The embryonic vascular system of the vitreous (vasa hyaloidea propria) attains its maximum prominence during the ninth week of gestation or 40-mm stage.¹ Atrophy of these vessels begins posteriorly with dropout of the vasa hyaloidea propria, followed by the tunica vasculosa lentis, the embryonic vessels of the lens. Recent studies² detected the onset of apoptosis in the endothelial cells of the tunica vasculosa lentis as early as day 17.5 in the mouse embryo. 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.² 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 from within the blood vessel lumen out to the perivascular adventitia. Recent studies⁷ have suggested that vasa hyoidea propria and the tunica vasculosa lentis regress via apoptosis and that macrophages are important in this process. Subsequent studies by a different group⁸ confirmed the importance of macrophages in promoting regression of the fetal vitreous vasculature and further characterized these macrophages as hyalocytes.

Understanding what stimulates regression of the hyaloid vascular system would have great potential in enabling new approaches to the treatment (and perhaps even prevention) of neovascular disorders of the eye, such as proliferative diabetic retinopathy and exudative age-related macular degeneration. Indeed, inhibiting angiogenesis could also significantly improve the management of nonophthalmic disorders such as metastatic carcinoma. Studies have identified a protein native to the vitreous that inhibits angiogenesis in various experimental models.^9,10 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 et al.² point out that the first event in regression of the hyaloid vasculature is endothelial cell apoptosis and propose that lens development separates the fetal vasculature from vascular endothelial growth factor-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, the resident macrophages, or tissue histiocytes, of vitreous. Meeson et al.¹¹ 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 single endothelial cell(s) of an otherwise healthy capillary segment with normal blood flow. The isolated dying endothelial cell(s) 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.

Dominant exudative vitreoretinopathy was first described in 1969 by Criswick and Schepens³⁵ 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 Oliver³⁶ 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 et al.³⁷ recently reported the same findings in four generations of three families, but found X-linked inheritance. Van Nouhuys^38,39 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 Nouhuys⁴¹ 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 et al.⁴⁰ 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. Others⁴¹ suggest that there may be a combined etiology involving anomalies of the hyaloid vascular system and primary vitreous as well as retinovascular dysgenesis.

Retinopathy of prematurity (ROP), a condition of premature infants, was first described in 1942 by Terry⁴² 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 ROP. We now identify acute stages of the disease that are not “retrolental” and do not have much “fibroplasia”.⁴³ The pathogenesis of ROP⁴⁴ 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. After the discontinuation of supplemental oxygen, arterial pO2 levels return to normal and the obliterated (or at best highly constricted) vessels cause the peripheral retina they subserve to become ischemic and release neovascular growth factors. An alternative hypothesis of pathogenesis⁴⁵ 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.

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. Neovascularization arises from the ridge that demarcates the developed posterior retina from the immature peripheral retina (Fig. 2). The new vessels grow into the vitreous body, similar to neovascularization in diabetic retinopathy,⁴⁶ although they grow farther anteriorly and more exuberantly. This is perhaps due to the participation of cells of the ocular fetal vasculature whose apoptosis has been retarded or arrested by the presence of high levels of vascular endothelial growth factor.⁴⁷

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 detect⁴⁸ such abnormalities. Indeed, the abundance of reactive oxygen species in the retina and vitreous of premature infants could induce widespread vitreous liquefaction.⁴⁹ 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.⁵⁰ This structure is most likely the consequence of underlying retinal immaturity in the periphery with consequent lack of typical gel vitreous synthesis, normally a Mueller 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.⁵⁰ 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.^9,10,11 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.⁵¹ 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.⁵² This configuration of neovascularization is probably the result of cell migration and proliferation along the anterior surface of the interface between gel vitreous posteriorly and liquid vitreous anteriorly (Fig. 2). 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.

Vitreoretinal dystrophy of Goldmann-Favre is an autosomal recessive condition first described in 1957 by Goldmann⁵³ as consisting of vitreous abnormalities with peripheral retinoschisis and chorioretinal atrophy. Francois⁵⁴ 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 collaborators⁵⁵ used fluorescein angiography to demonstrate cystoid macular edema (CME) and vascular occlusion with leakage in the peripheral retina corresponding to the areas of schisis. Schepens⁵⁶ described that there is vitreous organization attached to the areas of schisis. Histopathologic studies by Peyman et al.⁵⁷ 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 (PVD), thus inducing traction on the macula, as has been noted in cases of peripheral uveitis (or peripheral anterior vitreitis) with CME^58,59 and in cases of aphakic macular edema.^60,61 There can also be partial PVD with persistent attachment of vitreous fibrils to the macula (Fig. 3).

Collagen is one of the most important structural molecules in all connective tissues in the body, including vitreous. Thus, it is of interest to consider parallel phenomena occurring in the vitreous and connective tissues elsewhere, especially as related to collagen. For example, Gartner⁶² has pointed out the similarities between the intervertebral disk and vitreous, in which age-related changes with herniation of the nucleus pulposus were 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 PVD (Fig. 3).

Maumenee⁶³ has 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 disease,⁶⁴ 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 due 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.

Marfan syndrome is an autosomal dominant disorder featuring poor musculature, lax joints, aortic aneurysms, and arachnodactyly. Lens subluxation, thin sclera, peripheral fundus pigmentary changes, and vitreous liquefaction occur at an early age. The combination of myopia, vitreous syneresis, and abnormal vitreoretinal adhesions at the equator account for the frequency of rhegmatogenous retinal detachment due to equatorial or posterior horseshoe tears.⁵⁸

Ehlers-Danlos syndrome has some similarities with Marfan syndrome, most notably joint laxity, aortic aneurysms, and an autosomal dominant pattern of inheritance, although there are as many as six types of Ehlers-Danlos patients, and the genetics of this condition are probably more heterogeneous than in Marfan syndrome. A further distinction from Marfan’s patients is the hyperelastic skin and poor wound healing of all connective tissues in Ehlers-Danlos patients, including cornea and sclera. 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 cause bilateral retinal detachments.⁵⁸

In 1965, Stickler et al.⁶⁵ 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 Weil-Marchesani habitus. The skeletal abnormalities now accepted as characteristic of Stickler syndrome are radiographic evidence of flat epiphyses, broad metaphyses, and especially spondyloepiphyseal dysplasia.⁶⁶ Ocular abnormalities are high myopia, greater than -10 D in 72% of cases,⁶⁷ and vitreoretinal changes characterized by vitreous liquefaction, fibrillar collagen condensation, and a perivascular latticelike degeneration in the peripheral retina believed to be the cause of a high incidence (greater than 50%) of retinal detachment.⁶⁹ More recent studies⁶⁸ have correlated specific gene defects with particular phenotypes, thereby enabling the classification of Stickler syndrome patients into four subgroups. Those patients with abnormalities in the genes coding for type II procollagen and type V/XI procollagen are the ones who have severe vitreous abnormalities.

Knobloch⁶⁹ described a syndrome similar to Stickler syndrome with hypotonia, relative muscular hypoplasia, and mild to moderate spondyloepiphyseal dysplasia causing hyperextensible joints. The vitreoretinopathy is characterized by vitreous liquefaction, veils of vitreous collagen condensation, and perivascular latticelike changes in the peripheral retina. A recent case report⁷⁰ of Knobloch syndrome describes a deficiency in endostatin as the cause for persistent fetal vasculature.

Considering how frequently myopia is associated with the aforementioned arthro-ophthalmopathies, it is of interest to consider whether myopia itself is due, at least in part, to vitreous collagen abnormalities. Since myopia is considered to be caused by both genetic and environmental factors,⁷¹ the genetic effects upon vitreous can be considered myopic vitreous dystrophy while the effects of environmental factors are appropriately termed myopic vitreous degeneration. The combined effects are best referred to as myopic vitreopathy. Since vitreous formation contributes to ocular growth by generating internal swelling pressure, it is likely that derangements in this process could alter the ultimate size of the eye. It is important to note that myopia is associated with enlargement not only in the longitudinal (optical) axis, but the vertical and horizontal axes, as well (Fig. 4).

Almost all of the growth of the eye after 2 or 3 years of age is due to expansion of the eye between the region of the ora serrata and the equator of the globe.⁷² Much, if not all, of the force inducing this expansion derives from the burgeoning growth of the vitreous body. In 1963, Coulombre et al.⁷³ proposed that during development, vitreous growth was the major factor influencing intraocular pressure and eye growth. Subsequent studies⁷⁴ showed that vitrectomized eyes with normal intraocular pressure had less ocular growth than controls. More recent studies⁷⁵ showed that peripheral retinal ablation by cryopexy or laser photocoagulation in rabbits between 2 and 8 weeks of age caused significant reductions in axial length, equatorial diameter, corneal diameter, and total ocular volume. The investigators hypothesized that these effects were due to interference with peripheral retinal control of eye growth or destruction of hyalocytes with elimination of their synthesis of vitreous macromolecules, particularly the structural component hyaluronan (HA). Studies⁷⁶ in humans who underwent peripheral retinal cryoablation for retinopathy of prematurity confirmed the finding of decreased eye growth in treated cases. Thus, because vitreous plays such an important role in eye growth, it is likely to have an important contribution in myopia. This could result either from primary abnormalities in the vitreous, or vitreous could play a secondary role mediating the effects of a primary abnormality either in the retina or ciliary body.

Using slit lamp biomicroscopy in a clinical setting, Busacca⁹⁵ and Goldmann⁹⁶ observed that after the ages of 45 to 50 years there is a decrease in the gel volume and an increase in the liquid volume of human vitreous. Eisner⁹⁷ 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’Malley⁹⁸ 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 ages 80 to 89. Oksala⁹⁹ 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 Flood^100,101 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. 5). 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 begins¹⁰⁰ and where fibers are first observed^102,103 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.¹⁰⁶ In the posterior vitreous such age-related changes often form large pockets of liquid vitreous.¹⁰⁴

Age-related rheologic changes in the vitreous may result from an alteration in HA-collagen interaction. Chakrabarti and Park¹⁰⁵ 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 Chakrabarti¹⁰⁶ have 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 Chapman¹⁰⁷ have demonstrated that singlet oxygen can induce conformational changes in the tertiary structure of HA molecules. Ueno et al.⁵¹ have 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 since 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). The importance of vitreous liquefaction in the pathogenesis of PVD is discussed below.

Total vitreous collagen content does not change after the ages of 20 to 30 (Fig. 6). 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 < 0.05). Since 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 (Fig. 5), 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,¹⁰⁶ perhaps with cross-links between them. Aging of collagen throughout the body is associated with increased cross-linking as manifested by decreased solubility,¹⁰⁸ increased collagen “stiffness,”¹⁰⁹ and increased resistance to enzymatic degradation.¹¹⁰ There is also an increase in a reducible lysine-carbohydrate condensation product with increasing age.¹¹¹ Although similar investigations have not been performed on vitreous collagen, studies by Snowden et al.¹¹² 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 vitreous¹¹³ suggesting “precocious senescence” of vitreous collagen as has been described in diabetes for other organs and tissues.^114,115

Vitreous HA concentration increases until about the age of 20, when adult levels are attained (Fig. 7A). HA concentration does not change in either the liquid or gel vitreous from ages 20 to 60 (Fig. 7).^104,116 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 (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).

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 1.0 mg/mL above the age of 80.^103,104,121 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.

The most common age-related event in the vitreous is PVD (Fig.12). True PVD can be defined as a separation between the posterior vitreous cortex and the internal limiting lamina (ILL) of the retina.¹²⁴ 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.¹²⁵ Lindner¹²⁶ and Jaffe¹²⁷ have described that in some cases of PVD there is herniation of vitreous through the vitreous cortex of the posterior pole. As previously mentioned, Gartner⁶⁵ has drawn 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. 3).¹²⁸

Schepens¹⁵³ first described the clinical appearance of peripheral vitreoretinal traction as “white with or without pressure,” the former referring to the appearance of the peripheral fundus when examined during scleral depression and the latter being the appearance without scleral depression. Daicker¹⁵⁴ proposed that these appearances result from “collagenic” formations in the peripheral retina, while Gartner¹⁵⁵ suggested that they are due to irregularities of the internal limiting lamina. Green and Sebag¹⁵⁶ described that the appearance of these ophthalmoscopic findings results from incident light (from the ophthalmoscope) that is tangential to dense bundles of vitreous collagen. Watzke¹⁵⁷ 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 might therefore represent a variant of vitreoschisis (splitting of the vitreous cortex), which in this instance occurs in the peripheral fundus. Some¹⁵⁹ consider that “white with or without pressure” predisposes to peripheral retinal tears. However, Byer¹⁵⁸ does not believe that this ophthalmoscopic appearance has any diagnostic or prognostic significance.