PERSISTENT PRIMARY VITREOUS

Normally, the primary vitreous, or hyaloid system, regresses late in fetal development and is completely resorbed. However, remnants may persist, although they are usually curiosities, without functional significance. Rarely, at term the entire hyaloid system may be present in the eye.

Anteriorly, such remnants typically persist as Mittendorf's dot, a small whitish opacity on the posterior capsule, just inferonasal to the posterior pole, which corresponds to the anterior site of attachment of the hyaloid artery.¹

Posteriorly, glial and vascular remnants of the hyaloid artery may persist at the disc and extend into Cloquet's canal, the visible central space formed by the encroaching secondary vitreous. The glial remnant, called Bergmeister's papilla, existsas delicate strands or as a membrane overlying the optic nerve head (Fig. 1). Vascular remnants may be filled with blood and may be confused with neovascularization at the disc; however, the remnants do not leak fluorescein.¹

PERSISTENT HYPERPLASTIC PRIMARY VITREOUS

Persistent hyperplastic primary vitreous (PHPV) is present at birth and nearly always is unilateral. Because it can cause a white pupil and poor vision, it is part of the differential diagnosis of retinoblastoma.² However, these eyes are often microphthalmic, whereas eyes with retinoblastoma are normal in size unless there has been involution of the retinoblastoma and secondary shrinkage of the globe. As the name implies, PHPV is the hyperplastic counterpart of persistence of the hyaloid system. PHPV tends to be unilateral, especially in otherwise healthy patients, but has been reported to be bilateral.³ In patients with systemic abnormalities, such as trisomy 13, PHPV is more often bilateral.⁴

The anomaly consists of vascular mesenchymal tissue, which proliferates behind the lens and pushes it forward. This mesenchymal tissue can contain, in addition to fibroblasts and vessels, adipose tissue, smooth muscle, and cartilage.⁴ The proliferating tissue draws the ciliary processes inward so that they may be visible through a dilated pupil if the lens is clear. The lens usually becomes cataractous, and frequently the mesenchymal tissue extends through the ruptured capsule posteriorly.⁵ Rarely, capsular rupture can give rise to a phacoanaphylactic reaction.⁶

Glaucoma may result from a variety of mechanisms in this anomaly. The angle structures may be immature; therefore, PHPV is part of the differential diagnosis of congenital glaucoma, although angle immaturity is seldom an isolated cause.^4,5 These eyes are microphthalmic, so that the anterior segment is crowded and the lens is anteriorly placed. This situation is aggravated by the mesenchymal tissue mass pushing the lens further forward, allowing pupillary block glaucoma to ensue. Other mechanisms of increased intraocular pressure include uveitis and intraocular hemorrhage.⁴

CONGENITAL CYSTS

Congenital cysts are free-floating cysts in the vitreous cavity that may be clear or pigmented and range from 2 to 12 mm in diameter. They can be bilateral.⁷ If they are large or centrally located, they can interfere with vision.⁸ Some are probably traumatic in origin, but other patients have had no history of trauma or surgery. In two reports of congenital vitreous cysts, the cyst wall was composed of pigmented and nonpigmented epithelial cells.^8,9 The cells contained mature and immature melanosomes, implying a congenital origin.⁸ They are usually stable and do not require intervention.

POSTTRAUMATIC AND POSTSURGICAL

The vitreous can act as a scaffolding for fibrous proliferation when adherent to adjacent ocular tissues. Trauma and inflammation usually are the inciting causes. With fibrous proliferation, shrinkage and wrinkling of tissues occurs. Electron microscopic examination has shown that the fibrocytes and other proliferating cells often have condensations of filaments near the cell membrane.¹⁰ These 60- to 70-nm filaments are composed of actin; this contractile protein explains the ability of these fibrous membranes to shrink, pulling at whatever tissue to which they are attached.¹¹ This formation of contractile filaments is called myofibroblastic differentiation and is a frequent finding in fibrosis and fibrous ingrowth of any cause.¹² Actin, however, probably is not the only cause of membrane contractile behavior.¹³

Adhesion of vitreous to the ciliary body with fibrous proliferation can lead to cyclitic membranes.¹¹ Vitrectomy can lead to fibrous ingrowth overlying the pars plana, at the entry site of the instruments.¹⁴

The vitreous normally is adherent around the fovea. Increased traction on the macula by the vitreous is thought to play a role in postoperative cystoid macular edema¹⁵ and in the formation of macular holes.¹⁶ Previously, most macular holes were assumed to be traumatic in origin. However, with better techniques of biomicroscopy, it has been found that atraumatic holes in older patients are much more common than previously realized. The pathogenesis of these atraumatic idiopathic macular holes has been controversial. It now appears that tangential traction by the vitreous causes a detachment of the foveola with subsequent hole formation.¹⁶ Histologic examination of the surgically removed opercula has shown that many contain only glia, without photoreceptors.¹⁷

The vitreous is also often adherent along the major vessels. As the vitreous detaches, it peels away from the retina, so that if areas of increased adhesion exist (Fig. 2), a tear may result. There can be hemorrhage because this tear normally occurs across a blood vessel. The vitreous may pull out a fragment of partial-thickness retina, leaving retinal pits, or full-thickness retina, resulting in holes.^18,19 The fragment of removed retina, the operculum, gradually resorbs.

ACQUIRED VITREOUS STRANDS AND FLOATERS

Acquired vitreous strands and floaters are annoying but generally harmless fragments of formed vitreouswith glial proliferations. The strongest attachment of the vitreous to the retina posteriorly is around the optic nerve head. This entire ring sometimes will detach intact, so that a ring is visible in the visual field. Vitreous floaters move as the eye moves.

Vitreous detachment increases in frequency with increasing age. As the vitreous liquefies posteriorly, the formed vitreous collapses anteriorly (Fig. 3). The most firm area of vitreal attachment is the vitreous base, overlying peripheral retina and adjacent pars plana; the vitreous does not spontaneously detach from its base.²⁰

Vitreous liquefaction may occur in other areas besides posteriorly; these pockets of fluid vitreous are called synereses. They can be seen clinically with the slit lamp.²¹ Vitreous also is liquefied over areas of lattice degeneration of the retina.²²

INFLAMMATION

Inflammation in the vitreous may be infectious or noninfectious. Because the vitreous is a good culture medium, organisms of exogenous and endogenous origin may flourish there. Bacterial endophthalmitis often leads to diffuse vitreous haziness, decreased vision, and pain. Vitrectomy can be diagnostic and therapeutic,²³ but depending on the clinical setting, vitreous biopsy may be adequate and can be done under sterile conditions in the office.²⁴

Bacteria of exogenous origin generally gain access to the eye from traumatic injury, including surgical injury, either being introduced by a foreign body or through contamination of the inner eye by way of an open wound. Particularly with postoperative endophthalmitis, the normal colonizers of the periocular surface are the most frequent causes.²⁴ Occasionally, the inflammation is more low grade, with a chronic, smoldering course. Such cases can be difficult to diagnose and require biopsy.²⁵

An unusual cause of exogenous infection occurs in so-called sequestered endophthalmitis. Bacteria of low virulence, typically Propionibacterium acnes, apparently are introduced into the lens capsular remnants at the time of cataract surgery. Weeks to months later, they cause a low-grade uveitis.²⁶ In some cases, YAG laser capsulotomy has led to a fulminant endophthalmitis.²⁷ Several cases have been examined histologically after the lens remnants have been removed. The organisms appear as clusters within the capsular remnants.²⁸

Endogenous bacterial infection is usually seen in immunosuppressed patients; bacteremia in immunocompetent patients rarely leads to endogenous infection.²⁹

Whipple disease is an unusual disease of the gastrointestinal tract and manifests as malabsorption and steatorrhea. It is characterized by foamy, periodic acid-Schiff-positive macrophages in the intestinal mucosa. These macrophages also are occasionally present in the vitreous. Vitrectomy can be diagnostic.³⁰ The disease has been shown to be caused by a bacillus.³¹

Crohn disease is a granulomatous inflammation, typically of the small intestine, although any site in the gastrointestinal tract may be involved. It occasionally causes uveitis and vitritis. Ocular inflammation may precede the gastrointestinal manifestations.³² Some researchers have found mollicutes (so-called defective cell wall bacteria that are obligate intracellular parasites) in vitreal leukocytes in this disease and postulate that these are the causative organisms.³³

Fungal endophthalmitis often is manifest clinically as snowball opacities; these are microabscesses in the vitreous. The most common endogenous organism is Candida species, often from total parenteral nutrition,³⁴ but Aspergillus species and other fungi are also seen.³⁵ Endogenous fungal infections usually are associated with immunocompromised or debilitated patients. Exogenous fungal infections are caused by a variety of organisms and can enter the eye after ocular surgery, trauma, or by extension from fungal corneal ulcers, for example, from ocular penetration by contaminated vegetable matter.³⁶ Infected donor corneas have caused fungal endophthalmitis in patients undergoing penetrating keratoplasty.²⁴

Cysticercus cellulosae is the larval form of the tapeworm, Taenia solium. The cysts may occur in the vitreous and in the subretinal space and subconjunctivally. While alive, the worm elicits only minimal inflammation; when it dies, the reaction is intense. The worms have been successfully removed by vitrectomy.³⁷ Histologically, the larva consists of a cyst containing a scolex that contains birefringent hooklets.³⁸

Onchocerciasis is caused by a microfilarial organism, Onchocerca volvulus, which causes river blindness in endemic areas. Ocular involvement seems to depend on the amount of the initial cutaneous infestation and on the distance between the cutaneous site and the eye. Virtually any ocular tissue can be involved, including the vitreous. The worms cause little inflammatory reaction until they die.³⁹

Noninfectious retinal inflammation can also lead to an inflammatory reaction in adjacent vitreous, as seen in sarcoidosis and pars planitis. Sarcoid infrequently gives rise to vitreous exudates, described as candle wax drippings. The histology of these has not been described.⁴⁰

Pars planitis is a vasculitis of peripheral retinal vessels, which leads to accumulation of inflammatory cells in overlying vitreous. They settle inferiorly to form snowbanks. Clinically, this is a nongranulomatous inflammation; however, epithelioid histiocytes and giant cells have been described in the vitrectomy specimens from two patients with pars planitis.⁴¹

VITREOUS HEMORRHAGE

Vitreous hemorrhage (Fig. 4) has various causes. Literally, of course, the term is a misnomer; the vitreous is avascular, so that blood in normal vitreous is the result of hemorrhage from adjacent structures.⁴²

Vitreous hemorrhage can occur within the substance of the vitreous, between the vitreous and the retina (subvitreal or subhyaloid, (Fig. 5), or just beneath the internal limiting membrane of the retina (actually an intraretinal hemorrhage) (Fig. 6). Clinically, hemorrhages in the latter two locations are similar in appearance, except that when the blood is beneath the internal limiting membrane, Gunn's dots, the footplates of Müller cells, are visible ophthalmoscopically.

Trauma, either blunt or penetrating, is a frequent cause of vitreous hemorrhage, and the hemorrhage can be massive. Additionally, retinal tears often occur across a vessel, resulting in bleeding into the vitreous.

One recently characterized special form of trauma is shaken-baby syndrome. With shaking, a repeated flexion-extension injury is created because the baby's head is relatively large compared with the body and because the neck musculature is weak. At least some cases have been caused by shaking alone, although in most patients, there is also direct trauma to the head.⁴³ The classic findings include a partial vitreous detachment, circumferential retinal folds in the posterior pole, and hemorrhage in the retina and vitreous.⁴⁴ The severity of the ocular hemorrhages can predict neurologic injury.⁴⁵

Terson syndrome consists of vitreous hemorrhage along with subarachnoid hemorrhage, which results from sudden increased intracranial pressure from any cause. Histologically, blood is found in the sub-arachnoid space surrounding the optic nerve, in the retina, and in the overlying vitreous.⁴⁶

Intraocular causes of vitreous hemorrhage include retinal neovascularization. The most common cause of proliferative retinopathy is diabetic retinopathy;⁴⁷ however, any cause of retinal neovascularization, such as sickle cell disease⁴⁸ and branch retinal vein occlusion,⁴⁹ can also lead to vitreous hemorrhage. The vitreous acts as a framework for neovascular proliferation along the posterior surface or into the substance of the vitreous. With traction, the new vessels bleed.

Extravasated erythrocytes degenerate with time, so that old blood may appear yellow or white clinically. Histologically, the degenerated erythrocytes lose their hemoglobin and normal biconcave shape and become spherical red cell ghosts. Crystals of free hemoglobin can also be present.³⁵ The iron in hemoglobin is oxidized to the ferric form as the hemoglobin is degraded, producing a positive reaction with Perl's Prussian blue stain. These altered forms of erythrocytes may migrate anteriorly and cause secondary hemolytic (ghost cell) glaucoma.⁵⁰

Another sequela of vitreous hemorrhage is fibrous proliferation and shrinkage. The blood itself acts as a scaffold for fibrous proliferation, and preretinal neovascularization is accompanied by fibrous ingrowth. Fibrous proliferation can lead to traction retinal detachment.¹⁰

One result of old vitreous hemorrhage is synchysis scintillans, also sometimes called iridescent particles or cholesterolsis bulbi. These particles are cholesterol crystals, which appear shiny, flat, angular, and golden. They can be confused with asteroid hyalosis, although the latter particles are whitish and round. Another difference is that, unlike asteroid bodies, the cholesterol crystals are not attached to the fluid vitreous and tend to sink unless the eye is moved.⁵¹

The clinical observation of synchysis scintillans is relatively rare because old trauma usually leads to fibrosis and other secondary changes, in addition to the hemorrhage, and the crystals may not be visible. Histologically, however, cholesterol crystals are frequently found as a sequela of old intraocular hemorrhage (Fig. 7). The cholesterol dissolves out during processing, leaving slit-shaped clefts. Frequently, these elicit a foreign body giant cell reaction.⁵²

Pigment in the vitreous, when not caused by hemorrhage, is the result of previous trauma (including surgical trauma), inflammation, or retinal detachment.

CELLS

Malignancies of all types, both primary ocular and metastatic, can extend or metastasize to the vitreous cavity.

Endophytic retinoblastoma extends from the retina into the vitreous space, and fragments of the tumor can break free. This is an ominous prognostic sign because therapy directed at saving the eye while obliterating the tumor tends to be relatively ineffective at reaching retinoblastoma cells in the vitreous. These tumor seeds frequently become cystic as the inner cells of the cluster become necrotic from a lack of blood supply.⁵³

Malignant melanoma of the choroid typically causes thinning and cystic degeneration of the overlying retina. Less commonly, the retina may be entirely obliterated at the apex of the tumor, allowing melanoma cells to proliferate along the retinal surface and into the vitreous.^54,55 Melanoma cells can also be released into the vitreous as the result of hemorrhage into the tumor.⁵⁶

Medulloepithelioma is a tumor of the ciliary body epithelium. The tumor tends to grow as cysts, which sometimes detach and become free floating in the vitreous or even the anterior chamber. Because normal nonpigmented epithelium produces secondary vitreous, the cyst contents are filled with vitreouslike fluid.⁵⁷

Vitreous cells are sometimes the first manifestation of metastatic disease.⁵⁸ The choroid is the most common site of metastases from malignancies elsewhere in the body; however, tumors occasionally metastasize to the retina.⁵⁹ When this occurs or if choroidal tumor growth is so massive as to perforate the retina, cells extend into the vitreous. Examples of malignant cells in the vitreous include metastatic malignant melanoma,⁶⁰ breast carcinoma,⁵⁸ and mycosis fungoides.⁶¹ The diagnosis of metastatic disease can be made on vitreous biopsy.⁶² Leukemic cells can invade the vitreous from contiguous structures; this involvement means that vitrectomy can be used to diagnose the disease or a relapse.³⁵

An uncommon cause of apparent vitritis in older patients is ocular-central nervous system lymph-oma.⁶³ The cell of origin usually is the B lymphocyte. More rarely, however, the malignancy is derived from null cells, T lymphocytes, or histiocytes.⁶⁴ Response to therapy is limited, and prognosis for this type of lymphoma is poor, although the cells are radiosensitive.⁶⁵ Diagnostic vitrectomy discloses large cells that contain scant cytoplasm, coarse, clumped nuclear chromatin, and characteristic nuclear infolding.⁶⁶ Similar cells sometimes are found beneath the retinal pigment epithelium and in the brain.⁶³

OTHER OPACITIES

A relatively common vitreous opacity is asteroid hyalosis (Fig. 8). Some authors have found asteroid hyalosis to be more common in patients with diabetes mellitus,⁶⁷ but others have found no association.⁵¹ Patients with asteroid hyalosis are less likely to have posterior vitreous detachment.⁵¹ These spherical particles are suspended in intact vitreous and are usually of no visual consequence. Histologically, the particles appear granular and rather structureless, stain positively for lipid and for calcium, and can show focal birefringence under polarized light. Sometimes these particles incite a foreign body giant cell reaction.⁶⁸ By electron microscopy, asteroid bodies contain a granular matrix with multilaminar lipid membranes.⁶⁹ By x-ray microanalysis, they contain complex lipids, calcium, and phosphorus.^69,70

Amyloid protein can be deposited in the vitreous in familial and nonfamilial systemic amyloidosis. Several types of primary systemic familial amyloidosis with peripheral neuropathy exist; type 1 (Portuguese-Japanese) and type 2 (Indiana-Maryland) can cause diffuse vitreous deposits of amyloid, sometimes before other systemic manifestations.⁷¹ Several cases of primary systemic nonfamilial amyloid have also been reported; in one case, the amyloid simulated a bilateral vitreous hemorrhage.⁷²

Vitrectomy can be diagnostic and therapeutic, revealing Congo red-positive particles that show characteristic birefringence and dichroism with polarized light. Amyloid also stains with crystal violet and is fluorescent with thioflavin T stain. Ultrastructurally, amyloid consists of nonbranching fibrils of varying length that are 7 to 10 nm in diameter.⁷³ Transthyretin has been shown to be a major constituent of the amyloid in systemic types 1 and 2 and the vitreous amyloid in nonfamilial amyloidosis.⁷¹

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