opening into the peripapillary space, correlating exactly with the location, shape, and space-occupying nature of PHOMS on OCT. Because of the radial symmetry of these herniating optic nerve fibers, PHOMS are best thought of as a complete or partial torus (i.e., donut) in 3 dimensions. Conclusions: PHOMS are a common but nonspecific OCT marker of axoplasmic stasis in the optic nerve head. They are not themselves ODD or ODD precursors, although they can be seen in association with ODD and a wide spectrum of other conditions. They do not exclude papilledema and often accompany it. The circumferential extent and characteristic 3D toroidal nature of a PHOMS are best appreciated by scrolling through consecutive OCT images. Journal of Neuro-Ophthalmology 2021;41:431–441 doi: 10.1097/WNO.0000000000001203 © 2021 by North American Neuro-Ophthalmology Society O ptical coherence tomography (OCT) has revolutionized retinal and optic nerve imaging. Until the development of spectral-domain OCT (SD-OCT), imaging of the peripapillary region and deep prelaminar optic nerve head was limited. These regions were obscured by shadowing from overlying structures and appeared as dark hyporeflective spaces on OCT, with no distinct internal features (1,2). The development of SD-OCT in the mid-2000s (3,4), particularly the development of enhanced-depth imaging OCT (EDI-OCT) in 2008 (5), has improved both acquisition speed and depth of penetration. The lamina cribrosa, the inner edge of Bruch membrane opening (BMO), and the peripapillary region immediately overlying the rim of BMO, can be visualized in exquisite and reproducible detail, and anatomical structures can be imaged in vivo with unprecedented ease and resolution (Fig. 1A) (6–8). One such structure, which has attracted attention and stirred some degree of controversy over the past few years, is 431 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review optic neuropathies. Each letter of the acronym “PHOMS” describes a cardinal feature of the entity Peripapillary A PHOMS is peripapillary in location, situated just above Bruch membrane at the lip of BMO and external to the optic disc itself. It may have circumferential extent, after the edge of the circular BMO in a complete or partial torus (i.e., “donut”) configuration that correlates ophthalmoscopically with a pale C-shaped peripapillary “halo” obscuring the disk margin (8–11). Hyper-reflective FIG. 1. Enhanced-depth imaging OCT transecting the optic nerve head. A. Normal eye: features include Bruch membrane opening (BMO) (red double arrowhead) and lamina cribrosa (between pairs of white arrows). B. Papilledematous eye (in a patient with idiopathic intracranial hypertension): PHOMS (yellow arrows) are seen in the peripapillary region on either side of BMO (red double arrowhead), just above the Bruch membrane/retinal pigment epithelium complex; the PHOMS are hyper-reflective (light gray), stereotypically ovoid in shape, and deflect the retinal layers upward and laterally. PHOMS indicates peripapillary hyperreflective ovoid mass-like structure. the peripapillary hyper-reflective ovoid mass-like structure (PHOMS) (pronounced “fomms”). In this review, we describe the morphological appearance of PHOMS on EDI-OCT, outline the spectrum of conditions in which PHOMS may be seen, discuss the histopathological counterparts of PHOMS and the role of axoplasmic stasis in their pathogenesis, and review the current confusion surrounding their resemblance to optic disc drusen (ODD). Finally, we highlight some unanswered questions regarding these structures and suggest possible new directions forward. Throughout this review, we use the acronym “PHOMS” as both a singular and plural form. A PHOMS is diffusely hyper-reflective, indicative of OCT beam scattering, and implying an inhomogeneous optical density throughout. This suggests a fine internal substructure, and new evidence is emerging that PHOMS contain their own microvasculature (8,10–12). Ovoid A PHOMS appears ovoid in shape on a typical B-scan (cross-sectional) OCT image. There is seldom any lobulation or complexity to this morphology, regardless of the underlying optic nerve pathology accompanying the PHOMS. Although its oval cross-sectional appearance may initially suggest an ellipsoid-like “lump” underlying the peripapillary retina, analogous to an isolated ODD, a PHOMS in 3 dimensions is better thought of as a partial torus than a discrete lump—more inner tube than basketball (Fig. 2) (13,14). Mass-like Structure A PHOMS is a mass-like structure, occupying space in the peripapillary region, often deflecting 2 or more of the overlying retinal layers anteriorly and radially outward. This produces a “ski slope”–like appearance to the neighboring retinal architecture (6,15), which other authors have likened to a “boot shape” (16) or a “bend” (9). The degree of deflection of the overlying retinal layers depends significantly on the distance of the OCT slice plane from the center of the optic disc (Fig. 3). WHAT IS A PHOMS? Differentiation of PHOMS From Mimics A typical PHOMS is depicted in Fig. 1B. It is a common OCT accompaniment to many varieties of optic disc swelling, elevation, or tilt. Histopathological examinations and other lines of evidence indicate that a PHOMS is composed of herniated optic nerve fibers bulging centrifugally into the peripapillary region as a result of axoplasmic stasis, and we review this evidence below. For this reason, the discovery of a PHOMS on an OCT is no mere curiosity; as the outward manifestation of pathophysiological processes at the optic disc level, a PHOMS signifies deeper microscopic and ultrastructural changes within the optic nerve. An elucidation of the cause and significance of PHOMS can better inform our understanding of the diagnosis and management of various These 4 cardinal features of a PHOMS, described above, combined with an appreciation of the structure’s 3dimensional morphology (see Supplemental Digital Content, Supplemental Video, http://links.lww.com/WNO/ A456), can be used to differentiate it from similar ovoid structures in the optic disc and peripapillary regions—retinal blood vessels and ODD (Fig. 4). In this way, PHOMS are recognized with a high level of accuracy by different observers (interrater kappa 0.811–0.951) (15,17). The EDI-OCT appearance of blood vessels is distinct from that of a PHOMS (Fig. 4B). Although blood vessels appear ovoid when imaged in cross-section and can have a hyper-reflective interior similar to a PHOMS, blood vessels 432 Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. The toroidal nature of a PHOMS. A–D. An idealized torus (i.e., donut) transected at different distances from the center by a plane perpendicular to the torus’ central axis, representing B-scan OCT “slices” through a PHOMS. E–H. Corresponding “toric sections” (known as “Cassini’s ovals”) arising from each idealized cut in (A–D). I–L. Real-world B-scan EDIOCT slices although a papilledematous optic disc at the distances depicted in (A–D), confirming the toroidal nature of a PHOMS (yellow shading). (A–H created using the Geogebra applet at https://lucamoroni.it/simulations/intersection-torusplane-simulation/ (13)). EDI-OCT indicates enhanced-depth imaging OCT; PHOMS, peripapillary hyper-reflective ovoid masslike structure. FIG. 3. Salient features of a PHOMS in a patient with papilledema, left eye. Transverse axial OCT (A, C), optic disc photograph (B), confocal scanning laser ophthalmoscopic image (D), and sagittal cross-sectional OCTs through the nasal optic disc (E–H). The corresponding margins of the Bruch membrane opening and nasal edge of the PHOMS are identified with magenta dots in images (B, C, D). The yellow overlay in (D) shows that the PHOMS is a C-shaped partial torus that surrounds the disk nasally, superiorly, and inferiorly, sparing the temporal quadrant. The nasal bulge of the PHOMS abuts and splays the surrounding retina (E–H): the inner nuclear layer (INL) is displaced superiorly and appears as a fine hypodense line that forms the superior border of the PHOMS (small yellow arrows in C, F, G); (E) demonstrates widening of the outer nuclear layer just beyond the PHOMS9 border. Panel H depicts the junction between PHOMS and RNFL where the INL is no longer visible. As the level of the image slice in (E–H) approaches the center of the disk, the deflection of overlying retinal layers, likened to a “ski slope” becomes steeper; tangential B-scans may therefore underestimate the true mass effect of the PHOMS on the overlying retinal layers. PHOMS indicates peripapillary hyper-reflective ovoid mass-like structure; RNFL, retinal nerve fiber layer. Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 433 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 4. Enhanced-depth imaging OCT of PHOMS and mimics. A. A PHOMS (yellow arrow) in the peripapillary region appears hyper-reflective and deflects the retinal layers upward and laterally; although the left part of the PHOMS appears ovoid, the right part of the PHOMS is obscured by an overlying shadow. B. Blood vessels (red arrows) appear as superficial circular structures casting long dark shadows; their tubular 3D structures are revealed by scrolling through consecutive OCT slices. C. A large lobulated optic disc drusen (ODD) (green arrow) is identifiable by its hyper-reflective “shell” and hyporeflective core. PHOMS indicates peripapillary hyper-reflective ovoid mass-like structure. have a sharply defined hyper-reflective anterior and posterior border, cast a long shadow over deeper structures, and appear in the inner, superficial layers of the optic disc and not the peripapillary region immediately overlying Bruch membrane where PHOMS are found (6,18). The appearance of an ODD is likewise distinct from that of a PHOMS (Fig. 4C). An isolated ODD appears as discrete ellipsoid “lump” without cylindrical extent (such as a blood vessel) or toroidal extent (such as a PHOMS) on consecutive OCT slices. An ODD has a hyporeflective core and hyper-reflective margins and, unlike PHOMS, is found within the optic nerve head. Its cross-sectional shape may be simple and ovoid or complex and multilobulated, particularly when it forms conglomerations with other ODD. Occasionally, especially in longstanding cases with very large ODD, smaller ODD can be seen within the interior of the PHOMS, like raisins in a bagel. The Spectrum of Conditions in Which PHOMS are Seen PHOMS were first observed in the early SD-OCT era, during studies of optic disc swelling (16) and pediatric tilted disc syndrome, in which they were described as “dome-like hyper-reflective structures” (9). They have subsequently been observed in numerous contexts (Fig. 5), including in papilledema (10,17,19), in ODD (6,10,17,20,21), in nonarteritic anterior ischemic optic neuropathy (NA-AION) (10,22,23), in central retinal vein occlusion (10), in optic neuritis (10,17), and in myopic/tilted optic discs (9,10,24). Given this wide spectrum of conditions, one helpful way to categorize PHOMS is by etiology: 1) disk edema–associated PHOMS; 2) ODD-associated PHOMS; and 3) anomalous disk– associated PHOMS (25). Indeed, PHOMS are common in these conditions. Among young patients with NA-AION, PHOMS were seen with a prevalence of 28% of 36 eyes without any other concomitant optic nerve pathology (such as ODD) (23). Among 227 patients with MS, PHOMS were found prospectively in 10% of eyes affected by optic neuritis and in 0% of 62 healthy controls (17). A retrospective component of this study examined PHOMS in 267 patients with other conditions and revealed a PHOMS prevalence of 62% in idiopathic intracranial 434 hypertension (IIH), 47% in ODD, 44% in anomalous optic discs, and 19% in isolated non-MS optic neuritis (17). Histopathological Correlates of PHOMS Because PHOMS are so prevalent in patients with IIH, it is useful to consider the histopathology and pathogenesis of papilledema as a model for understanding how PHOMS may arise in other diverse conditions (Figs. 6, 7). Papilledema Histopathological studies of the optic nerve head in papilledema have shown distended and vacuolated optic nerve axons anterior to the lamina cribrosa, particularly in the peripapillary part of the nerve (26,27). These optic nerve fibers bulge laterally over the rim of BMO (Figs. 6C, 7A), often folding over themselves into an S-shape and displacing the peripapillary retinal layers laterally and upward, whereas the retinal pigment epithelium and Bruch membrane remain undistorted (Fig. 6D) (26–29). The location and morphology of this bulge of herniated nerve fibers on histopathology correspond exactly with the location and morphology of disk edema–associated PHOMS as detected on OCT (10). Numerous small dilated venules and capillaries are evident within the optic nerve tissue and are most numerous just inside these laterally bulging nerve fibers (27). Interstitial fluid, extravasated from these vessels, further increases the turgid buckling of optic nerve fibers into the peripapillary space adjacent to BMO (26,28). Radioactive isotope studies in primate models of papilledema demonstrate stasis of axoplasmic transport, with a chokepoint at the lamina cribrosa (26). Electron microscopy methods, too, confirm axoplasmic stasis, with disrupted neurofilament proteins and an accumulation of giant mitochondria inside the distended prelaminar axons (Fig. 8) (26). As papilledema resolves, clinically, and as centrifugally herniating nerve fibers recede back into the scleral canal, it is often observed that PHOMS regress too (Fig. 5A, B) (10). Optic Disc Drusen The histopathology of the optic nerve head in ODD shares several important features with the histopathology in papilledema. Although interstitial edema is largely absent Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 5. Enhanced-depth imaging OCT depicting PHOMS (yellow arrows) in a spectrum of conditions. A. Patient with papilledema from idiopathic intracranial hypertension, who had (B) significant reduction in the PHOMS after 6 months of weight loss and acetazolamide. C. Optic disc drusen. D. Acute nonarteritic anterior ischemic optic neuropathy. E. Acute central retinal vein occlusion. F. Patient with isolated acute demyelinating optic neuritis, who had (G) significant reduction in the PHOMS after treatment with high-dose corticosteroids. H. Tilted optic disc syndrome. PHOMS indicates peripapillary hyperreflective ovoid mass-like structure. in ODD because intracranial pressure is normal, axoplasmic stasis can nonetheless arise, in part due to mechanical compression of nerve fibers by the dense, rock-like, calcified ODD in the prelaminar optic nerve (Fig. 7B) (30–32). As with papilledema, distended and vacuolated axons are present, typically in the tissue anterior to the ODD, with increased mitochondria suggestive of impaired axonal transport. Electron microscopy of these distended fibers reveals distressed axolemma and mitochondria with embedded nee- dles of crystalline calcium (31). Neighboring small venules, too, may be compressed by ODD, causing upstream vascular congestion, although rarely frank edema. Consequently, a profusion of dilated small venules and capillaries may be seen in the vicinity of ODD (31). The typically narrow scleral canals of young patients with ODD may further aggravate this congestion (33). When such axoplasmic stasis ensues in the setting of ODD, engorged optic nerve fibers bulge over the rim of FIG. 6. Histomorphology of the optic nerve head; compare normal optic nerve head (A, B) with papilledema (C, D). A. Normal optic nerve head; note the relatively flat, layered architecture of the retinal layers extending right to Bruch membrane opening (BMO) and narrowing of scleral canal anterior to lamina cribrosa. B. Normal optic nerve head, peripapillary region; optic nerve fibers bend smoothly around BMO (asterisk) in a gentle C-shaped configuration. C. Papilledema; compared with (A), the peripapillary retinal layers are displaced laterally (right) or raised and folded (left) by the distended and tortuous prelaminar optic nerve fibers; adapted from (27). D. Papilledema, peripapillary region; compared with (B), herniating optic nerve fibers above BMO (asterisk) are bent into an S-shaped configuration; the bottom part of the S forms an ovoid mass-like structure (yellow arrows) that elevates and folds the neighboring retinal layers (red arrow); adapted from (27). Adaptations are themselves works protected by copyright. So to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 435 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 7. Histopathology in a spectrum of conditions, showing laterally bulging optic nerve fibers (yellow arrows) in response to axoplasmic stasis. A. Papilledema. B. Optic disc drusen. C. Acute nonarteritic anterior ischemic optic neuropathy. D. Acute central retinal vein occlusion. E. Experimental ligation of retrobulbar optic nerve (simian model). F. Acute demyelinating optic neuritis (juvenile guinea pig model). G. Tilted optic disc. Figures adapted with permission as follows: (A) (44); (C) (34); (D) (35); (E) (36); (F) (37); (G) (44). Adaptations are themselves works protected by copyright. So to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. BMO to form a lateral S-shaped bulge—the histopathological correlate of ODD-associated PHOMS (31,32). When ODD are large and multiple, the collective distention of axons causes a visible elevation of the disk (optic nerve “pseudoedema”). This concurrence of ODD and peripapillary nerve fiber bulging is not rare—in 1 retrospective study of 31 eyes with ODD (collected from a total of 1713 enucleated eyes), 5 eyes had localized peripapillary axonal bulging (32). The histological difference between ODD and peripapillary nerve fiber bulging remains stark, however, and it is abundantly clear that these bulges are neural tissue—and not anything reminiscent of ODD, “ODD precursors,” or “noncalcified ODD.” They even stain positive for nerve fibers using S100 immunostaining (10). ODD, by contrast, appear histologically as rounded, acellular, hyaline 436 FIG. 8. Features of axoplasmic stasis (experimental rhesus model of papilledema). A and B. Histopathology showing lateral bulge of optic nerve fibers (yellow arrows); axons appear vacuolated, abut the retinal pigment epithelium, and displace the retina laterally. C. Electron microscopy showing swollen and vacuolated axons (one shown within dotted oval) with disrupted neurotubules and numerous disorganized mitochondria. The most swollen axons (asterisk) contain large accumulations of giant mitochondria with irregularly arranged cristae and laminated dense bodies (asterisk). Radiotracer studies (not depicted) show obstruction of axonal transport at the level of the lamina cribrosa. Adapted with permission from (26). Adaptations are themselves works protected by copyright. So to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. deposits, and uniform in density with no significant internal substructure (18,30,31). They are found exclusively anterior to the lamina cribrosa and are always calcified (30–32). Other Entities The pathogenic mechanisms that produce peripapillary nerve fiber bulges in papilledema and in ODD—namely, axoplasmic stasis with or without interstitial edema—are seen in other causes of optic disc edema. It is not a surprise, therefore, to see disk edema–associated PHOMS in several other conditions. For example, in the histopathology of both NA-AION (Fig. 7C) (34) and central retinal vein occlusion (Fig. 7D) (35), swollen vacuolated optic nerve axons are seen to bulge over the edge of BMO and crowd the retina laterally. An identical image of lateral S-shaped bulging of swollen, distressed, mitochondria-laden prelaminar optic nerve fibers can even be produced experimentally in monkeys by ligating a portion of the immediately retrobulbar optic nerve (but avoiding the neighboring vessels) (Fig. 7E). In this animal model, radiotracer studies demonstrate that the characteristic histopathological changes are primarily the result of axoplasmic stasis and not interstitial fluid collection (36). A similar phenomenon can occur in the optic nerve heads of humans undergoing surgical enucleation. Clamping of the retrobulbar optic nerve during the Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review surgery results in abrupt axoplasmic stasis and vascular occlusion, resulting in a herniation (or “toothpasting”) of optic nerve fibers centrifugally over BMO (29). Ocular pathologists must be careful to recognize this optic nerve head abnormality as an artifact of surgery and not necessarily a feature of the underlying ocular disease. Human histopathological studies of the optic nerve head in acute demyelinating optic neuritis are lacking—presumably because of the rarity of enucleation or autopsy during the acute phase of inflammation. However, in one study using the juvenile guinea pig model of experimental autoimmune optic neuritis, the typical histopathological findings of optic neuritis included a mononuclear cell infiltration posterior to the lamina cribrosa accompanied by myelin loss and inflammatory perivascular cuffs (37). Anterior to the lamina cribrosa, this inflammation was not found, but optic disc edema was evident with markedly swollen axons displacing the peripapillary retina laterally in an S-shaped bulge (Fig. 7F) (37). Electron microscopy of these notably distended axons revealed an accumulation of degenerating mitochondria and a disorganized scaffold of neurofilament proteins—the hallmarks of axoplasmic stasis (38). Although prelaminar inflammatory congestion is one plausible mechanism for axoplasmic stasis in optic neuritis, emerging the literature in humans with MS suggests that impairments in the ocular glymphatic system could also impede axonal transport and may contribute to these histomorphological distortions underlying PHOMS (17,27,39,40). Tilted optic discs are a common optic nerve head variant in the general population and do not cause acute injury to the optic nerve; however, like disks with ODD, their abnormal morphology predisposes to chronic focal axoplasmic stasis. In the nasal prelaminar optic nerve, there are 2 main locations of nerve fiber bundle impingement: first, Bruch membrane protrudes toward the optic nerve along its upper extent, forcing the optic nerve fibers to bend sharply as they descend into the scleral canal (9,41); second, the nasal dragging of the lamina cribrosa relative to BMO and the slow stretching of the sclera and lamina cribrosa— believed to underlie the pathogenesis of optic disc tilt— may cause focal stress on optic nerve axons as they pass through pores of the lamina cribrosa, particularly in the fibers subserving the nasal optic disc (9,42,43). Some degree of chronic axoplasmic stasis ensues, with the familiar S-shaped peripapillary bulge of enlarged, vacuolated nerve fibers forming nasally (Fig. 7G) (44). Nasal pseudopapilledema and optic disc elevation occur, evident ophthalmoscopically and on en face OCT as a characteristic C-shaped halo. Cross-sectional EDI-OCT through this halo reveals an anomalous disk-associated PHOMS (Fig. 5H) (9,11,45,46). Given their high prevalence, tilted optic discs are a major cause of pseudopapilledema in clinical practice and, consequently, a commonly encountered cause of PHOMS (9,47). Over time, these congested axons can atrophy, and temporal visual field defects may emerge (9,48). In a recent study comparing children with PHOMS Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 to children without PHOMS, PHOMS were significantly associated with myopia, and optic disc tilt appeared to be the unifying explanation (24). Commonalities The histopathology of each of the above entities has shown the common feature of a peripapillary S-shaped bulge of nerve fibers, whose axons appear distended and vacuolated; these fibers are constipated with large degenerating mitochondria that are unable to move distally because of axoplasmic stasis (Fig. 8). Small dilated veins and capillaries permeate the bulge. In the case of papilledema, interstitial edema may further contribute to the tumescence of prelaminar tissue and the centrifugal expansion of optic nerve fibers. Irrespective of the underlying cause, this bulge herniates in a stereotyped fashion laterally between Bruch membrane and the inner layers of the retina in an S-shape, the bottom fold of the S forming an ovoid mass–like structure that displaces the overlying retina centrifugally and anteriorly. In the interior of the bulge, the myriad optical interfaces between nerve fibers, vacuoles, capillaries, and interstitial fluid compartments produce multiple internal reflections and refractions, which scatter light and render the structure diffusely hyper-reflective on OCT, appearing as a PHOMS. Not surprisingly, high-resolution OCT angiography has recently confirmed the presence of dense networks of small vessels within PHOMS of various different etiologies (11). Drusen Confusion A PHOMS has a superficial resemblance to an ODD on cross-sectional OCT B-scan imaging; a PHOMS appears approximately the same size as a moderate-sized ODD, and, like an ODD, a PHOMS occupies space and appears ovoid in cross-section (Fig. 4A, C). In the early days of SD-OCT and EDI-OCT, as the prelaminar optic nerve was being studied in vivo for the first time, it was sometimes believed that PHOMS were themselves ODD (16,20,49,50); however, our understanding of the distinction between PHOMS and ODD has evolved over the past 5–10 years, especially now that PHOMS have been observed ubiquitously in many other conditions besides ODD (Fig. 5) (9– 11,17,18,22,23), now that PHOMS have been reported to disappear as disk edema resolves (Fig. 5A, B, F, G) (10), and now that PHOMS have been observed to form a complete torus 360° around the optic disc (an implausible shape for an ODD) (14). In cross-sectional images of the optic nerve head (Fig. 3A, C, E–H), displacement of the inner nuclear layer defines a hyporeflective boundary between a PHOMS and the retinal nerve fiber layer (RNFL) (yellow arrows in Fig. 3C, F, G). Some have claimed that this border completely surrounds the PHOMS, forming an isolated non-neural mass, presumed to be an ODD (45). However, serial sagittal cross sections of PHOMS refute this, showing that 437 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review there is no border between PHOMS and the RNFL in the central regions of the optic nerve head (Fig. 3H), where distended axons double back around the inner nuclear layer to form the RNFL. The continuity between distended axons in a PHOMS and the RNFL can be demonstrated in patients with papilledema (Fig. 3), as well as in patients with ODD and tilted disks. Unlike ODD, PHOMS are not detectable with other imaging modalities such as orbital ultrasound, fundus autofluorescence imaging, or computed tomography orbits (6,12,51,52). It has been suggested that PHOMS may therefore be a form of noncalcified ODD (45,53). Although allusions to noncalcified ODD can be found in the literature, there is no actual histological basis for “noncalcified ODD”; among 48 eyes with true ODD, painstakingly extracted from a broad collection of more than 3000 eyes examined at autopsy (30) or after enucleation (32), not a single instance of an accompanying noncalcified ODD was found. Small hyperreflective dots have recently been documented inside PHOMS on OCT and proposed to represent microcalcifications and possible “ODD precursors” (46). This is highly speculative, however, as such dots are nonspecific, can be found throughout the retina, and are seen in PHOMS of all etiologies, not just ODD-associated PHOMS (54–57). Furthermore, they seem to resolve when the PHOMS does (Fig. 5A, B, F, G). The claim that PHOMS are a type of ODD has been refuted before (6,12,19,25), and key differences between the 2 entities are summarized in Table 1. Centrifugally bulging nerve fibers easily explain PHOMS in all clinical settings. Although some degree of confusion still persists in the literature (45,58,59), the evidence is overwhelming now that PHOMS are not ODD. Future Directions With the increasingly widespread availability of EDIOCT and SS-OCT technology, offering deeper penetration into the prelaminar optic nerve head at higher resolutions than ever before, neuro-ophthalmologists are in the vanguard for detecting, following, and studying PHOMS. Many unanswered questions about these fascinating structures remain, including the following: does PHOMS size correlate with other measurements of optic disc edema (e.g., Frisén grade in papilledema)? Can early detection of PHOMS on OCT predict papilledema TABLE 1. Summary of key differences between PHOMS and ODD PHOMS Location ODD Strictly peripapillary Rarely peripapillary; majority are found within the optic nerve head (may be superficial or deep) Histological Distended, vacuolated axons; dilated small venules Concentrically laminated hyaline deposits composed almost entirely of glassy translucent crystalline contents and capillaries. (In papilledema, interfascicular/intrafascicular edema may also be calcium phosphate. Minimal to no internal substructure. No blood supply. seen). Complicated internal substructure with many optical interfaces. 2D crossOvoid, stereotyped; simple with minimal complexity Sometimes a simple ovoid. Often a lobulated, sectional shape complex shape or conglomeration of a cluster of ODD. 3D shape Torus or partial torus; “donut-like” Ellipsoid; “lump-like” Reflectivity on Uniformly moderately hyper-reflective Brightly hyper-reflective outer shell with a darkly EDI-OCT hyporeflective core. OCTA appearanceDense network of fine blood vessels No internal microvasculature Appearance on Undetectable Detectable—unless deeply buried on FAF, FAF, US, and CT overlooked by US operator, or situated between slices on CT. Ophthalmoscopic Hazy peripapillary halo (often C-shaped or O-shaped),Glistening refractile lumps within the disk itself appearance most prominent nasally Associated Papilledema, ODD, NA-AION, CRVO, optic neuritis, Idiopathic, retinitis pigmentosa, pseudoxanthoma conditions and tilted optic discs/myopia elasticum, angioid streaks, and Alagille syndrome No short-term or medium-term change. Never shrink. Depends on etiology. Can develop de novo, Change in May grow slowly over decades. fluctuate/regress in concert with degree of disk appearance edema (e.g., papilledema), or may remain static over time (e.g., tilted optic disc and ODD-associated PHOMS) CRVO, central retinal vein occlusion; CT, computed tomography; EDI-OCT, enhanced-depth imaging optical coherence tomography; FAF, fundus autofluorescence imaging; NA-AION, nonarteritic anterior ischemic optic neuropathy; OCT, optical coherence tomography; OCTA, optical coherence tomography angiography; ODD, optic disc drusen; PHOMS, peripapillary hyper-reflective ovoid mass-like structures; US, ultrasound. 438 Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review recurrence in IIH? Can quantitative measurements of PHOMS (surface area and volume) be used to predict visual outcomes in neuro-ophthalmic disease? Does the size or location of a PHOMS predict visual field loss in ODD? In tilted disk syndrome, does the presence or size of a nasal PHOMS correlate directly with temporal visual field depression? What role does the translaminar pressure gradient play in the evolution of PHOMS? Although PHOMS are certainly a marker of axoplasmic stasis in many common neuro-ophthalmic conditions, are they strictly an epiphenomenon, or do they carry their own independent risks to vision (e.g., from kinking of nerve fibers around the S-shaped bend or from shear stresses on the intrinsic optic nerve microvasculature)? The study of PHOMS is in its early stages, and a fuller understanding of this novel OCT marker of axoplasmic stasis awaits. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann; b. Acquisition of data: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann; c. Analysis and interpretation of data: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann. Category 2: a. Drafting the manuscript: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann; b. Revising it for intellectual content: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann. Category 3: a. Final approval of the completed manuscript: J. Alexander Fraser, P. A. Sibony, A. Petzold, C. Thaung, and S. Hamann. APPENDIX: Members of the Optic Disc Drusen Studies (ODDS) Consortium are: Masoud Aghsaei Fard (Tehran University of Medical Science, Tehran, Iran); Shannon Beres (Stanford University Medical Centre, Palo Alto, CA); Valérie Biousse (Emory University School of Medicine, Atlanta); Lulu Bursztyn (Ivey Eye Institute, Western University, London, ON, Canada); Alison Crum (University of Utah, Salt Lake City, UT); Kathleen B. Digre (University of Utah, Salt Lake City, UT); J. Alexander Fraser (Western University, London, ON, Canada); Clare L. Fraser (Save Sight Institute, University of Sydney, Australia); Jesse Gale (Wellington, New Zealand); Steffen Hamann (Rigshospitalet, University of Copenhagen, Glostrup, Denmark); Ruth Huna-Baron (Sheba Medical Center, Tel Hashomer, Israel); Bradley Katz (University of Utah, Salt Lake City, UT); Mitchell Lawlor (Sydney Eye Hospital, University of Sydney, Australia); Yaping Joyce Liao (Stanford University Medical Centre, Palo Alto, CA); Lasse Malmqvist (Rigshospitalet, University of Copenhagen, Glostrup, Denmark); Peter M. Maloca (Institute of Molecular and Clinical Ophthalmology [IOB], Basel, Switzerland); Heather E. Moss (Stanford University Medical Centre, Palo Alto, CA); Nancy J. Newman (Emory University School of Medicine, Atlanta); Jason H. Peragallo (Emory University School of Medicine, Atlanta); Axel Petzold (Moorfields Eye Hospital, London, United Kingdom); Nailyn Rasool (University of California San Francisco, CA); Amadeo Rodriguez (McMaster University, Hamilton, ON, Canada); Simon P. Rothenbuehler. (University Hospital Basel, Switzerland); Marie-Bénédicte Rougier (Centre Fraser et al: J Neuro-Ophthalmol 2021; 41: 431-441 Hospitalier Universitaire de Bordeaux, France); Patrick A. Sibony (Department of Ophthalmology, State University of New York at Stony Brook, NY); Prem S. Subramanian (University of Colorado School of Medicine, Denver, CO); Judith E. A. Warner (University of Utah, Salt Lake City, UT); Marianne Wegener (Rigshospitalet, University of Copenhagen, Glostrup, Denmark); and Sui H. Wong (Moorfields Eye Hospital, London, United Kingdom). REFERENCES 1. Johnson LN, Diehl ML, Hamm CW, Sommerville DN, Petroski GF. Differentiating optic disc edema from optic nerve head drusen on optical coherence tomography. 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