Collagen

Collagen is the major structural protein, consisting of heterotypic fibrils (Fig. 21.1) similar to cartilage.^1,2 Following vitrectomy, a type II procollagen is secreted in humans,³ but vitreous is not reformed, since reoperations reveal that the gel state of vitreous is not re-established.

Fig. 21.1 Fibrillar structure of human vitreous collagen. Schematic diagram of the major heterotypic collagen fibrils of vitreous based upon the current knowledge of the structure and biophysical attributes of the constituent molecules.

(Reproduced with permission from Bishop P. The biochemical structure of mammalian vitreous. Eye 1996;10:64.)

Type II collagen⁴ comprises 75% of the total collagen content in vitreous. There are considerable similarities between vitreous and cartilage collagens,^5,6 perhaps explaining why inborn errors of type II collagen metabolism result in “arthro-ophthalmopathies,”⁷ manifesting similar phenotypic expression in joints and vitreous. Type IX collagen accounts for up to 15% of vitreous collagen,⁸ where it always contains a chondroitin sulfate glycosaminoglycan chain⁹ covalently linked to the α₂ (IX) chain at the NC3 domain, enabling the molecule to assume a proteoglycan form.

An important function of vitreous is maintaining transparency within the eye (Fig. 21.2).² Studies¹⁰ have shown that one of the minor collagens of vitreous is type XVIII, progenitor of endostatin, a potent inhibitor of angiogenesis.¹¹

Fig. 21.2 Dissected human vitreous. Vitreous body from a 9-month-old girl dissected from the sclera, choroid, and retina. The vitreous body is attached to the anterior segment and the specimen is placed on a surgical towel in room air. The exquisite gel state of the vitreous body and the crystal-clear transparency are evident.

(Specimen courtesy of the New England Eye Bank; originally published as cover photo in Sebag J. The vitreous: structure, function, and pathobiology. New York: Springer-Verlag, 1989.)

Hyaluronan

Hyaluronan (HA) was first isolated from bovine vitreous in 1937. HA appears after birth, perhaps synthesized by hyalocytes,² the ciliary body, and/or Müller cells. It is a large polyanion, which can influence the diffusion of drugs through vitreous.^12,13 As a result of HA’s entanglement within the vitreous collagen fibril matrix, the mechanical force of HA’s extension and contraction can be transmitted to the retina, optic disc, and neovascular complexes, inducing untoward effects in conditions with fluctuations in ionic balance and hydration, such as diabetes.¹⁴

Chondroitin sulfate

Most vitreous chondroitin sulfate is in the form of versican,¹⁵ believed to form complexes with HA as well as with microfibrillar proteins such as fibulin-1 and fibullin-2 and play a crucial role in maintaining the molecular morphology of vitreous.¹⁶ Mutations that alter the splicing of the central chondroitin sulfate-bearing domains of versican have been implicated in Wagner syndrome, a condition with excess vitreous liquefaction.¹⁷

Noncollagenous structural proteins

Vitreous body

Vitreous is a clear gel-like structure with a volume of 4.0 mL. During invagination of the optic vesicle the “primary” vitreous forms between the lens and the internal limiting lamina (ILL on Fig. 21.3A) of the retina. It is noteworthy that the ILL is continuous with Bruch’s membrane, demonstrating a common embryologic origin with analogous molecular composition and structure, suggesting important similarities later in life.²³ The “secondary” vitreous begins to develop at the 13-mm stage of embryogenesis and is derived from the retina and mesoderm of the hyaloid vascular system (Fig. 21.3B).

Fig. 21.3 Fetal human vitreous. (A) Human embryo eye stained with immunofluorescent anti-ABA (basement membrane lectin) antibodies revealing the continuity of the internal limiting lamina (ILL) and Bruch’s membrane, demonstrating a common embryologic origin with an analogous molecular composition and structure. This suggests similarities during aging and as participants in various disease processes, especially those that feature cell migration and proliferation: biologic processes that will occur along these interfaces. (Reproduced with permission from Sebag J, Hageman GS. Interfaces. Eur J Ophthalmol 2000;10:1.) (B) Photomicrograph of human fetal eye aged 13 gestational weeks. A prominent hyaloid artery and vasa hyaloidea propria can be seen arising from the optic nerve and extending anteriorly towards the lens to anastomose with the tunica vasculosa lentis. (Hematoxylin and eosin; bar = 100 µm.)

(Courtesy of Kenneth M.P. Yee and Fred Ross-Cisneros, University of Southern California.)

Classic depictions of human vitreous structure are shown in Fig. 21.4. Modern concepts proposed membranous (Fig. 21.5A)²⁴ and cisternal (Fig. 21.5)²⁵ systems. Sebag and Balazs²⁶ performed dark-field slit microscopy to define the posterior vitreous cortex as a thin, membranous structure continuous from the ora serrata to the posterior pole. Two round holes are present in the prepapillary and premacular areas (Fig. 21.6). Anteroposterior fibers (Fig. 21.7) comprised of parallel collagen fibrils (Fig. 21.8) arise from the vitreous base (Fig. 21.9A), where Gartner²⁷ found “lateral aggregation” in older individuals. Vitreous base collagen fibers insert anterior to the ora serrata forming the anterior loop (Fig. 21.9B), important in anterior proliferative vitreoretinopathy (PVR).²⁸ In the posterior pole, fibers extend through the premacular hole (Figs 21.6 and 21.7A), but a few attach to the rim of the hole. Condensed bundles of fibers insert into the vitreous cortex in the midperiphery and equator (Fig. 21.10).

Fig. 21.4 Classic depictions of vitreous structure. (A) Schematic representation of vitreous structure. (Redrawn with permission from Green WR. Pathology of the vitreous. In: Frayer WC (ed.) Lancaster course in ophthalmic histopathology, unit 8. Philadelphia: FA Davis, 1981.) (B) Schematic diagram of vitreous structure with classic nomenclature of internal and interface structures.

(Reproduced with permission from Sang DN. Embryology of the vitreous. Congenital and developmental abnormalities. In: Schepens CL, Neetens A, editors. The vitreous and vitreoretinal interface. New York: Springer-Verlag; 1987, p. 20.)

Fig. 21.5 Vitreous structure. (A) Membranelles, called tractae, course from the area of the ciliary body to the posterior pole. OS, ora serrata; LM, ligamentum medianum; LC, ligamentum coronarium; LR, ligamentum retrolentalis; TP, tractus preretinalis; TM, tractus medianus; TC, tractus coronarius; TR, tractus retrolentalis. (Reproduced with permission from Eisner G. Clinical anatomy of the vitreous. In: Duane TD, Jaeger EA, editors. Biomedical foundations of ophthalmology, vol. 1. Philadelphia: JB Lippincott; 1984, p. 21.) (B) Cisterns are identified by injecting with colored India ink. Light brown, Cloquet’s canal opening into the prepapillary area of Martegiani; light purple, equatorial cistern opening into the bursa premacularis.

(Reproduced with permission from Jongbloed WL, Worst JGF. The cisternal anatomy of the vitreous body. Doc Ophthalmol 1987;67:183–96.)

Fig. 21.6 The two “holes” in the posterior vitreous cortex correspond to the prepapillary (smaller, to left) and premacular (larger “hole,” to right) regions. Vitreous can be seen extruding through these holes. The bright pinpoint foci of intense light-scattering are hyalocytes embedded in the posterior vitreous cortex.

(Reproduced with permission from Sebag J, Balazs EA. Human vitreous fibres and vitreoretinal disease. Trans Ophthalmol Soc UK 1984;104:123–8.)

Fig. 21.7 Human vitreous morphology. Human vitreous structure visualized by dark-field slit illumination. All photographs are oriented with the anterior segment below and the posterior pole above. (A) Posterior vitreous in the left eye of a 52-year-old man. The vitreous body is enclosed by the vitreous cortex. There is a hole in the prepapillary (small, to the left) vitreous cortex. Vitreous fibers are oriented toward the premacular region. (B) Posterior vitreous in a 57-year-old man. A large bundle of prominent fibers is seen coursing anteroposteriorly and entering the retrocortical space by way of the premacular vitreous cortex. (C) Same photograph as B, at higher magnification. (D) Posterior vitreous in the right eye of a 53-year-old woman. There is posterior extrusion of vitreous out of the prepapillary hole (to the right) and premacular (large extrusion to the left) vitreous cortex. Fibers course anteroposteriorly out into the retrocortical space. (E) Horizontal optical section of the same specimen as D, at a different level. A large fiber courses posteriorly from the central vitreous and inserts into the premacular vitreous cortex. (F) Same view as E, at higher magnification. The large fiber has a curvilinear appearance because of traction by the vitreous extruding into the retrocortical space (see D). However, because of its attachment to the posterior vitreous cortex, the fiber arcs back to its point of insertion. (G) Anterior and central vitreous in a 33-year-old woman. Cloquet’s canal is seen forming the retrolental space of Berger. (H) Anterior and peripheral vitreous in a 57-year-old man. The specimen is tilted forward to enable visualization of the posterior aspect of the lens and the peripheral anterior vitreous. To the right of the lens there are fibers coursing anteroposteriorly that insert into the vitreous base. These fibers “splay out” to insert anterior and posterior to the ora serrata. (A, E, and F reproduced with permission from Sebag J, Balazs EA. Pathogenesis of CME: anatomic consideration of vitreoretinal adhesions. Surv Ophthalmol 1984;28 (Suppl):493. B, C from Sebag J, Balazs EA. Morphology and ultrastructure of human vitreous fibers. Invest Ophthalmol Vis Sci 1989;30:187. D, G, and H from Sebag J. The vitreous: structure, function, and pathobiology. New York, Springer-Verlag, 1989. Specimens were courtesy of the New York Bank for Sight and Restoration, New York, NY.)

Fig. 21.8 Ultrastructure of human vitreous fiber. The fibers of the human vitreous visible by dark-field microscopy result from bundles of parallel collagen fibrils such as the one shown here in cross-section (arrow).

(Reproduced with permission from Sebag J, Balazs EA. Morphology and ultrastructure of human vitreous fibers. Invest Ophthalmol Vis Sci 1989;30:187.)

Fig. 21.9A Vitreous base morphology. In this eye of a 58-year-old woman, postmortem dark-field slit microscopy studies showed vitreous fibers that are continuous from the posterior vitreous cortex (at the top of the photo) to the vitreous base, where they “splay out” to insert into the vitreous base (arrow).

(Reproduced with permission from Sebag J, Balazs EA. Pathogenesis of CME: anatomic consideration of vitreoretinal adhesions. Surv Ophthalmol 1984;28 (Suppl):493–8.)9B Anterior loop of the vitreous base. Central, anterior, and peripheral vitreous structure in a 76-year-old man. The posterior aspect of the lens is seen below. Fibers course anteroposteriorly in the central vitreous and insert into the vitreous base. The “anterior loop” configuration of those fibers inserting into the vitreous base anterior to the ora serrata is seen on the right side of the specimen (arrow).

Fig. 21.10 Fibers condense into bundles and insert into the vitreous cortex (arrows). Between these insertions are spaces seemingly devoid of structure, but probably filled with liquid vitreous.

(Reproduced with permission from Sebag J, Balazs EA. Human vitreous fibres and vitreoretinal disease. Trans Ophthalmol Soc UK 1984;104:123–8.)

Vitreoretinal interface

The equatorial and posterior vitreoretinal interfaces consist of the posterior vitreous cortex, the ILL of the retina, and an intervening extracellular matrix.

Posterior vitreous cortex

The posterior vitreous cortex is 100–110 µm thick and consists of densely packed collagen fibrils²⁹ (Fig. 21.11). There is no vitreous cortex over the optic disc (Figs 21.6 and 21.7A), and the cortex is thin over the macula. The prepapillary hole can sometimes be visualized clinically following posterior vitreous detachment (PVD). If peripapillary tissue is torn away during PVD and remains attached around the prepapillary hole, it is called Vogt’s or Weiss’s ring. Gupta et al.³⁰ demonstrated a lamellar organization of the posterior vitreous cortex (Fig. 21.12), confirmed in humans by three-dimensional optical coherence tomography (OCT) (Fig. 21.13).³¹ During anomalous PVD (APVD)³² these predispose to splitting along potential cleavage planes, resulting in vitreoschisis.³³

Fig. 21.11 Ultrastructure of human vitreoretinal interface. Scanning electron microscopy of anterior surface of the human retina (top) and the posterior surface of the posterior vitreous cortex (bottom).

(Reproduced with permission from Sebag J. The vitreous: structure, function, and pathobiology. New York: Springer-Verlag; 1989.)

Fig. 21.12 Lamellar structure of the posterior vitreous cortex. Immunohistochemistry with anti-ABA lectin antibodies of the monkey vitreoretinal interface demonstrates lamellae in the posterior vitreous cortex just above the internal limiting lamina of the retina (intensely staining yellow line). These lamellae represent potential cleavage planes during anomalous posterior vitreous detachment with vitreoschisis.

(Reproduced with permission from Gupta P, Yee KMP, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol 2011;95:376–80.)

Fig. 21.13 Human posterior vitreous cortex. Three-dimensional spectral-domain optical coherence tomography imaging of human posterior vitreous cortex demonstrates the lamellar structure that predisposes to vitreoschisis.

(Reproduced with permission from Sebag J. Vitreous – the resplendent enigma. Br J Ophthalmol 2009;93:989–91. Image courtesy of Dr Carl Glittenberg and Prof. Susanne Binder, Vienna.)

Hyalocytes

Hyalocytes are mononuclear cells embedded in the posterior vitreous cortex 20–50 µm from the ILL posteriorly (Figs 21.6 and 21.14). The highest density of hyalocytes is in the vitreous base followed by the posterior pole, with the lowest density at the equator.^34,35 Balazs³⁶ suggested that these cells synthesize vitreous HA,^37–40 but Swann⁵ disagreed. Evidence suggests that hyalocytes maintain ongoing synthesis and metabolism of glycoproteins^41,42 and may also synthesize collagen⁴³ and enzymes.⁴⁴

Fig. 21.14 Human hyalocytes. (A) Phase contrast microscopy of human hyalocytes in situ. (Reproduced with permission from Sebag J. The vitreous: structure, function, and pathobiology. New York: Springer-Verlag; 1989, p. 49.) (B) A mononuclear cell is seen embedded within the dense collagen fibril (black C) network of the vitreous cortex. There is a lobulated nucleus (N) with a dense marginal chromatin (white C). In the cytoplasm there are mitochondria (M), dense granules (arrows), vacuoles (V), and microvilli (Mi) (magnification = 11 670×).

(Courtesy of JL Craft and DM Albert, Harvard Medical School.)

The phagocytic capacity of hyalocytes has been described in vivo⁴⁵ and demonstrated in vitro.^46–48 Hyalocytes become phagocytic in response to inducting stimuli and are important in antigen processing and as initiators of the immune response, making possible intravitreal inoculation of antigens to promote systemic immunity.⁴⁹ HA may have a regulatory effect on hyalocyte phagocytic activity.^50,51 Various constituents of vitreous^52,53 may be immunogenic and play a role in ocular inflammatory diseases. Sakamoto and Ishibashi have recently published an excellent review of hyalocytes.⁵⁴

Hyalocytes are important in macular pucker when APVD²⁸ and vitreoschisis^26,29 leave these cells on the macula (Fig. 21.15). Under the influence of cytokines, hyalocytes proliferate⁵⁵ on the surface of the retina, resulting in hypercellular membranes. Hyalocytes also recruit cells from the circulation and the retina (glial cells) via the release of connective tissue growth factor and induce collagen gel contraction in response to platelet-derived growth factor and other cytokines,^56,57 causing tangential vitreoretinal contraction.

Fig. 21.15 Vitreoschisis (VS). Transmission electron microscopy of human hyalocyte (same as in Fig. 21.14B) demonstrating two potential levels splitting during vitreoschisis. Anomalous posterior vitreous detachment that induces vitreoschisis which splits the posterior vitreous cortex anterior to the level of hyalocytes (red dashes) leaves these cells attached to the macula, resulting in a hypercellular membrane. The lack of attachment to the optic disc allows inward (centripetal) tangential traction causing contraction and macular pucker. If vitreoschisis splits the posterior vitreous cortex posterior to the level of hyalocytes (blue dashes), the remaining membrane is thin and hypocellular. If there is also vitreopapillary attachment, the tangential forces will be outward (initially nasally), opening a central dehiscence and inducing a macular hole. ILL, internal limiting lamina; VS, vitreoschisis; MP, macular pucker; for other abbreviations see Fig. 21.14.

Fig. 21.16 Vitreoretinal vessel interface. A large gap (between arrows) in the internal limiting lamina (ILL) over and adjacent to a retinal artery is seen with a thin, fibroglial epiretinal membrane over the ILL (arrowheads) (periodic acid–Schiff; ×470).

Internal limiting lamina (ILL) of the retina

The ILL is a multilaminar structure of variable thickness topographically. Adjacent to Müller cell foot plates is the lamina rara externa (0.03–0.06 µm) with no species variations or changes with topography or age. The lamina densa is thinnest at the fovea (0.01–0.02 µm) and thicker in the posterior pole (0.5–3.2 µm) than at the equator or vitreous base, where Foos⁵⁸ found the ILL to be uniformly thin (51 nm) and the lamina rara to be 40 nm wide with traversing fibrils that were denser at sites corresponding to attachment plaques in Müller cells. The ILL is very thin over major retinal vessels (Fig. 21.16) where defects allow glial cells to extend on to the inner retina.⁵⁹ Acquired ILL defects are in the foveola, retinal pits, retinal tufts, and retinal lattice. The ILL progressively thickens posteriorly to about 306 nm at the equator and about 1887 nm posteriorly. Müller footplates are less numerous at the equator than at the vitreous base. Posteriorly, no Müller footplates were observed and the inner aspect of the ILL remains smooth, while the outer aspect is irregular. Peripherally, both inner and outer surfaces are smooth.^2,53

The ILL consists of type IV collagen, associated with glycoproteins,^23,60,61 type VI collagen, which may contribute to vitreoretinal adhesion, and type XVIII,⁶² which binds opticin.⁶³ Opticin binds to heparan sulfate, contributing to vitreoretinal adhesion.⁶⁴ Type XVIII collagen also prevents cell migration from the retina into vitreous.⁶⁵

Retinal sheen dystrophy⁶⁶

This ILL dystrophy has cystic spaces under the ILL and in the inner nuclear layer (Fig. 21.17), and numerous areas of separation of the ILL from the retina with filamentous material (Fig. 21.18). Endothelial cell swelling and degeneration, pericyte degeneration, and basement membrane thickening of retinal capillaries suggest that this condition is primarily a retinal vasculopathy with edema, swelling, and degeneration of Müller cells. Alternatively, the primary defect could be in Müller cells.

Fig. 21.17 Retinal sheen dystrophy. Area with microcysts (large arrows) beneath the inner limiting lamina (small arrow) and cystic edema in inner nuclear layer in area of cell bodies of Müller cells (periodic acid–Schiff; ×850).

(Reproduced with permission from Polk T, Gass JDM, Green WR, et al. Familial internal limiting membrane dystrophy: a new sheen retinal dystrophy. Arch Ophthalmol 1997;115:878–85.)

Fig. 21.18 Retinal sheen dystrophy. Inferior midperipheral area where the inner limiting lamina (arrow) is separated from Müller cells (M), and filaments (asterisk) and cellular debris (two asterisks) are interposed. The outer portion of the internal limiting lamina (arrowhead) is separated and remains attached to Müller cells with junctional densities (circles) (×15 000).

Degenerative remodeling

Foos⁶⁷ defined a spectrum of changes in the ILL as “degenerative remodeling.” Features include detachment and discontinuity of the ILL with vitreous collagen beneath the ILL (Fig. 21.19), cellular debris with macrophages, and absence of Müller cell attachment plaques. In larger lesions, vitreous may insinuate into degenerative crypts and adhere to the cell membrane of the lining Müller cells that have no basal lamina (Fig. 21.20). In the peripapillary area, retinal glial cells extend from the optic disc and are continuous with a glial epipapillary membrane that has vitreous fiber incarceration. Roth and Foos⁶⁸ observed nasal epipapillary membranes associated with Bergmeister papillae in 27.6% of autopsy eyes.

Fig. 21.19 Degenerative remodeling. Basal area with vitreous collagen located between detached inner limiting lamina (arrow) and glial cell process.

(Courtesy of Tsuyoshi Kimura.)

Fig. 21.20 Basal zone showing detached and degenerating internal limiting lamina under which the attachment plaques are missing in the surface of Müller cells and vitreous has become incarcerated. Vitreous in degeneration crypt has become firmly adherent to Müller cell (arrow) (×12 600).

(Reproduced with permission from Foos RY. Vitreoretinal juncture: topographical variations. Invest Ophthalmol 1972;11:801–8.)

Topographic variations

Strength of vitreoretinal adhesion

Vitreous is attached to all contiguous structures, but is most firmly adherent at the vitreous base,⁷² which includes the posterior 2 mm of the pars plana and extends 1–4 mm posterior to the ora serrata, varying with age⁷³ and topography (more posterior temporally). There are also topographic differences posteriorly, with greater adhesion at the posterior pole than the equator⁶⁰ (Fig. 21.21).

Fig. 21.21 Vitreomacular interface in youth. (A) Dark-field microscopy of the posterior vitreous from a 14-year-old boy. The sclera, choroid, and retina were dissected off the vitreous, which remains attached to the anterior segment. In contrast to adults, there is an extra layer of tissue that remained adherent to the posterior vitreous cortex when the retina was dissected off. The white arrow indicates the location of the fovea. The circular structure below this is the prepapillary hole in the posterior vitreous cortex. Emanating from this hole are linear, branching structures (black arrows) that correspond to the location of the retinal vessels. (B) Scanning electron microscopy of the tissue shown in (A) demonstrates round structures adherent to the posterior aspect of this tissue (bar = 1 µm). (C) Higher magnification of structures shown in (B). (D) Transmission electron microscopy of this specimen identified this tissue as the internal limiting lamina (ILL) of the retina (arrows) attached to the posterior vitreous cortex (p). The round structures shown in (B) are identified as the inner portion of Müller (m) cells that remained adherent to the posterior aspect of the ILL. The hole on the posterior aspect of these round structures is where the anterior portion of the Müller cell was torn away from the rest of the cell body. At the bottom of the photomicrograph are the collagen fibrils of the vitreous (Coll) (original magnification ×20 800).

(Panel C reproduced with permission from Sebag J. Age-related differences in the human vitreoretinal interface. Arch Ophthalmol 1991;109:966–71.)

Peripheral fundus and vitreous base

The vitreous base is a three-dimensional structure that straddles the ora serrata. There is a high density of collagen fibrils oriented at right angles to the inner surface of the ciliary epithelium and peripheral retina. The fibrils attach to the basement membrane of the nonpigmented epithelium of the pars plana and the ILL of the peripheral retina,⁷⁴ intimately interwoven with an intervening extracellular matrix. Within the vitreous base, there are several anatomic variations where vitreoretinal adhesion is firm⁷⁵ and associated with retinal breaks^76,77:

1. Ora bays^70,75,78 (Fig. 21.22)

2. Meridional folds^77,79 (Fig. 21.23)

3. Meridional complexes⁷⁷ (Figs 21.22 and 21.24)

4. Peripheral retinal excavations^77,80 (Fig. 21.24)

5. Retinal tufts

(a) Noncystic retinal tufts^81–83 (Fig. 21.25)

(b) Cystic retinal tufts^76,81,82,84 (Fig. 21.26)

(c) Zonular traction tufts^79,85–88 (Fig. 21.27)

6. Spiculate and nodular pigment epithelial hyperplasia⁸⁷ (Fig. 21.28)

7. Retinal lattice “degeneration”^{58,84,89–105} (Figs 21.29–21.33)

8. White-with-pressure, white-without-pressure^106–113

9. Verruca¹¹⁴ (Fig. 21.34).

Fig. 21.22 A meridional complex (arrow) and dentate process (arrowhead) are located at the margin of a nonenclosed ora bay.

Fig. 21.23 Meridional folds, one in line with a meridional complex (arrowhead) and the other (arrow) in line with a meridional complex and enclosed ora bay (asterisk).

(Reproduced with permission from Green WR. Pathology of the retina. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 9. Philadelphia: FA Davis; 1981.)

Fig. 21.24 Peripheral retinal excavation (arrowhead) in line with a meridional complex and an enclosed ora bay.

(Reproduced with permission from Green WR. Pathology of the retina. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 9. Philadelphia: FA Davis; 1981.)

Fig. 21.25 Noncystic peripheral retinal tuft. Most tufts consist of glial cells, and some have strands of vitreous attached (arrow) (hematoxylin and eosin, ×215).

(Reproduced with permission from Green WR. Retina. In: Spencer WH, editor. Ophthalmic pathology: an atlas and textbook, vol. 2. Philadelphia: WB Saunders; 1985.)

Fig. 21.26 Cystic retinal tuft. (A) The lesion consists of an area of retinal thickening caused by cystic changes (asterisks) and glial cell proliferation (hematoxylin and eosin, ×220). (B) Scanning electron microscopy (EM) demonstrates that the tuft is a cystoid formation of fibers, similar to those of the nerve fiber layer, and cells, similar to those found in the inner plexiform layer of the retina, that are connected to the internal limiting lamina of the retina. This scanning EM shows the insertion of the vitreous collagen fibers on the tuft’s apical surface.

(Reproduced with permission from Dunker S, Glinz J, Faulborn J. Morphologic studies of the peripheral vitreoretinal interface in humans reveal structures implicated in the pathogenesis of retinal tears. Retina 1997;17:124–30.)

Fig. 21.27 Zonular traction tuft. Gross (A) and microscopic (B) appearances of zonular tractional tuft (arrow in panel A) composed of a strand of glial cells whose anterior part consists of two layers of embryonal-like epithelium (arrows in panels B and C; hematoxylin and eosin, ×65). (C) Higher magnification (hematoxylin and eosin, ×290). (Panels A and B reproduced with permission from Green WR. Pathology of the retina. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 9. Philadelphia: FA Davis; 1981; panel C

reproduced with permission from Green WR. Retina. In: Spencer WH, editor. Ophthalmic pathology: an atlas and textbook, vol. 2. Philadelphia: WB Saunders; 1985.)

Fig. 21.28 Hyperplasia of pigment epithelium at ora serrata. Hyperplastic pigment epithelium (arrow) extends into the vitreous cavity at the ora serrata (periodic acid–Schiff; ×220).

(Reproduced with permission from Green WR. Pathology of the retina. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 9. Philadelphia: FA Davis; 1981.)

Fig. 21.29 Paravascular retinal lattice. Radial perivascular lattice with sclerotic vessel and hyperplastic retinal pigment epithelium, with migration into the retina in a paravascular location.

Fig. 21.30 Lattice wicker. Gross appearance of retinal lattice, with sclerotic vessels that have a wicker appearance.

Fig. 21.31 Histopathology of retinal lattice. Lattice lesion with retinal thinning, discontinuity of inner limiting membrane (arrows), pocket of fluid vitreous (asterisk), and glial cell proliferation in vitreous at margin (arrowheads) (Alcian blue stain; ×145).

Fig. 21.32 Trypsin digestion preparation of retina discloses relatively acellular capillaries in area of lattice degeneration (right) (hematoxylin and eosin and periodic acid–Schiff stains; ×185).

Fig. 21.33 Retinal tear at posterior margin of area of lattice degeneration.

Fig. 21.34 Verruca. Scanning electron microscopy shows cellular elements resembling cells of the inner plexiform layer near the retinal surface. The “trunk” of the verruca extends from the retina to the vitreous cortex. The “branches” of the verruca are intertwined with vitreous collagen fibers. There is local collagen destruction (arrows) and interruption of the internal limiting lamina of the retina.

(Reproduced with permission from Dunker S, Glinz J, Faulborn J. Morphologic studies of the peripheral vitreoretinal interface in humans reveal structures implicated in the pathogenesis of retinal tears. Retina 1997;17:124–30.)

Interface along major retinal vessels

The ILL thins and is sometimes absent over major retinal vessels^115,116 (Fig. 21.35). At such points, vitreous may be incarcerated into retina, directly continuous with perivascular tissue, attachments called “vitreoretinovascular bands,”¹¹⁷ or “spider-like bodies,”¹¹⁸ purported to be vitreous fibrils that traverse the ILL and coil about retinal blood vessels. It is common for retinal vessels to be associated with paravascular rarefaction (cystic degeneration), retinal pits and tears, and avulsion of retinal vessels.

Fig. 21.35 Vitreous interface over retinal vessels. There is a large gap in the inner limiting lamina (ILL) over and adjacent to retinal artery. A glial preretinal membrane (arrowhead) originates at a defect in the ILL overlying the retinal vessel. Arrow indicates one end of the discontinuous ILL (periodic acid–Schiff stain; ×170).

(Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.)

Vitreomacular interface

Attachment of vitreous to the macula occurs in an irregular, annular zone of 3–4 mm diameter,² generally not visible by clinical examination in normal adults but possibly evident in fetal and young adult eyes and in pathologic conditions. The posterior vitreous cortex is thinner over the macula in a disc-shaped area about 5 mm in diameter. Discontinuity of the ILL in the fovea may be a site where glial cells extend on to the inner surface of the retina (Fig. 21.36).

Fig. 21.36 Vitreomacular interface. The internal limiting lamina is discontinuous (between arrows), at which point glial cells extend on to the inner surface of the retina and form a thin, fibroglial premacular membrane (arrowheads) with no apparent contraction (periodic acid–Schiff stain; ×100).

Vitreopapillary interface

At the rim of the optic disc the ILL ceases, although the basement membrane continues as the inner limiting membrane of Elschnig.¹¹⁹ This membrane is 50 nm thick and is believed to be the basal lamina of the astroglia in the optic nerve head. At the centralmost portion of the optic disc the membrane thins to 20 nm, follows the irregularities of the underlying cells of the optic disc, and is composed only of glycosaminoglycans and no collagen (central meniscus of Kuhnt). Given that the ILL prevents the passage of cells,⁴⁷ the thinness and chemical composition of the central meniscus of Kuhnt and the membrane of Elschnig may account for frequent cell proliferation from or near the optic disc.

Vitreous attachment to the optic disc may persist even though the vitreous is detached elsewhere¹²⁰ (Fig. 21.37). This adhesion may be fortified by epipapillary membranes.⁶⁸ The entire complex may subsequently detach, resulting in a ring of tissue composed of fibrous astrocytes and collagen (Fig. 21.38) that flutters in and out of the visual axis, causing “floaters.” Vitreopapillary adhesion (VPA) contributes to macular holes¹²¹ and any vitreomaculopathy that features intraretinal cystoid spaces,¹²² presumably due to the influence upon the vectors of tangential traction upon the macula.

Fig. 21.37 Vitreopapillary adhesion. (A) Gross appearance illustrates partial posterior vitreous detachment with strand of vitreous remaining attached to the optic nerve head. Light reflexes in photograph taken with specimen out of fluid to depict the findings more clearly. (B) Combined optical coherence tomography-scanning laser ophthalmoscopy (OCT-SLO) imaging of vitreopapillary adhesion. The gray-scale image is coronal plane imaging by SLO, and the color image is the transverse OCT image through the optic disc.

Fig. 21.38 Weiss ring. Surgically removed Weiss ring contains fibrous astrocytes that have polarity, basement membrane (arrowhead), and large bundles of 10-nm filaments (arrows) (×20 000).

Biochemical

Vitreous is important in maintaining transparency for maximal photon transmission to the retina. Vitreous may also maintain lens transparency by mitigating the effects of reactive oxygen species on lens proteins and thus preventing cataracts.¹²³ This antioxidant effect is primarily the result of high concentrations of ascorbate in vitreous, an observation originally made in 1944 by Friedenwald and colleagues.¹²⁴

Gisladottir et al.¹²⁵ recently emphasized the influence of vitreous on various physiologic processes and showed that vitrectomy can have considerable effects, both beneficial and harmful.¹²⁶ Vitrectomy reduces the risk of retinal neovascularization, but increases the risk of iris neovascularization, reduces macular edema, but stimulates cataract formation.

Biophysical

During ocular saccades, the rotational force of the eye wall is transmitted to the vitreous body via attachments to adjacent structures.¹²⁷ During both acceleration and deceleration phases of saccades, vitreous movement lags behind the eye wall, resulting in markedly reduced acceleration.¹²⁸ This “slack and lag” results from vitreous viscoelasticity, dampening the force at any given internal vitreous attachment. The inferonasal displacement of the optic disc and the shorter distance between the disc and ora inferiorly and nasally make the relief of torsional strain on equatorial and anterior vitreoretinal attachments greater nasally and inferiorly. Accordingly, the greatest torsional strain on anterior and equatorial vitreous attachments should occur during lateral saccades, with the point of maximum strain located somewhere in the superotemporal quadrant, the site of most frequent retinal tears.¹²⁹

Liquefaction (synchysis)^130,131

After age 40 years there is a significant decrease in the gel volume and a concurrent increase in the liquid volume of vitreous, primarily centrally.^132,133 In the posterior vitreous such changes form pockets of liquid vitreous, called “lacunae” (Fig. 21.39). When a single, large pocket forms, the terms “bursa”²⁴ or “precortical pocket”¹³⁴ have been employed. This large posterior lacuna is a manifestation of age-related liquefaction (Fig. 21.39), and not an anatomic entity.¹³⁵ Balazs and Denlinger¹³⁰ found evidence of liquid vitreous after the age of 4 years and observed that, by the time the human eye reaches adult size (ages 14–18 years), 20% of the total volume is liquid vitreous. By the age of 80–90 years more than half the vitreous is liquid.

Fig. 21.39 Morphology of human vitreous liquefaction (synchysis). (A) Gross appearance of central vitreous liquefaction (synchysis). (B) Dark-field slit microscopy of human vitreous demonstrates the central vitreous has thickened, tortuous fibers. The peripheral vitreous has regions devoid of any structure which contain liquid vitreous. These regions correspond to so-called lacunae (arrows).

Aging changes and vitreous biochemistry

Biochemical studies support the rheologic observations described above. Total vitreous collagen content does not change after ages 20–30 years. However, collagen concentration in gel vitreous at the ages of 70–90 years (0.1 mg/mL) was significantly greater than at the ages of 15–20 years (0.05 mg/mL; P < 0.05).¹³⁰ Since the total collagen content does not change, this is likely due to the decreased volume of gel vitreous that occurs with aging and a consequent increase in the concentration of the collagen in the remaining gel. This concept is supported by the finding that vitreous HA concentration increases until about the age of 20, when adult levels are attained. Thereafter, until 70 years, there are no changes in the HA concentrations of either the liquid or gel compartments. This necessarily means that there is an increase in the HA content of liquid vitreous and a concomitant decrease in the HA content of gel vitreous, since the amount of liquid vitreous increases and the amount of gel vitreous decreases with age.

Structural changes

Vitreous body

The aforementioned rheologic and biochemical alterations induce significant structural changes during aging, consisting of a transition from a clear gel in youth (Fig. 21.2) to a fibrous structure in adults (Fig. 21.7A). In old age there is advanced liquefaction with thickening and tortuosity of vitreous fibers, and collapse (syneresis) of vitreous (Fig. 21.40). Postmortem studies¹⁴⁰ found syneresis in 70% of subjects in the eighth decade. Syneresis occurs earlier and is more extensive in myopic eyes,¹⁴¹ and is accelerated with inflammation, trauma, and arthro-ophthalmopathies.^7,142

Fig. 21.40 Gross appearance of posterior vitreous detachment in a phakic eye.

Posterior vitreous detachment

Due to inadequate diagnostics,¹⁴⁴ PVD is an inaccurate diagnosis. PVD begins at the posterior pole, perhaps in the perifoveal region.¹⁴⁵ An innocuous PVD is clean separation between the ILL of the retina and the cortical vitreous.¹⁴⁶ Whereas it is widely held that PVD is an “abnormal” event, it is possible that PVD may be a preprogrammed event that mitigates the risks of an attached vitreous, which in old age are more dangerous than a PVD.¹⁴⁷ Fortunately, PVD is innocuous in most cases.

Vitreous effects of APVD

An important consequence of APVD is vitreoschisis^29,32 (Fig. 21.42), i.e., splitting of the posterior vitreous cortex with forward displacement of the anterior portion of the cortex, leaving the posterior layer attached to the retina. Vitreoschisis has been detected in proliferative diabetic retinopathy,¹⁴ macular pucker, and macular holes.¹⁶⁰

Fig. 21.42 Vitreoschisis. (A) Ultrasonography of posterior vitreoschisis demonstrates the two layers of the schisis cavity rejoining into full-thickness posterior vitreous cortex (below). (Reproduced with permission from Green RL, Byrne SF. Diagnostic ophthalmic ultrasound. In: Ryan SJ, editor. Retina, 1st edn. St Louis: Mosby; 1989.) (B) Optical coherence tomography-scanning laser ophthalmoscopy imaging of posterior vitreoschisis demonstrates the two walls of the schisis cavity rejoining into full-thickness posterior vitreous cortex (to left). (Reproduced with permission from Gupta P, Yee KMP, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol 2011;95:376–80.) (C) Histopathology of vitreoschisis. Surgical specimen removed from a patient with macular pucker demonstrates the split in the posterior vitreous cortex and rejoining of the two walls into full-thickness posterior vitreous cortex. Hyalocytes (arrows) are seen within the posterior vitreous cortex. Note the lack of any additional cellularity on the surfaces of the split posterior vitreous cortex. (Periodic acid–Schiff; ×300.)

(Reproduced with permission from Gupta P, Yee KMP, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol 2011;95:376–80.)

Peripheral retinal effects of APVD

Retinal breaks

Retinal holes unrelated to PVD were observed in 326 (13.9%) of 2334 autopsy cases by Foos et al.⁹⁶ Retinal tears (Fig. 21.43) result from fluid movements.¹⁶¹ Vitreous remains attached to the posterior margin of the retinal flap, which may be avulsed leaving a round or oval hole. The flap of retina remains attached to the posterior surface of the detached vitreous (operculum). Large detached flaps may form a cystic structure (Fig. 21.44).

Fig. 21.43 Retinal pits and tears. Gross appearance of eye with posterior vitreous detachment, a string of retinal pits along vessels (arrows), and three horseshoe-shaped retinal tears (arrowheads).

(Reproduced with permission from Green WR. Pathology of the vitreous. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 8. Philadelphia: FA Davis; 1981.)

Fig. 21.44 Large retinal tear. Microscopic features include rounded anterior (arrowheads) and posterior margins of the hole and coiled-up, detached operculum (arrows) that remains attached to the posterior surface of the detached vitreous (periodic acid–Schiff stain; ×16).

(Reproduced with permission from Green WR. Pathology of the vitreous. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 8. Philadelphia: FA Davis; 1981.)

The clinical incidence of retinal tears¹⁶² varies from 7.2%¹⁶³ to 5.8%,¹⁶⁴ with a high of 13.75%⁷⁹ and a low of 0.59%.¹⁶⁵ Postmortem incidences were 3.9%,¹⁶⁶ 8.6%,¹⁶⁷ 4.7%,¹⁶⁸ 8.8%,¹⁶⁹ 3.7%,¹⁷⁰ and 7.3%.⁹⁶ Although the role of retinal tears in causing RD is undisputed, management is controversial. Byer¹⁷¹ concluded that prophylactic treatment is not justified for asymptomatic retinal breaks in phakic eyes. However, in a natural history study of 166 eyes with retinal breaks, Davis¹⁰⁵ observed that 31 (18%) progressed to RD. Neumann and Hyams¹⁷² reported that 2% of 153 eyes with retinal breaks developed RD. The incidence of retinal tears is much greater than RD, which varies between 9 (0.009%)¹⁷³ and 24.4 (0.02%) per 100 000 per year.¹⁷⁴ Benson¹⁷⁵ promoted patient education while Combs and Welch¹⁷⁶ concluded that prophylactic treatment of acute horseshoe tears with vitreous traction significantly reduces the incidence of RD. A particularly high-risk group are patients with vitreous hemorrhage that obscures fundus visualization. Ultrasound may be an effective means of identifying retinal tears in such eyes,¹⁷⁷ but misdiagnosis at presentation bodes poorly, since there is a 67% incidence of retinal tears.¹⁷⁸

Other sequelae

1. Retinal tags⁸¹

2. Retinal folds

3. Traction retinoschisis (Fig. 21.45)

4. Traction on retinal vessels ¹¹⁵ (Fig. 21.46A)

(a) Cystic degeneration^169,170 (Fig. 21.46B)

(b) Avulsion of retinal vessels^179,180

(c) Retinal pits¹⁶⁹ (Fig. 21.47)

Fig. 21.45 Traction retinoschisis. Gross appearance of large retinoschisis caused by vitreous traction. A sheet of vitreous (arrow) extends across the eye and temporally is attached to the apex of the tented-up inner layer of the extensive areas of retinoschisis. Posteriorly a hole in the outer layer (arrowhead) is present and allows visualization of some interbridging strands of tissue between two layers of schisis.

(Reproduced with permission from Green WR. Retina. In: Spencer WH, editor. Ophthalmic pathology: an atlas and textbook, vol. 2. Philadelphia: WB Saunders; 1985.)

Fig. 21.46 Anomalous posterior vitreous detachment effects on retinal vessels. (A) Retinal tear with bridging retinal blood vessel. (B) There is cystic degeneration of the nerve fiber layer near the retinal vessel (arrow) (periodic acid–Schiff stain; ×120). (Reproduced with permission from Green WR. Pathology of the retina. In: Frayer WC, editor. Lancaster course in ophthalmic histopathology, unit 9. Philadelphia: FA Davis; 1981.) (C) Section through a venous loop which is parallel to the axis of the vein shows the anterior (asterisk) and posterior (double asterisks) components of the loop as it extends through a discontinuity in the inner limiting membrane (between arrows). The wall of the loop is thin and tented at the points of attachment of thin delicate vitreous strands (arrowheads) anteriorly and posteriorly (periodic acid–Schiff stain; ×100).

(Reproduced with permission from Hersh PS, Green WR, Thomas JV. Am J Ophthalmol 1981;92:661–71.)

Fig. 21.47 Retinal pit. Margin of retinal pit with discontinuity of the internal limiting lamina (arrow) and a glial cell preretinal membrane (arrowhead). (Periodic acid–Schiff stain; ×185.)

(Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.)

Macular effects of APVD

Vitreomacular traction

For vitreomacular traction syndrome,^2,28,32 see Fig. 21. 48.

Fig. 21.48 Vitreomacular traction syndrome. This extreme example of anomalous posterior vitreous detachment with persistent full-thickness adhesion of the posterior vitreous cortex to the macula has induced sufficient traction upon the macula to induce prominent elevation of the central macula. Typically, there is only thickening of the macula without detachment.

Cystoid macular edema

For cystoid macular edema,^183–189 see Figs 21.49 and 21.50.

Fig. 21.49 Cystoid macular edema with cystic spaces in the outer plexiform and inner nuclear layers (hematoxylin and eosin stain; ×45).

Fig. 21.50 Irvine–Gass syndrome. Area near posterior pole showing edema and retinal phlebitis (arrow) (hematoxylin and eosin stain; ×185).

(Reproduced with permission from Martin NF, Green WR, Martin LW. Retinal phlebitis in the Irvine–Gass syndrome. Am J Ophthalmol 1977;83:377–86.)

Macular cysts¹⁹⁰

Macular cysts that result from chronic edema (Fig. 21.51) need to be distinguished from the cystoid spaces created by vitreous traction in macular holes (Figs 21.52 and 21.53), and macular pucker with VPA.¹²¹

Fig. 21.51 Cystic edema (arrows) and a large cyst (asterisk) are present in the macula (hematoxylin and eosin, ×40).

(Reproduced with permission from Green WR. Retina. In: Spencer WH, editor. Ophthalmic pathology: an atlas and textbook, vol. 2. Philadelphia: WB Saunders; 1985.)

Fig. 21.52 Lamellar macular hole. Combined optical coherence tomography-scanning laser ophthalmoscopy imaging of a partial-thickness macular hole with adjacent cystoid spaces.

Fig. 21.53 Macular hole. (A) Combined optical coherence tomography-scanning laser ophthalmoscopy imaging of macular hole demonstrating anomalous posterior vitreous detachment, a pseudo-operculum, pericentral intraretinal cystoid spaces, and a thin premacular membrane, particularly visible to the right. (B) Microscopy shows macular hole, detached posterior vitreous cortex with adherent pseudo-operculum, cystoid spaces in outer plexiform and inner nuclear layers, a small area of surrounding retinal detachment, demarcation chorioretinal adhesions on both sides of the elevated retina, and a premacular membrane particularly visible to the right (hematoxylin and eosin, ×55). (C) Higher-power view of B showing a thin hypocellular preretinal membrane (arrowhead), prominent cystoid spaces, and demarcation adhesion (arrow) (hematoxylin and eosin, ×140). (Reproduced with permission from Frangieh GT, Green WR, Engel HM. A histopathologic study of macular cysts and holes. Retina 1981; 1:311–36.) (D) Detached pseudo-operculum demonstrating lack of neural retina elements. (E) Composite low-power view of operculum. Thicker cellular ends are connected by a thinner segment. A thin collagenous layer along this region (cortical vitreous) identified the inner vitreal surface (arrows) of the operculum. A short segment of ILL (circle) is present in an area of folding (×550).

(Reproduced with permission from Madreperla SA, McCuen BW II, Hickingbotham D, et al. Am J Ophthalmol 1995;120:197–207.)

Macular holes

Macular holes are surrounded by a gray ring of cystoid spaces and slightly elevated retina, thinning and depigmentation of the underlying retinal pigment epithelium (RPE), yellow nodular opacities at the level of the RPE, a preretinal membrane in all cases with eccentric retinal pucker in 40%, and an operculum in 25% of patients (Fig. 21.53). Macular hole occurred in 8 of 37 (22%) fellow eyes in one study.¹⁹¹ Avila et al.¹⁹² reported axial traction as the cause, while Morgan and Schatz¹⁹³ proposed that involutional macular thinning predisposes to a macular hole.

Histopathology and pseudo-operculum

Minor RPE hypertrophy and hyperplasia occur in the area of lamellar and full-thickness macular hole. At the onset of macular hole, there is likely vitreoschisis,³² leaving a thin hypocellular layer of the posterior vitreous cortex attached to the macula^147,160,194 (Fig. 21.54). There is little cellular proliferation,¹⁹⁵ suggesting that fluid countercurrents or vitreoschisis (Fig. 21.55) may be important. Healing of macular hole following surgery¹⁹⁶ does, however, involve glial cell proliferation¹⁹⁷ and Müller cell processes.¹⁹⁸ Macular hole opercula are rarely composed of retinal tissue (Fig. 21.53), hence the name “pseudo-operculum.”

Fig. 21.54 Idiopathic macular hole with extensive photoreceptor cell atrophy. A thin, tapered layer of cortical vitreous with a hypocellular membrane on its inner surface (arrowhead) apparently exerts tangential traction with elevation of the hole margins (periodic acid–Schiff, ×340).

(Reproduced with permission from Guyer DR, Green WR. Idiopathic macular holes and precursor lesions. In: Franklin RM (ed.) Proceedings of the 1992 New Orleans Academy of Ophthalmology. New York: Kugler, 1993.)

Fig. 21.55 Membranes removed during macular hole surgery. (A) Tissue removed at surgery for macular hole demonstrates a hypocellular membrane with spindle and stellate-shaped cells (Millipore filter, modified Papanicolaou; ×340). (B) Internal limiting lamina (ILL) of retina. After peeling off the retina, this tissue demonstrates the characteristic “scrolled” configuration of the ILL following chromodissection. This does not occur with preretinal membranes (A), only with the ILL. (Millipore filter, modified Papanicolaou stain; ×340.)

Pathogenesis

There have been various theories of macular hole pathogenesis: trauma, foveal degeneration, vitreous traction, and involutional thinning with PVD. It is clear from surgical experience¹⁹⁹ that vitreous is the cause of macular hole. Johnson and Gass²⁰⁰ formulated the tangential traction theory by suggesting that shrinkage of the prefoveal vitreous induces macular hole formation in four stages. There are three possible mechanisms of tangential vitreous traction: (1) fluid vitreous movements and countercurrents; (2) cellular remodeling of cortical vitreous; and (3) contraction of a cellular membrane on the tapered cortical vitreous after vitreoschisis.^27,31,32 OCT scanning laser ophthalmoscopy (OCT-SLO) imaging found vitreoschisis in half of eyes with macular hole^29,160 (Fig. 21.56). In an ultrastructural study of epiretinal tissue removed during vitrectomy for impending macular holes, Smiddy et al.¹⁸⁷ observed cortical vitreous in all eyes. VPA may be important, as this is present in 88.2% of macular hole eyes.^121,122 VPA influences the vector of tangential forces on the macula and induces outward (centrifugal) traction, opening a central dehiscence. In macular pucker, there is usually no VPA and the vector of tangential traction is inward (centripetal), causing a macular pucker.

Fig. 21.56 Vitreoschisis in macular hole. Optical coherence tomography-scanning laser ophthalmoscopy imaging of vitreoschisis in a stage III macular hole. The inner wall of the schisis cavity (white arrow) is lifted off the retinal surface but remains adherent to the optic disc. The outer wall of the schisis cavity places centrifugal (outward) tangential traction of the macula opening a central dehiscence and inducing the macular hole. This layer must be removed at surgery, often done with chromodissection. Black arrow indicates the outer layer of the vitreoschsis split in the posterior vitreous cortex which is still attached to the retina.

Some surgeons²⁰¹ have advocated prophylactic surgery in symptomatic fellow eyes. However, a multicenter trial failed to demonstrate efficacy for vitrectomy in such eyes,²⁰² and thus surgery is not routinely performed.

Optic disc effects

Anomalous PVD with persistent adhesion to the optic disc can cause vitreopapillary traction inducing hemorrhage,²⁰³ exacerbating neovascularization in proliferative diabetic vitreoretinopathy,²⁰⁴ and even inducing gaze-evoked visual disturbances.²⁰⁵ Vitreopapillary adhesion also plays a role in the formation of macular holes and cysts.^121,122

Structural

Fig. 21.57 Traction retinal detachment in eye of a 23-year-old man with a previous history of traumatic cataract who underwent surgery complicated by vitreous incarceration in the wound. A vitreous strand (arrow) is seen attached to the anterior retina that is under traction and “tented” (arrowhead) (periodic acid–Schiff, ×60).

(Reproduced with permission from Smiddy WE, Green WR. Retinal dialysis: pathology and pathogenesis. Retina 1982; 2:94–116.)

Biochemical

Reduction of vitreous HA concentration²⁰⁸ results in decreased viscosity²⁰⁹ and shock absorption. This can be prevented by maintaining an intact posterior capsule.

PVD^210,211

PVD occurred in 84% following intracapsular cataract extraction, 76% following extracapsular cataract extraction (ECCE) and surgical capsular discission, and in 40% of eyes following ECCE with an intact posterior capsule. The incidence of rhegmatogenous RD increases following YAG capsulotomy.²¹²

Inflammatory

Iridovitreal synechiae have been associated with mild cyclitis, vitritis, retinal phlebitis, and cstoid macular edema.²¹¹

Blunt trauma

Blunt trauma may be transmitted to the retina in a direct and contrecoup fashion, resulting in a variety of rhegmatogenous sequelae (Fig. 21.58).²¹³ Dialysis at the anterior border of the vitreous base typically occurs inferonasally. Less common are avulsion of the vitreous base and retinal dialysis at the posterior border of the vitreous base. Concussive forces following blunt trauma can induce retinal edema (commotio retinae).

Fig. 21.58 (A) Retinal lesions caused by blunt trauma transmitted to retina. A, Dialysis at anterior border of vitreous base. B, Avulsion of vitreous base. C, Macular hole. D, Horseshoe-shaped tear on posterior margin of vitreous base. E, Horseshoe-shaped tear at posterior end of a meridional fold. F, Horseshoe-shaped tear at equator. G, Tear with operculum in overlying vitreous. H, Retinal dialysis at posterior border of vitreous base. (Modified with permission from Cox MS, Schepens CL, Freeman HM. Retinal detachment due to ocular contusion. Arch Ophthalmol 1966;76:679–85.) (B) Retinal dialysis at posterior aspect of vitreous base with retinal pigment epithelium extending through the dialysis, along the posterior surface of vitreous (arrowheads), and then along the anterior surface of the retina (arrows) (hematoxylin and eosin, ×20).

(Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.)

Shaken-baby syndrome

Circular macular folds with a sub-ILL schisis cavity containing serosanguineous material²¹⁴ and vitreous detachment with ILL throughout the fundus (Fig. 21.59A), especially at the vitreous base, and peripapillary hemorrhage are typical (Fig. 21.59B).

Fig. 21.59 Shaken-baby syndrome. (A) Sub-ILL schisis cavity containing serosanguineous material results from severe trauma in a young individual with firm vitreoretinal adherence (hematoxylin and eosin, ×457). (B) Extensive subdural hemorrhage that extends from the adjacent sclera (arrows). A peripapillary retinal hemorrhage (arrowhead) is present (hematoxylin and eosin, ×183).

Posterior penetrating and perforating trauma²¹⁵

Wound healing at the perforation site allows fibrocellular proliferation into the eye, inducing traction RD (Fig. 21.60). Histopathologic studies revealed cyclitic and periretinal membranes.²¹⁶ Intraocular proliferation starts 2–4 days after injury,²¹⁷ PVD develops at 1–2 weeks,²¹⁸ and traction RD occurs at 7–11 weeks. Poliferation can be prevented by vitrectomy,²¹⁹ less hazardous after 2 weeks because of the development of PVD^220,221 and more effective if complete.²²² Yet Miller et al.²²³ found that vitreous plays a role in normal healing of retinal wounds.

Fig. 21.60 Posterior perforation with fibrous tissue ingrowth (arrow) and traction retinal detachment (hematoxylin and eosin, ×25).

Premacular membranes

Primary premacular membranes occur in the absence of associated conditions and are most likely the result of vitreoschisis,³² where APVD³¹ splits the posterior vitreous cortex leaving the outermost layer attached to the macula. The level of this split can vary, as do the consequences from no effects, such as in the case of so-called simple epiretinal membranes (Fig. 21.61) which have no contractile features, to macular pucker.^147,160 Smiddy et al.²²⁴ observed the principal cell to be RPE in these cases, although it is likely that many of these cells are actually hyalocytes (Figs 21.6 and 21.14) and circulating monocytes recruited from retinal and choroidal vessels.^30,160 Secondary premacular membranes occur in association with inflammation, accidental or surgical trauma, and retinovascular disease. Fibrous astrocytes are the predominant cell in secondary preretinal macular membranes (PMMs).

Fig. 21.61 Simple premacular membrane. (A) Section illustrates thin, hypocellular epiretinal membrane (arrow) and wrinkling of internal limiting lamina (ILL) (hematoxylin and eosin, ×310). (Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.) (B) The ILL is discontinuous (arrow), at which point glial cells extend on to the inner surface of the retina and form a thin, fibroglial epiretinal membrane (arrowhead) with no apparent contraction (periodic acid–Schiff, ×300).

Macular pucker (Fig. 21.62) results from PMMs that induce centripetal tangential (inward to the fovea) traction upon the macula. Macular pucker can have as many as four separate centers of retinal contraction²²⁵ (Fig. 21.63). Eyes with three or four contraction centers had significantly more macular thickening and a higher prevalence of intraretinal cysts than eyes with one or two contraction centers.

Fig. 21.62 Macular pucker. (A) Coronal-plane optical coherence tomography (color) and scanning laser ophthalmoscopy (gray-scale) imaging of macular pucker with prominent retinal striae in a radial configuration centered in the fovea. (B) Thick fibroglial membrane (arrow) that apparently contracted and produced wrinkling of the internal limiting lamina (ILL) (arrowheads) and a large gap (asterisk) in the ILL (periodic acid–Schiff, ×90).

(Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.)

Fig. 21.63 Multifocal macular pucker. Coronal plane optical coherence tomography-scanning laser ophthalmoscopy (OCT-SLO) imaging with superimposition of OCT (color) on to SLO (gray-scale) images. (A) and (C) are reproduced with permission from Gupta P, Sadun AA, Sebag J. Multifocal retinal contraction in macular pucker analyzed by combined optical coherence tomography/scanning laser ophthalmoscopy. Retina 2008;28:447–52. (A) Unifocal macular pucker. (B) Bifocal macular pucker with two centers (arrows) of retinal contraction. (C) Trifocal macular pucker with three centers (arrows) of retinal contraction. (D) Four distinct centers (arrows) of retinal contraction are present.

Retroretinal membranes

These membranes typically occur after RD when RPE grows in sheets over the undersurface of the retina. Strands of fibrous tissue contract and prevent retinal reattachment.²²⁶

Complex membranes

Complex membranes (Fig. 21.64) develop after RD surgery or after trauma. Commonly called PVR,²²⁷ contraction of this proliferative tissue causes traction RD. Anterior PVR features anterior-loop contraction²²⁸ (Fig. 21.9).

Fig. 21.64 Complex membranes. Fibrous astrocytes in thick epiretinal membrane after anterior-segment surgery and severe intraocular inflammation. Membrane contains new collagen (asterisk) and fibrocytes in addition to fibrous astrocytes. Multiple layers of fibrous astrocytes line inner (vitreal) surface (between arrows). These cells show polarity with basement membrane (circles and bottom right inset), and cells contain numerous cytoplasmic filaments measuring 8–10 nm (rectangle and bottom left inset). Blood vessels (arrowheads) are also present in membrane (top left and top right insets). (Main figure ×6600; top insets, paraphenylenediamine hydrochloride stain; top left inset ×160; top middle and top right insets ×250; bottom left inset ×50 000; bottom right inset ×41 000.)

(Reproduced with permission from Michels RG. A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery. Trans Am Ophthalmol Soc 1982; 80:580–656.)

Histopathologically, retinal glial cells gain access to the inner retinal surface via ILL discontinuities, such as at the optic disc, foveola, along major vessels, and at retinal tufts. Acquired sites of ILL discontinuity include retinal tags, pits (lamellar holes), holes, and tears (Fig. 21.65), avulsed retinal vessels, areas of degenerative remodeling, and retinal lattice. Retinal glial cells are the principal cells in membranes at the optic disc, in simple PMMs, in most secondary membranes associated with inflammatory diseases or retinovascular disease, after photocoagulation or RD surgery, and in retinitis pigmentosa. RPE gains access to the vitreous via retinal breaks, the ora serrata, and retinal lattice. RPE can also migrate through intact retina. RPE is the principal cell in PVR (Fig. 21.66), but glial cells are present in about 50% of cases. Myofibrocytes (Fig. 21.67) were observed by electron microscopy in 91% of membranes studied by Kampik et al.,²²⁹ and actin has been observed in cells of PVR membranes.²³⁰

Fig. 21.65 Glial cell proliferation. (A) Peripheral retinal hole with glial membrane extending on the inner surface of the retina anteriorly and posteriorly (periodic acid–Schiff, ×65). (B) Higher-power view of anterior margin of retinal tear, showing glial preretinal membrane (arrow) extending along the inner surface of the internal limiting lamina (arrowhead) (periodic acid–Schiff; ×190).

(Reproduced with permission from Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.)

Fig. 21.66 Retinal pigment epithelium (RPE) cells in proliferative vitreoretinopathy. Pigmented membrane removed from peripapillary area is composed of RPE arranged in monolayer. Well-developed basement membrane (arrows) and basal laminar infoldings (circle, and top right inset) are present along retinal surface. Extensive villous processes are present on apical side of cells. Numerous apically located subplasmalemmal microfilaments that measure 4–5 nm and have fusiform densities are present (left insets). Occasional cytoplasmic lipid vacuoles are seen (arrowhead). (Main figure, ×4500; top left inset, ×17 000; top right inset, ×17 000; bottom left inset, ×36 000.)

(Reproduced with permission from Michels RG. A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery. Trans Am Ophthalmol Soc 1982;80:580–656.)

Fig. 21.67 Myofibrocyte. There is a characteristic spindle shape that contains large aggregates of subplasmalemmal microfilaments measuring 4–5 nm and small fusiform densities (circle and inset). (Main figure, ×14 000; inset, ×44 000.)

(Reproduced with permission from Michels RG. A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery. Trans Am Ophthalmol Soc 1982;80:580–656.)

Incomplete vitrectomy, intraoperative hemorrhage,²¹⁷ and excessive cryopexy²³¹ render most cases of PVR an iatrogenic disease. Fibronectin and platelet-derived growth factor are the chemoattractants that stimulate migration of RPE²³² and glial cells.²³³ Incomplete vitrectomy leaves behind hyalocytes (Figs 21.6 and 21.14), which are also the first cells to be exposed to these growth factors and other stimuli. When stimulated, these cells become phagocytic (Fig. 21.68). These resident macrophages play an important role in early PVR pathogenesis. Thus, targeting these cells for pharmacotherapy, similar to what has been done during vitrectomy for RD,²³⁴ may significantly mitigate PVR. Alternatively, eliminating the role of vitreous via pharmacologic vitreolysis²³⁵ will have a great impact in PVR and all aforementioned conditions.

Fig. 21.68 Phagocytic hyalocyte. Macrophage-like cell with multiple pleomorphic inclusions contained in membrane-bound secondary lysosomes (arrows) is most likely a hyalocyte embedded within the collagen fibrils of the posterior vitreous cortex. (Main figure, ×12 000; inset, ×22 600.)

(Reproduced with permission from Michels RG. A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery. Trans Am Ophthalmol Soc 1982; 80:580–656.)