Proliferative vitreoretinopathy (PVR) is a disease that develops as a complication of rhegmatogenous

retinal detachment Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...

. PVR occurs in about 8–10% of patients undergoing primary retinal detachment surgery and prevents the successful surgical repair of rhegmatogenous retinal detachment. PVR can be treated with surgery to reattach the detached

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

but the visual outcome of the surgery is very poor. A number of studies have explored various possible adjunctive agents for the prevention and treatment of PVR, such as

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

, although none have yet been licensed for clinical use. PVR was originally referred to as massive vitreous retraction and then as massive periretinal proliferation. The name Proliferative vitreo retinopathy was provided in 1989 by the Silicone Oil Study group. The name is derived from ''proliferation'' (by the

retinal pigment epithelial The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual ce ...

and

glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

s) and ''vitreo retinopathy'' to include the tissues which are affected, namely the

vitreous humor The vitreous body (''vitreous'' meaning "glass-like"; , ) is the clear gel that fills the space between the lens and the retina of the eyeball (the vitreous chamber) in humans and other vertebrates. It is often referred to as the vitreous humor ...

(or simply vitreous) and the

Predisposing factors

Predisposing factors for Postoperative PVR are preoperative PVR,

aphakia Aphakia is the absence of the lens of the eye, due to surgical removal, such as in cataract surgery, a perforating wound or ulcer, or congenital anomaly. It causes a loss of accommodation, high degree of farsightedness (hyperopia), and a deep a ...

, high levels of vitreous proteins, duration of retinal detachment before corrective surgery, the size of the retinal hole or tear, intra-ocular inflammation, vitreous hemorrhage, and trauma to the eye. An equation to calculate the patient's risk for acquiring PVR is: :PVR score = 2.88 × (Grade C PVR)+ 1.85 × (Grade B PVR) + 2.92 × (aphakia) + 1.77 × (anterior

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

) + 1.23 × (quadrants of detachment) + 0.83 × (vitreous haemorrhage) + 23 × (previous cryotherapy) 1 is added if the risk factor is present and 0 if the risk factor is absent. A patient is at a high risk for developing PVR if their PVR score is >6.33.

Pathology

During rhegmatogenous retinal detachment, fluid from the

enters a retinal hole. The mechanisms by which retinal holes or tears form are not fully understood yet. The accumulation of fluid in the subretinal space and the tractional force of the vitreous on the retina result in rhegmatogenous retinal detachment. During this process the retinal cell layers come in contact with vitreous cytokines. These cytokines trigger the ability of the

retinal pigmented epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual c ...

(RPE) to proliferate and migrate. The process involved resembles fibrotic wound healing by the RPE cells. The RPE cells undergo epithelial-mesenchymal transition (EMT) and develop the ability to migrate out into the vitreous. During this process the RPE cell layer-neural retinal adhesion and RPE-ECM (

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

) adhesions are lost. The RPE cells lay down fibrotic membranes while they migrate and these membranes contract and pull at the retina. All these finally lead to secondary retinal detachment after primary retinal detachment surgery. A number of studies have also shown that

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

metabolic cascade (one of the major inflammatory cascades) is important in the development of PVR.

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene. ...

expression was found in human idiopathic epiretinal membranes.

Phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyce ...

and

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prosta ...

blocking reduced structural abnormalities of the rat retina in

concanavalin Concanavalin A (ConA) is a lectin (carbohydrate-binding protein) originally extracted from the jack-bean (''Canavalia ensiformis''). It is a member of the legume lectin family. It binds specifically to certain structures found in various sugars, ...

model of PVR and reduced the frequency of membrane formation by 43% in the dispase model of PVR and by 31% in the

one.

Lornoxicam Lornoxicam, also known as chlortenoxicam, is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic (pain relieving), anti-inflammatory and antipyretic (fever reducing) properties. It is available in oral and parentera ...

not only normalized the expression of cyclooxygenases in both models of PVR, but also neutralized the changes of the retina and the choroid thickness caused by the injection of pro-inflammatory agents. PVR is graded as Grade A, B, or C by the Silicone Oil Study and as Grade A, B, C, or D by the

Retina Society Terminology Committee The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

. *Grade A is characterized by the appearance of vitreous haze and RPE cells in the vitreous. *Grade B is characterized by wrinkling of the edges of the retinal tear or the inner retinal surface. *Grade C is characterized by the presence of retinal membranes.

Retinal membranes

The RPE cells migrate out into the vitreous, proliferate excessively and lay down ECM on both side sides of the detached retina. The ECM laid on the vitreous side of the retina are referred to as epiretinal or preretinal membranes (ERM) and those laid down between the RPE layer and the photoreceptors are referred to as subretinal or retroretinal membranes (SRM) . The two membranes differ in composition in that the ERM is composed of RPE cells, glial cells,

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s and

fibrocyte A fibrocyte is an inactive mesenchymal cell, that is, a cell showing minimal cytoplasm, limited amounts of rough endoplasmic reticulum and lacks biochemical evidence of protein synthesis. The term ''fibrocyte'' contrasts with the term ''fibrobla ...

s, while the SRM is rich in RPE cells. The subretinal membranes are of two types. One forms as diffuse sheets, which are not contractile and either lack or contain very little ECM. The presence of this type of membrane does not usually affect retinal reattachment surgery. The retina can be reattached even with the membrane in place. The other type forms as very thick contractile membranes which pull at the retina. These are opaque and block the light falling on the retina so the retinal reattachment surgery needs to be performed after manually peeling the membrane off.

Cytokines involved in PVR

A number of cytokines such as

tumor necrosis factor alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

(TNFα),

transforming growth factor Transforming growth factor (, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ. The name "Transforming Growth Factor" is somewhat arbitrary, since the two classes of TGFs are not structurally or genetically rel ...

beta 2 (TGFβ₂),

platelet derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...

(PDGF) and

interleukins Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and relate ...

have been shown to play a role in PVR progression. TGFβ₂ levels have been shown to be elevated up to three times normal during the progression of PVR. TGFβ₂ is the most predominant

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

in the eye and is secreted as a latent inactive

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

into the vitreous by epithelial cells of the

ciliary body The ciliary body is a part of the eye that includes the ciliary muscle, which controls the shape of the lens, and the ciliary epithelium, which produces the aqueous humor. The aqueous humor is produced in the non-pigmented portion of the ciliar ...

and the lens epithelium and is also produced by the RPE cells and the

Muller cell Muller is a surname. Notable people with the surname include: A–H * A. Charles Muller (born 1953), translator *Bauke Muller (born 1962), Dutch bridge player *Bennie Muller (born 1938), Dutch footballer *Bill Muller (1965–2007), US journalist ...

s of the retina. TGFβ₂ is known to induce EMT in RPE cells and fibrosis in the eye. Expression of PDGF in particular PDGF-AA is triggered during ocular injury and contributes to PVR pathology. RPE cells express the receptor for

hepatocyte growth factor Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts o ...

(HGF). HGF stimulates RPE cell migration and its presence is also strongly detected in retinal membranes. Interleukin 6 levels are elevated in the vitreous humor during PVR.

References

External links

GeneReviews/NCBI/NIH/UW entry on VCAN-Related Vitreoretinopathy
{{DEFAULTSORT:Proliferative vitreoretinopathy Eye diseases