Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

Figure 12 An example of choroideremia demonstrating large areas of chorioretinal atrophy with some macular sparing.

and RP. Treatment with combined vitamin A and vitamin E has been shown to prevent or slow retinal degeneration and, in rare patients, reverse the dark adaptation and ERG defects.

Alstro¨m Syndrome

Alstro¨m syndrome is an autosomal recessive disease characterized by deafness, obesity, diabetes, cardiomyopathy, and RP. This syndrome shares many overlapping features with Bardet–Biedl syndrome (BBS) and, indeed, much like the genes implicated in BBS, the gene involved in this syndrome, Alstro¨m syndrome 1 (ALMS1), is thought to play an important role in the structure and function of the cilium.

Bardet–Biedl Syndrome

The details on Bardet–Biedl syndrome are discussed elsewhere in this encyclopedia.

Chronic Progressive External Ophthalmoplegia/

Kearns–Sayre Syndrome

Chronic progressive external ophthalmoplegia (CPEO) and Kearns–Sayre syndrome are mitochondrial myopathies that cause progressive muscle paralysis and pigmentary retinal degeneration. Kearns–Sayre syndrome is associated with sudden cardiac death.

Friedreich’s Ataxia

This is an autosomal recessive neurodegenerative disease caused by a trinucleotide repeat expansion in an intron of the frataxin gene (FXN), leading to silencing of the gene’s

protein product, frataxin. The resulting disease causes muscle weakness, ataxia, cardiac hypertrophy, deafness, and retinal degeneration.

Vitamin E Deficiency

Mutations in the alpha-tocopherol transferase protein gene lead to vitamin E deficiency and cause a Friedreich-like ataxia associated with RP. Treatment with oral vitamin E has been shown to halt both the neurological and visual manifestations of this disease.

Incontinentia Pigmenti (Bloch–Schulzberg

Syndrome)

Incontinentia pigmenti (Bloch–Schulzberg syndrome) is an X-linked dominant disorder caused by mutations in the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) essential modulator gene, NEMO, and is usually lethal in males. Affected females demonstrate abnormal teeth and nails, hyperpigmentation of the skin, and central nervous system defects. Retinal findings in these patients include peripheral telangiectasias, hypopigmentation of the fundus, and a pigmentary retinopathy.

Joubert Syndrome

Also known as cerebellooculorenal syndrome, Joubert syndrome is an autosomal recessive disease caused by mutations in 11 different genes. One causative gene, the centrosomal protein 290 (CEP290), has also been associated with Senior–Loken syndrome and nonsyndromic Leber congenital amaurosis. Patients with Joubert syndrome have hypoplasia of the cerebellar vermis, and also renal problems and retinal dystrophy. The hypoplasia of the cerebellar peduncles of the midbrain creates a characteristic radiological finding on CT scans termed the molar tooth sign.

Mucopolysaccharide Disorders

Mucopolysaccharide (MPS) disorders can also present with a pigmented retinopathy, some examples of which are Hurler syndrome (MPS type IH), Scheie syndrome (MPS type IS), and Hunter syndrome (MPS type II).

Neuronal Ceroid Lipofuscinosis (Batten

Disease)

Neuronal ceroid lipofuscinosis (Batten disease) is a group of autosomal recessive neurodegenerative diseases that result from the accumulation of lipofuscin. This disease is characterized by vision loss, seizures, progressive motor and cognitive dysfunction, and retinal degeneration. Eight genes (CLN1–CLN8) have been associated with this disease.

Infantile Refsum Disease

This disease is caused by defective peroxisomes and patients with this disease present with RP, hearing loss, hepatomegaly, and mental retardation. Unlike the adult form of the disease where specific peroxisomal enzymes are defective, the infantile form is characterized by a complete defect in perixosomal biogenesis. Levels of phytanic acid, very long chain fatty acids, and pipecolic acids are elevated. The disease is ultimately fatal.

Adult Refsum Disease

This disease is an autosomal recessive peroxisomal disorder characterized by elevated levels of phytanic acid, which lead to RP, anosmia, deafness, ataxia, cardiac arrhythmias, skeletal anomalies, and polyneuropathy. Mutations in the gene PAHX, which encodes phytanoylCoA 2-dydroxylases, have been shown to be responsible for some cases of adult Refsum disease. Treatment for adult Refsum disease includes plasmapheresis and dietary restrictions of phytanic acid and its precursors.

Senior–Loken Syndrome

This syndrome is an autosomal recessive disease that also falls under the umbrella of ciliopathies and can share some of the same features as Joubert syndrome (see the section titled ‘Syndromic forms of RP’). This disease is characterized by Leber’s congenital amaurosis and nephronophthisis (cystic kidneys).

Spinocerebellar Ataxia Type 7

This is an autosomal dominant neurodegenerative disease caused by a trinucleotide expansion in the ataxin 7 gene (ATXN7). The disease is characterized by cerebellar ataxias, dysphagia, dysarthria, and a cone–rod dystrophy.

Usher Syndrome

The details of Usher Syndrome are discussed elsewhere in this encyclopedia.

Visual Testing in RP

Terminology of Light Adaptation

The retina can respond to an astonishing 9 log units of light. Rods and cones differ in their sensitivity, temporal characteristics, and response to background lights. Depending on the intensity of a stimulus and background light present, different classes of cells respond. Scotopic refers to conditions under which only rods are functional. Mesopic refers to conditions under which both rods and cones are functional. Photopic refers to conditions under which only cones are functional.

Dark Adaptation

Dark adaption is measured with a Goldmann–Weekers dark adaptometer. Each eye is tested separately by first bleaching the rod and cone photopigments with an intense light and then measuring the brightness of a second light needed to achieve a threshold response. A dark adaptation curve can be drawn by repeating this threshold measurement over time after the bleaching light has been turned off. The normal recovery curve can be separated into two segments. The first segment occurs as cones recover from the bleaching light. The rods are much slower to recover and contribute to the second segment of the curve.

Visual Fields

The details on visual fields are discussed elsewhere in this encyclopedia.

ERG Terminology

The ERG is a fundamentally important test for studying RP and allied disorders. Different forms of RP can be classified based on the ERG response. Just as the electrocardiogram (EKG) measures the electrical activity of the heart through surface electrodes placed on the chest, the ERG measures the electrical activity generated by the retina to flashes of light through electrodes placed on the eye. The standard ERG is most commonly measured using an electrode embedded in a contact lens. Reference electrodes are placed on the forehead and ears. The International Society of Clinical Electrophysiology in Vision (ISCEV) has developed standardized methods for eliciting and recording the ERG.

Full-Field ERG

With the full-field ERG, flashes of light are delivered into a Ganzfeld diffuser, which ensures a uniform distribution of the light to the retina. It is important to realize that the full-field ERG measures a summed response from all of the cells in the retina. Therefore, the visual acuity and the ERG response may not correlate. For example, a patient could have a small scar in the center of the fovea that significantly decreases the vision, but the recordings of the ERG could be normal; the opposite can also be true. A patient could have an extinguished ERG due to peripheral degeneration, but still maintain 20/20 visual acuity due to preservation of the central fovea. For this reason, it is important to correlate visual acuity and ERG recordings along with visual-field results.

b-wave

b-wave

a-wave

(a)

200 V

100 V

b-wave

50 V

20 ms a-wave

(d)

Multifocal ERG

The full-field ERG can demonstrate a large disparity between the ERG signal and the visual acuity. To better detect localized retinal dysfunction in the macula, the multifocal ERG (mfERG) is very useful. The mfERG uses an m-sequence-derived check board pattern to selectively stimulate and isolate electrical activity from the retina. Specifically, the mfERG tests the macula under mesopic or photopic conditions, and therefore is primarily indicative of macular cone function.

Rod-Isolated ERG Response

The ERG can be recorded under dark-adapted (scotopic) conditions or light-adapted (photopic) conditions. When dim flashes are delivered under scotopic conditions, only the rod photoreceptors are stimulated. Such a flash elicits a positive electrical potential termed the b-wave. The scotopic b-wave arises from responses elicited by the rod bipolar cells. As the intensity of the flash increases, the b-wave grows in amplitude and, at higher intensities, a negative potential generated by the rod photoreceptors emerges and is termed the a-wave. Oscillations imposed on the b-wave are generated by higher-order retinal circuitry and are termed the oscillatory potentials.

Mixed Rod–Cone ERG Response

At even higher intensities, both the rod and cone photoreceptors are stimulated to generate a mixed scotopic response. Contributions from the cones contribute to the growing a-wave, while activity of the cone bipolar cells contributes to the b-wave. Once the intensity of the light has become intense enough to saturate the photoreceptors, the a-wave will cease to increase in amplitude.

The amplitude from baseline to the peak of the a-wave is termed the saturated a-wave amplitude and the time to the peak of the a-wave is the implicit time. The b-wave amplitude is measured from the trough of the a-wave to the peak of the b-wave.

Cone-Isolated ERG Response

The electrical activity of the cone photoreceptors can be isolated in two ways. The first is to measure the response to 30-Hz flicker flashes for which the cones have sufficient time to recover but the rods do not. The repetitive stimulus elicits a sinusoidal-like response. The peak-to-peak amplitude and the time to peak of this response relative to the stimulus can both be measured. The second method is to turn on a background light, which saturates the rod photoreceptors but minimally affects the cones (photopic conditions). Flashes under these conditions will elicit a cone-driven a-wave and b-wave as well as oscillatory potentials (Figure 13).

See also: Anatomically Separate Rod and Cone Signaling Pathways; Non-Invasive Testing Methods: Multifocal Electrophysiology; Primary Photoreceptor Degenerations: Retinitis Pigmentosa; Secondary Photoreceptor Degenerations: Age-Related Macular Degeneration.

Further Reading

Berson, E. L., Rosner, B., Sandberg, M. A., et al. (1993). A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Archives of Ophthalmology 111: 761–772.

Berson, E. L., Rosner, B., Sandberg, M. A., et al. (2004). Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Archives of Ophthalmology 122: 1297–1305.

Fishman, G. A., Farber, M. D., and Derlacki, D. J. (1988). X-linked retinitis pigmentosa. Profile of clinical findings. Archives of Ophthalmology 106: 369–375.

Grant, C. A. and Berson, E. L. (2001). Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.

International Ophthalmology Clinics 41: 103–110.

Grover, S., Fishman, G. A., Anderson, R. J., et al. (1999). Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older. Ophthalmology 106: 1780–1785.

Hamel, C. P. (2007). Cone rod dystrophies. Orphanet Journal of Rare Diseases 2: 7.

Hartong, D. T., Berson, E. L., and Dryja, T. P. (2006). Retinitis pigmentosa. Lancet 368: 1795–1809.

Heckenlively, J. R. (1988). Retinitis Pigmentosa. Philadelphia, PA: Lippincott.

Hoffman, D. R., Locke, K. G., Wheaton, D. H., et al. (2004).

A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. American Journal of Ophthalmology 137: 704–718.

Radu, R. A., Yuan, Q., Hu, J., et al. (2008). Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for

ABCA4-mediated retinal dystrophies following vitamin

A supplementation. Investigative Ophthalmology and Visual Science 49: 3821–3829.

Sieving, P. A., Caruso, R. C., Tao, W., et al. (2006). Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proceedings of the National Academy of Sciences of the United States of America

103: 3896–3901.

Weleber, R. G. and Gregory-Evans, K. (2006). Retinitis pigmentosa and allied disorders. In: Ryan, S. J. (ed.) The Retina, pp. 395–498. Philadelphia, PA: Elsevier.

Relevant Websites

http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information, OMIM.

http://www.sph.uth.tmc.edu – The University of Texas School of Public Health, Retinal Information Network (Retnet).

Glossary

Cytokeratins – A family of proteins found in the cytoskeleton (intermediate filaments) of epithelial cells.

Glial fibrillary acidic protein – A protein found in the cytoskeleton (intermediate filaments) of glial cells.

Immunohistochemistry – The localization of antigens, especially proteins, in tissue sections by antigen-antibody reactions. The reaction sites are visualized by a label such as a chromogen (typically a brown or red dye).

Myofibroblast – A fibroblast-like cell with some of the features of smooth muscle, including contractile properties.

Introduction

In 1983, the Retina Society Terminology Committee published a landmark paper in which the term proliferative vitreoretinopathy (PVR) was proposed for a condition that had been recognized as the major cause of failure of retinal detachment surgery. Previous names for this disease included preretinal organization, massive vitreous retraction (MVR), massive preretinal retraction (MPR), and massive periretinal proliferation (MPP) – terms that highlighted some of the main clinical features of the disorder.

In this condition, following a retinal detachment, cells leave their normal location in the retina and migrate to the retinal surfaces. Here, the cells proliferate to form membranes. Although many of these membranes consist of only a thin layer of (glial) cells and produce no clinical problems or symptoms, in about 10% of retinal detachment patients the membranes develop into thicker scar-like tissues that are able to contract. It is this ability of the membranes to contract that leads to the clinical picture of PVR.

Definition

PVR is strictly defined as a complication of rhegmatogenous retinal detachment that is characterized by the formation of membranes on both surfaces of the detached retina and on the posterior surface of the detached vitreous gel.

Location of PVR Membranes

The membranes on the vitreous surface of the retina are usually called epiretinal membranes and these are the most common membranes of PVR. Membranes that form beneath the detached retina (i.e., between the neuroretina and the retinal pigment epithelium) are termed subor retro-retinal membranes. Membranes on the posterior surface of the vitreous gel are known as posterior hyaloid membranes and typically are continuous with epiretinal membranes in PVR (hence they tend to have a similar composition). The expression periretinal membrane is sometimes used to encompass all membranes around the retina.

In addition, membranes can extend into the vitreous base and anteriorly over the pars plicata to the back of the iris: a condition known as anterior PVR. There is also evidence that PVR can have a distinct component within the neuroretina itself – a situation that may be called intraretinal PVR (iPVR).

It is clear that cellular proliferation can occur at several of the above sites in the same eye. It is also important to recognize that membrane formation can occur in a wide variety of diseases other than retinal detachment. For example, the ischemic retinopathies can also lead to epiretinal and posterior hyaloid membranes although the membranes in these conditions are usually heavily vascularized and thus differ from PVR membranes (see below).

The Significance of Membrane

Formation in PVR

In PVR, the membranes may contract so that they exert traction on adjacent tissues. Epiretinal membranes tend to produce tangential traction on the retinal surface. The effect of this retinal traction is to cause retinal folding and/or (re)detachment of the sensory retina (Figure 1). Such an effect can be localized, as for example when an epiretinal membrane over the macular (epimacular membrane) causes folding of the macular (macular pucker) or in a peripheral membrane causes a star fold (Figure 2). On the other hand, epiretinal membranes may be diffuse, rather than localized, covering much of the retinal surface.

The traction from epiretinal membranes can be mild, causing no more than subtle surface wrinkling of the inner retina. Moderate traction can cause marked folds of the retina. Severe traction can be associated with

displacement of retinal vessels and ectopia of the fovea. The effect of the traction is, however, not just two dimensional (2-D). The newer generation of Optical Coherence Tomography systems provides high-resolution crosssectional views or reconstructed 3-D images of the retina (Figure 2). These images clearly show that the traction may be superficial but sometimes the whole thickness of the retina is involved. Thus, these signs can indicate the development of PVR.

Clinically, we often see the effect of traction rather than the epiretinal membranes themselves: on the attached retina, epiretinal membranes can be difficult to visualize (Figure 1). Nonetheless, the epiretinal membranes are present and exerting isometric’ traction on the retina. The effect of this traction may only become apparent once the retina becomes detached, at which point one may observe star folds or retinal breaks with rolled edges when the traction in the tissue is focal. In addition,

when the epiretinal membrane is diffuse, the detached retina will appear to have reduced mobility. Anterior PVR membranes will draw the pre-equatorial retina anteriorly toward the ciliary processes, whereas epiretinal membranes in the post-equatorial retina tend to contract the retina into a cone configuration. The combination of the anterior and posterior traction systems on a totally detached retina will give rise to a so-called closed funnel (Figure 3).

Subretinal membranes, particularly in the form of bands, are apt to elevate the neuroretina like a sheet on a washing line or, in the case of a circular band, like a napkin in a napkin ring. Posterior hyaloid membranes can produce circumferential or, if the vitreous base is involved, anteroposterior traction.

Particularly in eyes that have undergone previous vitrectomy or trauma, proliferative tissue can extend into the vitreous base and anteriorly toward the pars plicata of the ciliary body, the iris and even as far as the pupil margin. Traction in this latter situation may lead to traction on the ciliary body (hypotony can result) and posterior displacement of the iris.

The Cells Involved in PVR

It is now accepted that PVR combines reaction to damage by astrocytes of the central nervous system (gliosis) with fibrosis. In this context, the gliosis involves Mu¨ller cells and retinal astrocytes, while the fibrosis includes metaplasia or transdifferentiation of the retinal pigment epithelial (RPE) cells. Although retinal glia and RPE cells are thus major players in PVR, it is also apparent that a variety of other cell types are involved in the disease.

Figure 2 OCT image of retina showing a thin epiretinal membrane and subjacent retinal distortion.

Figure 3 Section through an eye with PVR and a closed-funnel retinal detachment. Retinal folds can be seen. The eye is aphakic and there are anterior PVR membranes that also involve the iris.

Glial Cells

There is compelling evidence from a variety of morphological, immunohistochemical, in vitro, and experimental studies that astrocytes and Mu¨ller cells are involved in PVR membranes, particularly in epiretinal and, to a lesser extent, subretinal membranes.

Within PVR epiretinal membranes, glial cells often form layers in the tissue (Figure 4). These layers are adherent to fibrous components of the membranes and, in both human and experimental PVR, the cells can sometimes be traced through defects in the retinal inner limiting lamina into the retina itself. These observations

have led to the concept that glial cells traversing the vitreoretinal interface serve to anchor the epiretinal membrane to the retina and that the epiretinal glia may form a substrate or scaffold that other cells might use to produce the rest of the epiretinal tissue. In support of this notion, experimental models have demonstrated that glial cells can break through the retinal inner limiting lamina early in the formation of epiretinal membranes and spread across the retinal surface to form sheets that other cells may adhere to. Failure of glial sheets to become populated by other cells may account for arrest of the disease process at an early stage and the production of asymptomatic or nonproblematic subtle membranes on either surface of the neuroretina.

RPE Cells

The same sorts of methods that were used to detect glia in PVR membranes have been employed to demonstrate RPE cells. Indeed, it is now widely accepted that RPE cells are major components of PVR membranes and the presence of large numbers of RPE cells in epiretinal membranes is one of the distinguishing factors between PVR membranes and epiretinal membranes caused by other diseases. Early in the development of PVR, RPE cells leave their normal location at the chorioretinal interface and either migrate or are swept with subretinal fluid movements to the surfaces of the detached retina. Here, the cells may attach to early membranes (Figure 4). In the case of epiretinal membranes, RPE cells may adhere to glia that have already arrived, while in subretinal membranes it has been suggested that the cells may in addition settle on fibrin deposits. Some RPE cells may also migrate into or through the neuroretina.

RPE cells have a remarkable propensity to undergo metaplasia or transdifferentiation. As a result, an RPE cell may change from a polarized, sedentary pigmented cuboidal epithelial cell to a nonpigmented fibroblastic cell, a migratory macrophage-like cell, a cell in a gland-like structure or even a bone-forming cell (Figure 4). In PVR membranes, RPE cells most often adopt fibroblastic or macrophagic phenotypes, though they may attempt to (re-)form a polarized monolayer as well.

Fibroblastic Cells

PVR membranes often have a substantial fibrous element that consists of fibroblastic cells in extracellular matrix. Many of these cells are of RPE origin (Figure 4). Others may be derived from perivascular sources such as adventitial cells of larger retinal vessels.

There has been much interest in the role of fibroblastic cells in PVR membranes for two reasons. First, they are believed to be responsible for generating most of the tractional forces within the tissue. Second, the cells are

thought to be responsible for the production of the bulk of the extracellular matrix in the membranes. There is still debate about how these cells may produce traction: theories include smooth muscle-like contraction of the (myofibroblastic) cells and cell–matrix interactions that cause shortening of matrix elements.

Macrophages

In addition to macrophagic RPE cells, macrophages of hematogenous origin are involved in PVR. Macrophages are especially abundant in membranes arising in the presence of some tamponade agents (see below).

Irrespective of their origin, macrophages are believed to have a number of important roles in PVR. In the early stages of the disease, they produce mitogens, chemotactic agents, and growth factors that probably have a role in cell recruitment to and proliferation in the membranes. Growth factors and enzymes produced by macrophages later in the disease process may be involved in matrix synthesis and remodeling.

Vascular Elements

Blood vessels are found in around 10–20% of PVR membranes but, in contrast to periretinal membranes of conditions such as central retinal vein occlusion and proliferative diabetic retinopathy, blood vessels usually do not form a major component of the tissue. However, vessels are probably more abundant in anterior PVR membranes (Figure 5).

Other Cells

T lymphocytes, including CD4 and CD8 positive cells, have been found in PVR membranes. Some of these cells express interleukin-2 receptor, suggesting that they are activated and capable of promoting the cellular events in the tissue. Ciliary body epithelial cells have been reported in the membranes of anterior PVR (Figure 5). Hyalocytelike cells have been described in epiretinal membranes generally and it has been suggested that hyalocytes may give rise to some of the fibroblastic and macrophagic cells in the epiretinal tissues. Recently, ganglion cell neurites have been observed in experimental and human epiand subretinal membranes. They are co-localized with glia, suggesting active outgrowth into the periretinal tissues.

The Extracellular Matrix in PVR

Membranes

PVR membranes contain a matrix that, in terms of composition, is similar to the one seen in a healing skin wound (Figure 6). These components include structural proteins

CE

(b)

Figure 5 Anterior PVR membrane extending over distorted ciliary epithelium (CE) in an enucleated eye. (a) Stained with the immunohistochemical method for the endothelial marker CD34: note that there are blood vessels in the membranes (arrows).

(b) Stained with the immunohistochemical method for cytokeratins: note that in addition to cells in the membranes (arrowheads), the CE normally expresses cytokeratins too. Thus, it is possible that at least some of the epithelial cells in anterior PVR membranes are of CB rather than RPE origin (hematoxylin counterstain, scale bar: 200 mm).

Figure 6 Section through a surgically excised PVR epiretinal membrane. The tissue contains a fibrous element (stars). Convoluted retinal internal limiting membrane is also present (arrows). Periodic acid Schiff reagent, hematoxylin counterstain. Scale bar: 50 mm.

such as collagens and elastic fiber precursors, adhesive glycoproteins like fibronectins and laminins, glycosaminoglycans, matricellular proteins such as tenascins and thrombospondins, and matrix enzymes like matrix metalloproteinases together with their inhibitors.

Much of the matrix in PVR is produced locally by the membrane cells themselves, though there is evidence that some components enter from elsewhere. For example, some blood derivatives like plasma fibronectin are found in PVR membranes. Irrespective of origin, the extracellular matrix in PVR membranes increases with time and there is a corresponding decrease in cellularity of the tissue. Indeed, this change in cellularity together with the contractile nature of the tissue and the presence of fibroblastic cells in matrix gave rise to comparisons between PVR membranes and healing wounds.

As in healing wounds generally, the matrix is more than a passive space filler: there is good evidence that PVR matrix is an important regulator of cell behavior (notably migration and proliferation) in the tissue. For example, there have been a number of reports demonstrating that cells in PVR membranes express a range of cell-surface receptors for the various matrix components around them (e.g., integrins) and experimental studies implicating the importance of such receptors in contraction in PVR models. Moreover, early matrix may have adhesive properties that aid cohesion of the developing tissue. There is also evidence of matrix remodeling in more established membranes. Longstanding PVR membranes are often densely fibrous. It is also worth noting that, when surgically excised, PVR membrane specimens often contain internal limiting membrane from the retina. This material tends to become convoluted in the tissue (Figure 6), presumably as a result of tractional forces upon it.

Pathogenesis and Natural History

Although the pathogenesis of PVR is not fully elucidated, our understanding of the disease is at the point where logical therapies can be designed and implemented.

Fundamental to the development of PVR is retinal detachment, itself dependent upon degenerative changes in the vitreous and retina. Vitreous degeneration (syneresis) is a normal aging process that can be accelerated by conditions such as myopia or trauma and results in the formation of fluid and formed components. Attachments between formed vitreous and retina may permit rotational tractional forces, such as dynamic traction from saccadic eye movements, to be transmitted between the two structures. In turn, a retinal tear may form and fluid vitreous pass through the hole in the retina to give rise to a (rhegmatogenous) retinal detachment.

There is experimental evidence that some changes associated with PVR can occur within a day of retinal