Chapter 39
Vitreous Pathobiology
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The embryonic vascular system of the vitreous (vasa hyaloidea propria) and lens (tunica vasculosa lentis) attains its maximum prominence during the ninth week of gestation or 40-mm stage.1 Atrophy of the vessels begins posteriorly with dropout of the vasa hyaloidea propria, followed by the tunica vasculosa lentis. Recent studies have detected the onset of apoptosis in the endothelial cells of the tunica vaculosa lentis as early as day 17.5 in the mouse embryo.2 At the 240-mm stage (seventh month) in the human, blood flow in the hyaloid artery ceases.3 Regression of the vessel itself begins with glycogen and lipid deposition in the endothelial cells and pericytes of the hyaloid vessels.3 Endothelial cell processes then fill the lumen, and macrophages form a plug that occludes the vessel. The cells in the vessel wall then undergo necrosis and are phagocytized by mononuclear phagocytes.4 Gloor5 claimed that macrophages are not involved in vessel regression within the embryonic vitreous but that autolytic vacuoles form in the cells of the vessel walls, perhaps in response to hyperoxia. Interestingly, the sequence of cell disappearance from the primary vitreous begins with endothelial and smooth muscle cells of the vessel walls, followed by adventitial fibroblasts and lastly phagocytes,6 consistent with a gradient of decreasing oxygen tension. Recent studies have suggested that the vasa hyaloidea propria and the tunica vasculosa lentis regress via apoptosis.7 These studies concluded that macrophages are important in this process. Subsequent studies by a different group confirmed the importance of macrophages in promoting regression of the fetal vitreous vasculature and further characterized these macrophages as hyalocytes.8

It is not known what stimulates regression of the hyaloid vascular system, but studies have identified a protein native to the vitreous that inhibits angiogenesis in various experimental models.9–11 Activation of this protein and its effect on the primary vitreous may be responsible for the regression of the embryonic hyaloid vascular system as well as the inhibition of pathologic neovascularization in the adult. Mitchell and colleagues12 point out that the first event in hyaloid vasculature regression is endothelial cell apoptosis and propose that lens development separates the fetal vasculature from vascular endothelial growth factor (VEGF)-producing cells, decreasing the levels of this survival factor for vascular endothelium, inducing apoptosis. Following endothelial cell apoptosis, there is loss of capillary integrity, leakage of erythrocytes into the vitreous, and phagocytosis of apoptotic endothelium by hyalocytes. Meeson and colleagues13 proposed that there are actually two forms of apoptosis that are important in regression of the fetal vitreous vasculature. The first (“initiating apoptosis”) results from macrophage induction of apoptosis in a single endothelial cell of an otherwise healthy capillary segment with normal blood flow. The isolated dying endothelial cells project into the capillary lumen and interfere with blood flow. This stimulates synchronous apoptosis of downstream endothelial cells (“secondary apoptosis”) and ultimately obliteration of the vasculature. Removal of the apoptotic vessels is achieved by hyalocytes.


Regression of the hyaloid artery usually occurs completely and without complications. Persistence of the hyaloid vascular system occurs in 3% of full-term infants but in 95% of premature infants14 and can be associated with prepapillary hemorrhage.15 Anomalies involving incomplete regression of the embryonic hyaloid vascular system occur in more than 90% of infants born earlier than 36 weeks of gestation and in over 95% of infants weighing less than 5 lb at birth.16 There is a spectrum of disorders resulting from persistence of the fetal vasculature.17

Mittendorf's dot is a remnant of the anterior fetal vascular system located at the former site of anastomosis of the hyaloid artery and tunica vasculosa lentis. It is usually inferonasal to the posterior pole of the lens and is not associated with any known dysfunction.

Bergmeister's papilla is the occluded remnant of the posterior portion of the hyaloid artery with associated glial tissue. It appears as a gray, linear structure anterior to the optic disc and adjacent retina and does not cause any known functional disorders. Exaggerated forms can present as prepapillary veils.

Vitreous cysts are generally benign lesions that are found in eyes with abnormal regression of the anterior18 or posterior19 hyaloid vascular system; otherwise normal eyes20,21; and eyes with coexisting ocular disease, such as retinitis pigmentosa22 and uveitis.23 Some vitreous cysts contain remnants of the hyaloid vascular system,24 supporting the concept that the cysts result from abnormal regression of these embryonic vessels.25 However, one histologic analysis of aspirated material from a vitreous cyst purportedly revealed cells from the retinal pigment epithelium.26 Vitreous cysts are generally not symptomatic and thus do not require surgical intervention. However, argon laser photocoagulation has been employed, and a recent report27 described the use of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser therapy to rupture a free-floating posterior vitreous cyst.

Persistent hyperplastic primary vitreous (PHPV) was first described by Reese28 as a congenital malformation of the anterior portion of the primary vitreous appearing as a plaque of retrolental fibrovascular connective tissue. This tissue is adherent to the posterior lens capsule and extends laterally to attach to the ciliary processes, which are elongated and displaced centrally. Although 90% of cases are unilateral, many of the fellow eyes have Mittendorf's dot or other anomaly of anterior vitreous development.29 A persistent hyaloid artery, often still perfused with blood, arises from the posterior aspect of the retrolental plaque in the affected eye. In severe forms, there is microphthalmos with anterior displacement of the lens-iris diaphragm, shallowing of the anterior chamber, and secondary glaucoma. PHPV is believed to arise from abnormal regression and hyperplasia of the primary vitreous.28 Experimental data suggest that the abnormality begins at the 17-mm stage of embryonic development.30 The hyperplastic features result from generalized hyperplasia of retinal astrocytes and a separate component of glial hyperplasia arising from the optic nerve head.31 The fibrous component of the PHPV membrane is presumably synthesized by these astrocytes and glial cells.32 A recent case report with clinicopathologic correlation found that collagen fibrils in this fibrous tissue had diameters of 40 to 50 nm with a cross-striation periodicity of 65 nm. The investigators concluded that the collagen fibrils differed from those of the primary vitreous and suggested that they arose either from a different population of cells or were the result of abnormal metabolism by the same cells that synthesize vitreous collagen.33

The retina is usually not involved in anterior PHPV. Indeed, previous studies have suggested that the anterior form is due to a primary defect in lens development and that vitreous changes are all secondary.34 This postulate has never been substantiated. There are rare instances of posterior PHPV in which opaque connective tissue arises from Bergmeister's papilla and persistent hyaloid vessels (Fig. 1).32,35 These can cause congenital falciform folds of the retina and, if severe, can cause tentlike retinal folds, leading on rare occasions to tractional and/or rhegmatogenous retinal detachment. Font and investigators36 demonstrated the presence of adipose tissue, smooth muscle, and cartilage within the retrolental plaque and suggested that PHPV arises from metaplasia of mesenchymal elements in the primary vitreous.

Fig. 1. Persistent hyperplastic primary vitreous (PHPV). A wide-angle fundus photograph of the left eye in a 10-year-old boy with the posterior form of PHPV demonstrates a fibrous stalk arising from the optic disc and extending into the central vitreous. (Sebag J: The Vitreous: Structure, Function and Pathobiology, p 99. New York, Springer-Verlag, 1989.)


Dominant exudative vitreoretinopathy was first described in 1969 by Criswick and Schepens37 as a bilateral, slowly progressive abnormality of the vitreous and retina that resembles retinopathy of prematurity but with no history of prematurity or postnatal oxygen administration. Gow and Oliver38 identified this disorder as an autosomal dominant condition with complete penetrance. They characterized the course of this disease in stages ranging from posterior vitreous detachment with snowflake opacities (stage I), to thickened vitreous membranes and elevated fibrovascular scars (stage II), and vitreous fibrosis with subretinal and intraretinal exudates, ultimately developing retinal detachment due to fibrovascular proliferation arising from neovascularization in the temporal periphery (stage III). Plager and coworkers39 recently reported the same findings in four generations of three families, but found X-linked inheritance. Van Nouhuys40–42 studied 101 affected members in 16 Dutch pedigrees and five patients with sporadic manifestations. He found that the incidence of retinal detachment was 21%, all but one case occurring prior to the age of 30. These were all tractional or combined traction/rhegmatogenous detachments, and there were no cases of exudative retinal detachment. Van Nouhuys42 concluded that the etiology of dominant exudative vitreoretinopathy lies in premature arrest of development in the retinal vasculature, since the earliest findings in these patients were nonperfusion of the peripheral temporal retina with stretched retinal blood vessels and shunting with vascular leakage. Thus, Van Nouhuys considers dominant exudative vitreoretinopathy as a retinopathy with secondary vitreous involvement. However, Brockhurst and colleagues43 described that vitreous membrane formation begins just posterior to the ora serrata and that this precedes retinal vessel abnormalities, suggesting a vitreous origin to this disorder. Others suggested that there may be a combined etiology involving anomalies of the hyaloid vascular system and primary vitreous as well as retinovascular dysgenesis.44


Retinopathy of premature infants was first described in 1942 by Terry45 as “retrolental fibroplasia.” That term is no longer appropriate since it is actually a descriptive term of the pathology in advanced (stage V) cases of cicatricial retinopathy of prematurity (ROP). We now identify acute stages of the disease that are not retrolental and do not have much fibroplasia.46

The pathogenesis of ROP begins with birth, prior to complete maturation and development of the peripheral retina, followed by postnatal oxygen administration, triggering retinal vasoconstriction with endothelial cell necrosis and vaso-obliteration in response to hyperoxia.47 After the discontinuation of supplemental oxygen, arterial pO2 levels return to normal and the obliterated (or at best, highly constricted) vessels are not adequately reperfused, causing the peripheral retina they subserve to become ischemic and release neovascular growth factors. An alternative hypothesis of pathogenesis proposes that spindle cells in the immature peripheral retina are stimulated by excessive amounts of reactive oxygen species, whether related to oxygen therapy and subsequent relative hypoxia or other metabolic circumstances, to release angiogenic growth factors.48 In either case, the result is migration and proliferation of capillary endothelial cells that form new blood vessels at the posterior ridge of tissue between the vascularized and avascular retina. This results in neovascularization arising from the ridge that demarcates the developed posterior retina from the immature peripheral retina. The new vessels grow into the vitreous body, similar to neovascularization in diabetic retinopathy,49 although they grow farther anteriorly and more exuberantly. This is perhaps because of the participation of cells of the ocular fetal vasculature, whose apoptosis has been retarded or arrested by the presence of high levels of VEGF.50

There are no clearly identified vitreous changes during stages I and II of acute ROP, although this may simply be due to our present inability to detect such abnormalities.51 Indeed, the abundance of reactive oxygen species in the retina and vitreous of premature infants could induce widespread vitreous liquefaction.52 There are also likely to be localized areas of liquid vitreous, particularly at the periphery. At surgery for stage IV-A ROP with retinal detachment, there is a “trough” in the periphery.53 This structure is most likely the consequence of underlying retinal immaturity in the periphery, with consequent lack of typical gel vitreous synthesis, normally a Müller cell function, overlying the immature retina. The liquid vitreous trough is probably present early in the natural history of disease but goes undetected by present vitreous imaging techniques.54 Such disruption of normal vitreous composition and structure probably alters a number of physiologic processes within the vitreous, including the ability of vitreous to inhibit cellular and vascular invasion.9–11 Furthermore, the interface between posterior gel vitreous and peripheral liquid vitreous at the ridge causes vitreous traction to be exerted at the retinal ridge.

In stage III ROP, new blood vessels extend from the inner retina into the vitreous cortex. The cortex, overlying the rear guard of differentiated capillary endothelial cells, becomes opaque and contains linear, fibrous structures adjacent to a large pocket of liquid vitreous.55 In advancing from stage III to stage IV, the neovascular tissue arising from the rear guard grows through the vitreous body toward Wiegert's ligament on the posterior lens capsule.56 This configuration of neovascularization is probably the result of cell migration and proliferation along the walls of the future Cloquet's canal or the tractus hyaloideus of Eisner. Cells of the primary vitreous likely contribute to the formation of the dense central vitreous stalk and retrolental membrane seen in the cicatricial stage, since these cells could also undergo migratory and proliferative responses to intraocular angiogenic stimuli.


The autosomal recessive condition vitreoretinal dystrophy of Goldmann-Favre was first described in 1957 by Goldmann57 as consisting of vitreous abnormalities with peripheral retinoschisis and chorioretinal atrophy. Francois58 characterized the vitreous changes as syneresis (collapse), fibrillar degeneration with white strand formation, and punctate deposits. The retinal changes are pigmentary degeneration (with a different appearance from the bone spicules of retinitis pigmentosa), attenuated blood vessels, and microcystic degeneration of the macula and retinal periphery. Night blindness is an important feature, and the electroretinogram is markedly abnormal. Fishman and collaborators59 used fluorescein angiography to demonstrate cystoid macular edema (CME) and vascular occlusion with leakage in the peripheral retina corresponding to the areas of schisis. Schepens60 described that there is vitreous organization attached to the areas of schisis. Histopathologic studies by Peyman and coworkers61 showed attenuation of the outer nuclear layer and absence of photoreceptors. Based on the presence of normal retinal pigment epithelium and choriocapillaris, these investigators suggested that the etiology was a primary retinal degeneration. In this regard, Müller cell dysfunction could lead to the vitreous abnormalities as well as peripheral retinoschisis. It follows that in these cases, CME results from peripheral and central vitreous changes that occur in the absence of posterior vitreous detachment, thus inducing traction on the macula, as has been noted in cases of peripheral anterior vitritis with CME62,63 and in some cases of aphakic macular edema.64–66


Vitreous is one of many connective tissues in the body. Collagen is one of the most important structural molecules in all connective tissues. Thus, it is of interest to consider parallel phenomena occurring in the vitreous and connective tissues elsewhere, especially as related to collagen. For example, Gartner67 pointed out the similarities between the intervertebral disk and the vitreous, in which age-related changes with herniation of the nucleus pulposus was associated with presenile vitreous degeneration in 40% of cases. He proposed that a generalized connective tissue disorder resulted in disk herniation and presenile vitreous degeneration in these cases. Based on these findings, Gartner likened herniation of the nucleus pulposus in the disk to prolapse of vitreous into the retrohyaloid space by way of the posterior vitreous cortex following posterior vitreous detachment (see Fig. 9).

Fig. 9. Vitreomacular traction. Vitreous can remain attached to the macula even in the presence of posterior vitreous detachment. In such cases, vitreous can extrude through the premacular vitreous cortex and fibers can insert into the macula. B, C, and D are an artist's rendition of this phenomenon. A demonstrates vitreous extrusion into the retrohyaloid space in a specimen from a middle-aged human. (Adapted from Jaffe NS: The Vitreous in Clinical Ophthalmology. St. Louis, CV Mosby, 1969; and Jaffe NS: Vitreous traction at the posterior pole of the fundus due to alterations in the posterior vitreous. Trans Am Acad Ophthalmol Otolarynogol 71:642, 1967.)

Maumenee68 identified several different disorders with single-gene autosomal dominant inheritance in which dysplastic connective tissue primarily involves joint cartilage. In these conditions, there is associated vitreous liquefaction, collagen condensation, and vitreous syneresis (collapse). Since type II collagen is common to cartilage and vitreous, Maumenee suggested that the various arthro-ophthalmopathies may result from different mutations, perhaps of the same or neighboring genes, on the chromosome involved with type II collagen metabolism. In these disorders, probably including such conditions as Wagner's disease,69 the fundamental problem in the posterior segment of the eye is that the vitreous is liquefied and unstable, tending to syneresis at an early age. However, there is no dehiscence at the vitreoretinal interface in concert with the changes inside the vitreous body, perhaps owing to the fact that the internal limiting lamina of the retina is composed of type IV collagen. Thus, in these cases, abnormal type II collagen metabolism causes destabilization of the vitreous and results in traction on the retina that can lead to large posterior tears and difficult retinal detachments.

In Marfan's syndrome, an autosomal dominant disorder featuring poor musculature, lax joints, aortic aneurysms, and arachnodactyly, there is lens subluxation, thin sclera, peripheral fundus pigmentary changes, and vitreous liquefaction at an early age. The combination of myopia, vitreous syneresis, and abnormal vitreoretinal adhesions at the equator accounts for the frequency of rhegmatogenous retinal detachment due to equatorial or posterior horseshoe tears.60

Ehlers-Danlos syndrome has some similarities to Marfan's syndrome, most notably joint laxity, aortic aneurysms, and an autosomal dominant pattern of inheritance. However, there are as many as six types of Ehlers-Danlos patients, and the genetics of this condition are probably more heterogeneous than in Marfan's syndrome. A further distinction from Marfan's patients is the hyperelastic skin and poor wound healing of all connective tissues, including cornea and sclera, that is seen in Ehlers-Danlos patients. Ocular manifestations include lens subluxation, angioid streaks, thin sclera, and high myopia due to posterior staphyloma. Vitreous liquefaction and syneresis occur at a young age. Vitreous traction causes vitreous hemorrhage, perhaps also due to blood vessel wall fragility, and retinal tears with rolled edges, often causing bilateral retinal detachments.60

In 1965, Stickler and associates70 described a condition in five generations of a family that was found to be autosomal dominant with complete penetrance and variable expressivity. The features were a marfanoid skeletal habitus and orofacial and ocular abnormalities. Subsequent studies identified subgroups with short stature and a Weill-Marchesani habitus. The skeletal abnormalities now accepted as characteristic of Stickler's syndrome are radiographic evidence of flat epiphyses, broad metaphyses, and especially spondyloepiphyseal dysplasia.71 Ocular abnormalities are high myopia, greater than –10 diopters in 72% of cases,72 and vitreoretinal changes characterized by vitreous liquefaction, fibrillar collagen condensation, and a perivascular lattice-like degeneration in the peripheral retina believed to be the cause of a high incidence (greater than 50%) of retinal detachment.71 More recent studies correlated specific gene defects with particular phenotypes, thereby enabling the classification of Stickler syndrome patients into four subgroups.73 Patients with abnormalities in the genes coding for type II procollagen and type V/XI procollagen are the ones who have severe vitreous abnormalities.

Knobloch74 described a syndrome similar to Stickler's syndrome with hypotonia, relative muscular hypoplasia, and mild to moderate spondyloepiphysealdysplasia causing hyperextensible joints. The vitreoretinopathy is characterized by vitreous liquefaction, veils of vitreous collagen condensation, and perivascular lattice-like changes in the peripheral retina.

It is presently unknown whether myopia unrelated to the aforementioned arthro-ophthalmopathies should be considered a form of vitreous collagen disease as well. The extensive liquefaction of vitreous (myopic vitreopathy) and propensity for retinal detachment due to peripheral retinal traction and myopic peripheral retinal degeneration suggest that this postulate may deserve closer scrutiny.

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Using slit lamp biomicroscopy in a clinical setting, Busacca75 and Goldmann76 observed that after the ages of 45 to 50, there is a decrease in the gel volume and an increase in the liquid volume of human vitreous. Eisner77 qualitatively confirmed these clinical findings in his postmortem studies of dissected human vitreous and observed that liquefaction begins in the central vitreous. In a large autopsy study of formalin-fixed human eyes, O'Malley78 provided quantitative evidence to support these observations. He found that more than half of the vitreous body was liquefied in 25% of persons age 40 to 49 and that this increased to 62% of those age 80 to 89. Oksala79 used ultrasonography in vivo to detect echoes from gel-liquid interfaces in 444 normal human eyes and found progressive liquefaction with age. Vitreous liquefaction actually begins much earlier than the ages at which clinical examination or ultrasonography detects changes. Balazs and colleagues80,81 found evidence of liquid vitreous after age 4 and observed that by the time the human eye reaches its adult size (ages 14 to 18) 10% to 12.5% of the total vitreous volume consists of liquid vitreous (Fig. 2). In these postmortem studies of 610 fresh, unfixed human eyes, it was observed that after age 40, there is a steady increase in liquid vitreous that occurs simultaneously with a decrease in gel volume. By the ages of 80 to 90 years more than half the vitreous body is liquid. The finding that the central posterior vitreous is where liquefaction begins77 and where fibers are first observed82–84 is consistent with the concept that dissolution of the hyaluronic acid (HA)–collagen complex results in the simultaneous formation of liquid vitreous and aggregation of collagen fibrils into bundles of parallel fibrils seen as large fibers.83 In the posterior vitreous, such age-related changes often form large pockets of liquid vitreous.85

Fig. 2. Liquefaction of human vitreous. The volumes of gel and liquid vitreous in 610 human eyes were measured. The results are plotted versus the age of the donor. Liquid vitreous appears by the age of 5 and increases throughout life until it constitutes more than 50% of the volume of the vitreous during the tenth decade. Gel vitreous volume increases during the first decade while the eye is growing in size. The volume of gel vitreous then remains stable until about age 40, when it begins to decrease simultaneous with the increase in liquid vitreous. (Balazs EA, Denlinger JL: Aging changes in the vitreous. In: Aging and Human Visual Function, pp 45–57. New York, Alan R. Liss, 1982.)

Age-related rheologic changes in the vitreous may result from an alteration in HA-collagen interaction. Chakrabarti and Park86 claimed that the interaction between collagen and HA is dependent on the conformational state of each macromolecule and that a change in the conformation of HA molecules could result in vitreous liquefaction and aggregation or cross-linking of collagen molecules. Armand and Chakrabarti87 detected differences in the structure of the HA molecules present in gel vitreous and those in liquid vitreous, suggesting that such conformational changes occurred during liquefaction. Whether these changes are cause or effect is not known. However, Andley and Chapman88 demonstrated that singlet oxygen can induce conformational changes in the tertiary structure of HA molecules. Ueno and associates52 suggested that free radicals generated by metabolic and photosensitized reactions could alter HA and/or collagen structure and trigger a dissociation of collagen and HA molecules, ultimately leading to liquefaction. This is plausible because the cumulative effects of a lifetime of daily exposure to light may influence the structure and interaction of collagen and HA molecules by the proposed free radical mechanism(s). Enzymes, such as endogenous metalloproteinases, may also be involved in liquefying the gel vitreous. The importance of vitreous liquefaction in the pathogenesis of posterior vitreous detachment is discussed below.

Total vitreous collagen content does not change after the ages of 20 to 30 (Fig. 3). However, the collagen concentration in the gel vitreous at the ages of 70 to 90 (approximately 0.1 mg/mL) was found to be significantly greater than at the ages of 50 to 60 (slightly more than 0.05 mg/mL; p < .05). Because the total collagen content does not change, this finding is most likely due to the decrease in the volume of gel vitreous that occurs with aging (see Fig. 2) and a consequent increase in the concentration of the collagen remaining in the gel. The collagen fibrils in this gel become packed into bundles of parallel fibrils,83 perhaps with cross-links between them. Aging of collagen throughout the body is associated with increased cross-linking as manifested by decreased solubility,89 increased collagen “stiffness,”90 and increased resistance to enzymatic degradation.91 There is also an increase in a reducible lysine-carbohydrate condensation product with increasing age.92 Although similar investigations have not been performed on vitreous collagen, studies by Snowden and colleagues93 demonstrated that with aging, there is a decrease in the quantity of bovine vitreous collagen solubilized by heat alone. This could result from an increase in collagen cross-linking or, as suggested by the authors, from changes in the surrounding glycoproteins and proteoglycans. Abnormal collagen cross-links have been identified in diabetic human vitreous,94 suggesting “precocious senescence” of vitreous collagen as has been described for other organs and tissues in diabetic patients.95–97

Fig. 3. Age-related changes in human vitreous collagen levels. Collagen content (mg; right ordinate) is indicated by solid dots (means) and darkly hatched boxes in the upper portion of the graph (height = standard error). Collagen concentration (mg/mL; left ordinate) is indicated by asterisks (means) and lightly hatched boxes in the lower portion of the graph (height = standard error). Vitreous collagen concentration decreases during the first decade of life because there is no net synthesis of collagen during this period of active growth of the eye. There are no significant changes in collagen content following age 20, consistent with the lifelong “stability” of this molecule. However, collagen concentration in the gel vitreous increases after ages 40 to 50. This is due to the decrease in gel vitreous that occurs during this time (see Fig. 2), concentrating the remaining collagen in an ever-decreasing volume of gel vitreous. The increase in gel vitreous collagen concentration between ages 50 to 60 and 80 to 90 is statistically significant (p < .05). (Balazs EA, Denlinger JL: Aging changes in the vitreous. In: Aging and Human Visual Function, pp 45–57. New York, Alan R. Liss, 1982.)

Vitreous HA concentration increases until about the age of 20, when adult levels are attained (Fig. 4A). HA concentration does not change in either the liquid or gel vitreous from ages 20 to 60 (Fig. 4).81,98 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 (see Fig. 2). This is consistent with the concept that vitreous liquefaction is associated with a “redistribution” of HA from the gel to the liquid vitreous. With advanced liquefaction, there is a marked increase in the concentration of HA in liquid vitreous at ages 70 to 90 (Fig. 4B).

Fig. 4. Age-related changes in human vitreous hyaluronic acid (HA) concentration. The dots represent the means of the samples. The vertical height of the boxes represents the standard error of the means. The horizontal width of the boxes represents the age ranges in the sample group. A. HA concentration in the gel vitreous. There is a fourfold increase in the concentration of HA during the first two decades of life. Considering that this is also a period of active growth of the eye and substantial increase in vitreous volume, there must be prolific synthesis of HA to increase concentrations so dramatically. After age 20, HA concentrations in the gel vitreous are stable. Since this is a period of decreasing amounts of gel vitreous (see Fig. 2), there must be a net decrease in the HA content of the gel to result in no substantial changes in concentration. B. HA concentration in the liquid vitreous. There are no data for the first 4 years since there is no liquid vitreous during this time. From the ages of 5 to 50 to 60 there is a 50% increase in the concentration of HA in the liquid vitreous. After this time, there is a substantial increase in liquid vitreous HA concentration. The magnitude of this accumulation of HA in the liquid component of the vitreous is even greater when one considers that this occurs during the time when the volume of liquid vitreous is increasing by twofold (see Fig. 2). (Balazs EA, Denlinger JL: Aging changes in the vitreous. In: Aging and Human Visual Function, pp 45–57. New York, Alan R. Liss, 1982.)

Vitreous soluble protein concentrations also increase from 0.5 to 0.6 mg/mL at ages 13 to 50, to 0.7 to 0.9 mg/mL at ages 50 to 80, and to 1.0 mg/mL above the age of 80.80,81,98 This increase may result from an age-related breakdown in the blood–ocular barriers of the retinal vasculature, retinal pigment epithelium, and ciliary body epithelium.


Basal Laminae and Vitreous Base

The vitreoretinal interface is the site of many blinding vitreoretinal disorders.99 The basal laminae surrounding the vitreous thicken with age,100 a phenomenon that occurs in basal laminae throughout the body.101 Hogan and associates102 claimed that the thickening of the internal limiting lamina of the retina occurs during life as a result of synthesis by subjacent Müller's cells. This phenomenon may play a role in weakening vitreoretinal adhesion, thus contributing to the development of posterior vitreous detachment.

Teng and Chi103 found that the vitreous base posterior to the ora serrata varies in width depending on the age of the person. More than half of eyes from people older than age 70 had a posterior vitreous base wider than 1 mm. The width increased with advancing age to nearly 3 mm, bringing the posterior border of the vitreous base closer to the equator. This posterior migration of the vitreous base probably plays an important role in the pathogenesis of peripheral retinal breaks and rhegmatogenous retinal detachment, since this is the area of strongest vitreoretinal adhesion. The phenomenon of posterior migration of the posterior border of the vitreous base was recently confirmed and an explanation for increased vitreoretinal adhesion in this location was offered.104 It appears that there is intraretinal synthesis of collagen fibrils that penetrate the internal limiting lamina of the retina and ‘splice’ with vitreous collagen fibrils. Within the vitreous base, Gartner105 found no differences in the thickness of collagen fibrils when comparing five eyes from humans ages 9 months, 29, 39, 61, and 71. He did, however, note that there was “lateral aggregation” of collagen fibrils in the eyes from older persons, similar to aging changes within the central vitreous.82–84 All these aging changes at the vitreous base very likely contribute to increased traction on the peripheral retina and the development of retinal tears and detachment.

Central Vitreous

During postnatal development, there is a transition from a dense, highly light-scattering structure (Fig. 5), because at birth vitreous is mostly collagen, to homogeneous transparency that results when HA “swells” and spreads collagen fibrils apart (Fig. 6). The redistribution of HA and collagen during maturation to the adult results in the aggregation of collagen fibrils into packed bundles of parallel fibrils that appear as fibers. During the latter decades of life, these fine parallel fibers in the central vitreous become thickened and tortuous (Fig. 7). Immediately adjacent to these coarse structures are areas with little or no light-scattering properties that are filled with “liquid” vitreous. When advanced, this vitreous degeneration forms large pools of liquid vitreous identified clinically as “lacunae” (Fig. 8). When the posterior vitreous detaches from the retina, there is an overall reduction in the size of the vitreous body due to the collapse (syneresis) that occurs when liquid vitreous enters the space posterior to the vitreous cortex and anterior to the retina. This displacement of liquid vitreous occurs by way of the prepapillary “hole” and possibly the premacular vitreous cortex, and is important in the pathogenesis of posterior vitreous detachment.

Fig. 5. Vitreous structure in a human embryo at 33 weeks of gestation. The posterior aspect of the lens is seen below. The vitreous body is enclosed by the dense, highly light-scattering cortex. Parapapillary glial tissue was torn away during dissection and hangs from the prepapillary vitreous cortex. Within the vitreous body, Cloquet's canal arcs from the prepapillary vitreous toward the lens. Since its course undulates through the vitreous body, not all of Cloquet's canal can be visualized in a single horizontal section. (Sebag J: Age-related changes in human vitreous structure. Graefes Arch Clin Exp Ophthalmol 22:89, 1987. Specimens courtesy of the New England Eye Bank, Boston, MA.)

Fig. 6. Human vitreous structure during childhood. This view of the posterior and central vitreous from a 6-year-old child demonstrates a dense vitreous cortex with hyalocytes. There is vitreous extrusion into the retrohyaloid space through the premacular vitreous cortex. However, no fibers are present. (Sebag J: The Vitreous: Structure, Function and Pathobiology, p 79. New York, Springer-Verlag, 1989.)

Fig. 7. Fibrous structure of human vitreous during old age. The vitreous body of an 88-year-old woman has undergone substantial degeneration in the fibrous structure. Fibers are thickened and tortuous. The entire vitreous body appears to have undergone dissolution with empty spaces adjacent to the thickened fibers. (Sebag J: Age-related changes in human vitreous structure. Graefes Arch Clin Exp Ophthalmol 22:89, 1987. Specimens courtesy of the New England Eye Bank, Boston, MA.)

Fig. 8. Human vitreous lacunae in old age. The central vitreous has thickened, tortuous fibers. The peripheral vitreous has pockets devoid of any structure. These contain liquid vitreous and correspond to lacunae as seen clinically on biomicroscopy. (Sebag J, Balazs EA: Human vitreous fibres and vitreoretinal disease. Trans Ophthalmol Soc UK 104:123, 1985.)


The most common age-related event in the vitreous is posterior vitreous detachment (PVD). True PVD can be defined as a separation between the posterior vitreous cortex and the internal limiting lamina (ILL) of the retina.106 PVD can be localized, partial, or total (up to the posterior border of the vitreous base). PVD should be distinguished from other forms of vitreoretinal separation that clinically may be mistaken for PVD. One of these forms involves separation of the ILL and some of the inner retina along with the detached posterior vitreous cortex. This can follow severe tractional events in the young, in whom the posterior vitreous cortex/ILL adhesion is strong.107

Another form of vitreoretinal separation that can mimic true PVD features forward displacement of the anterior portion of the posterior vitreous cortex, leaving part of the posterior layer of the vitreous cortex still attached to the retina. Balazs4 has coined the term “vitreoschisis” to denote prominent liquefaction with cavitation in the posterior vitreous but persistent attachment of the outermost layers of the posterior vitreous cortex to the ILL. Clinically, this is often mistaken as true PVD and occurs in cases with prominent liquefaction and no PVD, such as advanced axial myopia. The skilled examiner can distinguish this from PVD, since true PVD displays a characteristic ascension/descension movement of the posterior vitreous cortex on vertical saccades. The term vitreoschisis should be reserved for cases in which an actual split has occurred in the posterior vitreous cortex. Green and Byrne108 recently reported that splitting of the posterior vitreous cortex may be present in eyes with proliferative diabetic retinopathy (PDR) and vitreous hemorrhage. It is possible that in these cases, vitreoschisis cavities in the posterior vitreous cortex result from dissection of blood. However, a split in the vitreous cortex can also cause bleeding, since neovascular complexes grow into the vitreous cortex.109 Chu and associates110 studied 140 patients with diabetic vitreous hemorrhage and found echographic evidence of vitreoschisis in 20% of cases.

Lindner111 and Jaffe112 described that in some cases of PVD, there is herniation of vitreous through the vitreous cortex of the posterior pole. As previously mentioned, Gartner67 drew an analogy between this phenomenon and the herniation of the nucleus pulposus in the intervertebral disks of the spine. When a PVD involves herniation of the vitreous into the retrovitreal space by way of the premacular vitreous cortex, there can be persistent attachment to the macula and traction (Fig. 9).113


In clinical studies, the incidence of purported PVD was found to be 53% in persons older than age 50, and 65% in those over age 65.111 Autopsy studies revealed an incidence of 27% to 51% in the seventh decade and 63% in the eighth decade.114 However, these figures may be overestimates due to the methods employed in these postmortem studies. PVD is more common in myopia, occurring 10 years earlier than in emmetropia and hyperopia.111,112 This likely results from effects of myopia on the structure of the vitreous. Cataract extraction in myopic patients introduces additional effects, causing PVD to develop in all but one of 103 myopic (greater than –6 D) eyes that were studied following cataract extraction (presumably intracapsular).115

Several studies114,116 found a higher incidence of PVD in women than in men, a finding that may be due to hormonal changes following menopause. This hypothesis is supported by studies in the vitreous117 as well as other organs and tissues.118,119


PVD results from rheologic changes within the vitreous that lead to synchysis (liquefaction), in conjunction with weakening of the vitreous cortex/ILL adhesion. O'Malley78 suggested that PVD was strongly correlated with synchysis since both are correlated with age, although PVD had a later onset than synchysis. Foos and Wheeler114 studied 4492 autopsy eyes and found a statistically significant correlation between the degree of synchysis and the incidence of PVD. Larsson and Osterlin120 studied 61 human eyes post mortem and correlated the degree of vitreous liquefaction with the extent of PVD. Once “liquid” vitreous forms (see previous section, Biochemical Changes) and the collagen network is destabilized, owing to a loss of the stabilizing effect of HA molecules and cross-linking due to the loss of type IX collagen on the surface of collagen fibrils, collapse (syneresis) of the vitreous body can occur. It is likely that dissolution of the posterior vitreous cortex/ILL adhesion at the posterior pole allows liquid vitreous to enter the retrocortical space by way of the prepapillary hole and perhaps the premacular vitreous cortex as well.84,111,113,121 With rotational eye movements, liquid vitreous can dissect a plane between the vitreous cortex and the ILL, leading to true PVD. This volume displacement from the central vitreous to the preretinal space causes the observed collapse of the vitreous body (syneresis). It is recognized114,121 that PVD begins at the posterior pole. Vitreoretinal dehiscence at the macula may result from a predisposition or an increased stimulus for vitreous degeneration in the premacular region. Indeed, it is here that studies85 have identified a large pocket of liquid vitreous related to aging. Foos and Wheeler114 proposed that liquefaction in the posterior pole results from light toxicity to the premacular vitreous, since this is where the eye focuses incident light. There can also be a contribution of toxicity caused by metabolic waste products resulting from the high density of metabolically active neurons in the macula. Both light irradiation and metabolic processes can generate free radicals, which could alter HA and/or collagen structure and disrupt the HA-collagen association, causing liquefaction.52 These phenomena could also influence the extracellular matrix components binding the vitreous cortex to the ILL, contributing to the pathogenesis of PVD.


In youth, the vitreous is transparent (see Fig. 6) and has little or no effect on glare sensitivity.122 In old age, the aggregation of vitreous collagen fibrils into thick, irregular, visible fibers (see Fig. 7) can induce glare sensitivity, which may be subjectively bothersome. Furthermore, the high incidence of PVD in old age may also induce glare due to scattering of light by the dense collagen fibril network in the posterior vitreous cortex. One group of individuals in whom glare discomfort is a common complaint are patients who have undergone scleral buckle surgery for rhegmatogenous retinal detachment. The complaint of glare appears to be due to postoperative vitreous turbidity and not a change in the threshold sensitivity of retinal receptors.123 Because vitreous biochemical and structural changes likely predispose these patients to rhegmatogenous retinal detachment, prominent vitreous changes are probably already present preoperatively. Scleral buckle surgery adds to the preexisting vitreous inhomogeneity by breaking down the normal blood–vitreous barriers and mechanisms that maintain vitreous clarity.124

“Floaters” are the most common complaint of patients with PVD. These usually result from entoptic phenomena caused by condensed vitreous fibers, glial tissue of epipapillary origin that adheres to the posterior vitreous cortex, and/or intravitreal blood.125 Floaters move with vitreous displacement during eye movement and scatter incident light, casting a shadow on the retina that is perceived as a gray hairlike or flylike structure. Although not considered a disease in the classical sense, this condition can be extremely bothersome, prompting some patients to undergo vitrectomy. While this form of treatment is considered by most ophthalmologists to be too aggressive for this problem, it is conceivable that the future will see the injection of pharmacologic agents to dissolve vitreous opacities and eliminate this problem more safely.126,127 In an autopsy series of 320 cases with complete PVD, 57% had glial tissue on the posterior vitreous cortex.128 Vogt's or Weiss' ring are the terms applied when peripapillary tissue is torn away during PVD and forms a ring around the prepapillary hole in the posterior vitreous cortex. Murakami and coworkers129 studied 148 cases of floaters and detected glial tissue on the posterior vitreous cortex in 83%. They claimed that patients complaining of multiple small floaters usually have minimal vitreous hemorrhage, frequently associated with retinal tears. Lindner111 found that minimal vitreous hemorrhage occurred in 13% to 19% of cases with PVD.

In 1935, Moore130 described that “light flashes” are sometimes a complaint resulting from PVD. Wise131 noted that light flashes occurred in 50% of cases at the time of PVD and were usually vertical and temporally located. These flashes are generally thought to result from vitreoretinal traction and thus are considered by most to signify a higher risk of retinal tears. However, Voerhoeff132 suggested that the light flashes are actually caused by the detached vitreous cortex impacting on the retina during eye movement. Once PVD occurs, there are differences in the characteristics of the detached vitreous that influence, for example, vitreous movement following displacement by ocular excursions. Differences in the “stiffness” of the detached vitreous have been identified using ultrasonic Doppler techniques.133 These probably relate to the biochemical composition and organization of the vitreous and are likely to change with time, depending on the effects of vitreous detachment on retinal and vitreous metabolism.

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When vitreous liquefaction occurs concurrently and in tandem with weakening at the vitreoretinal interface, an “innocuous” PVD occurs, resulting in the aforementioned phenomena. When there is discordance between the rates and extents of these two processes, anomalous PVD results. This is most often due to advanced vitreous liquefaction without concomitant dehiscence at the vitreoretinal interface. Anomalous PVD exerts traction at the vitreoretinal interface with a variety of potential sequelae. This unifying concept in vitreoretinal diseases is a useful way to conceptualize all vitreoretinal disorders.

In 1904, Best134 emphasized that every movement of the eye results in movement of the vitreous body and that this causes traction at any point of strong vitreoretinal adhesion. Normally strong adhesion occurs at the vitreous base, disc, and macula; over retinal vessels; and often as a sheetlike adhesion in the posterior pole of young persons.135 The following describes how anomalous PVD results in traction and the various vitreoretinal pathologies observed in humans. The spectrum of disorders can be categorized into two large groups: disruptions of retina and disruptions of vitreous.


Peripheral Traction

Schepens136 first described the clinical appearance of peripheral vitreoretinal traction as “white with or without pressure.” White with pressure refers to the appearance of the peripheral fundus when examined during scleral depression, and white without pressure is the appearance without scleral depression. Daicker137 proposed that these appearances result from “collagenic” formations in the peripheral retina, whereas Gartner138 suggested that they are due to irregularities of the internal limiting lamina. Green139 described that the appearance of these lesions results from incident light (from the ophthalmoscope) that is tangential to dense bundles of vitreous collagen. There are those who consider that these findings predispose to peripheral retinal tears.137 However, Byer140 does not believe that this ophthalmoscopic appearance has any diagnostic or prognostic significance. Watzke141 performed clinicopathologic correlation of a case with this finding and described that the lesion was due to portions of the vitreous cortex that remained attached to the retina following PVD. This would therefore represent a variant of vitreoschisis (splitting of the vitreous cortex), in this instance, at the peripheral fundus.

Peripheral Retinal Tears

Because the vitreous base is the site of strongest vitreoretinal adhesion, it is here, usually at the posterior border, that vitreoretinal traction causes peripheral retinal tears. Green139 reviewed many clinical and postmortem studies on the prevalence of peripheral retinal tears. Clinical studies found retinal tears in 0.59% to 7.2%, whereas autopsy studies showed a prevalence from 3.3% to 8.8%. Other studies have focused on the relationship between PVD and peripheral retinal tears. Autopsy studies found that PVD is associated with retinal breaks in 14.3% of all cases.142 Clinical studies found retinal tears in 8% to 15% of eyes with acute PVD.143–145 Lindner111 and Jaffe112 found that retinal tears occurred in the superior fundus in over 94% of cases. In the presence of high myopia (greater than –6 D), PVD is associated with peripheral retinal breaks in 11.1%.143 In high myopes who underwent uncomplicated cataract extraction (presumably by intracapsular techniques), the prevalence of retinal breaks following PVD was as high as 16.2%.144 Clearly, in all these cases, the PVD was anomalous.

In 1957, Teng and Chi145 claimed that “irregularities” of the vitreous base are responsible for the vitreoretinal traction that results in peripheral retinal tears. It is known that at the vitreous base, there are collagen fibrils oriented perpendicular to the wall of the eye,138,139,146 with insertions anterior and posterior to the ora serrata.82,147 Gartner100 found that with aging, there is aggregation of the collagen fibrils of the vitreous base similar to the aggregation of collagen fibrils seen within the central vitreous.84 Various conditions of the peripheral retina that are associated with increased vitreoretinal traction include meridional folds, peripheral pigment clumps, retinal rosettes, granular patches, and progressive lattice-like degeneration.144–152 Recently, two structures have been identified (Fig. 10) that are probably remnants of the fetal vasculature in the primary vitreous and are likely to play a role in transmitting traction to the peripheral retina.153

Fig. 10. A. Cystic retinal tuft. 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. The tuft is connected to the internal limiting lamina of the retina. This scanning electron micrograph shows the insertion of the vitreous collagen fibers on the tuft's apical surface. Their orientation changes toward the tuft's surface. B. Verruca. The verruca has a structure similar to that of a tree. Its “roots” are embedded in the inner layers of the retina. Cellular elements resembling cells of the inner plexiform layer can be seen near the retinal surface. The “trunk” of this structure extends from the retina to the middle parts of the vitreous cortex. The “branches” of the verruca are intertwined with interrupted vitreous collagen fibers. Local condensation of collagen fibers exists as well as local collagen destruction (arrows) and interruption of the internal limiting lamina of the retina. (Photographs courtesy of Dr. Stephan Dunker.153)


Discrete oval areas of retinal thinning are associated with localized vitreous liquefaction, separation of the overlying vitreous, and increased vitreoretinal adhesion at the margins of “lattice” lesions.146 Retinal breaks are found at these margins and posterior to the areas of lattice degeneration. Retinal tears resulting from vitreous traction are relatively infrequent as compared with atrophic retinal holes. Clinical studies found retinal tears in only 1% of eyes with lattice degeneration, wheras 16.3% to 18.2% of lattice lesions had atrophic retinal holes.146,147 The risk of retinal tears is greater when the area of lattice degeneration is located juxtabasal or extrabasal relative to the vitreous base.147,148 The retinal tears are believed to result from aggregated collagen fibrils inducing traction up the retina. Obliterative fibrosis of the blood vessels in areas of lattice degeneration is present in only 11.9% of lesions146 and is seen as a “lattice-wicker” of white lines, for which the condition is named. The presence of this vascular anomaly has led to the hypothesis that retinal circulatory abnormalities are the primary cause of this condition. According to this theory, the vitreous changes are secondary and only important in the subsequent development of retinal tears as a local phenomenon. Vitreous liquefaction149 and PVD150 may not be important contributing factors in this local traction, but may be important in the subsequent development of retinal detachment.151

Rhegmatogenous Retinal Detachment

In a study of 100 patients with bilateral surgical aphakia (presumably intracapsular) and rhegmatogenous retinal detachment in one eye, Hovland154 found that 26% eventually developed peripheral tears and retinal detachments in the fellow eye. In this study, the absence of PVD in the fellow eye at the time of retinal detachment in the first eye was the poorest prognostic sign for the fellow eye. Indeed, Bradford and coworkers155 found that in rhegmatogenous retinal detachments that developed within 6 months after cataract surgery, equatorial tears were significantly more common than in detachments that occurred 2 or more years after cataract extraction. Because this is not the typical profile of an “aphakic” retinal detachment, the authors hypothesized that these retinal tears occurred at the time of PVD and were due to the presence of anomalous vitreoretinal adhesions. Furthermore, since this appearance is no different from phakic rhegmatogenous retinal detachments, cataract surgery was probably not an important factor in these cases, although it may have precipitated the PVD as a result of biochemical changes within the vitreous. The authors concluded that the small anterior tears that cause most retinal detachments long after cataract extraction result from chronic vitreoretinal traction at the vitreous base, rather than acute (anomalous) PVD.

The relationship of a retinal tear to the vitreous base is an important prognostic feature that determines the risk of a peripheral retinal tear resulting in a retinal detachment.147 Juxtabasal tears are the most dangerous because of the degree of peripheral vitreous traction associated with these retinal tears; thus, they should be treated. Eyes with retinal breaks that occur at the time of symptomatic PVD are also considered appropriate candidates for prophylaxis, since treatment of retinal tears with continuing vitreous traction significantly reduces the risk of retinal detachment. How to best evaluate the presence or absence of vitreous traction and how to quantitate the degree of vitreous traction are presently not known.

Syneresis and PVD are important factors in the development of peripheral traction and retinal detachment. O'Malley156 found that in 23 eyes with peripheral breaks, all had more syneresis than did age-matched controls and 21 had extensive PVD. Pischel157 noted syneresis and PVD in 90% of cases with retinal detachment. This is consistent with the concept that excess liquefaction without concomitant vitreoretinal dehiscence is important in the pathogenesis of anomalous PVD. After Best,134 Lindner158 emphasized the importance of eye movements in the pathogenesis of retinal tears and detachment. Rosengren and Osterlin159 provided experimental evidence in support of the concept that PVD initiates the following sequence of events: After PVD, the retrocortical space is occupied by liquid vitreous. During eye movements, liquid vitreous, which is lighter than gel, is set in motion before gel vitreous. Because all eye movements are rotational, the liquid acts as a wedge in the retrocortical space, further separating detached vitreous from retina. Where the vitreous is firmly attached to the peripheral retina (at the vitreous base as well as at anomalous sites), traction will be exerted by the force of the liquid vitreous moving in the retrocortical space and pressing against the vitreous cortex. Furthermore, when an ocular saccade stops, it usually does so suddenly. The heavier gel vitreous continues moving because of inertia. It is believed that substantial traction is thus placed upon sites of firm vitreoretinal adhesion resulting in peripheral tears of the retina.60 Furthermore, once a retinal break develops, continued displacement of the vitreous cortex attached to a retinal flap can lift a tear, allowing the liquid vitreous behind the posterior vitreous cortex to enter the subretinal space, resulting in retinal detachment.


In “senile” or degenerative retinoschisis, there is a split in the outer nuclear layer of the neural retina. Studies have shown that in 85% of cases of senile retinoschisis, there is PVD but that the vitreous cortex remains attached to the inner layer of the schisis cavity.160 Schepens60 stated that liquefaction and PVD are frequent findings in senile retinoschisis and that a prominent fibrous structure in the gel adjacent to the schisis cavity may be responsible for peripheral retinal traction, contributing to schisis formation. This was confirmed by Caspers-Velu and colleagues,161 who found significant vitreous traction at surgery in 13 patients with “progressive degenerative retinoschisis.” This disorder clearly illustrates the principle of anomalous PVD.


During PVD, traction on retinal blood vessels can cause retinal and/or vitreous hemorrhage. Retinal hemorrhages resulting from PVD are most often located along the vitreous base.125,145 Peripapillary125 and macular162 hemorrhages have also been reported, corresponding to those locations known to have strong vitreoretinal adhesion. In addition to anatomic sources of increased vitreoretinal adhesion over retinal blood vessels,163 histopathologic studies in humans164 have shown the presence of paravascular retinal rarefaction, which was hypothesized to be associated with abnormal vitreous attachments. Foos165 noted a thinning of the ILL of the retina over blood vessels and hypothesized that this results in breaks through which vitreous fibers attach and/or glial cells migrate to form small epiretinal membranes, resulting in abnormal vitreoretinal adhesions. Furthermore, the absence of the stabilizing influence of Müller cell processes in these regions may make the retinal blood vessels more susceptible to the effects of vitreous traction.

Lindner111 found that vitreous hemorrhage was present in 13% to 19% of cases with PVD. Jaffe112 noted that in the presence of vitreous hemorrhage, PVD was associated with retinal breaks in 69% of cases. Spencer and Foos164 claimed that the strong vitreoretinal adhesion over blood vessels accounted for the presence of paravascular retinal tears in 11% of 252 eyes studied at autopsy. In eyes with PVD, 29% had full-thickness paravascular tears and 46% had full- or partial-thickness tears. These partial-thickness tears are sometimes referred to as “retinal pits.”

Several authors described a syndrome of recurrent vitreous hemorrhage due to avulsion of retinal vessels with persistent attachment of the intact vessel to an operculum overlying a retinal break.166,167 Lincoff and associates168 treated nine cases of avulsed vessels and noted that six were associated with retinal veins and three with arteries. There were retinal breaks in six cases and retinal detachments in five of these six cases.


Vitreomacular Traction

Vitreous traction at the macula has been implicated in contributing to the development of aphakic CME.64–66 The high prevalence of an attached posterior vitreous in youth is believed to contribute to the high incidence of CME in peripheral uveitis or peripheral anterior vitritis.63 Jaffe169 and Maumenee170 reported a vitreomacular traction syndrome in phakic patients that results in macular edema that does not have a petalloid pattern on fluorescein angiography. Jaffe169 described that in some patients with PVD, there is persistent attachment of vitreous to the macula with visible vitreous strands that traverse the retrocortical space and insert into the macula (see Fig. 9). He further described that in many cases, symptoms disappear and vision returns when the posterior vitreous completely detaches. Smiddy and colleagues171 found that all patients with this vitreomacular traction syndrome had PVD with persistent vitreous attachment to the macula. Cystic changes in the macula were present in 12 out of 16 cases, supporting the hypothesis that vitreous traction can cause, or at least contribute to, formation of CME. The authors reported favorable results following vitrectomy for macular traction.

Juvenile Retinoschisis

Juvenile X-linked retinoschisis is a bilateral condition that features splitting of the retina in the macula and sometimes the inferotemporal quadrant. In 50% of cases, there is no peripheral schisis cavity.172 The macular schisis cavity does not progress if the overlying vitreous is detached and is progressive in areas of persistent vitreous attachment.60 Yanoff and colleagues173 studied the histopathology of this condition and postulated that the causative defect may lie in Müller's cell. Selective b-wave reduction on electroretinography supports this postulate. Furthermore, this is consistent with the hypothesis that there is a localized failure of development of the secondary vitreous that enables the schisis cavity to form, since Müller's cells are at least in part responsible for local vitreous formation.

A recent study found that in 104 eyes of 52 patients with X-linked congenital retinoschisis, the electro-oculogram was normal, whereas the electroretinogram had a normal a wave, reduced b-wave amplitude, prolonged b-wave latencies and implicit times, and a reduced 30-Hz flicker response.174 The most frequent untoward events were retinal detachment (11%) and vitreous hemorrhage (4%). The recurrence rate following scleral buckle surgery was an astounding 40%, further supporting the concept that there are profound abnormalities in the vitreous, perhaps specifically at the vitreous cortex, that render the normally curative mechanisms of scleral buckle surgery ineffective.

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When there is sufficient vitreous liquefaction to destabilize the vitreous body and insufficient weakening at the vitreoretinal interface, there can be disruptions within the posterior vitreous cortex and secondary untoward effects upon the retina. In some of these conditions, the role of anomalous PVD is evident. In others, its role is putative, supported mostly by the efficacy of vitrectomy with membrane dissection and removal in curing the disease.

Macular Hole

There has recently been considerable discussion on the role of vitreous traction in macular hole formation and the nature of such traction. In the formation of spontaneous macular holes, sometimes called senile or idiopathic, there is an operculum lying immediately in front of the macular hole and no PVD in approximately 25% of cases.172 In these patients, vitreous traction is localized at the fovea due either to “tangential” contraction of the prefoveal vitreous cortex175 or to sagittal traction transmitted to this site by intravitreal fibers.64 In the latter case, vitreous fibers are sometimes seen attached to an operculum after the macular hole is formed.174–178

Gass was the first to propose that “tangential” prefoveal vitreous traction is the primary cause of spontaneous macular holes.172,175 Johnson and colleagues179 recently refined this concept by proposing that the cause of this traction is perifoveal vitreous detachment, localizing onto the fovea the dynamic vitreous traction associated with ocular saccades. According to Gass, this traction, by whatever mechanism, causes a retinal detachment localized to the fovea with radiating retinal folds (stage 1), whereas others believe that there is central cyst at this stage.180 Indeed the Paris group has proposed that foveal pseudocyst is the first step in macular hole formation.181,182 As a result of these changes, there is greater visibility of xanthophyll pigment, accounting for a central yellow spot (stage 1A) or ring (stage 1B). There is also a negative Watzke's sign at this stage. Several weeks later, a single or several minute holes develop near the center of the fovea (stage 2). These holes continue to enlarge, at times in a “can-opener” fashion, over the ensuing weeks and months until an operculated full-thickness hole develops (stage 3). If a PVD occurs, an operculum can be found attached to the posterior vitreous cortex in the midvitreous (stage 4). There are reports that this is actually a pseudo-operculum, but recent studies in London with optical coherence tomography support the possibility that, at least in some cases, a significant amount of retinal tissue is torn from the foveal area during macular hole formation.183 In 10% of cases, a true PVD occurs before stage 2 develops and patients experience spontaneous resolution of symptoms. In the majority of cases, however, the PVD is anomalous, as substantiated by the intraoperative finding of a preretinal membrane composed mostly of posterior vitreous cortex. An explanation for the claim that there is PVD preoperatively even though preretinal membranes are found at surgery is that there is a split in the posterior vitreous cortex with persistent attachment of the outer layer of the split vitreous cortex to the macula and anterior displacement of the anterior wall of this vitreoschisis cavity. In this disorder, anomalous PVD results from excess liquefaction of vitreous without concomitant weakening at the vitreoretinal interface and the consequent traction causes a split in the posterior vitreous cortex, known as vitreoschisis. This phenomenon has been described in proliferative diabetic vitreoretinopathy184 and may well be a factor in the pathogenesis of macular holes.

An alternate hypothesis describes that PVD can actually contribute to the pathogenesis of macular holes.185 Deficient choroidal blood flow and ischemia to the retinal pigment epithelium and fovea (step 1) initiate spontaneous macular hole formation. Cystic changes subsequently develop in response to this ischemia (step 2). The development of atrophic changes in the fovea (step 3) then results in “involutional macular thinning.” In step 4, PVD is believed to pull on this susceptible, thinned fovea, causing a macular hole. To support this hypothesis, the authors cited the finding that in their study, 10 out of 12 eyes (83%) with involutional macular thinning that developed PVD experienced a full-thickness macular hole. This was also noted by McDonnel and colleagues,186 who found that 11 out of 22 eyes (50%) with macular cysts developed a macular hole following PVD. The results reported by Frangieh and associates177 support the concept of a role for PVD in the development of macular holes. In their series of 35 cases with lamellar or full-thickness holes, partial or complete PVD was present in all 35 (100%) of the eyes. Vitreous fibers were found inserting to the macula or onto a detached operculum in eight out of 35 eyes (22.8%). Margherio and Schepens176 found evidence of vitreous traction in 36 out of 56 eyes (64.2%) with macular holes.

Since macular hole surgery was first devised by Kelly and Wendel,187 many patients have benefited from this innovation. Recent modifications of their original approach include attempts to dissect away the ILL of the retina. There are reports that this increases surgical success rates,188 which is understandable because by removing the ILL, one assures that the posterior vitreous cortex no longer exerts untoward effects on the central macula. Due to the tenacious attachment of Müller cells to the ILL, it is inconceivable that if the entire ILL were being dissected off the retina, the postoperative vision would be undisturbed. Thus, it is far more likely that only the inner lamina (lamina rara interna) or, at the most, the inner and central (lamina densa) laminae are being dissected away, leaving the lamina rara externa and intact Müller cells behind.


Premacular membranes arise from cell proliferation at or near the optic disc that extends into the macula. Vision is affected because of disruption of macular anatomy. However, this does not occur in all cases, since evidence of abnormal proliferation at the optic disc has been found in about one-half of normal human autopsy eyes.189 The high prevalence of cell proliferation at this site may be due to the absence of a true basal lamina at the optic disc (see Chapter 38 in this volume). Rather, the membrane of Elschnig and meniscus of Kuhnt replace the thicker ILL of the retina at the optic nerve head.190 It is likely that these thin structures have diminished barrier properties compared with a true basal lamina, such as the ILL. Furthermore, the absence of the posterior vitreous cortex in the prepapillary region would also diminish the inhibitory effects of the vitreous cortex on cell migration and proliferation.

Clinically, the prevalence of premacular membranes is 3.5%189 and the condition is unilateral in 80% of cases.191 Premacular membranes are usually only recognized clinically when the macula has an irregular surface and there are traction lines in the inner retina. With increasing severity, the retinal vessels become dilated and tortuous.191 Small white spots can be seen, as well as yellow exudates, blot hemorrhages, and microaneurysms.191 Gass172 classified premacular membranes according to the severity of retinal distortion, concurrent biomicroscopic changes, and associated ocular disorders, as a spectrum ranging from “cellophane maculopathy,” which can advance to a “surface-wrinkling retinopathy,” and then “macular pucker.” Vision may be reduced because of macular edema induced by incomplete PVD and vitreous traction on the macula. In a study of 250 cases with premacular membranes, there was a significantly higher prevalence of poor vision, cystoid macular edema, or angiographic macular edema in cases with a partial PVD.192 When there was no PVD or complete PVD, there were very few cases of such maculopathy. In certain cases, progression from partial to complete PVD can dissect the membrane off the macula and symptoms resolve.193

Histopathologic studies of premacular membranes show fibrocellular sheets with varying degrees of cellularity.194 Identifying the exact cell type(s) is difficult because astrocytes, hyalocytes, fibrocytes, macrophages, and retinal pigment epithelial cells can all transform into cells with similar appearances on light and electron microscopy.195 Many of these cell types also have the ability to develop the myofibroblast characteristics intrinsic to the pathophysiology of this disorder.196 Recent studies using immunofluorescent binding to cell surface antigens have begun to characterize these cells more precisely.

The pathogenesis of premacular membrane formation is poorly understood. PVD is present in 80% to 95% of cases.189,191 In a prospective study of 34 eyes with acute PVD, only 9% had evidence of epiretinal membranes at presentation.197 Follow-up 18 months later found that epiretinal membranes had formed in 41% of the eyes, suggesting that once the vitreous detaches away from the retina, there is a loss of some inhibitory influence. Gass172 pointed out that premacular membranes are often likely to develop following transient vitreomacular traction during PVD. There are two sequelae of PVD that could possibly explain this observation. First, during PVD with transient vitreoretinal traction, dehiscences could arise at the optic nerve head and along retinal blood vessels (where vitreoretinal adhesion is strong) that would allow migration and proliferation of fibrous astrocytes onto the anterior aspect of the ILL. Second, during PVD, vitreoretinal separation does not occur cleanly between the vitreous cortex and the ILL of the retina, but splits the vitreous cortex (vitreoschisis), leaving cortical remnants and hyalocytes adherent to the ILL.4 Indeed, an autopsy series of normal human eyes with spontaneous PVD found that 26 out of 59 (44%) had cortical vitreous remnants at the fovea.198 On scanning electron microscopy, the adherent vitreous cortex appeared either disc-shaped, ringlike, or cystic. It is likely that these vitreous cortex remnants also contained hyalocytes, although in this study, the use of the scanning electron microscope made it impossible to analyze this feature. Proliferation, fibrous metaplasia, and contraction of hyalocytes can result in epiretinal membranes that are confined to the central macula172 and are hypocellular on histopathology.194 In these cases, surgical membrane peeling procedures are technically easier and far less traumatic to the underlying retina. Membranes that arise following true PVD and proliferation of fibrous astrocytes from the retina are more difficult to dissect because their origin from the retina maintains firm connections between the membrane and the retina. Thus, there are probably subcategories of epiretinal membranes whose etiologies and responses to surgical intervention differ from one another. Preoperative identification of the more favorable cases would enable better case selection and improved surgical results.


Proliferative vitreoretinopathy (PVR) usually occurs following retinal tears and retinal detachment, especially after therapeutic interventions for these conditions, and is a major cause of failed retinal detachment surgery. Clinically, an increase in the number and size of pigmented cells in the vitreous (see Chapter 38 in this volume) of patients with retinal detachment (preoperatively or postoperatively) heralds the development of massive PVR.199 Early in the course of PVR, membranes are very cellular, whereas later, there is an increase in extracellular collagen.200 Experimental and clinical evidence suggests that this collagen is predominantly type I.201 Scheiffarth and coworkers202 found type II collagen in pathologic vitreous membranes of only six of 19 patients with PVR, whereas 12 of 13 patients with PDR had type II collagen. It is therefore likely that the collagen in PVR membranes is newly synthesized by cells that do not normally synthesize vitreous collagen. The finding of type II collagen in almost one-third of cases in Scheiffarth's series probably resulted from the fact that PVR membranes are often intimately associated with the posterior vitreous cortex.

The cells of PVR membranes are fibroblast-like but have several progenitors, particularly astrocytes194,203 and retinal pigment epithelial (RPE) cells.199,204 The prominence of RPE cells in PVR probably results from the access to the vitreous afforded RPE cells by the retinal break, the dispersion of viable RPE cells into the vitreous during cryopexy treatment of retinal tears,205 and their migration into the vitreous in response to chemoattractants.206 Because one of the functions of vitreous is to inhibit cell invasion of the vitreous cavity,124 it is not clear how the vitreous is altered to permit cell migration and proliferation in PVR. Campochiaro and coworkers207 found that vitreous from cases of PVR had much greater stimulatory activity of RPE migration than vitreous from patients with premacular membranes and uncomplicated retinal detachment. The presence of macrophages within the vitreous in PVR could stimulate RPE cell migration206 by means of chemoattractants such as platelet-derived growth factor208 and fibronectin, a chemoattractant for fibroblasts.209 Not surprisingly, macrophages are not a prominent cell type in premacular membranes, explaining why this condition does not feature aggressive cell proliferation. RPE cells could also migrate and proliferate in response to increased stimulatory factors endogenous to the vitreous.210 In addition to stimulatory factors, PVR may result from a decrease in the properties of the vitreous that normally inhibit cell migration and proliferation.9–11,124 There may be individual patient variations in the levels of these inhibitory properties, which, when suboptimal, predispose to the development of PVR. Disruption of the blood–vitreous barrier following retinal detachment and surgery may further reduce these inhibitory effects. Vitrectomy surgery could also result in a reduction of the antiproliferative, inhibitory properties of the vitreous. Indeed, Hsu and colleagues211 found that in a rabbit model, vitrectomy aggravated intraocular fibroblast proliferation and traction retinal detachment. Thus, although vitrectomy is indispensable in the management of PVR, it should be reserved for cases of established PVR. In the absence of appropriate indications, vitrectomy probably should not be performed as prophylaxis for PVR.

The consequence of traction by PVR membranes is not simply wrinkling of the retina, as is the case in premacular membranes, but actual retinal detachment. This may relate to the contractility of the cells in PVR212 and their linking to one another by gap junctions, resulting in compact sheets.213 Studies of human vitrectomy specimens have demonstrated the presence of myofibroblasts associated with extracellular collagen fibrils of about 20 nm diameter that are entwined with normal vitreous collagen and are thus able to transmit any contractile forces from the cells to the surrounding vitreous and, in turn, to the retina, wherever the posterior vitreous cortex is still attached.214


Cells can be found within the vitreous in association with severe chorioretinal or ciliary body inflammation. In such conditions, the presence of inflammatory cells within the vitreous is secondary to active inflammation at an adjacent site. Histologic evidence of cell infiltration of the vitreous base was found in eyes with iris or corneal inflammation.106 Hogan215 described three stages in the effects of inflammation on the vitreous: liquefaction and shrinkage; formation of a coarse membrane with further vitreous shrinkage and marked central liquefaction; and scar formation, which may occur along the retinal surface, at the disc, and/or at the ciliary body, where a cyclitic membrane may arise. Scarring in the posterior pole can result in macular traction if the vitreous cortex is still attached posteriorly.

Inflammatory cells within the vitreous tend to aggregate along the course of collagen fibrils.71 The presence of inflammatory cells within the vitreous may be associated with an aggregation of collagen fibrils into linear structures, originally described in 1932 by Koby as “elongated cylindroids.” Schlaegel216 believed these structures were primarily associated with ocular toxoplasmosis. However, as Roizenblatt and colleagues217 pointed out, these structures have also been reported in cases of uveitis, high myopia, retinal detachment, pars planitis, and tumors seeding the vitreous body. When such cases were studied histopathologically,217 the “cylinders” were found to be condensations of vitreous collagen fibrils coated by cells of different types, depending on the etiology of the infiltrate. These structures inserted into the vitreous base,217 following the course of fibers seen in the normal adult vitreous (see Chapter 38 in this volume).


Various disorders result in the outgrowth of blood vessels from the optic disc and retina into the vitreous. A factor common to many of these disorders is the presence of ocular, particularly retinal, ischemia,49,218 which is hypothesized to release an angiogenic factor or factors that stimulate neovascularization.49,219 It is important to note that the current concept of the phenomenon of intraocular neovascularization considers that in addition to the stimulatory factors promoting the growth of new blood vessels, there is a breakdown in the mechanism(s) normally involved in preventing neovascularization, similar to the situation encountered in PVR.

In ischemic retinopathies, new vessels arise from the optic disc to invade the vitreous. The absence of a prepapillary vitreous cortex and the thinness and biochemical composition of the membrane of Elschnig and the meniscus of Kuhnt at the optic disc (see Chapter 38 in this volume) probably diminish the inhibitory activity of the barriers at this site, thus predisposing the blood vessels of the optic disc to preferentially respond to stimuli that promote neovascularization. For new vessels to grow, they need a surface for cell migration and proliferation. Histologic studies have shown that in humans with PDR, new blood vessels grow into as well as on the posterior vitreous cortex (Fig. 11).109 As the disease progresses, these vessels continue to grow out of the retinal plane and along and/or into the posterior vitreous cortex. Any displacement of the vitreous due to eye movement, trauma, vitreous detachment, or osmotic fluxes would transmit traction to the new blood vessels. Experimental studies have shown that such traction can induce further growth of new vessels.220 These data explain the findings of Jalkh and associates,221 who noted that diabetic patients with a totally detached posterior vitreous had the lowest risk of progression in the severity of their retinopathy. This was confirmed by Wong and co-workers,222 who found “aborted neovascular outgrowths” at diabetic vitrectomy surgery in areas where the vitreous was detached. In the previously mentioned clinical study,221 patients with a partially detached vitreous had the highest risk of progressing to more severe proliferative diabetic retinopathy, possibly due to traction inducing further stimulation of the neovascular response and hemorrhage. Furthermore, prospective clinical studies have shown that panretinal laser photocoagulation induces posterior vitreous detachment.223 This may explain part of the therapeutic effect of laser therapy, since any subsequent neovascularization will not have a posterior vitreous cortex to grow into, and thus these new vessels will be “abortive” and have a better prognosis. Biochemical changes in human vitreous collagen224,225 are believed to result in the precocious senescence of vitreous structure in diabetic patients94 that contributes to vitreous liquefaction and partial detachment with traction on new vessels in these patients.226 Clinical studies have shown the presence of funnel-shaped vitreous attachment to the disc in PDR and/or focally to the walls of new blood vessels.227 Traction upon the fragile walls of these new vessels results in vitreous hemorrhage. Diabetic patients with vitreous attachment to neovascular fronds are at particular risk for traction on these vessels because of contraction and expansion of the diabetic vitreous following significant fluctuations in serum osmolarity.

Fig. 11. A–C. Proliferative diabetic vitreoretinopathy. Neovascularization from the disc and retina involves vascular endothelial cell migration and proliferation onto and into the posterior vitreous cortex. These photomicrographs demonstrate the growth of neovascular complexes into the posterior vitreous cortex of a human eye (bar = 10 μm). (Faulborn J, Bowald S: Microproliferations in proliferative diabetic retinopathy and their relation to the vitreous: Corresponding light and electron microscopic studies. Graefes Arch Clin Exp Ophthalmol 223:130, 1985.)

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In 1949, Berliner228 made very detailed descriptions of the vitreous changes in retinitis pigmentosa as seen by slit lamp biomicroscopy. The appearance of particulate structures is believed to result from melanin pigment granules embedded in the matrix of vitreous collagen fibrils.229 Cells that are found in retinitis pigmentosa vitreous include uveal melanocytes230 and macrophages derived from blood monocytes that gain access by way of abnormal retinal vessels, migrated retinal pigment epithelial cells, or hyalocytes. In favor of the hyalocyte origin are the histologic features of invaginated nuclei and long, slender pseudopodia.229 Newsome and Michels231 recently employed monoclonal antibody techniques to identify the cells in retinitis pigmentosa vitreous and found T helper and suppressor cells, activated T cells, and some B cells.


Synchysis scintillans, a condition of vitreous opacification, is related to any pathologic process that results in chronic vitreous hemorrhage. The vitreous opacities are noted when frank hemorrhage is no longer present and appear as flat, golden brown, refractile bodies that are freely mobile. They are associated with liquid vitreous, so they settle to the most dependent portion of the vitreous body when eye movement stops. The vitreous surrounding these opacities is degenerated and liquefied, leading to collagen displacement peripherally.71 Chemical studies have demonstrated the presence of cholesterol crystals in these opacities, and the condition is sometimes referred to as cholesterolosis bulbi.232 Free hemoglobin spherules in the vitreous have also been reported.233


Asteroid hyalosis is a generally benign condition characterized by small white or yellow-white spheric or disc-shaped opacities throughout the vitreous body. The prevalence of this condition in the general population is about 0.042% to 0.5%, affecting all races, but with a male-to-female ratio of 2:1. Curiously, asteroid hyalosis is unilateral in over 75% of cases. Asteroid bodies are intimately associated with the vitreous gel and move with typical vitreous displacement during eye movement. This fact led Rodman and colleagues234 to suggest that there was a relationship to vitreous fibril degeneration. However, posterior vitreous detachment, either complete or partial, occurs less frequently in asteroid hyalosis than in age-matched controls.235

Histologic studies demonstrated a crystalline appearance to asteroid bodies, with a positive staining pattern to fat and acid mucopolysaccharide stains that was unaffected by hyaluronidase pretreatment.234 Electron diffraction studies showed the presence of calcium oxalate monohydrate and calcium hydroxyphosphate.236 Streeten237 performed ultrastructural studies and found intertwined ribbons of multilaminar membranes with a 6-nm periodicity that she interpreted as characteristic of complex lipids, especially phospholipids, lying in a homogeneous background matrix. In these investigations, energy-dispersive x-ray analysis showed calcium and phosphorus to be the main elements in asteroid bodies. Electron diffraction structural analysis demonstrated calcium hydroxyapatite and possibly other forms of calcium phosphate crystals.

The etiology of asteroid hyalosis is not clearly understood. There have been reports suggesting an association between asteroid hyalosis and diabetes mellitus.238,239 Others dispute such an association.240,241 Asteroid hyalosis appears to be associated with certain pigmentary retinal degenerations as reported by Sebag and coworkers,242 although it is not known whether this is related to the presence of diabetes mellitus in these patients. Yu and Blumenthal243 proposed that asteroid hyalosis resulted from aging collagen, whereas other studies suggested that asteroid formation is preceded by depolymerization of hyaluronic acid.244


Amyloidosis may result in the deposition of opacities in the vitreous of one or both eyes. Bilateral involvement may be an early manifestation of the dominant form of familial amyloidosis, although rare cases of vitreous involvement in nonfamilial forms have been reported.245 The opacities first appear in the vitreous cortex adjacent to retinal blood vessels and later appear in the anterior vitreous.246 Initially, the opacities are granular, with wispy fringes, and later take on a “glass wool” appearance.71 When the opacities form strands, they appear to attach to the retina and the posterior aspect of the lens by thick footplates.237 Following PVD, the posterior vitreous cortex is observed to have thick, linear opacities that follow the course of the retinal vessels. The opacities seem to aggregate by “seeding” on vitreous fibrils and along the posterior vitreous cortex.237

When visually significant, the opacified vitreous can be safely removed surgically. Specimens that have been studied histopathologically have contained starlike structures with dense, fibrillar centers. The amyloid fibrils are 5 to 10 nm in diameter and are distinguished from the 10- to 15-nm vitreous fibrils by stains for amyloid and by the fact that the vitreous fibrils are very straight and long.237 Electron microscopic studies confirmed the presence of amyloid, and immunocytochemical studies247 identified the major amyloid constituent as a protein resembling prealbumin. Streeten237 considered that hyalocytes could perform the role of macrophage processing of the amyloid protein before its polymerization. This may further explain why the opacities initially appear at the posterior vitreous cortex, where hyalocytes reside (see Chapter 38 in this volume).


Cell invasion of the vitreous may occur as a result of intraocular neoplasia as well as ocular involvement in extraocular neoplasia. In retinoblastoma, especially the endophytic form, cells traverse the vitreous and adhere to basal laminae at various sites. Occasionally, clumps of retinoblastoma cells can pass through the vitreous body and form aggregates in the anterior chamber.

Choroidal melanoma cells can also enter the vitreous and are associated with intraocular hemorrhage and melanomalytic glaucoma.248

Reticulum cell sarcoma is a malignant histiocytic lymphoma in which cell invasion of the vitreous is often the only manifestation of the disease. Ocular disease may antedate neurologic symptoms by 3 months to 8 years.249 Cells arise from the optic nerve and retina and are initially localized to the vitreous cortex, where they form fluffy, nondiscrete opacities. Later in the course of the disease, cells may spread throughout the vitreous body. Histologic diagnosis can be achieved by vitreous biopsy,250 and immunologic identification of cell surface markers in such biopsies can influence the choice of treatment modalities.251

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