sign in sign up
<<
Home , Emmetropia, Floater

Progress in Retinal and Research 79 (2020) 100847

Contents lists available at ScienceDirect

Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/preteyeres

☆ Vitreous and Vision Degrading Myodesopsia T ∗ J. Sebaga,b,c, a VMR Institute for Vitreous Macula , Huntington Beach, CA, USA b Doheny Eye Institute, Pasadena, CA, USA c Department of , Geffen School of Medicine, University of California, Los Angeles, CA, USA

ARTICLE INFO ABSTRACT

Keywords: Macromolecules comprise only 2% of vitreous, yet are responsible for its gel state, transparency, and physiologic Vitreous function(s) within the eye. and aging alter collagen and hyaluronan association causing concurrent gel Myopia liquefaction and fibrous degeneration. The resulting vitreous opacities and collapse of the PVD during posterior vitreous detachment are the most common causes for the visual phenomenon of vitreous Vision degrading myodesopsia floaters. Previously considered innocuous, the vitreous opacities that cause floaters sometimes impact vision by Contrast sensitivity function profoundly degrading contrast sensitivity function and impairing quality-of-life. While many people adapt to vitreous floaters, clinically significant cases can be diagnosed with Vision Degrading Myodesopsia based upon echographic assessment of vitreous structure and by measuring contrast sensitivity function. Perhaps due to the ubiquity of floaters, the medical profession has to date largely ignored the plight of those with Vision Degrading Myodesopsia. Improved diagnostics will enable better disease staging and more accurate identification of severe cases that merit therapy. YAG laser treatments may occasionally be slightly effective, but vitrectomy is currently the definitive cure. Future developments will usher in more informative diagnostic approaches as well as safer and more effective therapeutic strategies. Improved laser treatments, new pharmacotherapies, and possibly non-invasive optical corrections are exciting new approaches to pursue. Ultimately, enhanced understanding of the underlying pathogenesis of Vision Degrading Myodesopsia should result in prevention, the ultimate goal of modern Medicine.

1. Introduction The role(s) of vitreous in normal ocular physiology is/are poorly understood, but probably quite important, especially with respect to Vitreous is the largest structure within the eye, yet our oxygen. The late David Beebe was a strong proponent of the importance understanding of this enigmatic tissue is perhaps less than any other of vitreous oxygen physiology regarding the and formation ocular structure (Sebag, 2009a). During the past several decades there (Beebe et al., 2011), while Stefánsson has underscored the role of has been an exponential expansion of vitreous knowledge. Sir Stewart vitreous oxygen metabolism as related to vitreous surgery (Stefánsson, Duke-Elder (1930) published a 72-page monograph that presented 2009), age-related (Stefánsson et al., 2011), and scientific observations on the nature of the vitreous body, but (Jonsdottir et al., 2018). An important aspect of how contained little clinical information. In 1989, a 173-page monograph vitreous modulates untoward effects of oxygen free radicals is the reviewed the physiologic and pathologic aspects of vitreous bridging presence of ascorbate. Studies have shown that although synthesized by the basic and clinical sciences (Sebag, 1989). Eisner (1973) followed by the , ascorbate levels are higher in the posterior vitreous Worst and Los (1995) published anatomical depictions of vitreous that than centrally (Murali et al., 2016), presumably to protect the retina were 192 and 150 pages long, respectively. By the turn of the century and from oxygen free radicals. Further evidence of a high the subject necessitated many co-authors and 528 pages to produce the degree of spatial organization derives from recent proteomic analyses of annual Rapport de la Société Française d’Ophtalmologie entitled four different areas of human vitreous, specifically the anterior hyaloid, Pathologie du Vitré (Brasseur, 2003). The fund of knowledge has since posterior vitreous cortex, central vitreous core, and vitreous base, expanded dramatically, so that in 2014 it took 90 co-authors and 925 concluding that proteins ostensibly localize to distinct vitreous sub­ pages to consider vitreous biochemistry, anatomy, physiology, pa­ structures to variably protect intraocular tissues from infection, oxida­ thology, surgery, and pharmacotherapy (Sebag, 2014a). tive stress, and energy disequilibrium (Skeie et al., 2015).

☆ Presented in part as The Inaugural Robert Machemer Keynote Lecture, European Society of Ophthalmology, Nice, France, June 14, 2019. ∗ 7677 Center Avenue, suite 400, Huntington Beach, CA, 92647, USA. E-mail address: [email protected]. https://doi.org/10.1016/j.preteyeres.2020.100847 Received 22 September 2019; Received in revised form 1 March 2020; Accepted 3 March 2020 Available online 06 March 2020 1350-9462/ © 2020 Published by Elsevier Ltd. J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

and those cases where vitreous floaters impact vision, primarily by degrading contrast sensitivity function (see below) creating considerable unhappiness and negatively impacting quality-of-life.

2. Vitreous biochemistry

The vitreous body is an extended extracellular matrix that fills the center of the eye with a clear viscous gel that has a dense peripheral cortex mistakenly referred to as the ‘hyaloid’, a term that should be reserved for the blood vessels of the embryonic vitreous. The peripheral vitreous cortex is attached to the basal laminae of surrounding cells. The two important structural macromolecules are hyaluronan (HA) and collagen, but more than 95% of the vitreous gel weight is water, with 15–20% of this water bound to glycosaminoglycans (GAGS), primarily HA. Viscosity arises, at least in part, from the viscoelastic HA, while the vitreous cortices [anterior (behind the lens) and posterior (anterior to Fig. 1. Human Vitreous Body. retina)] have significant amounts of collagen. HA is present inthe This specimen from a 9-month child has the , , and retina vitreous body of all species studied except for fishes (Crafoord et al., dissected off the vitreous body which is still attached to the anterior segment. 2014). Changes in vitreous collagen and viscosity of the gel vitreous Although situated on a surgical towel in room air, the vitreous body maintains play important roles in the development of vitreous floaters in aging its gel state because of the organization of its macromolecular components. and myopia. [Cover Photo, Sebag J: The Vitreous – Structure Function & Pathobiology. Springer-Verlag, New York, 1989; Specimen courtesy of New England Eye 2.1. Glycosaminoglycans (GAGs) Bank].

GAGs are polysaccharides with repeating disaccharide units consisting of hexosamine (N-acetyl glucosamine or galactosamine) glycosidically Vitreous may also be important in modulating growth of the eye by linked to either uronic (glucuronic or iduronic) acid or galactose. The generating internal swelling pressure and thus may play a role in the nature of the predominant repeating unit is characteristic for each GAG development of myopia, a burgeoning global epidemic (Holden et al., and the relative amount(s) and molecular size(s) and are said to be tissue 2016; Dong et al., 2019; Flitcroft et al., 2019). The viscoelasticity specific (Toledo and Dietrich, 1977). A sulfated group is attached to of vitreous has always seemed important as a shock absorber, a oxygen or nitrogen in all GAGs except HA. GAGs are synthesized directly phenomenon that has recently been studied experimentally (Shah et al., by adding sugar moieties to the protein core one by one, leading to the 2016). There are, of course, many roles for vitreous in retinal diseases formation of covalently-linked complex GAG chains, called proteoglycans. of various types (Sebag 1989, 2014a), but these will only briefly be There are three GAGs present in the vitreous body: hyaluronan discussed below, as they are not the focus of this review. Rather, (HA), chondroitin sulfate (CS) and heparan sulfate (HS). Studies in the vitreous clarity is the central theme. rabbit found a total vitreous GAG content of 58 ng with 13% CS and Invisible by design, vitreous is a remarkable extracellular matrix in 0.5% HS (Kamei and Totani, 1982). More recent studies in bovine that it is 98% water, yet it forms as an exquisite clear gel that fills the vitreous also found a predominance of HA (96.2%), with 3.5% CS, and center of the eye (Fig. 1). Many aspects of vitreous seem teleologically 0.3% HS (Peng et al., 2018). suited to achieve this principal role – to maintain central clarity. However, beginning early in life this changes and rearrange­ 2.1.1. Hyaluronan (HA) ment of the molecular constituents results in a variety of effects that Although HA is found throughout the body, Meyer and Palmer contribute to vision loss. It is not known whether these early changes (1934) first isolated this macromolecule from bovine vitreous. Thus, are due to developmental irregularities in fetal vitreous vasculature HA's former name derived from its site of discovery, i.e. the colorless regression that is in turn somehow related to the developmental clear vitreous (“hyalos” means glass, in Greek), and that it contains anomaly of myopia, but this is plausible, since myopic vitreopathy is uronic acid. The term “hyaluronic acid” was replaced in 1986 by the second leading cause of visually disturbing “floaters”. However, the Endre Balazs and colleagues with “hyaluronan” to conform with the most common cause of this visual phenomenon is related to aging when international nomenclature of polysaccharides (Balazs et al., 1986). The the vitreous body collapses and the posterior vitreous cortex separates new term also encompasses the different forms that the molecule can from the retina. Prevalent throughout human experience, vitreous attain, from the acid form (hyaluronic acid) to the salt (sodium floaters are often not severe, and many people are able to cope. hyaluronate) which forms at physiologic pH. The synthesis, However, in a surprisingly large number of individuals there is de­ degradation, physiologic properties, and roles of endogenous HA, as gradation of vision and patients are miserable, experiencing a well as pharmacokinetics and medical applications of exogenous HA significantly negative impact on their quality-of-life. In such instances, have been reviewed by Necas et al. (2008), where they emphasize the term “floaters” is not an adequate embodiment of the patient interactions with CD44, a ubiquitous transmembrane HA receptor, experience. Indeed, if certain structural and functional findings are suggesting an important role in various physiologic processes at the present (see below), the diagnosis of Vision Degrading Myodesopsia is cellular level, opening new avenues for commercial biomedical applicable. “Myodesopsia” is a term for floaters that is derived from developments (Kim et al., 2017a). Of great relevance to vision are the Greek [myiodes = flylike, + opsis = vision]. anti-inflammatory and anti-cicatricial properties of HA(Necas et al., This treatise will review the current state of knowledge regarding 2008) that promote transparency within the center of the eye. Changes vitreous biochemistry, morphology and physiology in development, in this property may play a role in the loss of transparency with Vision aging, diabetes, and myopia, emphasizing those aspects that are Degrading Myodesopsia. important to a better understanding and management of Vision HA is a long, unbranched polymer of repeating glucuronic acid Degrading Myodesopsia. This term has been coined to distinguish β-1,3-N,N-acetylglucosamine disaccharide moieties linked by β 1–4 between vitreous floaters, which are often not significantly bothersome, bonds (Swann, 1980), with a molecular weight of 3–4.5 × 106 in adult

2 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 human vitreous (Balazs, 1984). The HA polymer is a linear, left-handed, 2.1.2. Chondroitin sulfate (CS) three-fold helix with a rise per disaccharide on the helix axis of 0.98 nm CS is a major component of extracellular matrices throughout the (Sheehan et al., 1975). This periodicity can vary, however, depending body, including vitreous. John Scott (1992) proposed a role for CS in on whether the helix is in a “compressed” or “extended” configuration mediating interaction between HA and collagen in forming the (Chakrabarti and Park, 1980). Changes in the degree of “extension” of supramolecular organization of vitreous. More recent studies identified HA could be substantial, since the volume of the unhydrated HA that vitreous contains two chondroitin sulfate (CS) proteoglycans. The molecule is about 0.66 cm3/g, whereas the hydrated specific volume is minor type is actually type IX collagen (see below). The majority of 2000 to 3000 cm3/g (Balazs, 1984). Thus, the state of hydration of the vitreous CS is in the form of versican, whose concentration is 0.06 mg vitreous body and surrounding tissues can have significant influence on protein/mL, about 5% of the total protein content (Theocharis et al., the size and configuration of the HA molecular network. HA also 2002). This large proteoglycan has a globular N-terminus that binds HA interacts with the surrounding mobile ions and can undergo changes in via a 45-kDa link protein (Reardon et al., 1998). In human (but not its conformation that are induced by changes in the surrounding ionic bovine) vitreous, versican is believed to form complexes with HA as milieu (Comper and Laurent, 1978). A decrease in surrounding ionic well as microfibrillar proteins, such as fibulin-1 and fibulin-2 (Bishop, strength can cause the anionic charges on the polysaccharide backbone 2000). A mutation in the gene for versican CS was found to be the to repel one another, resulting in an extended configuration of the cause for profound vitreous liquefaction in Wagner's vitreo-retinal macromolecule. An increase in surrounding ionic strength can cause degeneration (Kloeckener-Gruissem et al., 2006). contraction of the molecule and, in turn, the entire vitreous body. A Elegant experiments by the late David Beebe's group used CS compressed HA chain has extensive “interdigitations” since it interacts proteoglycan mimics designed to bind to type II collagen in an attempt with nearest antiparallel as well as parallel neighbors (totaling to promote/maintain vitreous gel structure (Zhang et al., 2014). They 8 molecules), whereas extended forms only interact with 3 antiparallel found that CS protected against vitreous liquefaction induced by trypsin neighbors (Chakrabarti and Park, 1980). As a result of HA's digestion but less so than digestion by collagenase treatment. Western entanglement within the vitreous collagen fibril matrix, this mechanical blots indicated that the mimics provided only marginal protection force can be transmitted to the retina, optic disc, and other structures, against soluble collagen degradation, but deep-etch electron such as neovascular complexes. This can be important in certain microscopy showed increased density and isotropy of microstructural pathologic conditions that feature fluctuations in ionic balance and components in mimic-treated vitreous, suggesting that vitreous hydration, such as diabetes (Sebag, 1996) where the effects upon the structure was preserved. The authors proposed that proteoglycan optic disc and retina can be profound, especially in children with type I mimics may be useful in delaying or preventing degradation of the diabetes who have a solid vitreous body that is firmly adherent to the vitreous body with aging and disease, perhaps preventing Vision retina (Rosen et al., 2020). Degrading Myodesopsia. Because the solution domains are so large, the long unbranched HA chains form widely open coils, which at concentrations greater than 2.1.3. Heparan sulfate (HS) 1 mg/cm3, become highly entangled (Comper and Laurent, 1978). Balazs et al. (1958) first documented sulfated galactosamine-containing Entanglement in vitreous causes HA to act much like an ion-exchange GAGs in bovine vitreous (less than 5% HS). Breen et al. (1977) and Allen resin where electrostatic interactions occur between the small charges et al. (1977) identified these as chondroitin-4-sulfate and undersulfated of mobile ions in vitreous and surrounding tissues and the electrostatic heparan sulfate. Studies in the rabbit (Kamei and Totani, 1982) found a envelope of the stationary polyelectrolyte. This electrostatic interaction total vitreous GAG content of 58 ng with 13% CS and 0.5% HS, while more forms the basis for various properties of HA including its influence upon recent studies in bovine vitreous found 96.2% HA, 3.5% CS, and 0.3% HS osmotic pressure, ion transport and distribution, and electric potentials with an average molecular weight of 148 kDa for CS and 204 kDa for HS within the vitreous body (Comper and Laurent, 1978). Electrostatic (Peng et al., 2018). Although HS is present in vitreous in only small effects have also recently been shown to influence vitreous collagen amounts, it is presumed to be important in transparency by maintaining an fibril assembly (Morozona and Muthukumar, 2018). These interactions adequate distance between vitreous collagen fibrils (Goes et al., 2005). between HA and the other components of the extracellular matrix can Indeed, Peng et al. (2018) used surface plasmon resonance to identify that have important influence on the formation of opacities within the HS has a higher binding affinity (755 nM) than CS to type II collagen, vitreous body, especially the cross-linking and aggregation of collagen which is the predominant collagen type in vitreous (see below). which underlies the formation of vitreous opacities in myopia and Two specialized heparan sulfate proteoglycans that are present in aging. the inner limiting membrane of the retina and vitreous body are agrin HA first appears in vitreous after birth, probably synthesized and type XVIII collagen. (Bishop, 2014). It is unclear whether they play primarily by hyalocytes, though this remains to be proven. Other a role in maintaining the structural stability of the vitreous gel or plausible candidates are the ciliary body and retinal Müller cells. In whether their presence in vitreous represents a by-product of bovine vitreous there are age-related differences, with HA molecular ILM synthesis/degradation, but type XVIII collagen has potent weight dropping from 3 x l06 in newborn calves to 0.5 x l06 in old anti-angiogenic properties (Heljasvaara et al., 2017), likely contributing cattle. Whereas HA synthesis continues in the adult, there does not to the maintenance of vitreous clarity. appear to be extracellular degradation (Sheehan et al., 1975; Balazs, 1984; Swann et al., 1976). Rather, homeostatic levels of HA are 2.2. Vitreous collagens presumably maintained via outflow in aqueous, since HA is known to exit the eye via the anterior chamber (Laurent and Fraser, 1983). Egress Vitreous collagen synthesis begins in mid-first trimester (Bishop, of HA from the anterior chamber is independent of molecular weight, 2014; Kingston et al., 2014), mostly at the ciliary body region, although suggesting that this is controlled by bulk flow, a diffusion-controlled there is some evidence for synthesis by the retina. Indeed, Bishop process, and re-uptake by hyalocytes (Balazs, 1984). Studies by Itakara (2014) posits that the collagen of the posterior vitreous is synthesized et al. (2009) noted a marked linear decrease of vitreous HA levels by the retina while that of the central and anterior/peripheral vitreous with age in humans. This might increase exposure of collagen fibrils is synthesized by the ciliary body. Most evidence suggests that there is to one another (see section 2.4 below for descriptions of no ongoing vitreous collagen synthesis after 6 months of age (Bishop, HA-collagen interaction) resulting in cross-linking and aggregation 2014). Dynamic Scattering studies have shown that the highest forming increasingly larger bundles of collagen fibrils (see section 2.2 density of collagen fibrils is present in the vitreous base, followed by the below), perhaps accounting for the development of myopia- and age- posterior vitreous cortex anterior to the retina, and then the anterior related vitreous opacities in Vision Degrading Myodesopsia. vitreous cortex behind the posterior chamber and lens (Ansari et al.,

3 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

2.2.1. Type II collagen Type II collagen is the major collagen type in human vitreous. Swann et al. (1976; Swann, 1980) were perhaps the first to identify that vitreous collagen is most similar to articular cartilage, leading to the concept that inborn errors of type II collagen affect both vitreous and joints (Maumenee, 1979). These arthro-ophthalmopathies feature extreme joint laxity and vitreous liquefaction with frequent rhegmatogenous retinal detachments (Dotrelova et al., 1997). There are subtypes, however, that feature only ocular manifestations (see below). Type II collagen is a homotrimer composed of three identical alpha chains designated as [α1(II)]3. This collagen is highly soluble when first synthesized as a procollagen and secreted into the extracellular space. N-proteinase and C-proteinase enzyme activity reduces the solubility and enables type II collagen molecules to cross-link covalently in a quarter-staggered array to form fibrils. Within this array are likely to be N-propeptides, extending outward from the surface of the forming fibril (Bishop, 2000, 2014), which may influence the interaction of the Fig. 2. Human Vitreous Collagen Fibril. collagen fibril with other extracellular matrix components. Reardon The collagen types that comprise the human vitreous fibril are primarily type II et al. (2000a) combined immunolocalization with Western blot analysis that surrounds the central core of hybrid type V/XI. The chondroitin sulfate of macromolecules extracted from bovine vitreous collagen fibrils and chain of type IX collagen is located on the surface, probably playing an found that the pN-type IIA procollagen is located on the surface of the important role in mediating interaction(s) with other components of the vitreous collagen fibril. The findings that type IIA procollagen extracellular matrix [from Bishop PN, 1996. The biochemical structure of mammalian vitreous. Eye 10:664–70.]. propeptides bind growth factors such as transforming growth factor-β1 and bone morphogenic protein-2 support the concept that growth factors in vitreous fibrils could promote cell migration and 2001). The lowest density is found in the central vitreous and adjacent proliferation in proliferative vitreo-retinal disorders, such as to the anterior cortical gel (Bettelheim and Balazs, 1968). Gloor (1975) proliferative vitreoretinopathy in adults and of prematurity pointed out that collagen content is highest where vitreous is a gel, in infants (Zhu et al., 1999). suggesting a role for collagen in creating/maintaining the gel state of Alternative splicing of type II collagen propeptides is also important in the vitreous body. Comper and Laurent (1978) found that if collagen is the pathogenesis of the aforementioned hereditary vitreo- removed from the vitreous, the remaining HA forms a viscous solution; (Bishop, 2014). The most common of these conditions is Stickler if HA is removed, the gel shrinks. More recent in situ and in vitro studies syndrome, which is the most frequent cause of inherited (but not found increased liquefaction in collagenase-treated bovine vitreous congenital) . Snead and Richards (2014) have (Zhang et al., 2014). meticulously associated the genetic defects with phenotypic expression in Total human vitreous collagen concentration is approximately the various subtypes. 300 μg/ml (Balazs, 1960; Bishop et al., 1996). The highest concentration is at the vitreous base, possibly related to the anterior site of vitreous 2.2.2. Type IX collagen collagen synthesis (Bishop, 2014). Vitreous collagen fibrils are thin, Type IX collagen is a disulfide bonded heterotrimer with an [α1 (IX) α2 uniform, and heterotypic, i.e. they consist of more than one collagen (IX) α3 (IX)] configuration. It is secreted as a mature collagen and does not type: type II (75%), type IX (15%), and a hybrid of types V/XI (10%) undergo processing prior to incorporation onto the surfaces of the major (Le Goff and Bishop, 2008; Bishop, 2014). The different constitution of collagen fibrils in a “D periodic” distribution, where it is cross-linked onto these major collagen types of vitreous is demonstrated in Fig. 2. A the fibril surface. Type IX is not a fibril-forming collagen, but it is a member repetitive amino acid sequence allows three collagen alpha chains to of the group of fibrillar-associated collagens with interrupted triple helixes wind around each other into a triple helix forming a stiff, rod-like (FACIT). It contains collagenous regions described as COL1, COL2, and structure. Fibril formation is influenced by pH and temperature: at higher COL3 interspersed between non-collagenous regions called NC1, NC2, NC3, and lower pH, collagen triple helices remain stable in solution without and NC4 (Bishop et al., 1994). In vitreous (but not cartilage) the NC4 fibrillization, which occurs at physiological pH, but fibril growth is domain is small and not highly charged, thus it is not likely to exhibit slowed with either an increase in ionic strength or a decrease in extensive interaction with other extracellular matrix components (Brewton temperature (Morozova and Muthukumar 2018). et al., 1992). Vitreous type IX collagen always contains a chondroitin Vitreous collagen molecules cross-link as they assemble into fibrils, sulfate GAG chain (Bishop et al., 1994), which is covalently linked to the adding tensile strength and mechanical stability. Cross-linking between α2 (IX) chain at the NC3 domain, enabling the molecule to assume a lysyl and hydroxylysyl residues is catalyzed by copper-dependent lysyl proteoglycan form. Electron microscopy of vitreous stained with cationic oxidase. A subsequent series of chemical reactions form intra- and dyes visualizes the chondroitin sulfate chains of type IX collagen, intermolecular cross-links (Bishop, 2014). It is conceivable that occasionally found distributed along the surface of vitreous collagen fibrils collagen cross-linking can influence photon transmission through the (Asakura, 1985), often bridging between neighboring collagen fibrils. vitreous body and scatter light, reducing transparency. Recent studies Duplexing of GAG chains from adjacent collagen fibrils may result in a found that total light scattering is non-monotonic with respect to ionic “ladder-like” configuration (Scott, 1992). LeGoff and Bishop (2008) have strength as a result of a competing dependence of collagen fibril described that type IX collagen modulates the spatial arrangement of concentration and size on ionic strength. Collagen fibril concentration collagen fibrils by both bridging together and spacing apart was highest at lower ionic strengths and rapidly decayed with higher individual fibrils. Bishop (personal communication) is a strong proponent ionic strengths. On the other hand, fibril size was larger in solutions that changes in type IX collagen with aging play an important role in the with higher ionic strength (Morozova and Muthukumar 2018). It is age-related aggregation of vitreous collagen fibrils into larger fibers. These unclear whether this phenomenon plays a role in the vitreous fiber could contribute to Vision Degrading Myodesopsia (see below). aggregation seen in myopic vitreopathy, diabetic vitreopathy, and Similar to the aforementioned importance of type II collagen in both aging (see below), but if so, then there may be significant relevance to vitreous and joints, type IX collagen appears to play an important role the pathophysiology of Vision Degrading Myodesopsia. as a perifibrillar adapter protein to stabilize the type II collagen

4 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 network in both tissues. Degradation of these adapter proteins appears in a 1:1 M ratio with versican. The term “Versican Vitreo-Retinopathy’ to be a critical event in early osteoarthritis (Firner et al., 2017). There has recently been employed to refer to retinal detachment and retinal has also been consideration that abnormalities in type IX collagen play dystrophy corresponding to a genetic abnormality [heterozygous a role in degenerative intervertebral disc disease (Meng et al., 2016), adenine to guanine variant (c.4004-2A > G) predicted to result in exon 8 but recent meta analyses refute such an association (Wu et al., 2018). skipping or the deletion of 13 amino acids at the beginning of the GAGβ There are also reports of autosomal recessive Stickler syndrome with chain, a deletion in a putative matrix metalloproteinase cleavage site ocular manifestations caused by mutations in type IX collagen (Tang et al., 2019). Wagner syndrome of erosive vitreo-retinopathy is a (Nikopoulos et al., 2011; Nixon et al., 2019). hereditary condition with vitreous abnormalities caused by splice site mutations in the versican gene. The effects have been characterized by 2.2.3. Type V/XI collagen spectral domain optical coherence tomography (Rothschild et al., 2015), as A hybrid of types V/XI collagen comprises 10% of vitreous collagen well as perimetry and electrophysiology (Araújo et al., 2018). (Bishop et al., 1994). In bovine vitreous, this collagen was shown to Opticin is the only member of the family of extracellular matrix contain α1(XI) and α2(V) chains (Mayne et al., 1993), most probably as molecules called small leucine-rich repeat proteoglycans (SLRP) that has [α1(XI) 2 α2(V)]. This hybrid is situated in the central core (Fig. 2) of been conclusively identified in vitreous. This leucine-rich repeat protein is the major vitreous collagen fibrils (Zhidkova et al., 1995). Type V/XI bound to the surface of the heterotypic collagen fibrils (Reardon et al., collagen is secreted from cells as a procollagen with N- and C-propeptides. 2000b), and is expressed by the non-pigmented ciliary epithelium, with Whilst the C-propeptide is removed by processing, the N-propeptide is high levels maintained throughout life (Bishop, 2014; Bishop et al., 2002). only partially processed and a large globular region is retained on the type Immunohistochemistry demonstrated that opticin is present throughout V/XI collagen molecule (Smith and Birk, 2012). Along with type II the vitreous body, but especially strong labelling is found at the ILM collagen, the V/XI hybrid is a fibril-forming collagen that assembles (Ramesh et al., 2004). Because there is continued expression in the adult into heterotypic (mixed composition) fibrils in vitreous along with type II mouse eye, opticin may have other functions besides regulating vitreous and type IX collagen. Wenstrup et al. (2004) demonstrated that type V collagen fibrillogenesis. Indeed, studies have found that opticin is capable collagen plays an essential role in the initiation of collagen fibril of modulating neovascularization in the posterior segment (LeGoff et al., formation, suggesting that the hybrid V/IX collagen could play a similar 2012a) in a dose-dependent fashion (LeGoff et al., 2012b). The role in vitreous fibril assembly. It may also regulate collagen fibril anti-angiogenic mechanism of action is of particular interest in that diameter (Smith and Birk, 2012). involves vitreous collagen fibrils, which provide mechanical support for the growth of new blood vessels. There are also migratory and 2.2.4. Type VI collagen proliferative signals critical for angiogenesis to occur which are Although there are only small amounts of type VI collagen in vitreous, transmitted from collagen via the collagen binding integrins the ability of this molecule to bind both type II collagen and HA suggests a (including α1β and α2β1 integrins) into the endothelial cells. Opticin role in organizing and maintaining the supramolecular structure of gel coats the collagen fibrils, weakens integrin-mediated endothelial vitreous. There may also be a role for promoting vitreo-retinal adhesion, cell adhesion to the collagen, and inhibits the outside-to-inside since type VI collagen has been identified at the vitreo-retinal interface integrin-mediated signaling that is required for angiogenesis (Bishop, (Poinsioen et al., 2008) and is known to bind collagen type II, the 2014). Formerly called vitrican, opticin is also believed to be important in predominant type in the posterior vitreous cortex, as well as type IV, the collagen fibril assembly and in preventing the aggregation of adjacent predominant collagen type in the inner limiting membrane (Bishop, 2014). collagen fibrils into bundles. Thus, a breakdown in this activity may play Bu et al. (2015) found type VI collagen in lamellae that penetrated the ILM a role in Vision Degrading Myodesopsia. further suggesting a role in vitreo-retinal adhesion. 2.4. Supramolecular organization 2.2.5. Type VII collagen Studies employing immunohistochemistry, confocal microscopy, Collagen-proteoglycan interaction in all extracellular matrices immunoelectron microscopy, and Western blotting of human donor determines the morphology of the matrix. Throughout the human body found type VII collagen at the vitreo-retinal interface (Wullink there is a striking correlation between the presence of certain types of et al., 2015), suggesting a role in mediating vitreo-retinal adhesion. interstitial collagen and the association of certain GAGs (Junqueria and Montes, 1983). Extracellular matrices with predominantly type II collagen 2.3. Non-collagenous proteins are rich in proteoglycans and have strong collagen-proteoglycan interaction. The type II collagen fibrils of articular cartilage and vitreous Fibrillins-1 and -2 are found in vitreous, but it is unknown whether are widely spread apart and the spaces between are filled with significant these microfibrils make a significant structural contribution (Bishop, amounts of proteoglycan. Studies in bovine vitreous have determined that 2014). Fibrillin-containing microfibrils are 10–12 nm in diameter and average mesh size through which endogenous or exogenous materials can have a characteristic beaded appearance by rotary shadowing electron diffuse is 550 ± 50 nm (Xu et al., 2013). It has been hypothesized that in microscopy. Mutations in the gene encoding fibrillin-1 cause Marfan cartilage the hydroxylysine amino acids of collagen mediate syndrome, characterized in the eye by , myopia and polysaccharide binding to the collagen chain via O-glycosidic linkages. rhegmatogenous retinal detachment. The increased risk of retinal Thus, the number of hydroxylysine residues per alpha chain should detachment could be due to structural abnormalities of the vitreous gel correlate with the amount of polysaccharide bound. This was related to abnormal Fibrillin-1, myopia, or both. substantiated by the finding that type II collagen contains 4 to 9 times Fibulins are a family of extracellular matrix glycoproteins that are more hydroxylysine than collagen types I and III, which form extracellular thought to have bridging roles in extracellular matrix assembly (Bishop, matrices with distinctly different morphologies than joints and vitreous 2014). For example, fibulin-1 is known to interact with versican and (Junqueria and Montes, 1983). These polar amino acids are present in fibronectin, both of which are known to be present in vitreous. clusters along the type II collagen molecule, explaining why proteoglycans However, it is not known whether fibulins contribute significantly to attach to collagen with a periodic pattern. Indeed, Asakura (1985) has the structural stability of the vitreous gel. studied bovine vitreous by ruthenium red staining and demonstrated the Versican is a large chondroitin sulfate proteoglycan with a central presence of amorphous structures on collagen fibrils at 55–60 nm intervals chondroitin sulfate substituted domain, a C-terminal globular domain, along the fibrils that are believed to be HA(Fig. 3). A similar ultra­ and an N-terminal hyaluronan binding domain (Reardon et al., 1998). structural finding was described in sheep vitreous by Worst and Los The N-terminal domain binds to hyaluronan, stabilized by link proteins (1995).

5 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

osmotic contribution of hydrophyllic HA. Comper and Laurent (1978) found that if collagen is removed from the vitreous, the remaining HA forms a viscous solution; if HA is removed, the gel shrinks. Although chondroitin sulfate chains of type IX collagen bridge between adjacent collagen fibrils in a ladder-like configuration (Scott et al., 1992), depolymerizing with chondroitinase does not destroy the gel. Recent studies at UCLA have used a stress-controlled shear rheometer to measure dynamic deformation, shear stress–strain flow, and creep compliance in porcine vitreous humor. The first viscoelastic response (short timescale = 1 s) was associated with the collagen structure, while the second viscoelastic response with a much longer timescale (100 s) was related to the microfibrils and hyaluronan network, suggesting that both contribute to vitreous viscoelasticity (Sharif-Kashani et al., 2011). Bishop (2014) proposed that opticin is the predominant structural protein in short-range spacing of collagen fibrils. Bundles of collagen fibrils are then interlinked by collagen fibrils running from one bundle to another forming an extended network that maintains the gel state of vitreous (Bos et al., 2001). Scott (1992) and Mayne et al. (1997) have claimed that HA plays a pivotal role in stabilizing vitreous gel via long-range spacing. However, studies using HA lyase to digest vitreous HA demonstrated that the gel structure was not destroyed (Bishop et al., 1999), leading to the proposal that collagen alone is responsible for the gel state of vitreous (Bishop, 2000). Nevertheless, other components such as versican (Theocaris, 2008) and chondroitin sulfate (Zhang et al., 2014) may be important adjunctive players. The question remains, however, what normally prevents vitreous collagen fibrils from aggregating in youth, and what changes with myopia and during aging that results in the formation of structures large enough to Fig. 3. Supramolecular Organization of Vitreous. scatter light and reduce transparency, as well as contrast sensitivity The interaction of collagen and hyaluronan (HA) is demonstrated with function (Garcia et al., 2016, 2018; Khoshnevis et al., 2016a; Sebag ruthenium red staining of bovine vitreous and imaging with transmission et al., 2014a, 2018). electron microscopy. This section was not stained with uranyl acetate and lead Vitreous collagen fibrils run in small bundles through the vitreous citrate, yet displays the clusters of HA (“A”) attached to collagen fibrils (“C”) body and within these bundles, the collagen fibrils are spaced apart by the and interconnecting filaments (“IF”) of unknown composition. [From Asakura, 1985. Histochemistry of hyaluronic acid of the bovine vitreous body by electron chondroitin sulfate chains of type IX collagen on the surface of the fibrils microscopy. Acta Soc Ophthalmol Jpn 89(1):179–191]. (Bishop, 2014). Filas et al. (2014) used rheometry to assess the effects of enzymes on biophysical properties of bovine and porcine vitreous. Hyaluronidase significantly decreased the damping capacity of vitreous It is important to understand by what means vitreous macromolecules and increased adhesivity. Collagenase had the opposite effect, whereas interact to form a gel and maintain transparency, vital functions of the trypsin digestion of proteins and proteoglycans had no effect relative to vitreous body. The various collagen types described above organize into controls. Osmotic perturbations and double-enzyme treatments further fibrils (Fig. 2) with the hybrid types V/XI in the central core surrounded implicated hyaluronan and hyaluronan-associated water as a primary by the predominant type II collagen. The surface of the fibril has the regulator of adhesivity and material behavior in extension. These N-propeptide extensions of the hybrid type V/XI collagen and type IX investigators concluded that collagen, hyaluronan, and proteoglycans act collagen with extensions of its chondroitin sulfate chains. These synergistically to maintain vitreous stiffness, with hyaluronan as the key extensions are probably very important in mediating the interaction of mediator of vitreous adhesivity. Peng et al. (2018) used disaccharide vitreous collagen fibrils with other extracellular matrix molecules. analysis by liquid chromatography-mass spectrometry to determine the Morozova and Muthukumar (2018) determined that fibril concentration GAG composition of bovine vitreous. The interaction of GAGs with is the highest at lower ionic strengths and rapidly decays for higher ionic collagen type II was assessed using surface plasmon resonance. HA was strengths, while fibril size is larger in solutions with higher ionic strength. the predominant GAG (96.2%) followed by chondroitin CS (3.5%), and These investigators concluded that the process of vitreous collagen fibril HS (0.3%). Resonance studies showed that collagen type II binds to assembly is of an electrostatic nature, but it is not known whether this heparan (primarily composed of Tris) with a binding affinity (KD) of accounts for the heterogeneous distribution of collagen fibrils within the 755 nM and interacts with other GAGs, including CSB and CSE. Both vitreous body, most abundant in the vitreous base, followed the posterior bovine vitreous CS and HS interact with collagen type II, with vitreous HS vitreous cortex (not “hyaloid”), anterior vitreous cortex (vitreous face), showing a higher binding affinity. How this relates to human vitreous and and then the central vitreous. the effects of myopia and aging remain to be determined. Throughout the vitreous body vitreous collagen fibrils interpenetrate complexes of vitreous HA molecules, together forming the supramolecular 3. Development of the vitreous body organization of vitreous. Measurements of the dynamic viscoelasticity of bovine vitreous showed that the shapes of the master relaxation curves of Growth of the eye may be mediated by growth of the vitreous body. the vitreous are quite similar to those of lightly cross-linked polymer During invagination of the optic vesicle the “primary” vitreous forms systems (Tokita et al., 1984). Notably, the behavior of these relaxation between the lens and the inner limiting membrane (ILM) of the retina. curves is different from that of solutions of hyaluronic acid and collagen. It is noteworthy that the ILM is continuous with Bruch's membrane This suggests that the physicochemical properties of the vitreous in vivo are (Fig. 4), demonstrating a common embryologic origin with analogous not simply the result of a combination of these two molecular elements, molecular composition and structure, suggesting important similarities but that HA and collagen form a lightly cross-linked polymer system. The later in life (Sebag and Hageman, 2000). Halfter (2008) studied the fibrils provide structure to the vitreous body which is “inflated” bythe effects of introducing exogenous chondroitin sulfate and heparan

6 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

hemo-vasculogenesis as the mode of development (McLeod et al., 2012). These studies of embryonic vascular development support the view that similar to the choriocapillaris, the hyaloid vasculature develops via concurrent vasculogenesis, erythropoiesis, and hematopoiesis arising from common hemangioblast precursors (McLeod et al., 2012). Vitreous vascularization begins with the entering the nascent eye through the optic cup. By 10 weeks of gestation (WG), the hyaloid system is well established, branching to form the vasa hyaloidea propria (VHP) with anastomoses to a dense capillary network surrounding the lens, the tunica vasculosa lentis (TVL) (Kingston et al., 2014). Expansion of this fetal vasculature occurs at around GW 12 with budding from primordial vessels via angiogenesis (Lutty and McLeod, 2018). Maximal development of the hyaloid vasculature is reached by 12–13 WG, although evidence of regression is apparent as early as 11 WG. Fig. 4. Interfaces of the Embryonic . Fetal hyaloid vessels show clear signs of regression by 13–15 WG Immunofluorescent staining (anti-ABA) in the eye of a human embryo after beginning in the VHP followed by the TVL and then the pupillary invagination of the optic vesicle demonstrates looping of the neuroectoderm membrane (PM) (Zhu et al., 2000; Kingston et al., 2014). Atrophy of the basement membrane to form Bruch's membrane posteriorly and the Inner vessels begins posteriorly with dropout of the VHP, followed by the Limiting Membrane anteriorly. It can be seen at the upper corners of the image TVL, leading to the concept that posterior development of the avascular that these two interfaces are actually continuous and thus the same structure in the embryo. [Courtesy of Greg Hageman, PhD; from Sebag and Hageman, 2000: “secondary” vitreous induces regression of the vascular “primary” Interfaces. (Guest Editorial) Eur J Ophthalmol 10:1–3; cover photo, Sebag and vitreous in a posterior to anterior direction. This prevailing concept, Hageman, 2000. Interfaces. Farina Publishers, Roma, Italia]. which may date back to Ida Mann, has recently been challenged by Bu et al. (2015) who found that the reticular labelling pattern of collagen types IV and VI located in the anterior vitreous had strong similarity to sulfate into chick embryo eyes and found an increase in eye size that patterns of blood vessel walls. Such structural patterns in the human was accompanied by an increase in retinal cell numbers. Interestingly, vitreous body were long ago described by Eisner (1972), and more HA injection had no effect on eye size. Smith et al. (2018) recently recently by Pau (1996) who made the connection between Eisner's provided experimental evidence in the embryonic chick to support a membranelles and the fetal vitreous vasculature. It is not known whe­ model whereby retinoic acid production by the peripheral retina acts ther these and/or other residua of an incompletely regressed fetal downstream of the lens to promote synthesis of collagen types II and IX vitreous vasculature play a role in Vision Degrading Myodesopsia, but and support growth of the eye. These observations may have relevance this is plausible. to the pathophysiology of axial myopia, which is frequently associated with vitreous floaters. Another possible developmental phenomenon that may have relevance to the phenomenon of vitreous floaters in 3.1.1. Cellular events myopia relates to the embryonic vitreous vasculature. Studies in the mouse embryo detected the onset of apoptosis in endothelial cells of the TVL as early as day 17.5 (Mitchell et al. 1998). 3.1. Fetal hyaloid vasculature More recent studies, however, cast doubt on the validity of using the mouse model to understand human vitreous embryogenesis (Lutty and A unique aspect of vitreous development is growth and regression of McLeod, 2018). At the 240-mm stage (7th month) in the human, blood the fetal hyaloid vasculature during the first two trimesters of human flow in the hyaloid artery ceases. Regression of the vessel itself begins embryogenesis (Fig. 5). In contrast to previous studies which suggested with glycogen and lipid deposition in the endothelial cells and pericytes embryonic vitreous vessel formation via vasculogenesis (Saint-Geniez of the hyaloid vessels (Jack, 1972). Endothelial cell processes then fill and D'Amore, 2004), current concepts are more inclined towards the lumen, and macrophages form a plug that occludes the vessel. The

Fig. 5. Fetal Vitreous Vasculature. The hyaloid artery arises from the optic disc (left side in A, right side in B), branches throughout the vitreous body as the vasa hyaloidea propia, and anastomoses with the tunica vasculosa lentis. A: Photomicrograph; 1 = tunica vasculosa lentis, 2 = vasa hyaloidea propria, 3 = hyaloid artery B: Light Micrograph with H & E staining (bar = 100 μm).

7 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 cells in the vessel wall then undergo necrosis and are phagocytized by improved with the introduction of an artificial neural network to optimize mononuclear phagocytes identified as hyalocytes (McMenamin et al., the recovery of vitreous proteins and their detection with 2-dimensional 2002). Mitchell et al. (1998) point out that the first event in hyaloid electrophoresis analysis via combining the appropriate amount of vessel regression is endothelial cell apoptosis and propose that lens solubilizing agents with a suitable control of the temperature and voltage development separates the fetal vasculature from VEGF-producing to obtain high-quality gels, resulting in a 1.3-fold increment in protein cells, decreasing the levels of this survival factor for vascular detection (Santos et al., 2019). Vitreomics should not only improve endothelium, inducing apoptosis. Following endothelial cell apoptosis diagnostic acumen, but guide precision therapy for individual patients there is loss of capillary integrity, leakage of erythrocytes into the (Velez et al., 2018). vitreous, and phagocytosis of apoptotic endothelium by hyalocytes. Proteomic investigations of fetal vitreous composition found Meeson et al. (1996) proposed that there are actually two forms significant changes in protein composition as a function of vessel of apoptosis that are important in regression of the fetal vitreous formation and regression. In particular, studies of vitreous from human vasculature: the first (“initiating apoptosis”) results from macrophage embryos aged 14 to 20 WG and young adult human eyes have identified induction of apoptosis in a single endothelial cell of an otherwise 1217 proteins, 768 of which were not previously identified (Yee et al., healthy capillary segment with normal blood flow. The isolated dying 2015). The protein profile of human embryonic vitreous not only endothelial cells project into the capillary lumen and interfere with differed from young adults, but changed significantly during the second blood flow. This stimulates synchronous apoptosis of downstream trimester (14–20 WG). Alterations in protein levels occurred concurrent endothelial cells (“secondary apoptosis”) and ultimately obliteration of with regression of embryonic vitreous vessels. There was significant the vessel. Removal of the apoptotic vessels is achieved by hyalocytes diminution in profilin-1 actin-binding protein and significant increases (Zhu et al., 2000), but galectin-3+ neutrophils may play a supportive in cadherin-2 cell adhesion protein, cystatin-C protease inhibitor, role in the macrophage-mediated involution of the hyaloid vascular dystroglycan cell adhesion molecule, clusterin, as well as pigment system (Kishimoto et al., 2018). epithelium–derived factor (Yee et al., 2015). The presence of dystroglycan and profilin-1 was confirmed in the hyaloid vessels of 10, 3.1.2. Growth factors 14, and 18 WG embryonic human eyes by immuno-labeling. Clusterin Numerous studies have suggested critical roles for various growth was not present in the HA or TVL of 10 and 14 WG eyes, but was found factors in vascular development. Hypoxia-induced vascular endothelial in the HA of 18 WG eyes. Cadherin was not found in the hyaloid vessels growth factor (VEGF) may trigger the growth of the TVL and PM, with of the 10 WG eyes but was observed in the hyaloid vessels at 14 and decreased levels inducing vessel regression (Shui et al., 2003; Gogat 18 WG. et al., 2004). Recent studies using whole-mount immunostaining in Bioinformatic analysis of the protein profile of fetal (14–20 WG) mice identified a role for neurons in regulating vessel regression, but it human vitreous revealed that most proteins were members of either the is unclear how this could influence the fetal hyaloid vessels as opposed free radical scavenging, molecular transport, small molecule to remodeling of the retinal vasculature. On the other hand, Yoshikawa biochemistry, or connective tissue disorders networks (Yee et al., 2014). et al. (2016) demonstrated that retinal neurons were able to control the Those proteins involved in free radical scavenging, molecular transport, precise switch from the fetal to the postnatal circulatory systems by and small molecule biochemistry were all intracellular and decreased timely sequestering VEGF. Autophagy and apoptosis may also play a during the second trimester. In contrast, the proteins in the connective role in hyaloid vessel regression during development (Kim et al., 2010), tissue disorders network were all extracellular and increased during the especially under hypoxic conditions. Transforming growth factor (TGF) second trimester. This pattern is consistent with replacement of the has also been implicated in ocular vessel remodeling since all four cellular primary vitreous by the acellular collagenous secondary forms of TGF-β are found in vitreous hyalocytes (Lutty et al., 1993), and vitreous. This analysis further revealed that EIF2 signaling and protein there is evidence that members of the Wnt signaling pathway, ubiquitination were the top canonical pathways. particularly Wnt7b expressed in macrophages, are involved in hyaloid regression in the mouse (Lobov et al., 2005), although this mechanism 3.2. Developmental anomalies has not been confirmed in humans. Along with growth factors, several transcription factors have been A variety of developmental anomalies can occur as a result of inherited shown to regulate hyaloid vessel formation and regression. Using a genetic abnormalities, anomalous vitreous development, or abnormal mouse model, Chen et al. (2008) illustrated the mechanistic role of the regression of the fetal hyaloid vasculature. These are extensively reviewed transcription factor, Cited2 [Cbp/p300-interacting transactivator, with elsewhere (Asanad and Sebag, 2020), but worthy of mention here is the Glu/Asp-rich carboxy-terminal domain, 2]. They demonstrated the Persistent Fetal Vasculature syndrome, which accounts for 4.8% of role(s) of Cited2 together with Paired box-6 (Pax6) in the normal blindness in infants (Mets, 1999). Studies of abnormal hyaloid vessel formation/regression of the hyaloid vasculature through negative regression found that the germline deletion of Bim (pro-apoptotic factor) modulation of Hypoxia-inducible-factor-1 (HIF-1) signaling. results in persistent hyaloid vasculature, increased retinal vascular density and stunted retinal vessel regression in response to hyperoxia 3.1.3. Embryonic vitreous proteomics (Grutzmacher et al., 2010). Recently, researchers have sought to There is increasing use of proteomic analyses to explore the determine whether retinal vascular regression is attributable to Bim pathogenesis of various vitreo-retinal diseases. , a expression in endothelial cells (EC) or pericytes (PC) using transgenic leading cause of blindness in the Western world, has been extensively mice. Interestingly, these studies observed attenuation of hyaloid vessel studied with vitreous proteomics (AKA vitreomics), identifying the regression and postnatal vascular pruning specifically in mice lacking Bim important role of vascular inflammation concurrent with the known in EC or PC. In addition, apoptosis and proliferation were also decreased in effects of hyperglycemia (Youngblood et al., 2019). A small study of the retinal vasculature of BimEC and BimPC mice (Wang et al., 2017), patients with pathologic myopia found that the expression of 28 proteins, although the aforementioned limitation in extrapolating from mouse to related to cellular adhesion, protease inhibitors, proangiogenic factors, and human embryogenesis must be considered (Lutty and McLeod, 2018). antiangiogenic factors was significantly downregulated in eyes treated Studies in the human have identified that astrocytes ensheath with intravitreal conbercept than in controls, while α-smooth muscle actin persistent hyaloid arteries in cases of persistent fetal vasculature (PFV) (α-SMA) expression was significantly upregulated (Wei et al., 2019). The syndrome (Zhang et al., 2005), suggesting a role in the persistence of investigators hypothesized that this might contribute to contraction of the fetal vitreous vessels (Fig. 5). Subsequent studies confirmed these posterior vitreous cortex or retinal inner limiting membrane. The observations and found increased expression of aquaporin 4, proteomics approach to elucidating disease mechanisms has also recently presumably contributing to astrocyte migration to the hyaloid

8 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 vasculature (Zhang et al., 2011). The investigators propose that this abnormal association of astrocytes with the hyaloid artery may alter normal macrophage-mediated remodeling and impede regression of the hyaloid vessel system. A recent review found that in animal models lacking βA3/A1-crystallin, there are increased numbers of astrocytes that also migrate abnormally from the retina to ensheath the persistent hyaloid artery. The authors propose that the absence of functional βA3/A1-crystallin causes failure of the normal acidification of endolysosomal compartments in the astrocytes, which leads to the impairment of certain critical signaling pathways, including mTOR and Notch/STAT3, adversely affecting the vascular remodeling processes essential to regression of the fetal vasculature (Ziegler et al., 2016). Another recently proposed consideration is the role of integrins in PFV (Hegde and Srivastava, 2017), although these knockout studies were in the transgenic mouse model and may have limited relevance to the human syndrome. It is theoretically possible that subclinical anomalies in fetal Fig. 7. Vitreous Structure d'après Eisner. vitreous vascular regression result in subsequent structural changes Membranelles coursing form the peripheral anterior vitreous were named by within the vitreous body that interfere with photon transmission to the Georg Eisner of Bern, Switzerland as “tractae”, based upon their sites of origin retina and induce myodesopsia. While this is probably not a prominent and insertion. [TR = tractus retrolentalis (hyaloideus), TC = tractus coronarius, TM = tractus medianus, TP = tractus preretinalis; mechanism in older individuals who experience symptomatic posterior LR = ligamentum retrolentalis (of Weiger), LC = ligamentum coronarium, vitreous detachment, this might possibly be important in young patients LM = ligamentum medianum, OS = ora serrata; from Eisner G, 1984. Clinical with myopia and myopic vitreopathy (see below). Analysis of vitreous anatomy of the vitreous, In: Biomedical Foundations of Ophthalmology, Vol 1 removed at surgery in such patients might reveal elevated levels of fetal (TD Duane, EA Jaeger, Eds). JB Lippincott, Philadelphia, pg. 21]. vascular antigens compared to controls, providing some support for this hypothesis. Theory. The work of Retzius (1871) and Szent-Gyorgi (1917) produced findings that supported the Fibrillar Theory of Bowman. The invention 4. Vitreous structure of the biomicroscope by the Nobel Prize winning Swedish Ophthalmologist Gullstrand enabled investigators to examine vitreous Studying vitreous structure is challenging, as it is a quest to see the without tissue fixation. Yet, an equally varied set of descriptions invisible (Fig. 1; Sebag, 1997; Sebag, 2004a; Sebag et al., 2014a,b). As resulted, each promoted by leading authorities of their time. One was previously the fashion elsewhere in the body, classic anatomic contemporary concept of vitreous structure resulting from slit lamp depictions of vitreous bear the names of their ‘discoverers’ (Fig. 6). examination of unfixed human eyes post-mortem was proposed by Detailed description of vitreous body morphology has always been Georg Eisner of Bern, Switzerland (Eisner, 1972), who meticulously hampered by the significant amount of water in vitreous, rendering described membranelles he named “tractae”, that coursed from the standard histology fraught with artefact due to dehydration during anterior peripheral vitreous to the posterior pole (Fig. 7). In Holland, tissue fixation and the precipitation of hyaluronan (Redslob, 1932). Jongebloed and Worst (1987) injected India ink to visualize cisterns Thus, divergent descriptions resulted, ranging from Demours who within the vitreous body (Fig. 8A), the most famous being the Bursa formulated the Alveolar Theory, to Zinn who proposed that vitreous was Premacularis (Worst, 1977), currently being imaged in vivo with swept organized in lamellae (Lamellar Theory) like the layers of an onion, source OCT in young eyes (Liu et al., 2014), and even in adults (Stanga while the Radial Sector Theory (similar to the organization of an orange) et al., 2014). (Fig. 8B) was proposed by Hannover (Redslob, 1932). It was Sir William Bowman (1848) who proposed the most accurate description, The Fibrillar 4.1. Vitreous body

It has long been thought that the emmetropic human vitreous body has a volume of about 4.0 mL, however recent studies using CT scans and advanced image analysis software determined that mean vitreous chamber volume in humans was 4.65 ± 0.43 mm3 for women and 4.97 ± 0.47 mm3 for men, with a significant negative correlation between age and vitreous chamber volume (decreased with increasing age; P < 0.001) as well as axial length and vitreous chamber volume (increased with increasing axial length; P < 0.001) (Azhdam et al., 2020). It is important to note that while this analysis provides useful information about the volume of the human vitreous chamber as imaged by CT, there are age- and disease-related changes in the vitreous body (see below) that were not studied using this imaging modality. Internal vitreous structure has been characterized using dark-field slit microscopy (Sebag, 1989). In youth (Fig. 9) the peripheral and posterior vitreous cortex can be seen as a thin, membranous structure Fig. 6. Classic Vitreous Anatomy. continuous from the ora serrata to the posterior pole, yet there is no Schematic diagram of vitreous anatomy bearing the names of those who first significant light scattering within the vitreous body, except for Cloquet's identified these structures. [from Sang DN, 1987. Embryology of the vitreous. In: Canal, which is the remnant of the fetal hyaloid artery. This The Vitreous and Vitreo-retinal Interface (CL Schepens, A Neetens, Eds.) Springer- transparency results from the spacing of vitreous collagen fibrils by HA, Verlag, New York, pg. 20]. as described above. By middle age, there are visible fibers that arise

9 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 8. Vitreous Structure d'après Worst. A. Jan Worst of Holland injected colored India ink to identify structures he called “cisterns”, the most famous of which are the bursa premacularis (violet-colored) and Cloquet's Canal opening into the prepapillary Area of Martegiani (tan-colored) [from Jongebloed WL, Worst JGF, 1987. The cisternal anatomy of the vitreous body. Doc Ophthalmol 67:183-96] B. Swept Source OCT image of human vitreous demonstrating the appearance of the Bursa premacularis of Worst (“B”) and the Area of Martegiani anterior to the optic disc. [courtesy of Michael Engelbert, MD, PhD]. from the vitreous base and course continuously to the posterior pole phagocytosis and other activities (Forrester and Balazs, 1980; Sebag et al., (Fig. 9 center panel; Fig. 10). The configuration of these structures is 1981), and the anterior displacement of these cells following PVD might not dissimilar to Eisner's tractae (Eisner, 1972; Pau, 1996), however alter this modulation. Sakamoto and Ishibashi (2011) have recently ultrastructural studies failed to detect membranous structures. Rather, published excellent reviews of hyalocytes (Kita et al., 2014) which these fibers are composed of bundles of parallel collagen fibrils visible describe the capacity of hyalocytes to recruit monocytes from the by electron microscopy (Fig. 11). Vitreous base collagen fibers insert circulation and glial cells from the retina via the release of connective anterior to the ora serrata forming the anterior loop (Fig. 10h; Fig. 12), tissue and other growth factors. Hyalocytes can also induce collagen gel a structure that is important in anterior proliferative vitreo-retinopathy contraction in response to platelet-derived growth factor and other (Sebag, 2018a). The central aggregates of collagen can interfere with cytokines, causing tangential vitreo-retinal traction. photon transmission to the retina and induce considerable light scattering resulting in the phenomenon of floaters. Further fibrous 5. Vitreous aging aggregation occurs in aging (Fig. 9A right; Fig. 9B bottom), a process that begins earlier in life with myopia (see below). 5.1. Aging rheology and macromolecular changes

4.2. Vitreo-retinal interface 5.1.1. Vitreous rheology in aging Significant changes occur in the vitreous body with aging, beginning The posterior vitreous cortex is 100–110 μm thick and consists of with gel liquefaction, known as “synchisis senilis” (Foos and Wheeler, densely packed collagen fibrils (Fig. 13). Recent studies have shown 1982). Using clinical slit-lamp biomicroscopy, Busacca (1958) and that in addition to this layer of vitreous fibrils, there are there are larger Goldmann (1962) observed that after the fifth decade there is a fibers oriented perpendicular to the retina that insert into the decrease in the gel volume and an increase in the liquid volume of extracellular matrix between the retina and vitreous (Gal-Or et al., human vitreous. Post-mortem studies of dissected human vitreous by 2019). When separated from the retina following posterior vitreous Eisner (1975) qualitatively confirmed these clinical observations and detachment (PVD), the lamellar and fibrillar collagen of the posterior found that liquefaction appears to begin in the central vitreous. In a vitreous cortex can induce considerable light scattering noticed by the large autopsy study of formalin-fixed human eyes, O'Malley (1976) patient as floaters. Indeed, PVD is the most common cause of the visual found that more than half of the vitreous body was liquefied in 25% of phenomenon of vitreous floaters (see below). individuals aged 40 to 49 and that this increased to 62% of individuals There is no vitreous cortex over the optic disc, and the cortex is thin aged 80 to 89. Oksala (1978) used ultrasonography in vivo to detect over the macula (Fig. 9A center; Fig. 10a; Fig. 14). The pre-papillary echoes from gel-liquid interfaces in 444 normal human eyes. He hole can sometimes be visualized clinically following posterior vitreous observed evidence of liquefaction in 5% of individuals aged 21 to 40, in detachment (PVD). If peripapillary tissue is torn away during PVD and 19% of those aged 41 to 50, in 63% aged 51 to 60, and in greater than remains attached around the pre-papillary hole, it is called the Weiss 80% of individuals over the age of 60. However, these qualitative Ring (Fig. 15), often visible on clinical biomicroscopic examination and assessments would greatly benefit from an objective, non-invasive sometimes quite bothersome to patients who experience PVD. clinical measure of liquid vitreous. In vitro studies by Flood and Balazs There is a lamellar organization to both the inner limiting (Balazs and Denlinger, 1982; Sebag, 1989) found evidence of liquid membrane (ILM) of the retina (Henrich et al., 2012) and the posterior vitreous very early in life, increasing during youth and adulthood, and vitreous cortex (Gupta et al., 2011; Gal-Or et al., 2019) (Fig. 16), the accompanied by a decline in gel vitreous beginning in the fifth decade latter visible with high-resolution swept source OCT imaging (Akihito of life (Fig. 18). Zimmerman (1980) evaluated the rheologic state of and Nagahisa, 2016). Although conceivable, it is currently not known human vitreous by studying vitreous motion in vivo. Using head whether variations in the size or number of the lamellae might play a movement to displace the vitreous body, he found that vitreous motion role in the visual phenomenon of vitreous floaters. is overdamped with a settling time of 2 s and an overshoot of 25%–50%. Buschbaum et al. (1984) have derived a mathematical model for 4.2.1. Hyalocytes vitreous motion whose predictions fit well with Zimmerman's findings. Hyalocytes are mononuclear cells embedded in the posterior vitreous The phase separation of gel and liquid vitreous components has cortex 20–50 μm anterior to the ILM (Fig. 17). These sentinel cells become recently been confirmed by rheological studies showing that both the phagocytic in response to inducting stimuli and are important in antigen liquid and gel phases exhibit viscoelasticity, but with distinct rheological processing and as initiators of the immune response, making characteristics: the gel phase is mostly composed of collagen entangled by possible intravitreal inoculation of antigens to promote systemic immunity HA and the liquid phase is mainly composed of HA in aqueous solution (Sonoda et al., 2005). HA may have an inhibitory effect on hyalocyte (Silva et al., 2017). HA concentrations increase from anterior to posterior

10 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 10. Human Vitreous Structure Imaged by Dark-field Slit Microscopy. Fig. 9. Darkfield Slit Microscopy of Human Vitreous. All specimens had the sclera, choroid, and retina dissected off the vitreous body A. Unfixed post-mortem human eyes dissected of the sclera, choroid, and retina which was left attached to the anterior segment, located at the bottom of each were observed with dark-field slit microscopy to image internal structure. In the image. A slit-lamp beam illuminated a horizontal optical section imaging embryo (left) the only structures scattering light are the hyaloid artery vitreous structure. (destined to be Cloquet's Canal) and the peripheral vitreous cortex. In a: 52-year-old man. The pre-papillary hole in the vitreous cortex is to the left. middle-age (center), there are macroscopic fibers with an antero-posterior b: 57-year-old man. A large bundle of prominent fibers courses antero-posteriorly, orientation. The pre-papillary hole (smaller to left) and premacular dehiscence entering the preretinal space through the premacular vitreous cortex. (larger, to right) can be seen in the posterior vitreous cortex. By old age (right) c: Same view as 10.c at higher magnification. fibers have become thickened and tortuous. [from Sebag J: Vitreous – in Health d: 53-year-old woman with posterior extrusion of vitreous out the pre-papillary hole & Disease. Springer, New York, 2014, pg viii] (to the right) and premacular (large extrusion to the left) vitreous cortex. B. Vitreous structure in children (upper panel) is devoid of internal fibers which Fibers course antero-posteriorly in the central vitreous and out into the preretinal, are routinely present in the adult (middle panel). In old age (bottom panel) the space. fibers are thickened and associated with areas of liquefied vitreous that do not e: Same specimen as 10.d. A large fiber courses posteriorly from the central vitreous scatter light because they consist primarily of hyaluronan and water, but little, and inserts into the premacular vitreous cortex. if any, collagen. [from Sebag J: Vitreous – in Health & Disease. Springer, New f: Same view as 10.e at higher magnification. The curvilinear appearance is due to York, 2014, pg 197]. traction by vitreous extruding into the retro-cortical space. Because of its attachment to the posterior vitreous cortex the fiber arcs back to its point of insertion. g: Cloquet's canal in a 33-year-old woman, forming the retrolental space of Berger. h: Peripheral anterior vitreous in a 57-year-old man with vitreous fibers surrounding the lens, inserting into the vitreous base. These fibers splay out to insert anterior and and the reverse is true for viscosity, implying that the lower concentration posterior to the ora serrata. [from Sebag J: The Vitreous – Structure, Function, and of HA near the lens was offset by increased molecular size (Bettelheim and Pathobiology. Springer-Verlag, New York, 1989, pg 41]. Zigler, 2004). Recent shear rheometry studies of human vitreous found that samples from older individuals was stiffer than the vitreous from young individuals, with a positive linear correlation with increasing age. Vitreous dehydration due to a decrease in HA concentration with age result of changes in both HA and collagen that alter the interaction of (Itakura et al., 2009) was proposed as the cause of stiffening in the solid these two macromolecules, inducing dissociation from their joint su­ phase of the vitreous gel. Vitreous liquefaction, therefore, might be pramolecular configuration. The importance of HA is suggested by the characterized as a simultaneous increase in liquid volume and localized finding that eyes with PVD had a lower concentration of HA than eyes stiffening of the vitreous gel (Tram and Swindle-Reilly, 2018). with an attached vitreous (Larsson and Österlin, 1985). Myopic eyes are Liquid vitreous first appears in childhood (Fig. 18), increasing to known to have more liquefied vitreous than similarly aged emmetropes, 20% of the total vitreous volume in adolescence (Balazs and Flood, perhaps related to molecular abnormalities (Berman and Michaelson, 1978). By 70 years of age, this increases to 50% (Foos and Wheeler, 1964). However there is evidence refuting the theory that changes in 1982). Studies of premature, infant, and adult ovine vitreous found HA are responsible for liquefaction, since experiments showing that significant rheological differences attributed to structural breakdown of even if more than 90% of vitreous HA is depolymerized using Strep­ vitreous (Colter et al., 2015). Vitreous liquefaction likely begins as a tomyces HA lyse, the vitreous body does not liquefy, although the

11 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 12. Peripheral Vitreous Structure in the Adult Human. Dissected vitreous body still attached to the phakic anterior segment is tilted to expose the peripheral anterior vitreous. The anterior loop (AL) is seen coursing from the peripheral fundus across the ora serrata to the . This structure not only provides a scaffold for cell migration and proliferation in anterior proliferative vitreo-retinopathy, but also mediates membrane contraction to detach the peripheral retina as well as the ciliary body, resulting in hypotony. [from Sebag, 1989. Vitreous – Structure Function, and Pathobiology. Springer-Verlag, pg. 42].

Fig. 11. Ultrastructure of Human Vitreous Fibers. Transmission electron microscopy of human vitreous detected bundles of collagen fibrils shown longitudinally in the upper image and in cross section in the lower image. The inset in the upper image is a high-magnification view of the bundle of fibrils demonstrating their collagenous nature (from Sebag and Balazs, 1989: Morphology and ultrastructure of human vitreous fibers. Invest Ophthalmol Vis Sci 30:1867–71]. volume of the gel decreases (Bishop et al., 1999). Recent studies of phospholipid distribution in porcine vitreous found greater relative Fig. 13. Ultrastructure of Human Posterior Vitreous Cortex. Scanning electron microscopy of human vitreous after peeling off the retina, abundance of unsaturated species in the posterior vitreous, suggesting exposes the dense collagen matrix of the posterior vitreous cortex. Dehydration that these species may be able to disrupt the water-collagen-hyaluronan during specimen preparation imaging somewhat exaggerated the density of network and contribute to vitreous liquefaction (Schnepf et al., 2017). collagen fibrils. bar = 10 μm [Courtesy Dr. Charles L. Schepens, Eye Research Institute of Retina Foundation, Boston; from Huang LC, Yee KMP, Wa CA et al., 5.1.2. Aging vitreous collagen 2014. Vitreous floaters and vision: current concepts and management Changes in vitreous collagen may be important in vitreous paradigms. In: J. Sebag (Ed.) Vitreous – in Health & Disease. Springer, New York, pg. 774]. liquefaction. Post-natal synthesis of vitreous collagen in the peripheral fundus was suggested by Wang et al. (2003). Based on the rate of accumulation of pentosidine in non-diabetic individuals, the average immunohistochemistry (van Deemter et al., 2009b) found half-life of vitreous collagen was estimated to be around 15 years, breakdown products of type II collagen suggesting enzyme effects. similar to that of skin (van Deemter et al., 2009a). But in spite of claims by Subsequent studies identified trypsin-1 and trypsin-2 in human vitreous of Ponsioen et al. (2009, 2010), there are no definitive studies that autopsy eyes, suggesting these proteolytic enzymes may play a role in demonstrate vitreous collagen synthesis in the disease-free adult. vitreous liquefaction (van Deemter et al., 2013). Although Type IX collagen Indeed, recent studies found significantly higher pentosidine values in eyes only accounts for 15% of total human vitreous collagen, it's location on the with intraocular fibrosis (van Deemter et al., 2017), supporting the concept surface of the vitreous collagen fibril (Fig. 2) could make it that vitreous collagen synthesis in the adult typically occurs in pathologic very important to the maintenance of the gel structure via mediating conditions. Type II, the most prevalent of vitreous collagens, has alternative interactions with other components of the extracellular matrix, most notably splicing within the second exon (Le Goff and Bishop, 2008) where HA (Bos et al., 2001). With aging, there is loss of type mutations result in significant vitreous liquefaction in Stickler IX collagen from the surface of these heterotypic collagen fibrils (Bishop syndrome (Richards et al., 2008). Thus, there may also et al., 2004). These studies also showed that type IX collagen has a shorter be relevance to age-related liquefaction. Indeed, studies of human autopsy half-life (11 years) than other forms of vitreous collagen. Loss of type IX eyes by histopathology and ultrastructure (Los et al., 2003) and by collagen has been shown to cause type II collagen aggregation, seen by

12 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

5.2. Structural changes with aging

5.2.1. Vitreous body Following HA dissociation from collagen by any mechanism(s), vitreous collagen fibrils cross-link with one another fusing laterally into increasingly larger aggregates that by middle-age are visible in vivo with slit lamp biomicroscopy and in vitro by dark-field slit microscopy (Sebag 1985, 1987, 1989; Sebag and Balazs, 1985). (Figs. 9 and 10) Transmission electron microscopy has determined that these visible fibers are aggregated vitreous collagen fibrils organized into bundles (Sebag and Balazs, 1989) (Fig. 11). Ponsioen et al. (2010) have postulated that the formation of fibrous aggregates in the vitreous body is the result of active (enzyme-mediated) remodeling and not necessarily a degenerative process. The formation of large collagenous vitreous fibers could also result from fibrosis, a major cause of aging throughout the body. Indeed, fibrosis is claimed to be the fundamental process causing at least one-third of all deaths world-wide and nearly Fig. 14. Posterior Vitreous Structure in Adult Human. half of deaths in the developed world (Wynn and Ramalingam, 2012; Dark-field slit microscopy in a 59-year-old man after peeling the sclera, choroid, Zeisberg and Kalluri, 2013). In vitreous, this could be mediated by and retina off the vitreous body images the pre-papillary hole in the posterior fibroblasts, that constitute 10% of the cell population in the vitreous vitreous cortex (black arrows) with extruding vitreous (white arrows). To the body (Gärtner, 1971; Balazs et al., 1980) and appear to play a critical right is the larger circular dehiscence of the premacular posterior vitreous cortex with extruding vitreous. The highly-refractile pinpoint structures are role in fibrosis elsewhere in the body (Merl-Pham et al., 2019). Gärtner hyalocytes [from Sebag J and Balazs EA, 1985. Human vitreous fibres and (1986) has suggested that fibroblasts are responsible for aging changes vitreo-retinal disease. Trans Ophthalmol Soc UK 104:123–8). in the collagen network of the vitreous base, thus they may also play a role in the vitreous body itself. Concurrent with vitreous collagen fibril aggregation into fibers, liquid vitreous appears and ultimately forms lacunae (Fig. 19) that are enzymatically cleaving the CS chains of type IX collagen and observing different in origin and location from the Bursa Premacularis of Worst. subsequent type II collagen bundling (Bishop et al., 2004). Such These structures could influence pharmacotherapy of the macula and mechanisms could be very relevant to the pathogenesis of Vision Degrading via if the drug is injected into a Myodesopsia, especially in patients with myopic vitreopathy (see below). lacuna, likely affecting pharmacokinetics and resulting in altered pharmacodynamics. (Sebag, 2015; Sebag, 2018a,b,c). In spite of this important consideration, recent ocular pharmacokinetic models with

Fig. 15. Posterior Vitreous Detachment with Weiss Ring. A. Color fundus photograph of Weiss Ring. B. Ultrasound image of Weiss Ring C. Ultrasound image demonstrating the detached posterior vitreous cortex and the hole in pre-papillary posterior vitreous cortex that forms the Weiss Ring.

13 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 16. Lamellar Structure of the Posterior Vitreous Cortex. A. Immunohistochemistry in the adult monkey eye stained with fluorescein-conjugated ABA lectin stain features vitreous above and retina below. The ILM stains intensely bright as a horizontal line across the image. Above the ILM is the posterior vitreous cortex whose lamellar structure is clearly evident. These potential cleavage planes can separate during anomalous PVD or during vitrectomy surgery with membrane peeling, in each instance leaving a layer of vitreous attached to the macula. [Courtesy of Greg Hageman, PhD; original magnification = 400X; from Sebag, 2008. Vitreoschsis. Graefe's Arch Clin Exp Ophthalmol 246:329–32; Cover Photo] B. 3D-OCT imaging of the vitreo-retinal interface in a normal adult demonstrates a multi-lamellar structure anterior to the retina. In this image at least 3 layers of the posterior vitreous cortex can be discerned. During vitrectomy with membrane peeling there can be splitting between these lamellae leaving the outermost layer attached to the retina, perhaps accounting for cases of failed surgery. [courtesy of Carl Glittenberg and Susanne Binder, Vienna, Austria; from Sebag J. et al., 2014. Anomalous PVD and vitreoschisis. In: Sebag J. (Ed). Vitreous – in Health & Disease. Springer, New York, 2014, pg. 247].

Fig. 18. Rheology of Human Vitreous Throughout Life. Gel vitreous (blue line) increases with growth of the eye and plateaus during the second decade of life, remaining stable until the fifth decade when fibrous Fig. 17. Ultrastructure of Vitreoschisis (VS). degeneration causes a decline in the volume of gel vitreous. Liquid vitreous Transmission electron micrograph of human vitreous shows hyalocyte increases slightly during all decades, but moreso after the fifth decade in embedded in the dense collagen matrix of the posterior vitreous cortex (original conjunction with decreasing levels of gel vitreous. [(Graph is courtesy of Endre magnification, x11,670). The anterior portion of the posterior vitreous cortex is A. Balazs, MD; data first presented byBalazs EA, Flood MT (1978): Age-related above, and the posterior portion is below in this image. If during Anomalous changes in the physical and chemical state of human vitreous. Third PVD the vitreoschisis split occurs anterior to the level of hyalocytes (red dashed International Congress for Eye Research, Osaka, Japan)]. line), a relatively thick and hypercellular membrane is left on the macula. If the split occurs posterior to the level of the monolayer of hyalocytes (blue dashed interface (Sebag, 1991). Using a rotational peel device in human line), then a thin and hypocellular membrane is left attached to the macula. autopsy eyes, Creveling et al. (2018) determined that the maximum [Modified from Sebag J: The Vitreous - Structure, Function, and Pathobiology. peel force at the equator (7.24 ± 4.13 mN) was greater than in the Springer-Verlag, New York, 1989]. posterior pole (4.08 ± 2.03 mN), especially in younger eyes (donors 30–39 years of age). After 60 years of age, there was a significant computational methods have not factored regional variability in a given decrease in the maximum equatorial (4.69 ± 2.52 mN, p = 0.016) and vitreous body, and inter-individual variability when applying posterior pole adhesion (2.95 ± 1.25 mN, p = 0.037). computational fluid dynamic modelling to the drug distribution phase The processes underlying these observations are not known, because following intravitreal drug injection, assuming that a quasi steady-state little is known about the mechanism(s) of vitreo-retinal adhesion distribution is achieved (Missel and Sarangapani, 2019). Perhaps this (Halfter et al., 2014). Russell (2012) proposed that vitreous maintains approach could be improved with a more individualized assessment of adhesion to the retina via a proteoglycan with a 240 kDa protein core vitreous anatomy and an enhanced localization of intravitreal drug that is bound to the type IV collagen of the ILM. Attached to the protein administration. core are chondroitin sulfate glycosaminoglycans (GAGs) located on the vitread side of the ILM. The GAGs bind to opticin (see above), which 5.2.2. Vitreo-retinal interface aging then interacts with type II collagen of the posterior vitreous cortex. In youth there is firm adhesion between the posterior vitreous Through this chain of interactions (ILM to core protein to GAG to cortex and ILM of the retina. Vitreo-retinal adhesion is reported to be opticin to cortical vitreous) a relatively strong biochemical adhesion is greater at the equator than the posterior pole, but greatest at the formed. Ponsioen et al. (2010) suggest dynamic remodeling with vitreous base (Gandorfer et al., 2001), although there is evidence collagen synthesis and deposition at the interface, beginning at a very (Fig. 20) that in youth, posterior vitreo-retinal adhesion is stronger than early age and continuing throughout life. Oxidative stress (Wert et al., retinal Mueller cells, since peeling of the retina off the posterior 2018) and neurodegeneration (Öhman et al., 2018) have also been vitreous cortex in post-mortem donor eyes from young subjects resulted implicated. Halfter has shown that ILM thickness increase with age in rupture of the Muller cells and not dehiscence of the vitreo-retinal (Halfter et al., 2014), perhaps weakening vitreo-retinal adhesion.

14 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 19. Senescent Human Vitreous Structure. Dark-field slit microscopy of fresh unfixed, dissected eye from an 88-year-old woman demonstrates the appearance of advanced fibrous degeneration of the vitreous body with prominent lacunae of liquid vitreous. Injection of drugs or other agents into a lacuna (arrows) will likely have very different distribution than injection into an area of gel vitreous (to right). [Modified from Sebag J: The Vitreous - Structure, Function, and Pathobiology. Springer-Verlag, New York, 1989, pg. 88].

5.3. Posterior vitreous detachment (PVD)

PVD is defined as separation of the posterior vitreous cortex from the optic disc and ILM of the retina (Sebag, 2018b). (Fig. 21) There is a recent report of anterior vitreous detachment (Anisimova et al., 2019), but it is unlikely that this occurs in the absence of disruption of zonules and Wieger's ligament during . PVD is the most Fig. 20. Vitreo-Retinal Interface in Youth. common event to occur in the human vitreous, but the exact epide­ Top: Dark-field slit microscopy of posterior vitreous in a 14-year-old boy after dissection of the sclera, choroid, and retina. A cap of tissue adheres to the miology is not known because the clinical diagnosis is unreliable (Tozer posterior vitreous with a hole corresponding to the previous location of the et al., 2014; Sebag, 2018b), even when a Weiss Ring is visualized. optic disc, linear structures resembling retinal vessel patterns (black arrows), Post-mortem studies employing the suspension-in-air technique at and a foveal imprint (white arrow). UCLA by Foos and Wheeler (1982) found a PVD prevalence of 51% in Middle: Scanning electron microscopy of specimen shown in top panel. Mueller the seventh decade of life, which increased to 63% by the eighth decade cell (MC) endplates can be seen as round protuberances (with a central (Foos and Wheeler, 1982). These studies found a correlation between “dimple”) inserted onto the inner limiting membrane (“ILM”) of the retina. the presence of PVD and the degree of vitreous liquefaction (synchisis [bar = 1 μm]. senilis), with a marked increase in PVD prevalence when more than Bottom: Transmission electron microscopy identifies the tissue as the inner 60% of the vitreous gel was liquefied. However, these post-mortem limiting membrane of the retina (R) attached to the posterior vitreous cortex studies may be influenced by artefact induced by the effects of gravity (V), with the broken inner segments of Mueller cells adherent to the posterior aspect of the ILM. (courtesy of the Eye Research Institute of Retina Foundation, during suspension-in-air evaluation as well as dehydration artefacts Boston, Mass; from Sebag J, 1991. Age-related differences in the human from tissue fixation. Contact lens examination estimated the prevalence vitreo-retinal interface. Arch Ophthalmol 109:966–71.). of PVD to be 65% after the age of 65 (Favre and Goldmann, 1956). Yonemoto et al. (1994) evaluated 994 eyes by physical examination and determined that the average age of PVD onset was 61 years. In least in part explained by altered vitreous biochemistry and viscosity in addition to myopia (see below), female gender represents a risk factor pseudophakic eyes (Neal et al., 2005). Additional risk factors for PVD for earlier onset of PVD (Novack and Welch, 1984). The mechanism has are hereditary disorders of collagen metabolism (Snead and Richards, been attributed to postmenopausal loss of estrogen (Chuo et al., 2006) 2014), trauma, inflammation, retinovascular disorders, and vitreous influencing HA metabolism (Larsson and Österlin, 1985) and the hemorrhage (Johnson, 2010). accumulation of advanced glycation end-products (van Deemter et al., OCT imaging in 566 subjects ranging in age from 10 to 97 years 2009a). Preset lens biomicroscopy (Fig. 21) performed in 551 eyes of found no PVD until 40–49 years of age, and a prevalence of 1.5% from Caucasian patients and 528 eyes of Japanese patients found no 40 to 49 years, increasing to 100% from 90 to 99 years (Palacio et al., differences between the two groups, with a prevalence of 72–82% in the 2017). In spite of sizable numbers in each age group, the findings may ninth decade of life (Hikichi et al., 1995). Hruby lens examination in not be accurate since the use of OCT to diagnose PVD is not reliable 1481 patients found that PVD was correlated with increasing age unless the posterior vitreous cortex is close enough to the retina to be (p < 0.001), myopic refractive error (p < 0.001), female gender imaged. A recent study found that when compared to intraoperative (p < 0.001), and surgical aphakia (p < 0.001) (Hayreh and Jonas, findings, pre-operative OCT was reliable only when the posterior 2004). It has been suggested that persistent vitreo-papillary adhesion vitreous was attached; i.e. when Worst's bursa premacularis or other (VPA) contributes to the pathogenesis of optic neuropathies such as structures of the posterior vitreous were seen on OCT. The positive gaze-evoked amaurosis (Katz and Hoyt, 2005), and recent studies have predictive value of OCT in diagnosing PVD was only 53% (Hwang et al., found a higher prevalence of VPA in certain vitreo- 2020). This confirmed the findings of a prior Scandinavian study of 271 (see section 5.4.2. below). The relationship to cataract surgery is at patients with a mean age of 76 ± 8 years that found only 18.5% had

15 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

within 6 months in 8%, 1 year in 24%, 18 months in 47%, 2 years in 65% and within 3 years in 90% of cases (Hikichi and Yoshida, 2004; Hikichi, 2007). Recent wide-field (montaged) OCT imaging of 144 eyes from 98 normal participants found that PVD first appeared more anteriorly in the paramacular to peripheral fundus, not the posterior pole (Tsukahara et al., 2018). Interestingly, 40% of the patients in this study were found to have evidence of vitreoschisis, confirming earlier studies (Sebag, 2008). There are various physiologic effects of PVD, primarily an increase in oxygen levels within the vitreous body (Holekamp et al., 2014). This has both beneficial and deleterious effects. In the case of the former, increased levels of vitreous pO2 can ameliorate ischemic retinopathies (Stefansson, 2014). In the case of the latter, elevated vitreous pO2 levels play a role in cataractogenesis, an important consideration when performing vitrectomy for Vision Degrading Myodesopsia (see below), but also an opportunity to develop preventative therapies against Fig. 21. Posterior Vitreous Detachment. by preventing vitreous degeneration. Trans-vitreous diffusion Preset lens biomicroscopy demonstrates the sigmoid shape of the detached of injected drugs or viruses is also likely influenced by the presence or posterior vitreous cortex (black arrows) in a patient's left eye; note optic disc absence of PVD, as modeled mathematically by Ferreira et al. (2017), and retinal vessels to left of vertically-oriented linear light reflex. The sigmoid and studied with respect to the effects of eye movement by Loch et al. configuration of the detached posterior vitreous cortex is due the effects of (2014). PVD can also influence VEGF levels in exudative age-related gravity on the superior vitreous body. [courtesy C.L. Trempe, MD; from Tozer et al., 2014. Vitreous aging and PVD. In: Sebag J. (Ed.) Vitreous – in Health & macualr dgneration (Nomura et al., 2016). Disease. Springer, New York, 2014, pg. 144].

5.3.1. PVD and floaters PVD by OCT, but ultrasound diagnosed PVD in 68% of these cases The most common consequence of PVD is the sudden onset of the (Schwab et al., 2012). This is likely due to the ability of ultrasound to visual phenomenon of floaters. The literature and common vernacular image a posterior vitreous cortex that is displaced far anteriorly unfortunately use this term to refer to the opacities within the vitreous following PVD. Thus, ultrasonography currently seems to be the most body that induce the visual phenomenon, thus greater linguistic accurate way to objectively diagnose PVD (Abraham and Ehlers, 2020). precision is desirable. An early publication in the popular periodical (Fig. 22). Hopefully, future research (see below) may develop a Scientific American attributed the phenomenon of floaters solely to combination of sound and light to better image the invisible vitreous. hemorrhage in the vitreous body (White and Levitan, 1962). In reality, PVD was previously perceived as a relatively acute process that is this is a minor cause and the overwhelming majority of vitreous floater the consequence of gel liquefaction and concurrent weakening of cases result from shadows cast by Weiss ring (Fig. 15), aggregates of vitreo-retinal adhesion. With the advent of OCT, early PVD can now be central vitreous fibers (Fig. 9; Fig. 22), and/or the posterior vitreous identified (Mirza et al., 2007) since initially the posterior vitreous cortex (Fig. 13; Fig. 22), all occurring with late stage PVD and not the cortex remains close to the retina, typically still attached at the fovea. early perifoveal PVD described by Johnson (2005). Fincham et al. Underscored by Mark Johnson in his AOS thesis (Johnson, 2005), (2018) recently identified type IV collagen within the posterior vitreous perifoveal PVD is now perceived as a slow process occurring over the of eyes with PVD. This most likely derives from the ILM of the retina, course of many years, with a prevalence of 62% over the age of 30 suggesting that during PVD in some (perhaps many) cases, an unusually (Uchino et al., 2001), increasing to 90% in eyes with vitreo-macular firm adhesion between the posterior vitreous cortex and anterior ILM pathology (Johnson, 2005). Early stages of PVD are asymptomatic. results in splitting between the lamellae of the ILM (Henrich et al., Longitudinal studies found slow progression of PVD with only 10% of 2012). The anterior lamellae of the ILM then separate from the retina stages 1 and 2 PVD progressing to complete PVD over the course of 30 with the detached posterior vitreous. Greater amounts of ILM on the months (Johnson, 2005). An interesting study in Asahikawa, Japan detached posterior vitreous might induce more light scattering and found that following PVD in one eye, the fellow eye developed PVD result in more bothersome floaters.

Fig. 22. Ultrasonography of PVD. A: Vertical B-Scan of PVD demonstrating the posterior vitreous cortex positioned anterior (left of fundus in this image) to the retina, but still quite close. B: Vertical B-Scan of PVD showing the posterior vitreous cortex positioned anterior (left of fundus in this image) to the retina, but considerably farther from the fundus than in Fig. 22A. Such anterior displacement of the detached posterior vitreous cortex would be difficult, in not impossible to detect with conventional OCT imaging.

16 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

5.4. Anomalous PVD

Anomalous PVD (APVD) results from vitreous gel liquefaction with persistent vitreo-retinal adhesion, resulting in various untoward manifestations (Sebag 2004b, 2010; Sebag et al., 2014c). These manifestations will vary depending upon where the gel is most liquefied and where vitreo-retinal adhesion is strongest (Fig. 24). An extreme example of this are the various hereditary vitreo-retinopathies that feature profound disorders of collagen (Snead and Richards, 2014) inducing significant vitreous liquefaction, far out of proportion to vitreo-retinal dehiscence, resulting in rhegmatogenous retinal events. Less severe but far more common manifestations of this imbalance between vitreous body rheology and weakening of vitreo-retinal adhesion occur in myopic eyes (see below). Diabetic vitreopathy/retinopathy (Sebag, 1996) is another very common condition influenced by this form of APVD (see below). Abnormal traction at the vitreo-retinal interface can have deleterious effects upon the retina as well as vitreous.

Fig. 23. Posterior Vitreous Cortex Folds After PVD. Slit lamp video showing folds in the posterior vitreous cortex in an eye with 5.4.1. Retinal effects of anomalous PVD PVD. [courtesy of Martin Snead, MD]. APVD that features full-thickness (no splitting of the posterior vitreous cortex) separation of the peripheral and posterior vitreous cortex can have residual attachment and traction in either the peripheral fundus or posterior pole. In the periphery, full-thickness APVD can tear the retina. Another consideration as to how a detached posterior vitreous can When there is obscuring the fundus, there is a high cause perceptible and disturbing light scattering (floaters) is that once incidence of retinal tears (67%) and retinal detachments (39%) separated away from the retina, the normally spherical posterior (Sarrafizadeh et al., 2001). Although ultrasound may occasionally identify vitreous surface now occupies a smaller surface area, inducing surface retinal tears in such eyes (DiBernardo et al., 1992), exploratory/therapeutic folding (Fig. 23). Increased folding might result in increased light vitrectomy is probably the current standard of care. There can also be scattering and symptoms. In support of this hypothesis are the multiple damage to the inner retina in the posterior pole. Recent post-mortem reports that increased gel liquefaction is related to PVD (see above). analysis of 36 eyes with PVD found immunohistochemical evidence of type Increased liquefaction probably results in farther anterior displacement IV collagen on the detached posterior vitreous cortex. (Fincham et al., of the posterior vitreous (Fig. 22) forcing the outer vitreous surface into 2018). The lamellar morphology of the ILM probably accounts for the fact an increasingly smaller surface area, inducing more folding and more that in such cases the neural retina itself is not damaged, since the outer light scattering symptoms of floaters. Thus, measures of the surface area lamellae of the ILM are intact. Yet, the presence of ILM elements on the of the detached posterior vitreous cortex similar to imaging studies that detached posterior vitreous cortex could account for disturbed photon measured the surface area of the retina (Nagra et al., 2017) might be transmission to the retina and the visual phenomenon of floaters. Light revealing, especially when correlated with vision, specifically contrast scattering by this tissue could also underlie the degradation of contrast sensitivity function (see below). sensitivity function in some patients, constituting Vision Degrading During head turning and ocular there is movement of the Myodesopsia. vitreous opacities that induce floaters, characterized by a lag and Vitreo-Macular Traction (VMT) is defined as vitreo-macular adhesion overshoot before coming to rest. Consequently, patients complain of with structural alteration of the underlying neural retina (Duker et al., increased disturbance during reading and driving. Motion of the 2013). A report on 2980 eyes in 1913 participants of the Beaver Dam Eye vitreous body during ocular saccades has been studied by mathematical Study found vitreo-macular abnormalities in 45.3% (Meuer et al., 2015). A modeling, particularly as related to retinal detachment (Meskauskas recent study of 2225 eyes in 1130 elderly (mean age = 82.3 ± 3.8 years) et al., 2012) traumatiuc and ocular deformation (Tůma et al., 2018). subjects in Burgundy found vitreo-macular interface abnormalities in more Since the vitreous opacities that induce floaters have a different than half (Blanc et al., 2019). The cause of vision loss in these patients is acoustic reflectivity than normal gel vitreous, they can be visualized on APVD with either full-thickness vitreo-macular adhesion placing B-scan ultrasound, not only in the central vitreous body, but also the significant axial traction and considerably impacting central vision, or detached posterior vitreous cortex (Fig. 22). By quantifying vitreous tangential traction (Sebag, 2014b). Full-thickness vitreo-macular adhe­ motion on ultrasound, vitreous viscosity can be measured in vivo sion/traction also seems to also be important in exudative age-related (Walton et al., 2002). These studies found that vitreous of subjects macular degeneration (AMD) (Krebs et al., 2007; Robison et al., 2009; younger than 46 years old demonstrated significantly less speckle Sebag et al., 2018). Recent immunohistochemical analysis of tissue density (p < 0.001) and less overshoot time (p < 0.001) when removed from eyes with intermediate AMD revealed the presence of compared to older subjects. These findings are consistent with the vitreoschisis in all 27 cases (100%) and a predominance of hyalocytes, experience of older patients with acute symptomatic PVD whose leading the investigators to conclude that vitreoschisis and symptoms likely arise from both opacities in the central vitreous body vitreous-derived cells appear to play an important role in traction as well as the detached posterior vitreous cortex. These are important formation of this subgroup of eyes (Zaida et al., 2018) considerations because vision is a dynamic process, yet our methods of Macular edema unrelated to vein occlusion or diabetic retinopathy evaluating ocular structure and visual function are primarily static. can also be due to persistent full-thickness vitreo-macular adhesion and Enhanced evaluation and management of ophthalmic disorders and traction that's either focal (Bottos et al., 2012) or broad (Khoshnevis vision will likely result from a paradigm shift to dynamic evaluations and Sebag, 2016), even though there is peripheral separation of the (Sebag et al., 2017), discussed in the 'future directions' section of this entire (full-thickness) vitreous cortex. In the case of diabetic macular treatise (below). edema that is unresponsive to pharmacotherapy there is increasing consideration to surgical separation and removal of the posterior vitreous from the macula (see below).

17 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 24. Anomalous PVD. Schematic diagram of Anomalous PVD shows how this unifying concept explains the pathogenesis of several vitreo-retinal diseases often considered very disparate in etiology. Yet, they are actually manifestations of the same underlying pathophysiology - Anomalous PVD. Note that vitreo-papillary adhesion and traction may not only cause gaze-evoked amaurosis, but might also contribute to anterior ischemic . This could also play a role in facilitating/promoting cell migration and proliferation during pathologic neovascularization of the disc. Additionally, vitreo-papillary adhesion might alter the vector of tangential forces exerted by a premacular membrane, in some cases full-thickness posterior vitreous cortex and in some cases the outer layer of a split (vitreoschisis) posterior vitreous cortex left attached to the macula after Anomalous PVD. Also, not all cases of macular holes have vitreoschisis but can feature full-thickness vitreo-macular adhesion and traction. [from: Sebag et al., 2014c. Anomalous PVD and vitreoschisis. In: Sebag J. (Ed.) Vitreous – in Health & Disease. Springer, New York, 2014, pg 252].

5.4.2. Vitreous effects of anomalous PVD APVD with vitreoschisis is whether the split occurred anterior or posterior PVD is associated with vitreous cortex remnants at the fovea in 44% to the location of hyalocytes (Sebag et al., 2014c) (Fig. 17). If the split of human eyes studied at autopsy with scanning electron microscopy occurs anterior to the level of hyalocytes, these cells will remain attached (Kishi et al., 1986). When these remnants are due to splitting between to the macula and recruit monocytes from the circulation as well as glial the layers of the posterior vitreous cortex (Fig. 16), the result is a sheet cells from the retina to form a relatively thick hypercellular membrane comprised of the outer posterior vitreous cortex that remains attached (Sebag, 2018a) that has been shown by immunohistopathology to contain to the posterior pole, a condition known as vitreoschisis (Fig. 25; Sebag, hyalocytes (Zhao et al., 2013; Schumann et al., 2014). Indeed, a recent 2008). Intraoperative findings in patients undergoing vitrectomy for immunohistochemical study of tissue removed during surgery found a macular pucker found splits at various levels within the posterior predominance of hyalocytes in macular pucker, concluding that vitreous cortex, leading the investigators to conclude that macular hyalocytes may be the driving element in tractional vitreo-maculopathies pucker results from APVD with vitreoschisis, leaving the outermost (Schumann et al., 2019). layer of posterior vitreous cortex attached to the macula (Yamashita Because there is very high prevalence (around 90%) of PVD with et al., 2008) supporting previous reports (Sebag 2004b, 2008, 2018a). separation from the optic disc in cases of macular pucker, the usual An important factor in any potential consequences of partial-thickness untoward consequence is tangential traction with force vectors oriented

Fig. 25. Vitreoschisis. A: SD-OCT imaging of Anomalous PVD with persistent vitreo-macular adhesion and associated inner retinal cyst at the point of vitreo-macular attachment. Prominent vitreoschisis can be seen to the left (in this image) of the attachment site with cysts. [courtesy of Jay Duker, MD; from Sebag et al. (2014c). Anomalous PVD and vitreoschisis. In: Sebag J. (Ed.) Vitreous – in Health & Disease. Springer, New York, 2014, pg. 256] B: Histopathology of specimen removed at surgery from a patient with vitreoschisis and macular pucker stained with Periodic Acid Schiff to demonstrate the split (purple arrow) in the membrane removed at surgery. Embedded in this tissue are two hyalocytes (black arrows), supporting that this tissue is the posterior vitreous cortex (courtesy of N. Rao, MD; original magnification = 225x). [fromGupta et al., 2011. Vitreoschisis in macular diseases. Brit J Ophthalmol 95(3):376-80].

18 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 inward towards the fovea (centripetal tangential traction), resulting in glucose levels correlated more closely with serum glycated hemoglobin underlying retinal folds and macular pucker. En face OCT has also than did serum glucose, leading the investigators to suggest that determined that there can as many as four foci of retinal contraction in subclinical alterations in vitreous biochemistry may forewarn a risk for the fundus, with 3 or 4 more often associated with intraretinal cysts and diabetic retinopathy and cardiovascular events. These observations greater macular thickening than 1 or 2 (Gupta et al., 2008). Although confirm previous studies that found elevated levels of glucose (Lundquist the term “idiopathic (ERM)” is often used to refer and Osterlin, 1994) and advanced glycation end-products (Sebag et al., to this condition, that term is imprecise for several reasons. The 1992, 1994) in human diabetic vitreous, underscoring the importance of condition is not “idiopathic”; we now know that it is the consequence of considering diabetes effects upon vitreous independent from the effects on anomalous PVD. Furthermore, “epi” refers to a location next to or be­ retina (Sebag, 1996). Indeed, morphologic studies in diabetic children side (even under) the retina, yet the problem resides only in front of the have identified structural differences from non-diabetics that likely result macula, not elsewhere. Thus, the term “premacular membrane,” or from glucose-induced cross-linking of vitreous collagen. An understanding “PMM” is preferable to refer to the membrane, and “macular pucker” of vitreous biochemistry is thus critical for the interpretation of clinical should be used to refer to the effects of this pathologic membrane. findings and improved patient care in this disease. Thus, the term diabetic There can, of course, also be migration of cells from breaks in the ILM vitreopathy was coined (Sebag, 1996) to refer to the distinct molecular near retinal blood vessels or elsewhere. and structural effects of diabetes on vitreous, as a phenomenon separate If the vitreoschisis split occurs posterior to the level of hyalocytes and apart (but ultimately intimately related to) effects upon the vessels (Fig. 24), a thin hypocellular membrane remains attached to the and nerves of the retina. These vitreous effects are molecular, structural, macula, often with persistent vitreo-papillary adhesion (VPA) (Wang and physiologic. et al., 2009). In full-thickness macular holes, the prevalence of VPA is nearly 90% (Wang et al., 2009). This anchor point could promote nasal 6.1. Molecular manifestations of diabetic vitreopathy tangential traction with a nasal vector outward from the fovea (centrifugal), inducing central macular dehiscence and macular AGEs were first identified in human vitreous when Sebag et al. (1992) holes (Sebag et al., 2009; Nguyen et al., 2019). In many instances assayed vitreous excised at surgery from patients with proliferative vitreo-papillary adhesion is accompanied by eccentric foci of retinal diabetic retinopathy. Subsequent studies characterized the molecular contraction seen on en face OCT imaging (Sebag et al., 2007a) serving profiles using Raman spectroscopy (Sebag et al., 1994). Although the as additional anchor points promoting superior, inferior, and temporal presence of vitreous hemorrhage may have been a confounder in many centrifugal tangential traction, furthering central macular dehiscence cases, there have since been confirmatory studies (Stitt et al., 1998), and (Sebag et al., 2007a; Nguyen et al., 2019). In the case of lamellar some recent ones have offered refinements in this fund of knowledge that macular holes (LMH) there are differences that depend upon the are worthy of mention. Firstly, there is a relationship between vitreous subtype of LMH – tractional or degenerative (Govetto et al., 2016). In AGE levels and glycemic control (Loho et al., 2018). There is also a tractional LMH the prevalence of VPA was 64%, while only 20% of relationship with the existence and severity of diabetic retinopathy and degenerative LMH had VPA (Nguyen et al., 2019). Surgery that nephropathy (Fokkens et al., 2017; Katagiri et al., 2017). This led the included release of VPA was associated with more improvement in investigators to propose that the evaluation of vitreous levels of AGEs and vision for the tractional form of LMH than the degenerative form angiogenic factors could serve well as biomarkers of diabetic retinopathy (Figueroa et al., 2019). severity (Katagiri et al., 2018). As pointed out by Bejarano and Taylor (2019), it is likely that HA is also subject to modifications resulting from 6. Diabetic vitreopathy glycation, but this has yet to be determined in vitreous.

Diabetes is already a major global health problem, but it is anticipated 6.2. Structural manifestations of diabetic vitreopathy to increase in world prevalence from 382 million in 2013 to 592 million by 2030 (Stitt et al., 2016). Although the incidence of diabetic retinopathy is The aforementioned molecular effects of diabetes on vitreous have falling, it is still the most common microvascular complication of diabetes structural consequences both within the vitreous body as well as at the (Sebag and McMeel, 1986; Antonetti et al., 2012). Along with oxidative vitreo-retinal interface. stress (Dos Santos et al., 2019), one of the fundamental impacts of diabetes is the formation of advanced glycation end products (AGEs) throughout 6.2.1. Vitreous body the body (Vlassara and Uribarri, 2014). AGEs comprise a heterogeneous Dark-field slit microscopy of dissected human eyes from patients with group of compounds that arise via non-enzymatic post-translational diabetes but no evidence of diabetic retinopathy revealed prominent modification in which a carbonyl group of reducing sugars is covalently structural abnormalities within the vitreous body (Sebag, 1993). The most linked to proteins and other compounds as well (Rowan et al., 2018). It is striking is the case of a 9-year-old girl with a 5-year history of type 1 important to note, however, that these biochemical changes also occur in diabetes but no evidence of diabetic retinopathy. Vitreous morphology the absence of diabetes and have been causally linked with a number of was far different from non-diabetic age-matched controls (Fig. 26). Rather age-related diseases (Rowan et al., 2018). than the homogeneous appearance typical of children, vitreous In the eye, most attention has been focused upon diabetes-induced morphology in this child resembled non-diabetic adult vitreous structure AGE cross-linking in retinal vessel basement membranes with loss of (Fig. 10) far more than non-diabetic children. The fibrous structure in protein degradability and vessel elasticity, causing basement membrane diabetic vitreopathy is likely the consequence of AGE-mediated thickening (Stitt et al., 2013). However, there are similar changes in cross-linking of vitreous collagen as occurs in extracellular matrices vitreous as well that can impact the progression of diabetic retinopathy throughout the body, including joints (Saudek and Kay, 2003; Chen et al., (Sebag and McMeel, 1986; Vaz-Pereira et al., 2017). Recent biochemical 2018; Kumar Dubey et al., 2019), the most similar extracellular matrix to analyses of 27 patients undergoing vitrectomy found significant amounts vitreous anywhere in the body. Indeed, the biochemical and structural of electrolytes and metals including copper, zinc, selenium, and iron effects of AGEs in joints play an important role in osteoarthritis, where (Kokavec et al., 2016). In contrast to previous studies that utilized animal research is providing insights for new pharmacotherapies that may be models or post-mortem human samples, this study analyzed undiluted effective in vitreous as well (Tong et al., 2019). Of note is that studies in human vitreous samples, yet the fact that all subjects underwent joints found that glycosaminoglycans have protective effects against AGE vitrectomy for vitreo-retinal diseases suggests that the results may not be damage to type II collagen (Pouran et al., 2018). It is of interest to note applicable to healthy eyes (Sebag, 2016). The study also compared that diabetic patients (even those with diabetic retinopathy) do not vitreous from diabetic patients to non-diabetics. In the former, vitreous generally complain of vitreous floaters, except, of course, those with

19 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 26. Diabetic Vitreopathy. Dark-field slit microscopy of human vitreous bodies dissected of sclera, choroid, and retina, illuminated from the side with a slit lamp beam and examined from above at a 90° illumination-observation angle, maximizing the Tyndall effect. A: In non-diabetic children (top panel) there is light scattering from the posterior and peripheral vitreous cortex, but not the central vitreous body. In adults (bottom panel), there are visible fibers composed of collagen fibrils (see text). B: In whole eye specimens from a 9-year-old girl with a 5-year history of type 1 diabetes but no evidence of clinical diabetic retinopathy, there are fibers adjacent to areas of liquid vitreous. This appearance is far more similar to non-diabetic adults and very different from age-matched non-diabetic children. [from: Sebag, 1993. Abnormalities of human vitreous structure in diabetes. Graefe's Arch Clin Exp Ophthalmol 231(5):257-60]. vitreous hemorrhage. This is surprising, given the aforementioned alterations with increased protein carbonylation and increased antioxidant structural changes in the vitreous body (Fig. 26). One study, however, did levels (Géhl et al., 2016). Another physiologic consequence of diabetic find that intraocular light scattering was increased in 27 diabetic subjects vitreopathy is the reduction of vitreous permeability due to AGE without diabetic retinopathy compared with 27 non-diabetic controls accumulation (Lee et al., 2015). As pointed out by Bejarano and Taylor (Liu et al., 2019). (2019), changes in vitreous permeability might increase the retention of cytokines or drugs, having implications in the pathogenesis and therapy of 6.2.2. Vitreo-retinal interface in diabetic vitreopathy diabetic retinopathy. Histopathologic studies have found that the ILM is thickened in eyes with diabetic macular edema (Matsunaga et al., 2005), but it is not 7. Myopic vitreopathy clear whether this is due to effects of diabetes or edema. The presence of increased immunoreactivity for heparan sulfate proteoglycan in the As cited by Magnus (1877), the concept of myopia was first developed ILM of the diabetic subjects suggests the former. Recent swept-source by Aristotle in 350 B.C.E. According to Bourke et al. (2019) myopia was OCT imaging identified thickened posterior vitreous cortex in 4 of 21 first associated with elongation of the around the year 1700. This (19%) eyes with NPDR, 11 of 20 (55%) eyes with PDR, and 11 of 27 view has prevailed throughout the years culminating in a recent proposal (41%) eyes with DME (P = 0.0001) (Adhi et al., 2016). This is not by the International Myopia Institute to define myopia as an abnormality surprising given the dense concentration of collagen fibrils in the posterior of eye growth resulting in excess axial length (Flitcroft et al., 2019). Over vitreous cortex (Fig. 13) and the predilection of non-enzymatic glycation the past 3 decades, myopia has reached epidemic proportions, especially to target collagen throughout the body, including vitreous collagen (Sebag in urban areas of East Asia where it has been estimated that 80% of et al., 1992; Stitt et al., 1998). individuals are myopic by early adulthood (Wojciechowski and Ching-Yu Splitting of the posterior vitreous cortex, called vitreoschisis (see above), Cheng, 2018). In the year 2000, myopia afflicted 1.4 billion and high was originally identified by Chu et al. (1996) using ultrasonography in myopia 163 million people world-wide (Flitcroft et al., 2019). It is diabetic patients with PDR, a finding that was confirmed histologically. predicted that the prevalence of myopia and high myopia will significantly Using swept-source OCT, Adhi et al. (2016) found vitreoschisis in 48% of increase in the future, so that by the year 2050 myopia will afflict nearly 5 eyes with NPDR, 65% of eyes with PDR, and 63% of eyes diabetic macular billion people and high myopia 1 billion people (Holden et al., 2016). A edema (p = 0.007) confirming previous reports (Sebag, 2011a). The similar study in China predicted that by 2050, myopia prevalence among importance of this phenomenon relates to diabetes-related ocular events children and adolescents aged 3–19 years will be about 84% (Dong et al., such as vitreous hemorrhage that can be induced by vitreoschisis rupturing 2019), with the prevalence of high (pathologic) myopia being several new blood vessels that have grown out of the retina and optic disc into the times higher than in older non-myopic cohorts (Morgan et al., 2012). posterior vitreous cortex (Faulborn and Bowald, 1985) resulting in a typical Duke-Elder and Abrams, 1970 described pathologic myopia as high boat-shaped preretinal hemorrhage that has lamellae of vitreous cortex myopia accompanied by degenerative changes in the sclera, choroid, both anterior and posterior to the blood. Pre-operative awareness of this and retinal pigment epithelium, all compromising visual function. situation can guide surgical intervention to assure removal of both layers of Apart from uncorrected , the most commonly recognized vitreous cortex, since leaving the outer layer can exacerbate diabetic cause of due to myopia is myopic . macular edema (Sebag, 2011a) and perhaps induce macular pucker Meta-analysis and modelling studies on 137,514 participants estimated (see above). that in 2015, 10 million people had visual impairment from myopic maculopathy, 3.3 million of whom were blind (Fricke et al., 2019). 6.3. Physiologic effects of diabetic vitreopathy These investigators further estimated that by 2050, visual impairment will grow to 55.7 million people, 18.5 million of whom will be blind. There are considerable physiologic consequences of the aforemen­ Studies that separated visual impairment due to uncorrected myopia tioned diabetes- and age-related molecular and structural changes in from that due to myopic maculopathy found that in 2015 the economic vitreous. These primarily involve inflammation and oxidative stress (Fang impact of this was significant, with ametropia accounting for global Yan et al., 2008; Dos Santos et al., 2019). Indeed, there is even a study that productivity loss of US $244 billion, while myopic maculopathy found evidence of autoimmunity to type II collagen, the most prevalent accounted for losses of US $6 billion (Naidoo et al., 2019). However, in type in human vitreous (see above), in the serum and of patients with the overwhelming majority of scientific, clinical, and economic diabetic retinopathy, leading the investigators to conclude that develop­ publications on myopia there is no mention of the changes in vitreous ment and progression of diabetic retinopathy may be related the that constitute myopic vitreopathy. Indeed, in a recently proposed disruption of the blood–retinal barrier and consequent exposure of the OCT-based classification of myopic maculopathy, the word “vitreous” normally sequestered vitreous type II collagen with subsequent activation does not appear (Fang et al., 2019). Yet, vitreous might play an of autoimmune mechanisms (Nakaizumi et al., 2015). Such activation of important role in the development of myopia. Curtin et al. (1998) and inflammation in vitreous apparently induces diabetes-associated redox Seltner and Sivak (1987) suggested that excess vitreous formation

20 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 during growth could cause excess ocular enlargement. Furthermore, Curtin et al. (1998) reported that within the myopic vitreous body myopia is the second-leading cause of Vision Degrading Myodesopsia there is visible liquefaction with filaments and localized nodules. These (Millston et al., 2016; Sebag et al., 2018), yet little is known about the structures (Fig. 27) likely produce incident light scattering and Vision biochemistry and morphology of the myopic vitreous. Degrading Myodesopsia, when severe. Vitreous liquefaction can manifest in a variety of ways. Swept-source OCT imaging has shown a 7.1. Biochemistry of myopic vitreopathy nearly two-fold enlargement of the Bursa Premacularis of Worst (Itakura et al., 2014). Liquefaction also promotes PVD, which Quite some time ago, Berman and Michaelson (1964) found reduced can exacerbate the light scattering by myopic vitreopathy and worsen a protein concentration, collagen content, and hyaluronate concentrations in patient's complaints of vitreous floaters (see below). PVD is not only myopic vitreous compared to controls. More recent studies in mouse more frequent in myopia, but more frequently anomalous via either models (Cases et al., 2017) identified markedly lower levels of vitreous vitreoschisis or via traction upon the retina. potassium, sodium and chloride, as well as proteins involved in ocular tissue homeostasis and repair. Proteins of the inflammatory response class 7.2.1. Myopic posterior vitreous detachment were over-expressed in the mutants. Structural and biochemical findings in Early studies found PVD more frequently in moderate or high the retinal pigment epithelium (RPE) led these investigators to conclude myopia than in emmetropia (Kobayashi and Ogino, 1985). Akiba that impairment of the RPE contributes to the vitreous modifications and (1993) employed preset lens biomicroscopy in 224 myopic (> - 6 D) the pathogenesis of high myopia. Another pathogenic mechanism could be and 222 emmetropic eyes, finding that in emmetropia, no patients upregulation of oxidative stress and lipid metabolism pathways (Yu et al., under 39 years of age had PVD, with increasing prevalence at 2017), which could promote vitreous gel liquefaction. In a relatively large advancing ages. High myopia, however, had PVD in the 4th decade study of 44 non-myopic eyes, 42 eyes with low-to-moderate myopia, and (23% compared to 0% in emmetropia), increasing prevalence with age, 51 eyes with pathologic myopia undergoing vitrectomy, Peng et al. (2019) and 100% prevalence in those 70 years or older. Akiba concluded that recently reported a strongly positive correlation (β = 0.714, p < 0.0001) PVD develops nearly 10 years earlier in highly myopic than in emme­ between axial length and vitreous levels of Dickkopf 1, a natural tropic eyes and is more prevalent throughout life. Itakura et al. (2014) antagonist of the canonical Wnt/β-catenin pathway. Whether this is cause found that highly myopic patients with partial and complete PVD were or effect and the possible significance are unclear at the present time. younger (p < 0.0001). Yonemoto et al. (1994) found that the average Gale and Ikuno (2014) nicely summarized the various considerations age of PVD onset was 61 years for emmetropia, and younger ages of in the precocious and excess formation of liquid vitreous in myopic eyes. onset with increasing degrees of myopia. Based upon this, they de­ The finding of 50% higher levels of matrix metalloproteinases in vitreous termined that for each diopter of myopic refractive error, 0.91 years of myopic eyes than controls suggests that liquid vitreous in myopia might could be subtracted from the average age of PVD onset in emmetropes. arise from enzymatic breakdown of existing gel vitreous (Zhang et al., The only caveat in all these studies is that refractive error was 2014). However, others have suggested that in myopic eyes an increase in employed to define myopia and not axial lengths. Furthermore, it is not liquid vitreous synthesis may be more important than an increase in certain that the clinical diagnosis of PVD is accurate. In one recent liquefaction of existing gel vitreous (Balazs et al., 1965; Pickett-Seltner study (Garcia et al. 2018), ultrasound was used to diagnose PVD in et al., 1992). Future experiments with animal models might shed light on subjects with age or myopia as the cause. The mean age in the former this important aspect of myopic vitreopathy. group was 65.1 ± 3.5 years, which was significantly (p < 0.001) greater than the myopic group (52.7 ± 3.1 years). This translates to 7.2. Morphology of myopic vitreopathy PVD occurring 13 years earlier in myopes, a rather important finding, especially from the perspective of anomalous PVD (see above). Another Mathematic models that assumed the vitreous body is spherical useful approach is to consider studies that diagnosed PVD during determined that a highly myopic eye continuously experiences shear vitreous surgery, although it isn't certain that PVD wasn't induced stresses that are significantly higher than those of an emmetropic eye, during the early stages of vitrectomy surgery. In a monocentric study of purportedly providing a mechanical explanation for the more frequent intraoperative findings in 96 eyes with high myopia (mean age = 62 occurrence of PVD and retinal detachment in myopic eyes (Meskauskas years), complete PVD was observed in 52.1% of eyes, but this varied et al., 2012). Subsequent MRI studies of the shape of the myopic depending on the disease: PVD prevalence in retinal detachment (85%) vitreous body found that posterior to the equator the emmetropic and macular pucker (74.2%) was much higher than myopic foveoschisis vitreous is shaped like an oblate ellipse, while in myopia it (14.3%) and myopic macular hole (10%); p < 0.0001 (Philippakis approximates to a sphere (Gilmartin et al., 2013). The investigators et al., 2016). There are also limitations of standard imaging modalities. concluded that these findings supported the equatorial model of myopia Recent studies that employed ultra-widefield swept-source OCT imaging in pathogenesis and that the spherical shape in myopia may constitute a 167 highly myopic eyes (defined as axial length > 26.5 mm) found that biomechanical limitation of further axial elongation. in contrast to emmetropic eyes, PVD progressed asymmetrically and that A hallmark of myopic vitreopathy is the presence of liquid vitreous. over one-third had evidence of macular (Takahashi et al., In hereditary vitreo-retinopathies, the co-existence of high myopia and 2019). The authors concluded that vitreous traction spanning a wide vitreous liquefaction at any early age suggests a causal relationship, distance may lead to myopic traction maculopathy. perhaps involving abnormal metabolism(s) of collagen (Snead and Richards, 2014) and/or other extracellular matrix component(s) of 7.2.2. Myopic vitreo-retinal traction vitreous (Miyamoto et al., 2005). Many years ago, Favre and Goldmann Vitreous liquefaction that exceeds vitreo-retinal dehiscence is the (1956) reported that vitreous liquefaction and syneresis occurred at an hallmark of anomalous PVD (see above). This is especially pertinent in early age in myopia, but as pointed out by Van Alphen (1990), it is myopia where liquefaction and collapse occur at an early age, much difficult to distinguish between myopic and age-related sooner than the development of sufficient weakening of vitreo-retinal vitreous liquefaction. Recent studies in myopic mice confirmed that the adhesion to allow vitreous to separate away from retina without volume of liquid vitreous was much higher in myopic eyes (Cases et al., untoward sequelae. Anomalous PVD in the peripheral fundus 2017). A significant problem in improving our understanding of liquid can induce retinal tears and detachments, both known to occur more vitreous in myopic vitreopathy, however, is the lack of an objective frequently in myopic eyes. The Case Control Study Group measure in vivo, as described above. (1993) determined that an eye with a spherical equivalent refractive

21 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 27. Myopic Vitreopathy. A: Ultrasonography in a myopic eye images focal and linear echodensities in the vitreous body. B: Video of myopic vitreopathy demonstrating SD-OCT imaging of opacities in the vitreous body that can induce Vision Degrading Myodesopsia [courtesy of Carl Glittenberg, MD]. error of −1 to −3 diopters had a four-fold increased risk of retinal diagnostic evaluation of patients with intermediate has been detachment compared with a non-myopic eye; refractive error greater vitrectomy (Sato et al., 2018), non-invasive diagnostic approaches are than −3 diopters was associated with a 10-fold increased risk of retinal being sought. The degree of vitreous opacification is being measured detachment. In another study, bilateral retinal tears were noted in with OCT imaging (Keane et al., 2014; Montesano et al., 2018) although 18.2% of eyes, with 86.4% of these being myopic eyes (p = 0.01) recent studies suggest that there is no useful correlation between (Crim et al., 2017). These authors also studied the development vitreous haze and inflammation in multiple sclerosis (Coric et al., subsequent retinal tears following PVD, concluding that the risk is 2020). Another group of individuals presenting with vitreous floaters 4.5-fold greater in myopic eyes. In the posterior pole, Itakura et al. are those with vitreous hemorrhage due to diabetic retinopathy, (2014) found that after complete PVD (defined as a visible Weiss ring), retino-vascular disorders, and anomalous PVD with disruption of the vitreous cortex was present on the macula in 40.5% of the eyes with retinal or optic disc vasculature. Clearly, these individuals need high myopia, but only 8.7% of controls (p < 0.0001). accurate diagnosis and appropriate therapy for the underlying cause of their vitreous floaters. 8. Vision Degrading Myodesopsia In the absence of uveitis or vitreous hemorrhage it is not clear why some individuals with vitreous opacities are extremely bothered by Vitreous floaters are not structures within the vitreous body, but vitreous floaters, while others are not. When there is not only entoptic images that create visual phenomena experienced by many unhappiness but also measurable alteration of vitreous structure and people. Ivanova et al. (2016) coined the term ‘symptomatic vitreous degradation in vision, the term Vision Degrading Myodesopsia is appropriate. opacities’ to refer to the structures in the vitreous body that cause Although not extensively studied, the degree of unhappiness has been floaters. A 2002 survey of 74 optometrists in the United Kingdom determined, and the results are quite revealing. determined that an average of 14 patients per month per optometrist presented with concerns referable to symptomatic vitreous opacities 8.1. Impact on psychosocial well-being & quality-of-life (Alwitry et al., 2002). The authors concluded that these patients make up a sizeable part of the community optometrist's workload. Yet, in that Health-related quality of life is becoming increasingly important in same year, Delaney et al. (2002) stated that “Patients' symptoms from every aspect of medicine because of greater awareness that patients are vitreous floaters are often underestimated resulting in no intervention”, consumers of health care and that the rising costs of care have introduced reflecting a perception that has long prevailed in the ophthalmic the concept of “value” to health care (Brown et al., 1999; Wagle et al., community. 2011). Utility values are a method to allow objective quantification of the A recent electronic survey through a smartphone app asked various functional quality of life associated with a specific disease state, ranging demographic and health questions, including whether respondents from 1.0 (perfect state-of-health) to 0.0 (death). Brown et al. (1999) experience “floaters” in their vision (Webb et al., 2013). Of the 603 who defined utility values for eye diseases emphasizing that the closer a utility completed the survey, 76% reported seeing floaters and 33% claimed value is to 1.0, the better is the patient's perceived visual quality-of-life. that their floaters caused vision impairment. Multivariate logistic Employing this approach to a group of 266 patients in Singapore (90% regression analysis found that this floater prevalence was not affected Chinese, mean age = 53 years) with vitreous floaters, Wagle et al. (2011) by respondent age, race, gender, or eye color. It is difficult to determined the time trade-off and standard gamble (blindness) utility extrapolate these findings to the general population, however, given the values. The former utility measures the numbers of years of remaining life selection bias for smartphone users which produced a very young that an individual is willing to trade off for a hypothetical restoration of demographic: < 5% were older than 50 years. Nevertheless, the perfect vision, whereas the latter utility assesses the risks that the patient is findings are noteworthy and consistent with other lines of evidence, willing to take in order to undergo a hypothetical cure and return to leading the authors to conclude that “vitreous floaters should be viewed “perfect health”. The study found that patients with floaters are willing to not just as a physiologic curiosity, but rather as a real health concern trade off an average 1.1 years out of every 10 years of remaining life to get deserving more intensive study into its causes and potential treatment.” rid of floaters. Furthermore, these patients are willing to take a 7% risk of An important subset of patients presenting with vitreous floaters are blindness to be rid of floaters. In this study, the mean utility values for those afflicted with uveitis, particularly , but also floaters were found to be comparable to utility values of age-related panuveitis (Duplechain et al., 2020). Although the gold standard for macular degeneration, diabetic retinopathy, and myopia (with similar

22 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 of 20/20 to 20/25), as well as the systemic diseases Dynamic light scattering (DLS) enables in vitro and in vivo molecular hypertension, mild angina, mild stroke, colon cancer, and asymptomatic assessment of particle size distributions in the lens and vitreous (Ansari HIV infection. Interestingly, half the subjects had acute-onset floaters et al., 2001; Datiles et al., 2008). Studies in bovine vitreous (likely due to PVD), and these patients did not report significantly different demonstrated the ability of DLS to distinguish between collagen and utility values from patients with long-standing symptomatic floaters (likely hyaluronan macromolecules (Ansari et al., 2001) and to evaluate the due to myopic vitreopathy). The investigators concluded that the impact of effects of pharmacologic vitreolysis (Sebag, 2005; Sebag et al., 2007b). vitreous floaters is noteworthy in its magnitude and significance, as was In vitro studies of diabetic human vitreous showed increased particle the conclusion of an accompanying editorial (Sebag, 2011b). size distributions (Sebag et al., 1999), consistent with the molecular Although patients are often told that no intervention is necessary and structural effects of diabetic vitreopathy described above. and their symptoms will improve spontaneously, this is often not the Fankhauser (2012) confirmed these findings with clinical DLS which he case. In a study of 107 patients in Shanghai with “visually disabling performed in patients with diabetes and varying degrees of diabetic vitreous floaters”, utility values for vitreous floaters were significantly vitreo-retinopathy, concluding that “vitreous in normals and even different than in 91 control subjects (p < 0.01), confirming the moreso in diabetics with diabetic vitreo-retinopathy is optically a findings described above. Furthermore, the study found that one month highly non-isotropic, multi-dispersive structure”. It is hoped that a after initial evaluation the time trade-off utility values were unchanged similar clinical approach to patients with Vision Degrading from the initial evaluation (Zou et al., 2013). While one could argue Myodesopsia will produce not only enabling technology but a that one month of coping with floater symptoms is insufficient time, methodology for objectively quantifying vitreous opacification as an these findings are consistent with the experience of many patients and integral part of patient evaluation and management. Currently, vitreous their doctors; i.e. that “settling” of the vitreous opacities and excised from patients with Vision Degrading Myodesopsia is being neuroadaptation are not very powerful mechanisms. In a small compared to controls using DLS. Preliminary results found a two-fold study performed in northern Italy, Cipoletta et al. (2012) determined that increase in particle numbers as well as a doubling of particle sizes in each individuals' ways of experiencing and reacting to eye floaters differed patients complaining of bothersome vitreous floaters (Kershaw et al., depending on the perception of the disease, the personal explanation (by the 2017). Multi-wavelength photon correlation spectroscopy has been health care provider), the solutions tried, the trust placed in medicine, employed on model vitreous solutions in vitro as well as vitreous excised self-construction, and the dispersion of dependency. This suggests that with from patients with Vision Degrading Myodesopsia. The results found a further study, better coping mechanisms might be developed. positive correlation between light scattering and degradation in Kim et al. (2017b) compared 61 floater patients to 34 controls with contrast sensitivity function (Khoshnevis et al., 2016b). standardized psychologic testing paradigms: Major Depression, using the As described by Huang et al. (2014) the optical effects of the penumbra Patient Health Questionnaire-9 (PHQ-9; Korean version by Lee et al., cast by an opacity in the vitreous body may be more disturbing to vision 2012) derived from the Diagnostic and Statistical Manual of Mental than the umbra (Fig. 28). This consideration is highlighted by a comparison Disorders, 4th Edition (DSM-IV); Perceived Stress, derived from the of vitreous opacities that cause clinically significant floaters in myopia, Perceived Stress Scale (PSS) of Cohen et al. modified for Korea; and aging, and PVD as compared to the opacities in (Fig. 29). Anxiety, using the State-Trait Anxiety Inventory (STAI) by Spielberger It is well-known that in spite of filling the vitreous body with dense et al. (1983). Compared to controls, the symptomatic floater group opacities, Asteroid Hyalosis does not often cause subjective complaints nor showed more depression (p < 0.001), higher perceived stress level impact vision (Khoshnevis et al., 2019). It has been postulated (Huang (p = 0.027), and higher anxiety (p = 0.014). Severity of floaters et al., 2014) that the reason relates to the smooth surfaces of asteroid symptoms may be a factor in this phenomenon, since mild & moderate bodies which probably do not scatter light in as ‘disturbing’ a manner as the disturbance groups (based on subjective declaration) had less tortuous aggregates of vitreous fibers with nodularities (Fig. 9B, bottom) depression, stress, and anxiety than those in the severely disturbed and the detached posterior vitreous cortex with its dense matrix of collagen group (p < 0.001). However, based upon OCT diagnosis of PVD, there fibrils (Fig. 13; Fig. 21; Fig. 22) and folding (Fig. 23). Mathematical were no significant differences between subjects with PVD compared to modelling and actual light scattering measurements would be helpful in those with no PVD. While this might be consistent with the findings of testing this hypothesis. Wagle et al. reported above (i.e., that the impact of PVD on the visual phenomenon of floaters is equivalent to that of vitreous opacification due to aging and/or myopic vitreopathy), there may be limitations due to the use of OCT alone in diagnosing PVD (Hwang et al., 2020). It is quite evident, therefore, that vitreous floaters are perceived by patients as an important health issue, and not just a nuisance, as perceived by most doctors. To better understand the visual experience of these patients requires a consideration of the molecular mechanism(s) that underlie the structural changes in vitreous which induce the optical effects as well as the functional impact(s) of this disease.

8.2. Molecular mechanisms of Vision Degrading Myodesopsia

The aforementioned molecular changes associated with aging and myopia result in aggregation of vitreous collagen into structures of various numbers, sizes, and shapes. In addition, remnants of Fig. 28. Optical Effects of Vitreous Opacities. incompletely regressed fetal hyaloid vessels appear as tubular linear Schematic diagram of the umbra and penumbra effects by asteroid bodies as opacities. Vitreous body opacities interfere with photon transmission compared to aggregates of vitreous collagen, showing how the convergence of from the anterior segment to the retina, causing a variety of effects. light on an opacity with a smooth, spherical surface (asteroid body) results in a With aging, additional interference arises from the detached posterior small umbra and penumbra (a), while the diffraction and scatter of light off an vitreous cortex, resulting in both subjective and objective disturbances irregularly-shaped vitreous opacity of the same size results in a larger in vision. The exact molecular mechanisms of these optical effects are penumbra having more damaging effects upon vision. [fromHuang et al., 2014. not currently known, but recent investigations have provided some Vitreous floaters and vision: Current concepts and management paradigms. In: insight(s). J. Sebag (Ed.) Vitreous – in Health & Disease. Springer, New York, pg. 779].

23 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 29. Asteroid Hyalosis. A. Multiple small white/yellow focal opacities fill the vitreous body obscuring clear imaging of the fundus, except for a hazy view of the optic disc (to right). B. Ultrasonography of Asteroid Hyalosis demonstrates significant echodensity induced by the asteroid bodies. In contrast to sound, however, photon transmission through Asteroid Hyalosis appears to be relatively unhindered. [from Khoshnevis et al., 2019. Asteroid Hyalosis - A comprehensive review. Surv Ophthalmol. 64(4):452–462. https://doi.org/10.1016/j.survophthal. 2019.01.008.

Fig. 30. Fetal Hyaloid Vessel Remnants. Slit lamp photographs of linear, tubular structures with branches that are remnants of incompletely regressed fetal hyaloid blood vessels. [courtesy of Marie-Jose Tassignon, MD].

8.3. Structural aspects of Vision Degrading Myodesopsia

The structural changes that result in the visual phenomenon of Fig. 31. Scanning Laser of vitreous floaters have been demonstratedin vitro, but available methods Human Vitreous Opacification. to image these structures in patients are limited. These structures vary Scanning laser ophthalmoscopy of human vitreous opacification that causes in shape, depending upon their origin. Aggregates of collagen fibrils floaters and at times Vision Degrading Myodesopsia. [from Huang et al., 2014. appear linear (Fig. 9; Fig. 10), at times with nodularities (Fig. 9B, Vitreous floaters and vision – current concepts and management paradigms. In: bottom) that may represent bends in the fibrils or aggregates of Sebag J. (Ed.) Vitreous – in Health & Disease. Springer, New York, 2014, pg. 777]. proteoglycans, although there is no evidence of this to date. Tubular structures with branches are remnants of the fetal hyaloid vasculature directly imaged with current OCT technology. Thus, ultrasonography is (Fig. 5; Fig. 30). Membranous structures are possibly Eisner's presently the most useful imaging technology for the evaluation of patients membranelles or more likely the detached posterior vitreous cortex complaining of vitreous floaters (Huang et al., 2014; Sebag et al., 2014b; (Fig. 21; Fig. 22; Fig. 23). Ring-like structures are the hole in the Mamou et al., 2015), primarily because it enables evaluation of the entire pre-papillary posterior vitreous cortex surrounded peri-papillary glial vitreous body, not just the posterior aspects. Furthermore, dynamic tissue that was pulled off during PVD (Fig. 15). ultrasonography can assess vitreous movement with ocular saccades (Fig. 33), an important aspect of the impact vitreous has on visual tasks 8.3.1. Clinical imaging such as reading and driving. Ultrasonography is especially useful in Physical examination can reveal opacities in the vitreous body when diagnosing PVD (Abraham and Ehlers, 2020) (Fig. 22), an important sufficiently prominent, but this is usually not the case due to limitations in consideration in the work-up of patients complaining of floaters. However, the illumination-observation angle with slit lamp biomicroscopy. routine ultrasonography is not very useful for assessing severity, except Similarly, routine fundus photography is unable to adequately image small subjectively by the observer. to medium sized vitreous opacities that can cause Vision Degrading Therefore, quantitative ultrasonography (QUS) was developed in Myodesopsia. Scanning Laser Ophthalmoscopy can image these structures collaboration with the College of Physicians & Surgeons, Columbia when large (Fig. 31), but there are currently no methods which can University and Riverside Research (New York) to provide objective quantitate the images to index the severity of disease. Optical Coherence assessment of vitreous density with a probe (Quantel Medical, France) Tomography (OCT) has relatively high resolution, but it is limited to optimized for vitreous imaging (Mamou et al., 2015). This approach has imaging only the posterior vitreous when situated close to the retina. In shown significant utility in obtaining objective assessment of the some instances, OCT can be indirectly useful, since central vitreous severity of vitreous opacification, with good reproducibility (intraclass opacities can occasionally cast a shadow, or “floater ” onto the correlation R ≥ 0.828). In patients complaining of bothersome vitreous retina in B-scan OCT images (Schwartz et al., 2013; Huang et al., 2014). floaters, QUS correlated strongly with the composite index of the N.E.I. (Fig. 32) However, changes within the central vitreous body cannot be Visual Function Questionnaire of visual well-being (R = −0.634,

24 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 32. Floater Scotoma. Combined SD-OCT/SLO imaging of “scotoma” cast upon the retinal image created by light scattering and shadowing induced by vitreous opacities. Fig. 34. Structure of Aging Vitreous and Vision Degrading Myodesopsia. Fl = vitreous opacity causing floater Subjects with PVD (blue squares) had considerably greater vitreous echodensity P = penumbra U = umbra [from Huang et al., 2014. Vitreous floaters and than subjects without PVD (799 ± 76 AU vs. 513 ± 59 AU, p < 0.001). vision – current concepts and management paradigms. In: Sebag J. (Ed.) There was no correlation between age and vitreous echodensity in subjects with Vitreous – in Health & Disease. Springer, New York, 2014, pg. 778]. no PVD (red dots), but a positive correlation in subjects with PVD (blue line; r = 0.649, p = 0.010), suggesting that with further aging there is increasing echodensity, likely due to ongoing collagen aggregation after PVD (from Garcia G, Sebag J, 2019. Letter to the Editor - Impact of dry eye on visual acuity and contrast sensitivity: Dry eye assessment and management study. Optom Vis Sci 96(11):890-891. doi: 10.1097/OPX.0000000000001449.)

PVD occurs there is either progressive aggregation of vitreous collagen fibrils, or increased folding of the detached posterior vitreous cortex, or both, impacting vision even more. Lastly, QUS was found to be sensitive to structural improvement following limited vitrectomy surgery, showing diminution of 94.1% post-operatively (p < 0.0001) in 75 cases (Sebag et al., 2018).

8.4. Functional aspects of Vision Degrading Myodesopsia

8.4.1. Visual acuity Most studies of patients with vitreous floaters did not detect significant diminution in visual acuity upon presentation, confirming anecdotal clinical impressions. A study in Seoul, South Korea performed subgroup analysis and found that visual acuity was worse in the subgroup with Fig. 33. Vitreous Displacement During Horizontal Ocular Saccades. complete PVD (logMAR = 0.07 ± 0.13) as compared to no PVD controls Dynamic ultrasonography demonstrates displacement of the vitreous body with (logMAR = 0.02 ± 0.05, p = 0.029). A short-term study (Mason et al., horizontal ocular saccades in a 65-year-old myopic man. Imaging was achieved 2014) compared visual acuity pre- and post-vitrectomy, finding with Verasonics Vantage-128 ultrasound engine with an L22-14vXLF probe, improvement from 20/40 pre-operatively to 20/25 post-operatively which has an 18 MHz center frequency, an elevation focus of approximately (p < 0.0001). In a long-term study of 195 cases (Sebag et al., 2018), 18 mm and aperture of 12.8 mm. 32 plane-wave images acquired over angle increments from ± 9° were compounded producing 500 compound images per visual acuity was 0.68 ± 0.21 before surgery, improving at each second acquired for 5 s. During acquisition, the eye performed repeated post-operative time point after 1 month to an average of 0.77 ± 0.19 horizontal saccades over a 30-degree angle. [video courtesy of Ron Silverman, (p < 0.0001), which was sustained for the duration of the 5-year PhD and Raksha Urs, College of Physicians & Surgeons, Columbia University]. follow-up period. This was not the case, however, in a study of 69 patients undergoing 27G vitrectomy for vitreous opacities, who had no p < 0.001) as well as with contrast sensitivity function (R = −0.811, post-operative improvement in visual acuity (Khan et al., 2018). It should p < 0.0001). Thus, QUS was able to measure structural abnormalities be emphasized that although post-operative improvements in visual acuity in vitreous that correlated with both subjective and objective aspects of were statistically significant in some studies, these were not clinically Vision Degrading Myodesopsia. In a study of 57 eyes in 57 subjects, significant. Garcia et al. (2018) determined that QUS was able to measure greater vitreous density in subjects with PVD as compared to controls without 8.4.2. Contrast sensitivity function PVD (Fig. 34). What's more, this study detected increasing vitreous Contrast sensitivity function (CSF) is an important component of echodensity in the PVD group with increasing age (R = 0.649, vision that can impact quality-of-life, in spite of normal visual acuity p = 0.010) (Fig. 34), suggesting that not only do eyes with PVD have (Ekici et al., 2015). It was originally the suggestion of Alfredo Sadun, greater vitreous opacification than eyes without PVD, but that after MD, PhD at the Doheny Eye Institute of UCLA that contrast sensitivity

25 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 function be measured in patients complaining of bothersome vitreous floaters. The rationale was based upon a consideration of how incident light is scattered by ocular media opacities (Fig. 28). As described above, a collagenous vitreous opacity with uneven surfaces and edges will theoretically scatter more light rays, creating a larger penumbra than a smooth structure of the same size, such as an asteroid body (Huang et al., 2014). To test this hypothesis, CSF measurements were performed on patients using the Freiburg Acuity Contrast Test (FrACT). This well-established CSF testing paradigm (Bach 1996, 2007; Bach and Schäfer, 2014; Bartholomew et al., 2016) has previously been shown to produce similar results to the Pelli-Robson test (Neargarder et al., 2003) and was found to be useful in evaluating the effects of refractive corneal surgery (Dennis et al., 2004) and cataract surgery with bifocal intraocular lenses (Anton et al., 2014). Unusual circumstances such as low vision (Schulze-Bonsel et al., 2006; Jolly et al., 2019), autism (Tavassoli et al., 2011), and anisometropic (Mohammadi et al., 2018) are also amenable to evaluation with FrACT. Even the effects of hyperthermia have been assessed using FrACT (Jensen et al., 2017). Initial studies at the VMR Institute for Vitreous Macula Retina in Huntington Beach, California determined a reproducibility of 92.1% (Sebag et al., 2014a), using the Weber Index as the measure of CSF:

Weber Index ≡ %W = [(Luminancemax − Luminancemin) / Luminancemax] Fig. 35. Contrast Sensitivity Function and Aging Vitreous. Subjects with PVD (blue dots) had considerably worse CSF (higher Weber Index Note: the higher the Weber Index, the worse the Contrast Sensitivity on y-axis) than subjects without PVD (3.0 ± 0.3 %Weber vs. 2.0 ± 0.2 % Function (CSF). Weber; p < 0.001). There was no correlation between age and CSF in subjects In a retrospective study of patients with Vision Degrading with no PVD (red dots), but a positive correlation in subjects with PVD (blue Myodesopsia, CSF was diminished by 67.4% (4.0 ± 2.3 %W) compared line; r = 0.661, p = 0.008), suggesting that after PVD there is further with age-matched controls (Sebag et al., 2014a). A prospective study degradation in CSF with increasing age, probably due to the observed (Garcia et al., 2016) of patients with normal CSF found that after a PVD increasing vitreous (echo)density (from Garcia G, Sebag J, 2019. Letter to the Editor - Impact of dry eye on visual acuity and contrast sensitivity: Dry eye that induced bothersome floaters, there was a 52.5% reduction in CSF assessment and management study. Optom Vis Sci 96(11):890-891. doi: from an average of 1.81 ± 0.61 %W to an average of 2.76 ± 0.30 %W 10.1097/OPX.0000000000001449.) (p < 0.001). This was reversed by vitrectomy (see below), returning CSF to baseline levels in each case at 1 month, 3 months, and 12 months 1.34 ± 0.34 %W; p = 0.0001, when these eyes attained the same CSF as 8.5. Myopic Vision Degrading Myodesopsia the unaffected fellow eyes (1.34 ± 0.20 %W). A very interesting study (Garcia et al., 2018) evaluated CSF in eyes Myopic Vitreopathy (see above) is the second leading cause of with PVD, finding that CSF was 51.2% worse in eyes with PVD Vision Degrading Myodesopsia, playing a role in the etiology of (2.98 ± 0.31 %W) compared to no PVD controls (1.97 ± 0.24 %W; bothersome vitreous floaters in 44% of patients seeking vitrectomy P < 0.001). This difference corresponded to a large effect size of 1.14, surgery (Sebag et al., 2018). Myopic patients presenting with clinically and, not surprisingly, QUS was 55.8% greater in the eyes with PVD than significant vitreous floaters tend to be about 20 years younger, at a time those without (P < 0.001). What was surprising, however, was that in in life when visual demands are usually greater, and thus these patients the group with PVD, there was worse CSF with increasing age (Fig. 35) are quite bothered during professional and recreational activities. From that was statistically significant (R = 0.661, p = 0.008). This is clinical and scientific perspectives, analysis of the various structural understandable, given the increase in vitreous echodensity that was and functional aspects of these patients can improve understanding of observed in these patients (Fig. 34). the underlying mechanism(s). Nguyen et al. (2020) undertook a study to determine whether myopic vitreopathy is associated with reduced contrast sensitivity 8.4.3. Ocular straylight function (CSF) compared to emmetropic controls, and whether PVD Opacities in ocular media can cause increased ocular straylight, further lowers CSF. The presence or absence of PVD was determined which is the spreading of light around a bright light source, also known with ultrasound, which was also used to measure vitreous echodensity as disability glare (van den Berg et al., 2013). Patients perceive (Mamou et al., 2015). Preliminary findings (reported at ARVO) in 35 straylight effects as haziness, decreased color and contrast, difficulty myopes (mean age = 52.5 ± 14.1 years; average degree of recognizing faces, and glare hindrance (Huang et al., 2014). Straylight myopia = −5.2 ± 2.9 D) with clinically significant vitreous floaters is influenced by pigmentation (IJspeert et al., 1999) and increases with were compared to age-matched controls. Visual function was evaluated age (Rozema et al., 2010). To date, most studies employing straylight by visual acuity (VA, Snellen decimal) and by measuring CSF with the measurements have been performed on (Pircher et al., 2015; van Freiburg Acuity Contrast Test (Weber Index, %W). Myopes without de Wouw et al., 2016; de Jong et al., 2018) and the lens (van der PVD were compared to age-matched controls, while myopes with PVD Meulen et al., 2012; Gholami et al., 2017; de Jong et al., 2019). Castilla- were compared to older age-matched controls. There was no significant Marti et al. (2015) studied 15 patients complaining of unilateral difference in VA between myopes with and without PVD (p = 0.22). vitreous floaters, finding that ocular straylight was 1.426 ± 0.23 log CSF in myopes without PVD was significantly worse than young (s), compared to 1.275 ± 0.23 log(s) in the fellow eyes (p = 0.0009). controls (p = 0.0001). CSF in myopes with PVD was significantly worse While this is statistically significant, it is not clear that a 12% difference than older controls (p < 0.0001) and than myopes without PVD is clinically significant. Nonetheless, in another study straylight (p < 0.01) (Fig. 36). Echodensity in the premacular vitreous was measurements improved following vitrectomy for floaters (Mura et al., 2011). significantly higher in myopic eyes with PVD compared to myopic eyes without PVD (P = 0.034). Pending further investigation,

26 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

work, since these activities are greatly impacted by vitreous opacities. While patients have routinely been advised that the structures within the vitreous body that induce floaters will “settle”, it is not known whether this is in fact true. Moreover, many young people are less willing to take the chance that their symptoms may not lessen in severity and impact, as they strongly wish to ‘get on with their lives’. A plausible physiologic adjustment to the visual phenomenon of vitreous floaters is neuroadaptation. Using adaptive optics in patients, neuroadaptation has been shown to be an important compensatory mechanism for ocular aberrations (Artal et al., 2004). Two visual phenomena capable of erasing visual stimuli from conscious awareness are binocular rivalry and visual crowding. Suppression of these has been shown to involve a reduction in neural activity (Blake et al., 2006), but it is not known how the brain adapts (if at all) to the phe­ nomenon of vitreous floaters. Furthermore, too little is known about the psychological aspects of the coping paradigm(s) for vitreous floaters. Based on only 5 patients, Schiff et al. (2000) posited that patients who are more professionally successful and intelligent notice vitreous floaters more and have increased desire to be treated.Roth et al. (2005) Fig. 36. Myopic Vitreopathy and Contrast Sensitivity Function (CSF). found a correlation between subjective distress and education level, CSF was worse (increasing Weber Index on y-axis) in non-myopes complaining whereas Mason et al. (2014) associated higher levels of dissatisfaction of floaters than in non-floater controls (p < 0.01). CSF was even worsein patients with myopia complaining of floaters (p < 0.01) and non-myopes with with vitreous floaters and active lifestyles in patients who read and PVD (p < 0.01), but was worst in myopic eyes with PVD (p < 0.01). write more frequently. Kershner (2008) emphasized the importance of [from: Nguyen et al., 2020: Vitreous structure and visual function in myopic psychological studies that identified a potential link between addictive vitreopathy and posterior vitreous detachment. Invest Ophthalmol Vis Sci personalities and failure to accept and adapt to refractive visual change (ARVO) 58(8):5485]. (s). Indeed, it is the impression of many clinicians treating “floater” patients that a particular personality profile is present in many patients the researchers concluded these preliminary results indicate that who are bothered by vitreous floaters, perhaps consistent with the myopic eyes with vitreous floaters have worse CSF than age-matched aforementioned psychological profile(s). While this is certainly a controls without floaters and that myopes with PVD have worse CSF subject worthy of scientific investigation, the personality profile of and QUS than eyes with only myopic vitreopathy. These results suggest patients afflicted with Vision Degrading Myodesopsia need not bea that myopic vitreopathy diminishes CSF via increased internal vitreous major determinant in the decision-making process regarding collagen aggregation as reflected by vitreous echodensity and that PVD therapy. Because of the availability of objective metrics of vitreous induces even greater premacular vitreous echodensity, further lowering structure and visual function that enable staging of disease severity, CSF probably due to light scattering by the detached (folded?) posterior decisions regarding therapy can be made without extensive vitreous cortex. consideration of the patient's personality, apart from the usual considerations that govern a developing patient-physician relationship, especially one that may include a future therapeutic intervention. In 9. Therapy of Vision Degrading Myodesopsia this regard, it is important to clearly and honestly manage a patient's expectations, as the success of any treatment relies upon a clear The development of treatments for Vision Degrading Myodesopsia has understanding of the risks and benefits and available alternative been hampered by reluctance on the part of the medical professional to options, including observation. accept this condition as a true disease worthy of therapeutic consideration. For the most part, patients are advised that they should try to cope with 9.1. Nd:YAG laser vitreolysis the symptoms, as these will purportedly lessen in severity with time. But to date, there are no scientific studies determining whether this is true. In Ophthalmology, Nd:YAG lasers are most often used to treat Mathematical modelling by Serpetopoulas and Korakitis (1998) showed opacification of the posterior capsule after cataract surgery, andfor that the shadow of a vitreous opacity on the retina is determined by the performing peripheral iridotomy. This laser has also been used to lyse diameter of the opacity, its distance from the retina and the overall vitreous strands in the anterior chamber and has recently been distance between the pupillary plane and the retina. If vitreous opacities employed to attempt breaking vitreous opacities. Unfortunately, few move forward over time, their conical shadow no longer reaches the retina studies have explored the molecular effects of YAG laser treatments to and the patient does not perceive them as bothersome. This is plausible for vitreous. Abdelkawi et al. (2014) found increased protein content, patients experiencing bothersome floaters due to PVD. However, there is a refractive index, and viscosity following YAG laser treatment of difference between older patients with PVD-induced floaters that are of mid- and posterior vitreous in rabbits, concluding that YAG laser should sudden onset, and young patients with myopic vitreopathy and chronic be restricted to the anterior vitreous body to prevent untoward effects vitreous floaters. Forward movement of vitreous opacities would only on the gel state of vitreous. Extrapolating this information to patients is apply to patients with PVD and not those with myopic vitreopathy. Thus not straightforward, however, since most (if not all) patients with advising young people with myopic vitreopathy to try coping may not be floaters already have liquefied vitreous (see above). as useful advice as recommending watchful waiting in older patients with Clinically, the procedure is performed with the patient seated at a PVD. Coping is also likely to be a very different process for these two slit lamp and with a contact lens on the cornea to enable the laser to be groups, influenced not only by the insidious onset in young myopes as focused onto those vitreous opacities that are visible to the treating compared to the sudden onset in patients with PVD, but also their young doctor (Singh, 2018). Typically, only opacities relatively far (2–4 mm) age and life expectations. It is not uncommon for younger patients to fear from the fundus are treated, while those closer to the fundus are left making career choices that involve extensive reading or back-lit computer untouched to avoid collateral damage. It is not clear how the distance

27 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 from the fundus is measured and with what degree of accuracy. Also, On the other hand, one study from the United States used objective since a detached posterior vitreous cortex may not be more than 3 mm indices of vitreous structure and visual function to compare patients anterior to the fundus (Routledge et al., 2019), many vitreous opacities who had previously undergone YAG laser vitreolysis to those who had might not be treatable with this approach. Lastly, it can be quite not, as well as to controls without vitreous floaters (Nguyen et al., challenging to visualize the specific vitreous opacities that are 2019). While this study was retrospective and influenced by some disturbing to the patient. Attempts to improve visualization of vitreous selection bias, insofar as it was conducted at a tertiary level referral opacities for YAG laser treatment and evaluate their role in causing center, it did employ objective quantitative evaluations of vitreous floaters have been undertaken with scanning laser ophthalmoscopy structure and visual function. Compared to age-matched controls (Vandorselaer et al., 2001) and spectral domain OCT (Schwartz et al., without vitreous floaters, patients with untreated vitreous floaters 2013). (n = 60) had worse subjective satisfaction with vision (VFQ-39), 38% To date, the efficacy of YAG laser vitreolysis has been difficult to greater vitreous echodensity by quantitative ultrasound, and 2.3-fold determine due to the lack of any studies employing objective, quantitative more CSF degradation (p < 0.0001 for each). Compared to 60 outcome measures (Milston et al., 2016). In general, the studies have been untreated subjects with vitreous floaters, 37 patients previously treated small, and the results have been disappointing. Little and Jack (1986) (elsewhere) with YAG lasers had 17% less vitreous echodensity treated 59 cases finding that vision was improved in 18 eyes, unchanged in (p = 0.003), but no differences in VFQ-39, BCVA, or CSF. The 40 eyes, and worse in 1 eye. Tsai et al. (1993) treated 15 cases with investigators postulate that because YAG lasers have a photo-disruptor “serious psychological reactions” to vitreous floaters, with purported effect but cannot photo-ablate (Sebag, 2018c), they produce smaller 100% success, but this was based solely on symptoms and thus very vitreous opacities but a larger number of them. Consequently, structural possibly a placebo effect.Delaney et al. (2002) found that in 42 cases, 38% assessment with quantitative ultrasonography showed a difference in reported moderate improvement while 62% had no improvement at all, YAG-treated vitreous, but the net effect on vision was the same, i.e. compared to significant improvement in 93% of patients treated with degradation in CSF and unhappiness with vision and quality-of-life. vitrectomy. Vandorselaer et al. (2001) suggested that treatment success Interestingly, of the 37 YAG-treated eyes with vitreous floaters, 25 were can be improved by treating only vitreous opacities that are suspended in unhappy and desired vitrectomy surgery, while 12 were satisfied and vitreous strands, rather than those located loosely within the vitreous chose observation alone. The unhappy subjects had 57% worse CSF body. However, no objective measures or imaging studies were performed (p = 0.005). Thus, as a group, eyes that were previously treated with to support this contention. A recent review (Milston et al., 2016) found Nd:YAG for bothersome vitreous floaters had less dense vitreous, but that multiple (1–6) sessions were ‘required’, with variable reported similar visual function as controls with vitreous floaters who were success, concluding that the heterogeneity in treatment protocols and case untreated. That some treated eyes had better visual function than selection made it difficult, if not impossible, to draw conclusions about the untreated controls and were thus satisfied with observation alone is efficacy of YAG laser vitreolysis. This was similarly the conclusion ofa difficult to assess due to the retrospective study design and the lack of recent Cochrane review (Kokavec et al., 2017) which determined that pre-treatment evaluations with quantitative ultrasonography and randomized clinical trials are needed with a sham intervention control measurement of contrast sensitivity function, which would have group to compare Nd:YAG laser vitreolysis with pars plana vitrectomy for determined whether the two groups were similar prior to treatment. the treatment of symptomatic floaters. Furthermore, there is no information regarding the treatment A recent randomized prospective study used YAG laser to treat only parameters such as number and power of laser applications, the visible Weiss rings in 52 subjects and compare the findings to a sham focusing lens employed, the location of targeted vitreous opacities, the treatment control group (Shah and Heier, 2017). The study design was number of treatment sessions, etc. Consequently, the investigators flawed, however, because the study was not truly masked, the concluded that a prospective randomized study of Nd:YAG laser sham techniques were not properly validated, and a number of biases treatment of vitreous is warranted, using uniform laser treatment existed (Kokavec et al., 2018). While the YAG laser group reported parameters and objective quantitative outcome measures. greater symptomatic improvement (54%) than controls (9%) (difference = 45%; 95% CI, 25%–64%; p < 0.001), this only 9.2. Vitrectomy for Vision Degrading Myodesopsia represented improvement in little more than half of the subjects (Sebag, 2018c). Thus, the use of YAG laser to treat Weiss rings alone helped Since the monumental invention of vitrectomy by Machemer and only half of the subjects and the improvement was only by half. Buettner, and the instrumental innovations of the brilliant engineer Furthermore, using the VFQ-25 as an outcome measure revealed that Jean-Marie Parel, the lives of millions of people have been vastly dependency improved by only 4.6%, role difficulties by 11.5%, near improved. Blinding disorders that were previously considered vision by 5.9%, color vision by 2.8%, peripheral vision by 5.5%, and untreatable are now routinely cured (Parel, 2014). Although technically distance vision by 9.4% (Sebag, 2018c). Although these results had not a ‘blinding’ disorder, Vision Degrading Myodesopsia can now be statistical significance, it is dubious that they represent findings of any included in that discussion. Delaney et al. (2002) reported a small series clinical significance. In fact, general vision actually worsened by 3.5% of 39 eyes that underwent YAG laser treatment to vitreous opacities (Sebag, 2018c). That this study only addressed Weiss rings and not with less than desirable results (see above). In that same study, pars vitreous floaters in general was emphasized by the author ­of anac plana vitrectomy was performed in 15 eyes with full resolution of companying guest editorial (Lim, 2017) who concluded that “an open floater symptoms in 93.3%, leading the authors to conclude that YAG mind with a healthy dose of skepticism is necessary”. This is especially laser is minimally effective (only one-third improved) and that true when considering that in spite of the non-invasive nature of YAG vitrectomy offers superior results. Nevertheless, the authors claimed laser treatments, there are reported complications (Little and Jack, that vitrectomy should be reserved for patients who remain markedly 1986; Hahn et al., 2017). Summarizing available information in an symptomatic following YAG laser vitreolysis, pending future studies to extensive review, Ivanova et al. (2016) concluded that there is very clarify the role of vitrectomy in treating patients with floaters and little evidence to support the use of YAG vitreolysis for vitreous floaters, posterior vitreous detachment. Those studies are now available, and the as the results and complications reported in the few studies vary larger ones are summarized in Table 1. considerably. There have recently been a few more small, non-randomized In 2016 Milston et al. reviewed the results from several studies (728 studies reported from China (Luo et al., 2018; Sun et al., 2019) and cases) of vitrectomy for vitreous floaters, many from small studies. Germany (Brasse et al., 2019). Unfortunately, no validated objective Among the largest studies, Schulz-Key et al. (2011) had mean follow-up quantitative outcome measures were employed in these studies. of 37 months after 20-gauge vitrectomy and reported a 6.8% incidence of retinal detachment as well as a 60% incidence of cataracts. Using a

28 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Table 1 Larger studies of vitrectomy for Vision Degrading Myodesopsia.

STUDY N F/U (mos) Gauge PVD Outcomes Retinal Tears/Detachment Cataract Induced

Schulz-Key et al. (2011) 73 37 20G "few" 88% “satisfied” (non-standard Q) 1.3%/6.8% 60.0% de Nie et al. (2013) 110 26.4 51.8% 20G 37.3% 85% “satisfied” (modif VFQ-25) 10.0%/10.9% 33.6% 48.2% 23G

Tan et al. (2011) 116 10.1 20G & 25G 25.9% 100% “happy” (non-standard Q) 16.4%/16.4% 50.0%

Mason et al. (2014) 168 18 25G 7.1% 100% “happy” (non-standard Q) 7.1%/0 37.5% VA improved

Sebag, 2014a,b 76 17.5 25G 0.0% 100% normalized CSF 0/0 23.5% 29.2% improved VFQ-25

Sebag et al. (2018) 195 32. 6 25G 0.0% 100% normalized CSF 1.5%/1.5% 16.9% 13.2% improvement VA 19.3% improvement VFQ-39 vitreous echodensity decreased by 94.1%

F/U = follow-up; PVD = posterior vitreous detachment; G = gauge; Q = questionnaire. VFQ = Vision Function Questionnaire; VA = visual acuity. non-standardized questionnaire, they concluded that 88% were Vitreous echodensity decreased by 94.1% (p < 0.0001) and VFQ re­ satisfied with the results. Tan et al. (2011) used both 20- and 23-gauge sults improved by 19.3% (p < 0.0001). Regarding complications, instruments, inducing PVD during surgery, which was associated with there were no cases of , but acute vitreous hemorrhage retinal tears in 30% of cases, probably iatrogenic. Cataracts developed developed in the immediate post-operative period in 2 patients (1%), in 50% of cases, but follow-up averaged only 10.1 months, and more clearing spontaneously. There were 3 retinal tears (1.5%) and 3 retinal patients probably developed cataracts later, consistent with the findings detachments (1.5%) that underwent successful repair. Two macular of Schulz-Key at al. (2011). In a study of 110 eyes that had 20-gauge puckers (1%) and 4 recurrent floaters (2%) from new-onset PVD (no vitrectomy in half and 23-gauge in half, de Nie et al. (2013) PVD was present pre-operatively and PVD was not induced experienced a 10.9% incidence of retinal detachment, which is intraoperatively) were cured by re-operation. These risks were thus all significant. They employed the N.E.I. VFQ-25 to assess outcomes, 2% or less. Cataract surgery occurred in 21 of 124 phakic patients finding that 85% were either “satisfied” or “very satisfied withthe (16.9%; mean age = 64 ± 7 years; none younger than 53 years old), results. But visual function was not assessed in any of the early studies. an average of 13.1 ± 6.8 months after vitrectomy. This confirmed the Improved vision following vitrectomy for Vision Degrading findings of a previous study (Yee et al., 2017) that compared Myodesopsia was first reported by two separate groups in the same the incidence of cataract surgery after extensive vitrectomy (surgical 2014 publication of the journal Retina. In 168 cases, Mason et al. (2014) PVD induced with extensive removal of gel vitreous) to that after observed improved visual acuity by one line or more in 37.5% of cases. limited vitrectomy. Visual acuity just before cataract surgery was A study of 76 cases by Sebag et al. (2014a,b,c) determined that contrast comparable in each group (0.47 ± 0.18 in the limited vitrectomy sensitivity function in eyes with vitreous floaters was 67% degraded group vs. 0.54 ± 0.30 in the extensive vitrectomy group; p = 0.23). compared to controls (p < 0.013). The NEI Visual Function Although extensive vitrectomy patients were younger than limited Questionnaire composite was 28.3% lower in floater patients than in vitrectomy patients (p < 0.015), only 17 of 96 eyes (18%) required age-matched controls (p < 0.001), but post-operatively improved by cataract surgery after limited vitrectomy (mean follow-up = 20 ± 17 29.2% (p < 0.001). There were no cases of retinal detachment and months), which is comparable to the 16.9% cumulative incidence found only 23.5% of cases required cataract surgery, although the mean in a larger series with longer mean follow-up of 32 months (Sebag et al., follow-up was only 17.5 months. Following limited vitrectomy (no PVD 2018). In cases with a minimum follow-up of 24 months after extensive induction and preservation of retrolental gel vitreous), contrast vitrectomy, cataract surgery was performed in 20 of 23 eyes (87%), but sensitivity function normalized in each case at 1 week post-op in just 17 of 48 eyes (35%) after limited vitrectomy (p < 0.0001). In (p < 0.01), remaining normal at 1 month (p < 0.003) and 3–9 months this study, cataract surgery occurred an average of 12.4 ± 5.1 months (p < 0.018) post-operatively. Studies of ocular straylight are consistent after limited vitrectomy, compared to 7.3 ± 3.9 months after with and may explain these findings (Mura et al., 2011), since light extensive vitrectomy (p < 0.002). Thus, it appears that scattering is the likely cause of degradation in CSF (see above). Upon limited vitrectomy offers patients a low risk profile for complications extensive review of the subject, Ivanova et al. (2016) concluded that of and the best chances of attaining satisfaction with vision, as well as all treatment options, vitrectomy offers the best solution to alleviate the experiencing objective improvement in vitreous structure and visual impact of vitreous floaters, in spite of potential associated risks. function. Efficacy as well as risks were addressed in a more recent study of limited vitrectomy (no surgical PVD induced and gel vitreous left intact 9.2.1. Cost effectiveness of vitrectomy for Vision Degrading Myodesopsia behind the lens) in the largest number of subjects reported to date A final consideration of ever-increasing importance in health care is (n = 195) with long follow-up: 32.6 months, on average; 3 years or value. The cost-effectiveness of vitrectomy for Vision degrading more in 69 cases, 4 years or more in 51 cases, and 5 years or more in 24 Myodesopsia in 67 patients suffering from unilateral vitreous floaters (20 cases (Sebag et al., 2018). Preoperatively, VA was non-myopic patients with PVD, 17 myopic patients without PVD, and 30 0.68 ± 0.21, improving to 0.77 ± 0.19 post-operatively myopic patients with PVD) was evaluated with NEI VFQ-39 as well as (p < 0.0001). Compared to controls, there was 91.3% degradation of BCVA and CSF measurements before and after limited vitrectomy CSF pre-operatively (p < 0.0001), which normalized at 1, 3, 6, 12, 24, (Rostami et al., 2019). Mean BCVA improved 13.5% post-operatively 36, and 48 months after surgery (p < 0.00005 for each; Fig. 37). (p < 0.00001) and CSF improved 53% (p < 0.00001). The mean

29 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Fig. 37. Impact of Limited Vitrectomy on CSF in Vision Degrading Myodesopsia. Contrast sensitivity function (CSF) in 139 consecutive eyes (4.59 ± 2.34 %Weber) was reduced by 91.3% compared to 70 age-matched controls (2.40 ± 0.90%W; p < 0.001). Within 1 week following limited vitrectomy, there was normalization in each eye, that was sustained for more than 4 years. [from: Sebag et.al., 2018: Long-term safety and efficacy of vitrectomy for Vision Degrading Myodesopsia from vitreous floaters. Ophthalmology Retina 2:881–7.].

VFQ-39 increased 19% (p < 0.00001) after surgery, with general vision ubiquitous phrase, ‘‘The right treatment for the right patient at the right improving 27% for the entire group and 37% for non-myopic PVD time.’’ (Krepline and Tsai, 2019). The following will consider future (p < 0.00001 for each). A reference case cost-utility analysis was directions in vitreous research that might enable this for patients with performed. VFQ-39 correlations with time tradeoff utilities indicated a Vision Degrading Myodesopsia in two general categories: diagnostic 14.4% improvement in quality of life. The incremental patient value gain and therapeutic. conferred by limited vitrectomy was 2.38 quality-adjusted-life-years (QALYs), and the average cost-utility ratio in 2018 U.S. real dollars was 10.1. Future directions in diagnosing Vision Degrading Myodesopsia $1574/QALY. This average cost-utility ratio vs. no therapy is superior to cataract surgery ($2262/QALY), amblyopia therapy ($2710/QALY), and A recent white paper published by The American Ophthalmological retinal detachment repair ($45,304/QALY) (Brown et al., 1999). Society outlined future prospects for significant paradigm shifts Interestingly, myopic patients without PVD had the lowest cost-utility in ophthalmic diagnostics, emphasizing conversion from disease-oriented ratio of all ($1338/QALY). This seems quite important as these are the diagnostics to evaluations of psychophysical function(s) and health (Sebag youngest individuals to experience Vision Degrading Myodesopsia and et al., 2017). Consistent with the principles of personalized health care thus the health and economic benefits of limited vitrectomy will have described above, just how an individual's level of visual function meets very long-lasting effects. Thus, in addition to efficacy and safety, their specific visual needs will be an important aspect to evaluate, cost-effectiveness appears to be another hallmark of limited vitrectomy for beginning perhaps with better self-administered questionnaires. Measures Vision Degrading Myodesopsia. of the quantity of vision, done to date primarily with Snellen visual acuity, will likely be expanded to include assessment of other aspects of vision, such as contrast sensitivity function. But there are other areas to explore. 10. Future directions

In recent decades, the rate of change in Medicine, and 10.1.1. Visual function diagnostics Ophthalmology in particular, has been rapid and will likely continue in Ambient lighting seems to markedly influence vision in patients many areas, including our understanding and ability to evaluate and with Vision Degrading Myodesopsia. Yet, other than measuring ocular treat vitreous floaters. To improve the care of patients with Vision straylight (van den Berg et al., 2013), there have been no studies of Degrading Myodesopsia, optimal implementation of the knowledge to visual function such as visual acuity, contrast sensitivity function, and be gained in the coming years should take into account the subtle but reading in different levels of ambient lighting, including glare from distinct differences between precision medicine and personalized oncoming automobile headlights (see below). Judging by patient medicine (Krepline and Tsai, 2019). The US National Research Council descriptions of how they see in bright outdoor lighting, out on the (2011) has defined “precision medicine” as a population-based ocean, or on a hill of snow, it seems predictable that bright ambient approach to classifying individuals through genomic, environmental, or lighting will have deleterious effects upon some, if not all, aspects of social characteristics, with the goal of identifying effective therapeutics vision in patients afflicted with bothersome vitreous floaters. To date, based on a combination of these factors. The Council proposed the this has not been extensively studied (Aslam et al., 2007). formation of a “Knowledge Network of Disease” and the development of a more accurate, molecular-based taxonomy of disease. In contrast, 10.1.1.1. Vitreous Floaters Functional Questionnaire. Patient Reported “personalized medicine” concerns the development of therapeutics for Outcomes questionnaires have become an integral part of health specific individuals based upon their unique attributes. As pointed out outcome measurement, deserving of a more rigorous and scientific by Krepline and Tsai (2019), all patients should receive personalized approach (Patrick, 2019). However, many previous studies that used medicine, while precision medicine should serve as the foundation for questionnaires to evaluate visual well-being of patients with vitreous the application of population-based observations at an individual level. floaters did not employ validated questionnaires nor any proven form of Ultimately, the promise of precision medicine is captured in the quantifying the information obtained with self-administered

30 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 questionnaires. Although the validated N.E.I. Visual Function 2011). Rheological differences between gel and liquid vitreous have Questionnaire has indeed been employed in a few studies of Vision also been characterized in the rabbit, finding distinct rheological Degrading Myodesopsia, these questions address more general aspects characteristics consistent with a gel phase mostly composed of collagen of vision, perhaps not capturing the full essence of how vitreous floaters entangled by hyaluronan, and a second phase mainly composed of can impact quality-of-life. Thus, for example, studies that looked at hyaluronan in aqueous solution (Silva et al., 2017). These rheologic efficacy following YAG laser treatment found improvements ranging changes influence the motion of the vitreous body with head and eye from 2.8% to 11.5% for the different subscales of the NEI VFQ-25 (Shah movement. How this motion is distinct from its mechanical properties and Heier, 2017; Sebag, 2018c). While part of the reason for these has been modeled in theory (Tůma et al., 2018) and may have future disappointingly limited results could be the lack of efficacy of YAG laser relevance to the aforementioned disturbance of reading in patients with treatments (Sebag, 2018c; Nguyen et al., 2019), there could also be Vision Degrading Myodesopsia. Ultrasonography with high-frequency limitations imposed by the questions in the VFQ-25 that do not linear arrays in combination with plane-wave technique has been adequately assess the impact of vitreous floaters. Indeed, even a far proposed by Urs et al. (2016) as a new methodology with which to more definitive treatment like vitrectomy found only a 19.3% evaluate -induced vitreous motion (Fig. 33), but this has not improvement in the VFQ-39 post-operatively (Sebag et al., 2018). been done to date. Studies in humans at different ages were performed Although statistically significant, this seems surprisingly minor in by Tram and Swindle-Reilly (2018) who found a positive correlation contrast to the considerable subjective improvement described by between stiffness of gel vitreous and age, leading them to propose that a patients who have been cured of their bothersome vitreous floaters decrease in HA caused vitreous dehydration and stiffening of the and are by-and-large extremely happy with the results. Thus, there is a vitreous gel. They concluded that vitreous liquefaction can be need for better assessment of the impact of vitreous floaters on characterized as simultaneous liquefaction and localized stiffening of psychosocial and functional well-being. gel vitreous, a phenomenon that should be measured in vivo, yet there A patient group headquartered in Manchester, England named One are currently no ways to evaluate this in humans during clinical Clear Vision (http://www.oneclearvision.org/) is an international evaluation. One potential approach could be the use of cross-sectional English-speaking charity for sufferers of vitreous floaters with the key depth-resolved OCT to non-invasively measure the diffusion coefficient aim to promote medical research into effective management and and viscosity of vitreous, as has been proposed for the evaluation of treatment. They have generated a group of questions that were middle ear effusions in children (Monroy et al., 2017). Dynamic reviewed, modified, and selected to form a Vitreous Floaters Functional Light Scattering (see below) has been employed to do this in vitro, Questionnaire (VFFQ). This questionnaire was found to have good (Sebag, 2005; Sebag et al., 2007b), but not clinically. correlation with the N.E.I. VFQ (r = 0.689, p < 0.003), as well as with Assessing scattering by vitreous body structures has been done with CSF (r = −0.509, p < 0.04). More importantly, however, a light since the beginning of the 20th century when Gullstrand invented subsequent preliminary study found that the VFFQ was able to gauge the slit lamp (Ehringer and Grzybowski, 2011). Not much changed until the benefits of limited vitrectomy on visual well-being far better than many years later with the invention of optical coherence tomography the N.E.I. VFQ (Nguyen-Cuu et al., 2017). (OCT) by Jim Fujimoto at M.I.T. However, in spite of improving resolution of posterior vitreous structure and its relation to the optic 10.1.1.2. Reading. Displacement of the vitreous body during ocular disc and macula, OCT has failed to provide adequate imaging of the saccades (Fig. 33) appears to be very bothersome to patients with vitreous body itself. Recent attempts have provided new information vitreous floaters as this seems to invariably bring vitreous opacities into regarding anterior vitreous structure (Grulkowski et al., 2019), but the visual axis and interfere with reading by the mechanisms described still lack the ability to image the entire vitreous body, ideally in 3 above. Patients often complain that this particularly interferes with dimensions. Dynamic light scattering holds great promise to provide reading from a back-lit computer screen. Subjectively, reading valuable information about the macromolecular organization of improves following limited vitrectomy, but to date no prospective vitreous (Ansari et al., 2001; Sebag, 2005; Sebag et al. 2007b, 2014b; studies have been performed to measure reading speed and accuracy Fankhauser, 2012), but there are challenges to using this technology to before and after vitrectomy, or therapy of any type. A useful approach image and evaluate the entire vitreous body clinically. might be the continuous-text-reading-acuity test MNREAD, which is On the other hand, imaging of the vitreous body has been done with designed to measure reading performance in people with normal and ultrasound since the 1950s (Silverman, 2016). Recent advances in low vision by estimating maximum reading speed, critical print size, ultrasound technology have produced linear and annular transducer arrays reading acuity, and the reading accessibility index (Calabrèse et al., that offer synthetic focusing with precise timing of the excitation of 2016). Radner charts might be useful, as was found in a recent study independent elements that allows formation of a converging wave front to that successfully employed these to measure reading score and reading create a focus at one or more desired depths (Silverman, 2016). That same speed in patients with fovea-sparing due to year, Oelz and Mamou (2016) reviewed the use of quantitative ultrasound age-related macular degeneration (Lindner et al., 2019). Future (QUS), pointing out the utility of spectral-based techniques that enable prospective studies should employ these and/or other methods to evaluate estimation of backscatter coefficients, attenuation, and scatterer properties reading before and after treatment of Vision Degrading Myodesospia. such as the correlation length associated with an effective scatterer diameter and the effective acoustic concentration of scatterers. This 10.1.2. Future diagnostics of vitreous structure approach has proven useful in characterizing human tissues, such as The molecular changes that occur with aging and in different prostate cancer (Rohrbach et al., 2018). Initial applications to human diseases states such as myopia have profound effects upon vitreous vitreous and specifically Vision Degrading Myodesopisa were presented structure. These changes induce Vision Degrading Myosesopsia and are above, but future developments could produce even more useful thus important aspects to assess in the evaluation of patients, as well as information. Specifically, the development of a novel, spherically curved, the assessment of efficacy with different treatment modalities. As 20-MHz, five-element annular array ultrasound transducer and the described above, there are two concurrent manifestations of the implementation of a synthetic-focusing algorithm to extend the molecular changes – vitreous gel liquefaction and the formation of depth-of-field, as well as pulse-encoding to increase sensitivity have light-scattering structures, each worthy of expanded future exploration. enabled visualization of the gel and fluid compartments of human vitreous The rheological properties of porcine vitreous were studied at with improved sensitivity and resolution compared to conventional B-scan human body temperature (37 °C) with stress-controlled shear ultrasonography (Silverman et al., 2012). This annular array technology rheometer and the role of each macromolecular component of vitreous has recently been combined with high-frequency (> 20 MHz) and QUS was related to the overall viscoelastic properties (Sharif-Kashani et al., methods to improve accuracy and extend depth-of-field, demonstrating

31 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847 stable analysis over an extended axial range (Mizoguchi et al., 2019). Vision Degrading Myodesopsia, thus obviating the need for stiffer There have also been recent attempts to combine sound and light with instruments. A study of 390 cases undergoing 27G vitrectomy included opto-acoustic approaches that have been described both in theory 69 cases with vitreous floaters that underwent surgery using (Kalkhoran and Vray, 2018) and practice (Kalkhoran and Vray, 2019). The subconjunctival anesthesia (Khan et al., 2018). Visual acuity did not stated aim of this approach is to provide accurate anatomical localization improve following surgery, but there were no complications other than of functional information via hybridizing optoacoustic and ultrasound slight elevation of intraocular pressure at one year (p < 0.01), which imaging, with the promise of early stage diagnosis. This seems perfectly was still within the normal range. suited for future developments in diagnostic evaluation of vitreous Another aspect of future developments in vitrectomy for Vision structure in Vision Degrading Myodesopsia. Degrading Myodesopsia is the transfer of care to an office setting. Most vitrectomy surgery has already transitioned from hospital operating 10.2. Future therapeutic directions for Vision Degrading Myodesopsia rooms to ambulatory surgery centers. The next iteration in this dynamic is the transition to office-based vitrectomy surgery. In 2002, a Medical therapeutics of all types evolve from doing nothing when we multi-center study in the U.S. reported that in 225 eyes undergoing 23 know nothing, to surgery, which often seems to be the first approach taken gauge vitrectomy in an office setting, there were 15 complications in 14 when only a little bit is known about a disease. The old adage “When in eyes (6.3%): “fish-egg” gas bubbles (one eye), doubt, cut it out” seems appropriate in the context of vitreous opacities and (9 eyes), choroidal detachment (2 eyes), new retinal breaks (one eye), Vision Degrading Myodesopsia. However, in all fields it has been observed retinal detachment (one eye), and temporary elevation of intraocular that with increased knowledge about pathophysiology and refinement of pressure (one eye). The investigators concluded that office-based, instrument technology, extensively invasive surgery is replaced by sutureless, transconjunctival pars plana vitrectomy is an effective minimally invasive surgery, including laser therapies. The introduction of operation for selected diseases of the posterior segment (Hilton et al., small gauge vitrectomy instruments and minimally invasive 2002). A more recent study in Mexico found that in 34 cases done in an surgery (Lavia et al., 2017) are good examples. Further expansion of office setting under topical anesthesia, the mean surgical timewas knowledge in disease pathogenesis typically spurs the development 12.35 ± 8.21 min and surgical objectives were achieved in 100% of of pharmacotherapies to replace all forms of surgery. True understanding cases (Trujillo-Sanchez et al., 2018). Of all procedures currently of disease pathogenesis enables the institution of effective preventative performed in operating rooms, limited vitrectomy for Vision Degrading treatments obviating the need for therapies of any type. Myodesopsia seems the best-suited for transfer to an office-setting, since Future directions to improve the therapy of Vision Degrading it is routinely performed under local anesthesia in approximately Myodesopsia are multiple and quite varied, ranging from vitrectomy to 10 min, making it very suitable. However, there may be post-operative non-invasive optical corrections. Minimally-invasive laser treatments issues related to patients complaining of a peripheral “frill” in their are understandably attractive to patients and some doctors, but vision, probably arising from the edge of the cut vitreous gel in the pharmacotherapies may be even more appealing. In the coming years peripheral fundus. In our experience, this occurs less than 2% of the all these approaches will likely see considerable research and time and those patients who are bothered can undergo re-operation development, hopefully to the benefit of patients suffering from this with peripheral vitrectomy using larger instruments, perhaps in an disease. The following will consider future directions in therapy for operating room. Furthermore, in those patients who ask about the Vision Degrading Myodesopsia, beginning with vitrectomy, the current “frill” and express some concern pre-operatively, it is rather easy to standard of care, then considering lesser invasive and non-invasive extend the central vitrectomy to the periphery, but this may necessitate treatments, ending with a consideration of prevention, the ultimate the selection of larger gauge instruments and scheduling in an O.R. goal of modern Medicine. rather than the office. Another potential issue is the new-onset of vitreous floaters 10.2.1. Future advances in vitrectomy for Vision Degrading Myodesopsia post-operatively, which can occur in younger patients who do not have Limited knowledge about disease pathogenesis is often initially met with a PVD pre-operatively and in whom PVD is not induced surgically. The surgical solutions. The introduction of vitrectomy to the armamentarium of largest (n = 195) study reported to date (Sebag et al., 2018) found that ophthalmic surgeons has revolutionized the treatment of vitreo-retinal this occurred in 4/43 (9.3%) cases. Symptomatic PVD occurred at diseases (Parel, 2014; Parel and Sebag, 2014), including Vision 1 month, 5 months (2 eyes), and 13 months after limited vitrectomy. Degrading Myodesopsia. A recent review on the future of vitrectomy The patients were unhappy because their average CSF diminished by (Hubschman et al., 2014) emphasized three areas of future R & D: 36% (1.75 ± 0.64 %Weber to 2.38 ± 0.12 %Weber). At their request, surgical instrumentation, augmented reality in the operating room, and repeat vitrectomy was performed without complications, completely targeted surgical delivery of drugs, genes, and stem cells. Regarding resolving floater symptoms. Mean CSF improved from 2.38 ± 0.12 % instrumentation, the large instruments originally built in the 1970s by Weber to 1.47 ± 0.36 %Weber (P < 0.01), confirming previous Jean Marie Parel have been miniaturized to what is currently most reports. (Sebag et al., 2014a,b,c; Garcia et al., 2016). One way to avoid commonly used, 25- and 27-gauge sizes, but there has even been this in the future, however, might be to insert artificial vitreous at the development of 29- and 30-gauge vitrectomy instruments for pediatric end of surgery. Crafoord et al. (2014) have recently reviewed the vitreo-retinal surgery (Binder et al., 2009). Other instrument subject and determined that an ideal artificial vitreous should be a modifications, such as port size, internal lumen diameter, instrument volume filler (mitigating against hypotony) that can provide internal wall thickness, and manufacturing material are all features that might tamponade (preventing retinal detachment), provide slow elution drug influence the ideal instrument characteristics to be employed in delivery (treating exudative maculopathies), provide hemostasis performing vitrectomy for Vision Degrading Myodesopsia. Surgery in (preventing vitreous hemorrhage), be a free-radical scavenger the larger series to date (Sebag et al. 2014a,b,c, 2018a,b; Mason et al., (mitigating cataracts), and above all maintain optical clarity (curing 2014) has been performed with 25 gauge instruments, but the future Vision Degrading Myodesopsia). These lofty goals may not all be may see the use of smaller size instruments, if advantages can be shown, attainable, but attempts are underway with cross-linked hyaluronic such as faster healing and lower rates of complications like cataracts, acid (Fig. 38), synthetic hydrogels such as polyethylene glycol retinal detachments, and macular edema. Smaller gauge instruments (an FDA-approved injectable hydrogel), polyalkylimide gel polymers might be especially reasonable to employ in treating vitreous floaters, (used in reconstructive plastic surgery), and thermogels (Cai and Chen, since extensive peripheral vitrectomy is not required in surgery for 2019).

32 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

10.2.3. Future pharmacotherapies of Vision Degrading Myodesopsia Consistent with the aforementioned description of how medical therapeutics evolve with increased knowledge of disease pathogenesis, surgery for Vision Degrading Myodesopsia will one day be replaced by pharmacotherapies. This is already happening to vitrectomy for the treatment of vitreo-maculopathies with pharmacologic vitreolysis to induce vitreo-retinal separation and relieve vitreo-macular traction (Sebag, 1998, 2002; 2005). Based upon the mechanism(s) of action, these agents were classified as liquefactants (drugs that liquefy gel vitreous) and interfactants (drugs that lyse vitreo-retinal adhesion). (Sebag, 2009b). Ocriplasmin, a non-specific protease that has both liquefactant and interfactant properties has received FDA and EU approval for clinical use (Khoshnevis and Sebag, 2015). However, neither this drug nor any other agents have been tested to promote dissolution of vitreous opacities that induce vitreous floaters. The Fig. 38. Artificial Vitreous. availability of collagenases and matrix metalloproteinases (Apte and A more stable hydrogel was achieved via cross-linking sodium hyaluronic acid Parks, 2015) would seem fertile ground for future R & D to develop an into a hydrogel (Healaflow®). [from: Crafoord S, Ghosh F, Sebag J, 2014. injectable drug that would dissolve the vitreous opacities that cause Vitreous biochemistry and artificial vitreous. In: Sebag J. (Ed.) Vitreous -in Vision Degrading Myodesopia. Health & Disease, Springer, New York, pp 81–94]. There is increasing interest in the role of vitreous as a repository for protective anti-oxidants and how nutrition can be used to modulate intravitreal levels to prevent as well as treat Vision Degrading 10.2.2. Future laser therapy of Vision Degrading Myodesopsia Myodesopsia (Ankamah et al., 2020). As a result, there are ongoing The absence of pigment within vitreous opacities that cause floaters studies employing nutritional/dietary approaches to treat vitreous has to date precluded the use of conventional lasers that generate floaters. The Floater Intervention Study (FLIES) is an ongoing wavelengths in the visible spectrum. Consequently, Nd:YAG lasers have nutritional supplementation trial for the reduction of visual been attempted, with mixed results (see above). While there may be disturbances associated with vitreous floaters [http://www.isrctn.com/ some future improvements in contact lenses to enhance visualization ISRCTN15605916; https://doi.org/10.1186/ISRCTN15605916]. Hopefully, and focusing, and although there may be modifications of the treatment objective quantitative outcome measures will be employed to evaluate technique that might improve results (Vandorselaer et al., 2001), it is the results. A pilot study in Taiwan orally administered varying doses of unlikely that Nd:YAG vitreolysis will have a major impact on the future pineapple to patients with vitreous floaters for a period of 3 months treatment of Vision Degrading Myodesopsia. This is because Nd:YAG (Horng et al., 2019). The rationale was presumably to harness the lasers work via a photo-disruptor effect, not photo-ablation (Vogel proteolytic effects of bromelain found in pineapples. The investigators et al., 1999). Femtosecond lasers, on the other hand, have more of a claimed that in 120 eyes with only one floater there was resolution in photo-ablative effect and thus would theoretically be more effective in 70.8%. In 70 subjects with multiple floaters, there was resolution in ablating vitreous opacities. Future studies should determine if there 72.9%. Unfortunately, subjective declaration by patients was the sole is a role for this approach in the treatment of Vision Degrading outcome measure and there was no control group. Further lessening the Myodesopsia. value of this study is the fact that when they administered low, medium and high doses of pineapple, the efficacy was 45.5%, 37.8% and 30.2%, What may also play a role in future treatments, however, is a novel i.e. the opposite of what one would expect if indeed pineapple ingestion approach developed by Dr. Felix Sauvage and Professor Stefaan deSmedt lessened vitreous floaters. Yet, nutritional approaches might bea at the University of Ghent, Belgium (Sauvage et al., 2019). They have future direction in the non-surgical treatment of Vision Degrading developed a nanotechnology-based approach for more efficient Myodesopsia, perhaps not with pineapples, though. photo-ablation of human vitreous opacities that relies upon the surface plasmon properties of gold nanoparticles (AuNPs), which tremendously 10.2.4. Future optical correction of Vision Degrading Myodesopsia enhance laser light absorption. Using nanosecond pulsed-laser A variety of things have been tried to reduce suffering from the illumination, AuNPs rapidly heat to several hundred degrees, evaporating symptoms of Vision Degrading Myodesopia. Dark glasses are limiting and water in the treatment area to form vapor nanobubbles (VNBs) around the at times worsen vision. Polarized lenses do not appear to help with glare, surface of the AuNPs. These VNBs expand and contract although Essilor promotes the sale of glasses for floaters claiming on their generating high-pressure shockwaves. To enhance adherence of the gold website that “Xperio Polarised are the perfect glasses for floaters” [https:// nanoparticles to vitreous collagen and enhance diffusion through vitreous, www.essilor.co.uk/vision/by-needs/lenses-for-floaters]. Yellow lenses are the AuNPs were coated with hyaluronan. The investigators tested this similarly promoted, yet a recent study comparing pedestrian recognition approach in vitro using artificial models of vitreous opacities, then treated in simulations of night driving with oncoming headlight glare found no vitreous opacities that were removed from patients during surgery for benefit to yellow lenses (Hwang et al., 2019). However, optical correction Vision Degrading Myodesopsia. Laser light (wavelength = 561 nM, 7 ns of Vison Degrading Myodesopsia might be possible if the specific optical pulses, 150 μM spot size) was able to ablate human vitreous opacities aberrations can be adequately characterized. Recent studies (Lee et al., using power settings 1000 times less than typically used in Nd:YAG laser 2019) have modeled human vitreous floaters using optical software and therapy. Cell culture toxicity studies found no untoward effects. While image processing to study the Fresnel diffraction pattern. Non-sequential these preliminary results are exciting, there is much more work to be done software based on Mie scattering theory was applied, determining that the to assure in vivo efficacy without deleterious effects. distance between the vitreous opacities and the retina is inversely proportional to the sharpness of the edge of the shadow that will be cast.

33 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

This led the investigators to conclude that this approach to modelling the Declaration of competing interest optical effects of vitreous opacities enables quantitative identification of the induced vision deficiency. It would seem, however, that such No conflicts of interest to disclose. information might also be very useful to design and implement countermeasure optical therapies similar to what has recently been Appendix A. Supplementary data described for the correction of cataracts (Arias and Artal, 2019). The approach, which has so far only been done on an optical bench, Supplementary data to this article can be found online at https:// employed a liquid crystal device spatial light modulator to implement a doi.org/10.1016/j.preteyeres.2020.100847. feedback-based wave front shaping technique with different spatial resolutions of the corrector phase maps. Future applications of this References approach to treat Vision Degrading Myodesopsia might be quite rewarding. Abdelkawi, S.A., Abdel-Salam, A.M., Ghoniem, D.F., et al., 2014. Vitreous humor rheology after Nd:YAG laser photodisruption. Cell Biochem. Biophys. 68 (2), 267–274. 10.3. Future directions in preventing Vision Degrading Myodesopsia Abraham, J.R., Ehlers, J.P., 2020. Posterior vitreous detachment: methods for detection. Ophthalmol. Retina 4 (2), 119–121. Adhi, M., Badaro, E., Liu, J.J., et al., 2016. Three-dimensional enhanced imaging of As described above, vitreous is an extended extracellular matrix vitreo-retinal interface in diabetic retinopathy using swept-source optical coherence (ECM) that constitutes the largest structure within the eye. Collagen is tomography. Am. J. Ophthalmol. 162, 140–149. https://doi.org/10.1016/j.ajo.2015. essential for vitreous morphology, but it's aggregation in the vitreous 10.025. e1. Afratis, N.A., Klepfish, M., Karamanos, N.K., Sagi, I., 2018. The apparent competitive body is central to the formation of light-scattering structures that cause action of ECM proteases and cross-linking enzymes during fibrosis: applications to Vision Degrading Myodesopsia, especially in myopic vitreopathy. It is drug discovery. Adv. Drug Deliv. Rev. 129, 4–15. https://doi.org/10.1016/j.addr. entirely possible that prevention of myopia (Morgan et al., 2018) will 2018.03.004. also prevent myopic vitreopathy and vitreous floaters. However, as also Akiba, J., 1993. Prevalence of posterior vitreous detachment in high myopia. Ophthalmology 100 (9), 1384–1388. mentioned above, irregular or incomplete regression of the fetal hyaloid Akihito, U., Nagahisa, Y., 2016. Microarchitecture of the vitreous body: a high-resolution vasculature might represent an important predisposition to collagen optical coherence tomography study. Am. J. Ophthalmol. 168, 24–30. aggregation later in life. Thus, a better understanding of vitreous Allen, W.S., Otterbein, E.C., Wardi, A.H., 1977. Isolation and characterization of the sulfated glycosaminoglycans of the vitreous body. Biochem. Biophys. Acta 498, embryogenesis might reveal important secrets to understanding and 167–175. preventing Vision Degrading Myodesopsia. But in many ways, the Alwitry, A., Chen, H., Wigfall, S., 2002. Optometrists' examination and referral practices process(es) that form(s) light scattering structures within the vitreous for patients presenting with flashes and floaters. Ophthalmic Physiol. Optic. 22 (3), 183–188. body can be considered “fibrosis”, which is a connective tissue disorder Anisimova, N.S., Arbissa, L.B., Shilova, N.F., et al., 2019. Anterior vitreous detachment: featuring an increase in the amount of fibrillar ECM components in a risk factor for intraoperative complications during phacoemulsification. J. Cataract tissue or organ (Afratis et al., 2018). These authors go on to describe Refract. Surg. https://doi.org/10.1016/j.jcrs.2019.08.005. (in press) published online Aug 9, 2019. that ECM enzymes such as matrix metalloproteinases (MMPs), via their Ankamah, E., Sebag, J., Ng, E., Nolan, J.M., 2020. Vitreous antioxidants, degeneration, catalytic activity, and lysyl oxidases (LOXs), that mediate collagen and vitreo-retinopathy: exploring the links. Antioxidants 9, 7. https://doi.org/10. cross-linking and stiffening, play crucial roles in extracellular matrix 3390/antiox9010007. Ansari, R.R., Suh, K.I., Dunker, S., et al., 2001. Quantitative molecular characterization of biology and pathology. Thus, neutralization of MMP and LOX activity bovine vitreous and lens with non-invasive dynamic light scattering. Exp. Eye Res. 73 could form a basis for future for preventative therapies of Vision (6), 859–866. Degrading Myodesopsia, at least in myopic patients, but perhaps in Anton, A., Böhringer, D., Bach, M., et al., 2014. Contrast sensitivity with bifocal in­ older individuals as well. traocular lenses is halved, as measured with the Freiburg Vision Test (FrACT), yet patients are happy. Graefes Arch. Clin. Exp. Ophthalmol. 252 (3), 539–544. https:// PVD is the most common cause for Vision Degrading Myodesopsia. doi.org/10.1007/s00417-014-2565-y. Apart from variability in the degree of folding that occurs in the posterior Antonetti, D.A., Klein, R., Gardner, T.W., 2012. Diabetic retinopathy. N. Engl. J. Med. 366 vitreous cortex following PVD, the relative contributions to Vision 1227e1239. Apte, S.S., Parks, W.C., 2015. Metalloproteinases: a parade of functions in matrix biology Degrading Myodesopsia of collagen content, collagen density, and and an outlook for the future. Matrix Biol. 44–46, 1–6. https://doi.org/10.1016/j. collagen cross-linking in the posterior vitreous cortex are not known. matbio.2015.04.005. Elsewhere in the body collagen deposition is an adaptive response that Araújo, J.R., Tavares-Ferreira, J., Estrela-Silva, S., et al., 2018. Wagner syndrome: anatomic, functional and genetic characterization of a Portuguese family. Graefes aims to preserve tissue integrity and maintain normal function, but excess Arch. Clin. Exp. Ophthalmol. 256 (1), 163–171. https://doi.org/10.1007/ activation significantly increases collagen deposition and accumulation in s00417-017-3800-0. the ECM (El Hajj et al., 2018). Were this to occur in the posterior vitreous Arias, A., Artal, A., 2019. Wavefront shaping for the correction of cataracts. Optica. https://doi.org/10.1364/optica.99.099999. (in press). cortex, excess synthesis and activation of LOX will increase collagen Artal, P., Chen, L., Fernandez, E.J., et al., 2004. Neural compensation for the eye's optical cross-linking, significantly decreasing the efficacy of MMPs to normally aberrations. J. Vis. 16 (4), 281–287 4. modulate collagen content, resulting in accumulation of collagen within Asakura, A., 1985. Histochemistry of hyaluronic acid of the bovine vitreous body by electron microscopy. Nippon. Ganka Gakkai Zasshi 89 (1), 179–191. the ECM, in this case vitreous, a tissue intended to be clear of light Asanad, S., Sebag, J., 2020. Vitreous and Developmental Vitreo-Retinopathies. In: scattering structures. Indeed, elevated LOX levels and activity in the heart Hartnett (Ed.), Pediatric Retina, third ed. Wolters Kluwer Health ISBN-10: play a key role in the progression of heart failure, and the inhibition of 1975110714. ISBN-13: 978-1975110710. LOX in rats prevented the development of cardiac dysfunction (El Hajj Aslam, T.M., Haider, D., Murray, I.J., 2007. Principles of disability glare measurement: an ophthalmological perspective. Acta Ophthalmol. Scand. 85 (4), 354–360. et al., 2018). Recent studies in the knockout mouse have shown that loss of Azhdam, A.M., Goldberg, R.A., Ugradar, S., 2020. In vivo measurement of the human Thromospondin 2 leads to a significant decrease in ECM fibrillar collagen, vitreous chamber volume using computed tomography imaging of 100 eyes. Trans. matricellular, and structural ECM protein production in the skin (Calabro Vis. Sci. Techol. 9 (1), 2. https://doi.org/10.1167/tvst.9.1.2. 2020. Bach, M., 1996. The Freiburg Visual Acuity test–automatic measurement of visual et al., 2019). All these represent potential future directions for the acuity. Optom. Vis. Sci. 73 (1), 49–53. development of preventative therapeutic strategies in Vision Degrading Bach, M., 2007. The Freiburg visual acuity test-variability unchanged by post-hoc Myodesopsia. re-analysis. Graefe’s Arch. Clin. Exp. Ophthalmol. 245 (7), 965–971. Bach, M., Schäfer, K., 2014. Visual acuity testing: feedback affects neither outcome nor reproducibility, but leaves participants happier. PloS One 11 (1), e0147803. https:// doi.org/10.1371/journal.pone.0147803.eCollection.2016. Funding Balazs, E.A., 1960. Physiology of the vitreous body. In: Schepens, C.L. (Ed.), Importance of the Vitreous Body in Retinal Surgery with Special Emphasis on Re-operation. C.V. VMR Research Foundation provided funds for research-related Mosby Co., St. Louis, pp. 29–57. expenses and academic activity expenses by the author.

34 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Balazs, E.A., 1984. The vitreous. In: In: Davson, H. (Ed.), The Eye, vol. 1a. Academic Calabro, N.E., Barrett, A., Chamorro-Jorganes, A., et al., 2019. Thrombospondin-2 Press, London, pp. 533–589. regulates extracellular matrix production, LOX levels, and cross-linking via Balazs, E.A., Denlinger, J., 1982. Aging changes in the vitreous. In: Aging and Human downregulation of miR-29. Matrix Biol. https://doi.org/10.1016/j.matbio.2019.03. Visual Function. Alan R Liss, New York, pp. 45–47 1982. 002. 2019 Mar 13. pii: S0945-053X(18)30438-4, [Epub ahead of print]. Balazs, E.A., Flood, M.T., 1978. Age-related Changes in the Physical and Chemical State of Cases, O., Obry, A., Ben-Yacoub, S., et al., 2017. Impaired vitreous composition and Human Vitreous. Third International Congress for Eye Research, Osaka, Japan. retinal pigment epithelium function in the FoxG1::LRP2 myopic mice. Biochim. Balazs, EA, Sundblad, L, Toth, LZJ, 1958. In vitro formation of hyaluronic acid by cells in Biophys. Acta (BBA) - Mol. Basis Dis. 1863 (6), 1242–1254. https://doi.org/10.1016/ the vitreous body and by comb tissue. Abstr Fed Proc 17, 184. j.bbadis.2017.03.022. Balazs, E.A., Toth, L.Z., Jutheden, G.M., Collins, B.-A., 1965. Cytological and biochemical Castilla-Marti, M., van den Berg, T.J., de Smet, M.D., 2015. Effect of vitreous opacities on studies on the developing chicken vitreous. Exp. Eye Res. 4 (3), 237–248. straylight measurements. Retina 35 (6), 1240–1246. https://doi.org/10.1097/IAE. Balazs, E.A., Toth, L.Z., Ozanics, V., 1980. Cytological studies on the developing vitreous 0000000000000456. as related to the hyaloid vessel system. Graefe’s Arch. Clin. Exp. Ophthalmol. 213, Chakrabarti, B., Park, J.W., 1980. Glycosaminoglycans: structure and interaction. CRC 71–85. Crit. Rev. Biochem. 8 (3), 225–313. Balazs, E.A., Laurent, T.C., Jeanloz, R.W., 1986. Nomenclature of hyaluronic acid. Chen, Y., Doughman, Y.Q., Gu, S., et al., 2008. Cited2 is required for the proper formation Biochem. J. 235 (3), 903. of the hyaloid vasculature and for lens morphogenesis. Development 135, Bartholomew, A.J., Lad, E.M., Cao, D., et al., 2016. Individual differences in scotopic 2939–2948. visual acuity and contrast sensitivity: genetic and non-genetic influences. PloS One 11 Chen, J.H., Lin, X., Bu, C., et al., 2018. Role of advanced glycation end products in (2), e0148192. mobility and considerations in possible dietary and nutritional intervention Beebe, D.C., Holekamp, N.M., Siegfried, C., Shui, Y.B., 2011. Vitreoretinal influences on strategies. Nutr. Metab. 15, 72. https://doi.org/10.1186/s12986-018-0306-7. lens function and cataract. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366 (1568), eCollection.2018. 2018 Oct 10. 1293–1300. https://doi.org/10.1098/rstb.2010.0228. Chu, T.G., Lopez, P., Cano, M.R., et al., 1996. Posterior vitreoschisis: an echographic Bejarano, E., Taylor, A., 2019. Too sweet: problems of protein glycation in the eye. Exp. finding in proliferative diabetic retinopathy. Ophthalmology 103, 315–322. Eye Res. 178, 255–262. Chuo, J.Y., Lee, T.Y., Hollands, H., Morris, A.H., 2006. Risk factors for posterior vitreous Berman, E., Michaelson, I., 1964. The chemical composition of the human vitreous body detachment: a case–control study. Am. J. Ophthalmol. 142 (6) 931–937.e1. as related to age and myopia. Exp. Eye Res. 3 (1), 9–15. Cipolletta, S., Beccarello, A., Galan, A., 2012. A psychological perspective of eye floaters. Bettelheim, F.A., Balazs, E.A., 1968. Light-scattering patterns of the vitreous humor. Qual. Health Res. 22 (11), 1547–1558 (ISSN: 1049-7323). Biochim. Biophys. Acta 158 (2), 309–312. Colter, J., Williams, A., Moran, P., et al., 2015. Age-related changes in dynamic moduli of Bettelheim, F.A., Zigler, J.S., 2004. Regional mapping of molecular components of human ovine vitreous. J. Mech. Behav. Biomed. Mater. 41, 315–324. https://doi.org/10. liquid vitreous by dynamic light scattering. Exp. Eye Res. 79 (5), 713–718. 1016/j.jmbbm.2014.09.004. Binder, S., Wimpissinger, B., Kellner, L., 2009. Current clinical data and future for small- Comper, W.D., Laurent, T.C., 1978. Physiological function of connective tissue gauge vitreoretinal surgery. In: Rizzo, S., Patelli, F., Chow, D.R. (Eds.), Vitreo-Retinal polysaccharides. Physiol. Rev. 58 (1), 255–315. Surgery. Springer, Berlin/Heidelberg, pp. 213–222. Coric, D., Ometto, G., Montesano, G., et al., 2020. Objective quantification of vitreous Bishop, P.N., 2000. Structural macromolecules and supramolecular organisation of the haze on optical coherence tomography scans: no evidence for relationship between vitreous gel. Prog. Retin. Eye Res. 19 (3), 323–344. uveitis and inflammation in multiple sclerosis. Eur. J. Neurol. 27, 144–151. https:// Bishop, P.N., 2014. Vitreous proteins. In: Sebag, J. (Ed.), Vitreous – in Health & Disease. doi.org/10.1111/ene.14048. e3. Springer, New York, pp. 3–12. Crafoord, S., Ghosh, F., Sebag, J., 2014. Vitreous biochemistry and artificial vitreous. In: Bishop, P.N., Crossman, M.V., McLeod, D., et al., 1994. Extraction and characterization of Sebag, J. (Ed.), Vitreous - in Health & Disease. Springer, New York, pp. 81–94. the tissue forms of collagen types II and IX from bovine vitreous. Biochem. J. 299, Creveling, C.J., Colter, J., Coats, B., 2018. Changes in vitreoretinal adhesion with age and 497–505. region in human and sheep eyes. Front. Bioeng. Biotechnol. 6 (153), 1–11. https:// Bishop, P., Ayad, S., Reardon, A., McLeod, D., et al., 1996. Type VI collagen is present in doi.org/10.3389/fbioe.2018.00153. human and bovine vitreous. Graefes Arch. Clin. Exp. Ophthalmol. 234, 710–713. Crim, N., Esposito, E., Monti, R., et al., 2017. Myopia as a risk factor for subsequent Bishop, P., McLeod, D., Reardon, A., 1999. Effects of hyaluronan lyase, hyaluronidase, retinal tears in the course of a symptomatic posterior vitreous detachment. BMC and chondroitin ABC lyase on mammalian vitreous gel. Invest. Ophthalmol. Vis. Sci. Ophthalmol. 17 (1), 226. https://doi.org/10.1186/s12886-017-0629-6. 40 (10), 2173–2178. Curtin, D.T., Smye, S., Dabbs, T., et al., 1998. A model for the fluid motion of vitreous Bishop, P.N., Takanosu, M., Le Goff, M., et al., 2002. The role of the posterior ciliary body humour of the human eye during saccadic movement. Phys. Med. Biol. 43 (6), in the biosynthesis of vitreous humour. Eye 16, 454–460. 1385–1399. https://doi.org/10.1088/0031-9155/43/6/001. Bishop, P.N., Holmes, D.F., Kadler, K.E., et al., 2004. Age-related changes on the surface Datiles, M.B., Ansari, R.R., Suh, K.I., et al., 2008. Clinical detection of precataractous lens of vitreous collagen fibrils. Invest. Ophthalmol. Vis. Sci. 45 (4), 1041–1046. protein changes using dynamic light scattering. Arch. Ophthalmol. 126 (12), Blake, R., Tadin, D., Sobel, K.V., et al., 2006. Strength of early visual adaptation depends 1687–1693. https://doi.org/10.1001/archophthalmol.2008.507. on visual awareness. Proc. Natl. Acad. Sci. U.S.A. 103 (12), 4783–4788. de Jong, B., van der Meulen, I.J., Lapid-Gortzak, R., van den Berg, T.J., 2019. Straylight in Blanc, J., Seydou, A., Ghezala, I.B., et al., 2019. Vitreomacular interface abnormalities posterior polar cataract. J. Cataract Refract. Surg. 45 (1), 72–75. https://doi.org/10. and glaucoma in an elderly population (The MONTRACHET Study). Invest. 1016/j.jcrs.2018.08.035. Ophthalmol. Vis. Sci. 60, 1996–2002. https://doi.org/10.1167/iovs.18-26510. de Jong, B., van der Meulen, I.J.E., van Vliet, J.M.J., Lapid-Gortzak, R., et al., 2018. Bos, K.J., Holmes, D.F., Meadows, R.S., et al., 2001. Collagen fibril organisation in Effects of corneal scars and their treatment with rigid contact lenses on quality of mammalian vitreous by freeze etch/rotary shadowing electron microscopy. Micron vision. Eye Contact Lens 44 (Suppl. 1), S216–S220. https://doi.org/10.1097/ICL. 32, 301–306. 0000000000000384. Bottos, J., Elizalde, J., Arevalo, J.F., et al., 2012. Vitreomacular traction syndrome. J. de Nie, K.F., Crama, N., Tilanus, M.A., et al., 2013. Pars plana vitrectomy for disturbing Ophthalmic Vis. Res. 7 (2), 148–161. primary vitreous floaters: clinical outcome and patient satisfaction. Graefe’s Arch. Bourke, C.M., Loughman, J., Flitcroft, D.I., et al., 2019. We can't afford to turn a blind eye Clin. Exp. Ophthalmol. 251 (5), 1373–1382. to myopia. QJM: Int. J. Med. 1–5 0(0). Delaney, Y.M., Oyinloye, A., Benjamin, L., 2002. Nd:YAG vitreolysis and pars plana Bowman, W., 1848. Observations on the structure of the vitreous humour. Dublin Quar. J. vitrectomy: surgical treatment for vitreous floaters. Eye (Lond) 16 (1), 21–26. Med. Sci. 6, 102. Dennis, R.J., Beer, J.M., Baldwin, J.B., et al., 2004. Using the Freiburg acuity and contrast Brasse, K., Schmitz-Valckenberg, S., Jünemann, A., et al., 2019. [YAG laser vitreolysis for test to measure visual performance in USAF personnel after PRK. Optom. Vis. Sci. 81 treatment of symptomatic vitreous opacities]. Ophthalmologe 116 (1), 73–84. (7), 516–524. https://doi.org/10.1007/s00347-018-0782-1. DiBernardo, C., Blodi, B., Byrne, S.F., 1992. Echographic evaluation of retinal tears in Brasseur, G., 2003. Pathologie du Vitré. Elsevier Masson. patients with spontaneous vitreous hemorrhage. Arch. Ophthalmol. 110 (4), Breen, M., Bizzell, J.W., Weinstein, M.G., 1977. A galactosamine-containing proteoglycan 511–514. in human vitreous. Exp. Eye Res. 24, 409–412. Dong, L., Kang, Y.K., Li, Y., et al., 2019. Prevalence and time trends of myopia in children Brewton, R.G., Ouspenskaia, M.V., van der Rest, M., et al., 1992. Cloning of the chicken and adolescents in China: a systemic review and meta-analysis. June 21, 2019. alpha 3(IX) collagen chain completes the primary structure of type IX collagen. Eur. Retina. https://doi.org/10.1097/IAE.0000000000002590. [Epub ahead of print]. J. Biochem. 205 (2), 443–449. Dos Santos, J.M., Tewari, S., Mendes, R.H., 2019. The role of oxidative stress in the Brown, M.M., Brown, G.C., Sharma, S., Garrett, S., 1999. Evidence-based medicine, development of diabetes mellitus and its complications. J. Diabetes Res. 4189813. utilities, and quality of life. Curr. Opin. Ophthalmol. 10, 221–226. https://doi.org/10.1155/2019/4189813. 2019. Bu, S.C., Kuijer, R., van der Worp, R.J., et al., 2015. The ultrastructural localization of Dotrelova, D., Karel, I., Clupkova, E., 1997. Retinal detachment in Marfan's syndrome. type II, IV, and VI collagens at the vitreoretinal interface. PloS One 10 (7), e0134325. Characteristics and surgical results. Retina 17, 390–396. https://doi.org/10.1371/journal.pone.0134325. Duke-Elder, W.S., 1930. The nature of the vitreous body. Br. J. Ophthalmol. 14 (Suppl), 6. Busacca, A., 1958. La structure biomicroscopique du corps vitré normal. Ann d'Ocullist Duke-Elder, S., Abrams, D., 1970. Pathological refractive errors. In: In: Duke-Elder, S. 91, 477–499. (Ed.), Systems of Ophthalmology, vol. 5. CV Mosby, St Louis, pp. 297–374. Buschbaum, G, Sternklar, M, Litt, M, et al., 1984. Dynamics of an oscillating viscoelastic Duker, J.S., Kaiser, P.K., Binder, S., et al., 2013. The International Vitreomacular Traction sphere-A model of the vitreous humor of the eye. Biorheology 21, 285–296. Study Group classification of , traction, and macular hole. Cai, P., Chen, X., 2019. Hydrogels for artificial vitreous: from prolonged substitution to Ophthalmology 120 (12), 2611–2619. elicited regeneration. ACS Mater. Lett. 1 (2), 285–289. https://doi.org/10.1021/ Duplechain, A., Conrady, C.D., Patel, B.C., Baker, S., 2020. Uveitis. StatPearls [Internet]. acsmaterialslett.9b00145. Treasure Island (FL). StatPearls Publishing 2020-. 2019 Nov 25. https://www.ncbi. Calabrèse, A., Cheong, A.M., Cheung, S.H., et al., 2016. Baseline MNREAD measures for nlm.nih.gov/books/NBK540993/. normally sighted subjects from childhood to old age. Invest. Ophthalmol. Vis. Sci. 57 Ehringer, B., Grzybowski, A., 2011. Allvar Gullstrand (1862–1930) – the gentleman with (8), 3836–3843. https://doi.org/10.1167/iovs.16-19580. the lamp. Acta Ophthalmol. 89 (8), 701–708.

35 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Eisner, G., 1972. Biomicroscopy of the peripheral fundus. Surv. Ophthalmol. 17 (1), 1–28. Gloor, B.P., 1975. The vitreous. In: Moses, R.A. (Ed.), Adler's Physiology of the Eye. Eisner, G., 1973. Biomicroscopy of the Peripheral Fundus. Springer-Verlag, Berlin & Mosby, St. Louis, pp. 246–267. Heidelberg. Goes, R.M., Nader, H.B., Porcionatto, M.A., et al., 2005. Chondroitin sulfate Eisner, G., 1975. Zur Anatomie des Glaskörpers. Graefe’s Arch. Clin. Exp. Ophthalmol. proteoglycans are structural renewable constituents of the rabbit vitreous body. Curr. 193, 33–56. Eye Res. 30 (5), 405–413. Ekici, F., Loh, R., Waisbourd, M., et al., 2015. Relationships between measures of the Gogat, K., Le Gat, L., Van Den Berghe, L., et al., 2004. VEGF and KDR gene expression ability to perform vision-related activities, vision-related quality of life, and clinical during human embryonic and fetal eye development. Invest. Ophthalmol. Vis. Sci. 45 findings in patients with glaucoma. JAMA Ophthalmol. 133 (12), 1377–1385. (1), 7–14. El Hajj, E.C., El Hajj, M.C., Ninh, V.K., Gardner, J.D., 2018. Inhibitor of lysyl oxidase Goldmann, H., 1962. Senescenz des Glaskörpers. Ophthalmologica 143, 253–279. improves cardiac function and the collagen/MMP profile in response to volume Govetto, A., Dacquay, Y., Farajzadeh, M., et al., 2016. Lamellar macular hole: two distinct overload. Am. J. Physiol. Heart Circ. Physiol. 315 (3), H463–H473. https://doi.org/ clinical entities? Am. J. Ophthalmol. 164, 99–109. 10.1152/ajpheart.00086.2018. Grulkowski, I., Rodriguez-Aramendia, A., Ruminski, D., et al., 2019. Vitreous body Eye Disease Case Control Study Group, 1993. Risk factors for idiopathic rhegmatogenous imaging with long-range swept-source optical coherence tomography for detection of retinal detachment. Am. J. Epidemiol. 137 (7), 749–757. opacities. Invest. Ophthalmol. Vis. Sci. 60 (9), 1291. Fang, Y., Du, R., Nagaoka, N., et al., 2019. OCT-based diagnostic criteria for different Grutzmacher, C., Park, S., Elmergreen, T.L., et al., 2010. Opposing effects of bim and bcl-2 stages of myopic maculopathy. Ophthalmology 126, 1018–1032. on lung endothelial cell migration. Am. J. Physiol. Lung Cell Mol. Physiol. 299 (5), Fang Yan, S., Ramasamy, R., Ann Schmidt, A.M., 2008. Mechanisms of Disease: advanced L607–L620. https://doi.org/10.1152/ajplung.00390.2009. glycation end-products and their receptor in inflammation and diabetes Gupta, P., Sadun, A.A., Sebag, J., 2008. Multifocal retinal contraction in macular pucker complications. Nat. Clin. Pract. Endocrinol. Metabol. 4, 285–293. analyzed by combined optical coherence tomography/scanning laser ophthalmo­ Fankhauser, F., 2012. Analysis of diabetic vitreopathy with dynamic light scattering scopy. Retina 28, 447–452. spectroscopy – problems and solutions related to photon correlation. Acta Gupta, P., Yee, K.M.P., Garcia, P., et al., 2011. Vitreoschisis in macular diseases. Br. J. Ophthalmol. 90 (3), 173–178. Ophthalmol. 95 (3), 376–380. Faulborn, J., Bowald, S., 1985. Microproliferations in proliferative diabetic retinopathy Hahn, P., Schneider, E., Tabandeh, H., 2017. Reported complications following laser and their relationship to the vitreous: corresponding light and electron microscopic vitreolysis. JAMA Ophthalmol. 135 (9), 973–976. https://doi.org/10.1001/ studies. Graefe’s Arch. Clin. Exp. Ophthalmol. 223, 130–138. jamaophthalmol.2017.2477. Favre, M., Goldmann, H., 1956. Zur genese der hinteren glaskörperabhebung. Halfter, W., 2008. Change in embryonic eye size and retinal cell proliferation following Ophthalmologica 132 (2), 87–97. intravitreal injection of glycosaminoglycans. Invest. Ophthalmol. Vis. Sci. 49 (8), Ferreira, J.A., Oliveira, P., Silva, R., 2017. Mathematics of aging: diseases of the posterior 3289–3298. https://doi.org/10.1167/iovs.07-1421. segment of the eye. Comput. Math. Appl. 73 (1), 11–26. Halfter, W., Cunningham, E., Sebag, J., 2014. Vitreo-retinal interface and inner limiting Figueroa, M.S., Govetto, A., Steel, D.H., et al., 2019. Pars plana vitrectomy for the membrane. In: Sebag, J. (Ed.), Vitreous O- in Health & Disease. Springer, New York, treatment of tractional and degenerative lamellar macular holes - functional and pp. 165–191. anatomical results. Retina 39 (11), 2090–2098. Hayreh, S.S., Jonas, J.B., 2004. Posterior vitreous detachment: clinical correlations. Filas, B.A., Zhang, Q., Okamoto, R.J., Shui, Y.-B., Beebe, D.C., 2014. Enzymatic de­ Ophthalmologica 218 (5), 333–343. gradation identifies components responsible for the structural properties of the Hegde, S., Srivastava, O., 2017. Different gene knockout/transgenic mouse models vitreous body. Invest. Ophthalmol. Vis. Sci. 55, 55–63. https://doi.org/10.1167/iovs. manifesting persistent fetal vasculature: are integrins to blame for this pathological 13-13026. condition? Life Sci. 171, 30–38. https://doi.org/10.1016/j.lfs.2016.12.019. Fincham, G.S., James, S., Spickett, C., et al., 2018. Posterior vitreous detachment and the Heljasvaara, R., Aikio, M., Ruotsalainen, H., Pihlajaniemi, T., 2017. Collagen XVIII in posterior hyaloid membrane. Ophthalmology 125, 227–236. https://doi.org/10. tissue homeostasis and dysregulation - lessons learned from model organisms and 1016/j.ophtha.2017.08.001. human patients. Matrix Biol. 57–58, 55–75. Firner, S., Zaucke, F., Michael, J., et al., 2017. Extracellular distribution of collagen II and Henrich, P.B., Monnier, C.A., Halfter, W., et al., 2012. Nanoscale topographic and perifibrillar adapter proteins in healthy and osteoarthritic human knee joint cartilage. biomechanical studies of the human internal limiting membrane. Invest. Ophthalmol. J. Histochem. Cytochem. 65 (10), 593–606. Vis. Sci. 53, 2561–2570. https://doi.org/10.1167/iovs.11-8502. Flitcroft, D.I., He, M., Jonas, J.B., et al., 2019. International Myopia Institute—defining Hikichi, T., Yoshida, A., 2004. Time course of development of posterior vitreous de­ and classifying myopia: a proposed set of standards for clinical and epidemiologic tachment in the fellow eye after development in the first eye. Ophthalmology 111 (9), studies. Invest. Ophthalmol. Vis. Sci. 60 M20–30. 1705–1707. Fokkens, B.T., Mulder, D.J., Schalkwijk, C.G., et al., 2017. Vitreous advanced glycation Hikichi, T, 2007. Time course of posterior vitreous detachment in the second eye. Curr. endproducts and α-dicarbonyls in retinal detachment patients with type 2 diabetes Opin. Ophthalmol. 18 (3), 224–227. mellitus and non-diabetic controls. PloS One 12 (3), e0173379. https://doi.org/10. Hikichi, T., Hirokawa, H., Kado, M., et al., 1995. Comparison of the prevalence of PVD in 1371/journal.pone.0173379. whites and Japanese. Ophthalmic Surg. 26 (1), 39–43. Foos, R., Wheeler, N., 1982. Vitreoretinal juncture - synchysis senilis and posterior Hilton, G.F., Josephberg, R.G., Halperin, L.S., et al., 2002. Office-based sutureless vitreous detachment. Ophthalmology 89 (12), 1502–1512. transconjunctival pars plana vitrectomy. Retina 22 (6), 725–732. Forrester, J.V., Balazs, E.A., 1980. Inhibition of phagocytosis by high molecular weight Holden, B.A., Fricke, T.R., Wilson, D.A., et al., 2016. Global prevalence of myopia and hyaluronate. Immunology 40, 435–446. high myopia and temporal trends from 2000 through 2050. Ophthalmology 123, Fricke, T.R., Jong, M., Naidoo, K.S., et al., 2019. Global prevalence of visual impairment 1036–1042. associated with myopic macular degeneration and temporal trends from 2000 Holekamp, N.M., Beebe, D.C., Shui, Y.-B., 2014. Oxygen in vitreo-retinal physiology and through 2050: systematic review, meta-analysis and modelling. Br. J. Ophthalmol. pathology. In: Sebag, J. (Ed.), Vitreous – in Health & Disease. Springer, New York, pp. 102 (7), 855–862. https://doi.org/10.1136/bjophthalmol-2017-311266. pp459–p476. Gal-Or, O., Ghadiali, Q., Dolz-Marco, R., et al., 2019. In vivo imaging of the fibrillar Horng, C.-T., Chen, F.-A., Kuo, D.-H., et al., 2019. Pharmacologic vitreolysis of vitreous architecture of the posterior vitreous and its relationship to the premacular bursa, floaters by 3-month pineapple supplement in Taiwan: a pilot study. J. Am. Sci. 15 (4), Cloquet's canal, prevascular vitreous fissures, and cisterns. Graefe’s Arch. Clin. Exp. 17–30. https://doi.org/10.7537/marsjas150419.03. Ophthalmol. 257 (4), 709–714. https://doi.org/10.1007/s00417-018-04221-x. Huang, L.C., Yee, K.M.P., Wa, C.A., et al., 2014. Vitreous floaters and vision: current Gale, J., Ikuno, Y., 2014. Myopic vitreopathy. In: Sebag, J. (Ed.), Vitreous – in Health & concepts and management paradigms. In: Sebag, J. (Ed.), Vitreous – in Health & Disease. Springer, New York, pp. 113–130. Disease. Springer, New York, pp. 771–788. Gandorfer, A., Putz, E., Welge-Lussen, U., et al., 2001. Ultrastructure of the vitreoretinal Hubschman, J.P, Shah, S.U, Voleti, V.B, 2014. The future of vitrectomy. In: Sebag, J (Ed.), interface following plasmin assisted vitrectomy. Br. J. Ophthalmol. 85, 6–10. https:// Vitreous - in Health & Disease. Springer, New York, pp. 699–712. doi.org/10.1136/bjo.85.1.6. Hwang, E.S., Kraker, J.A., Griffin, K.J., Sebag, J., et al., 2020. Accuracy of spectral do­ Garcia, G., Khoshnevis, M., Yee, K.M., Nguyen-Cuu, J., Nguyen, J.H., Sebag, J., 2016. main OCT of the macula for detection of complete posterior vitreous detachment. Degradation of contrast sensitivity following posterior vitreous detachment. Am. J. Ophthalmol. Retina 4 (2), 148–153. https://doi.org/10.1016/j.oret.2019.10.013. Ophthalmol. 172, 7–12. https://doi.org/10.1016/j.ajo.2016.09.005. Hwang, A.D., Tuccar-Burak, M., Peli, E., 2019. Comparison of pedestrian detection with Garcia, G., Khoshnevis, M., Nguyen-Cuu, J., Yee, K.M.P., Nguyen, J.H., Sadun, A.A., and without yellow-lens glasses during simulated night driving with and without Sebag, J., 2018. The effects of aging vitreous on contrast sensitivity function. Graefes headlight glare. JAMA Ophthalmol. https://doi.org/10.1001/jamaophthalmol.2019. Arch. Clin. Exp. Ophthalmol. 256, 919–925. https://doi.org/10.1007/s00417-018- 2893. (in press). 3957-1. IJspeert, J.K., de Waard, P.W., van den Berg, T.J., de Jong, P.T., 1999. The intraocular Gärtner, J., 1971. The fine structure of the vitreous base of the human eye and the pa­ straylight function in 129 healthy volunteers; dependence on angle, age and thogenesis of pafrs planitis. Am. J. Ophthalmol. 71, 1317–1327. pigmentation. Vis. Res. 30, 699–707. Gärtner, J., 1986. Electron microscopic study on the fibrillar network and fibrocyte-col­ Itakura, H., Kishi, S., Kotajima, N., Murakami, M., 2009. Decreased vitreal hyaluronan lagen interactions in the vitreous cortex at the ora serrata of human eyes with special levels with aging. Ophthalmologica 223 (1), 32–35. regard to the role of disintegrating cell. Exp. Eye Res. 42, 21–33. Itakura, H., Kishi, S., Li, D., et al., 2014. Vitreous changes in high myopia observed by Géhl, Z., Bakondi, E., Resch, M.D., et al., 2016. Diabetes-induced oxidative stress in the vitreous swept-source optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 55 (3), humor. Redox Biol. 9, 100–103. https://doi.org/10.1016/j.redox.2016.07.003. 1447–1452. https://doi.org/10.1167/iovs.13-13496. Gholami, S., Reus, N.J., van den Berg, T.J., 2017. Changes in intraocular straylight and Ivanova, T., Jalil, A., Antoniou, Y., et al., 2016. Vitrectomy for primary symptomatic visual acuity with age in cataracts of different morphologies. J. Ophthalmol. vitreous opacities: an evidence-based review. Eye 30, 645–655. https://doi.org/10. 5649532. https://doi.org/10.1155/2017/5649532. 2017. 1038/eye.2016.30. Gilmartin, B., Nagra, M., Logan, N.S., 2013. Shape of the posterior vitreous chamber in Jack, R., 1972. Regression of the hyaloid artery system: an ultrastructural analysis. Am. J. human emmetropia and myopia. Invest. Ophthalmol. Vis. Sci. 54 (12), 7240–7251. Ophthalmol. 74 (2), 261–272. https://doi.org/10.1167/iovs.13-12920.

36 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Jensen, B.H., Bram, T., Kappelgaard, P., et al., 2017. Visual function and retinal vessel Kokavec, J., Min, S.H., Tan, M.H., Jaglit, S.G., Newland, H.S., Durkin, S.R., Grigg, J., diameters during hyperthermia in man. Acta Ophthalmol. 95, 690–696. https://doi. Casson, R.J., 2016. Biochemical analysis of the living human vitreous. Clin. Exp. org/10.1111/aos.13361. Ophthalmol. 44, 597–609. https://doi.org/10.1111/ceo.12732. Johnson, M.W., 2005. Perifoveal vitreous detachment and its macular complications. Kokavec, J., Wu, Z., Sherwin, J.C., et al., 2017. Nd:YAG laser vitreolysis versus pars plana Trans. Am. Ophthalmol. Soc. 103, 537–567. vitrectomy for vitreous floaters. Cochrane Database Syst. Rev. 6https://doi.org/10. Johnson, M.W., 2010. Posterior vitreous detachment: evolution and complications of its 1002/14651858.CD011676.pub2. CD011676. early stages. Am. J. Ophthalmol. 149 (3), 371–382. Kokavec, J., Ang, G.S., Sherwin, J.C., 2018. Methodological and efficacy issues in a Jolly, J.K., Gray, J.M., Salvetti, A.P., et al., 2019. A randomized crossover study to assess randomized clinical trial investigating vitreous floater treatment. JAMA Ophthalmol. the usability of two new vision tests in patients with low vision. Optom. Vis. Sci. 96 136 (4). https://doi.org/10.1001/jamaophthalmol.2018.0207. 447-8. (6), 443–452. https://doi.org/10.1097/OPX.0000000000001380. Krebs, I., Brannath, W., Glittenberg, K., et al., 2007. Posterior vitreo-macular adhesion: a Jongebloed, W.L., Worst, J.F., 1987. The cisternal anatomy of the vitreous body. Doc. potential risk factor for exudative age-related macular degeneration. Am. J. Ophthalmol. 67, 183–196. Ophthalmol. 144, 741–746 2007. Jonsdottir, K.D., Einarsdottir, A.B., Stefánsson, E., 2018. Why does vitreoretinal traction Krepline, A., Tsai, S., 2019. Has personalized medicine for pancreatic cancer arrived? create macular oedema? Acta Ophthalmol. 96 (4), e533–e534. https://doi.org/10. Adv. Surg. 53, 103–115. 1111/aos.13410. Kumar Dubey, N., Wei, H.-J., Yu, S.-H., et al., 2019. Adipose-derived stem cells attenuates Junqueria, L.C.U., Montes, G.S., 1983. Biology of collagen-proteoglycan interaction. Arch. diabetic osteoarthritis via inhibition of glycation-mediated inflammatory cascade. Histol. Jpn. 46, 589–629. Aging Dis. 10 (3), 483–496. Kalkhoran, M.A., Vray, D., 2018. Theoretical characterization of annular array as a Larsson, L., Österlin, S., 1985. Posterior vitreous detachment. Graefes Arch. Clin. Exp. volumetric optoacoustic ultrasound handheld probe. J. Biomed. Optic. 23 (2), 1–9. Ophthalmol. 223 (2), 92–95. https://doi.org/10.1117/1.JBO.23.2.025004. Laurent, U.B., Fraser, J.R., 1983. Turnover of hyaluronate in the aqueous humour and Kalkhoran, M.A., Vray, D., 2019. Sparse sampling and reconstruction for an opto-acoustic vitreous body of the rabbit. Exp. Eye Res. 36 (4), 493–503. ultrasound volumetric hand-held probe. Biomed. Optic Express 10 (4), 1545–1556. Lavia, C., Dallorto, L., Maule, M., et al., 2017. Minimally-invasive glaucoma surgeries https://doi.org/10.1364/BOE.10.001545. (MIGS) for open angle glaucoma: a systematic review and meta-analysis. PloS One 12 Kamei, A., Totani, A., 1982. Isolation and characterization of minor glycosaminoglycans (8), e0183142. https://doi.org/10.1371/journal.pone.0183142.eCollection.2017. in the rabbit vitreous body. Biochem. Biophys. Res. Commun. 109 (3), 881–887. Le Goff, M., Bishop, P., 2008. Adult vitreous structure and postnatal changes. Eye 22 (10), Katagiri, M., Shoji, J., Kato, S., et al., 2017. Relationships between vitreous levels of 1214–1222. soluble receptor for advanced glycation end products (sRAGE) and renal function in Le Goff, M.M., Lu, H., Ugarte, M., et al., 2012a. The vitreous glycoprotein opticin inhibits patients with diabetic retinopathy. Int. Ophthalmol. 37 (6), 1247–1255. https://doi. preretinal neovascularization. Invest. Ophthalmol. Vis. Sci. 53 (1), 228–234. org/10.1007/s10792-016-0389-y. Le Goff, M.M., Sutton, M.J., Slevin, M., et al., 2012b. Opticin exerts its anti-angiogenic Katagiri, M., Shoji, J., Inada, N., et al., 2018. Evaluation of vitreous levels of advanced activity by regulating extracellular matrix adhesiveness. J. Biol. Chem. 287, glycation end products and angiogenic factors as biomarkers for severity of diabetic 28027–28036. retinopathy. Int. Ophthalmol. 38 (2), 607–615. https://doi.org/10.1007/s10792- Lee, C.H., Lee, J., Shin, C., Ko, Y.H., et al., 2012. The reliability and validity studies of the 017-0499-1. Korean version of the perceived stress scale. Kor. J. Psychosom. Med. 20, 127–134. Katz, B., Hoyt, W.F., 2005. Gaze-evoked amaurosis from vitreo-papillary traction. Am. J. Lee, O.-T., Good, S.D., Lamy, R., et al., 2015. Advanced glycation end-product Ophthalmol. 139 (4), 631–637. accumulation reduces vitreous permeability. Invest. Ophthalmol. Vis. Sci. 56, Keane, P.A., Karampelas, M., Sim, D.A., et al., 2014. Objective measurement of vitreous 2892–2897. https://doi.org/10.1167/iovs.14-15840. inflammation using optical coherence tomography. Ophthalmology 121, 1706–1714. Lee, C.-H., Woo, G.C., Huang, S.-Y., et al., 2019. Imaging vitreous floaters and cataracts Kershaw, K., Nguyen, D., Yee, K.M., Nguyen, J.H., et al., 2017. Dynamic light scattering of with optical simulations. Optik 194, 163075. https://doi.org/10.1016/j.ijleo.2019. vitreous in patients with vitreous floaters compared to macular pucker. Invest. 163075. Ophthalmol. Vis. Sci. 58 (8), 4829. Lim, J.I., 2017. YAG laser vitreolysis-is it as clear as it seems? JAMA Ophthalmol. 135 (9), Kershner, R.M., 2008. NeuroAdaptation. In: Chang, D. (Ed.), Transitioning to Refractive 924–925. https://doi.org/10.1001/jamaophthalmol.2017.1683. IOLs - the Art and Science. Slack, Inc., Thorofare, NJ, pp. 1–9. Lindner, M., Pfau, M., Czauderna, J., et al., 2019. Determinants of reading performance in Khan, M.A., Kuley, A., Riemann, C.D., et al., 2018. Long-term visual outcomes and safety eyes with foveal-sparing geographic atrophy. Ophthalmol. Retina 3 (3), 201–210. profile of 27-gauge pars plana vitrectomy for posterior segment disease. https://doi.org/10.1016/j.oret.2018.11.005. Ophthalmology 125, 423–431. Little, H.L., Jack, R.L., 1986. Q-switched neodymium:YAG laser surgery of the vitreous. Khoshnevis, M., Sebag, J., 2015. Pharmacologic vitreolysis with ocriplasmin - rationale Graefes Arch. Clin. Exp. Ophthalmol. 224 (3), 240–246. for use and therapeutic potential in vitreo-retinal disorders. BioDrugs 29 (2), Liu, J.J., Witkin, A.J., Adhi, M., et al., 2014. Enhanced vitreous imaging in healthy eyes 103–112. https://doi.org/10.1007/s40259-015-0120-y. using swept source optical coherence tomography. PloS One 9 (7), e102950. https:// Khoshnevis, M., Sebag, J., 2016. Management of macular edema in vitreo-maculopathies. doi.org/10.1371/journal.pone.0102950. In: Schaal, S., Kaplan, H. (Eds.), Cystoid Macular Edema. Springer, New York, pp. Liu, J., Wang, X., Wang, J., et al., 2019. Optical quality and intraocular scattering in the 91–120. https://doi.org/10.1007/978-3-319-39766-5_6. 2016. diabetic eye without diabetic retinopathy. Optom. Vis. Sci. 96 (4), 248–255. https:// Khoshnevis, M., Nguyen-Cuu, J., Sebag, J., 2016a. Floaters and reduced contrast doi.org/10.1097/OPX.0000000000001360. sensitivity after successful pharmacologic vitreolysis with ocriplasmin. AJO Case Lobov, I.B., Rao, S., Carroll, T.J., et al., 2005. Wnt7b mediates macrophage-induced Reports 4, 54–56. https://doi.org/10.1016/j.ajoc.2016.08.005. programmed cell death. Nature 437, 417–421. Khoshnevis, M., Sampathkumar, A., Garcia, G.A., Sebag, J., 2016b. Optical sensing of Loch, C., Bogdahn, M., Stein, S., et al., 2014. Simulation of drug distribution in the molecular structure in vitreous of patients with decreased contrast sensitivity. Invest. vitreous body after local drug application into intact vitreous body and in progress of Ophthalmol. Vis. Sci. 57 (12), 3198. posterior vitreous detachment. J. Pharmacol. Sci. 103 (2), 517–526 (ISSN: 1520- Khoshnevis, M., Rosen, S., Sebag, J., 2019. Asteroid Hyalosis - a comprehensive review. 6017). Surv. Ophthalmol. 64 (4), 452–462. https://doi.org/10.1016/j.survophthal.2019.01. Loho, T., Venna, V., Setiabudy, R.D., et al., 2018. Correlation between vitreous advanced 008. glycation end products, and d-dimer with blood Hba1c levels in proliferative diabetic Kim, J.H., Kim, J.H., Yu, Y.S., et al., 2010. Autophagy–induced regression of hyaloid retinopathy. Acta Med. Indones. 50 (2), 132–137. vessels in early ocular development. Autophagy 6 (7), 922–928. https://doi.org/10. Los, L.I., van der Worp, R.J., van Luyn, M.J.A., et al., 2003. Age-related liquefaction of the 4161/auto.6.8.13306. human vitreous body: LM and TEM evaluation of the role of proteoglycans and col­ Kim, H., Jeong, H., Han, S., et al., 2017a. Hyaluronate and its derivatives for customized lagen. Invest. Ophthalmol. Vis. Sci. 44 (7), 2828–2833. biomedical applications. Biomaterials 123, 155–171. https://doi.org/10.1016/j. Lundquist, O., Osterlin, S., 1994. Glucose concentration in the vitreous of nondiabetic and biomaterials.2017.01.029. diabetic human eyes. Graefes Arch. Clin. Exp. Ophthalmol. 232 (2), 71–74. Kim, Y.K., Moon, S.Y., Yim, K.M., et al., 2017b. Psychological distress in patients with Luo, J., An, X., Kuang, Y., 2018. Efficacy and safety of yttrium-aluminium garnet (YAG) symptomatic vitreous floaters. J. Ophthalmol. 191576. https://doi.org/10.1155/ laser vitreolysis for vitreous floaters. J. Int. Med. Res. 46 (11), 4465–4471. https:// 2017/3191576. 2017. doi.org/10.1177/0300060518794245. Kingston, Z.S., Provis, J.M., Madigan, M.C., 2014. Development and developmental dis­ Lutty, G.A., McLeod, D.S., 2018. Development of the hyaloid, choroidal and retinal vas­ orders of vitreous. In: Sebag, J. (Ed.), Vitreous - in Health & Disease. Springer, New culatures in the fetal human eye. Prog. Retin. Eye Res. 62, 58–76. https://doi.org/10. York, pp. 95–111. 1016/j.preteyeres.2017.10.001. Kishi, S., Demaria, C., Shimizu, K., 1986. Vitreous cortex remnants at the fovea after Lutty, G.A., Merges, C., Threlkeld, A.B., et al., 1993. Heterogeneity in localization of spontaneous vitreous detachment. Int. Ophthalmol. 9 (4), 253–260. isoforms of TGF-beta in human retina, vitreous, and choroid. Invest. Ophthalmol. Vis. Kishimoto, A., Kimura, S., Nio-Kobayashi, J., et al., 2018. Histochemical characteristics of Sci. 34 (3), 477–487. regressing vessels in the hyaloid vascular system of neonatal mice: novel implication Magnus, H., 1877. The knowledge of visual disturbances among the Greeks and Romans. for vascular atrophy. Exp. Eye Res. 172, 1–9. https://doi.org/10.1016/j.exer.2018. Graefe’s Arch. Clin. Exp. Ophthalmol. 23, 24–48. 03.024. Mamou, J., Wa, C.A., Yee, K.M., et al., 2015. Ultrasound-based quantification of vitreous Kita, T., Sakamoto, T., Ishibashi, T., 2014. Hyalocytes – essential cells in vitreo-retinal floaters correlates with contrast sensitivity and quality-of-life. Invest. Ophthalmol. health and disease. In: Sebag, J. (Ed.), Vitreous – in Health & Disease. Springer, New Vis. Sci. 56, 1611–1617. https://doi.org/10.1167/iovs.14-15414. York, pp. 151–164 2014. Mason 3rd, J.O., Neimkin, M.G., Mason, J.O., 2014. Safety, efficacy, and quality of life Kloeckener-Gruissem, B., Bartholdi, D., Abdou, M.T., et al., 2006. Identification of the following sutureless vitrectomy for symptomatic vitreous floaters. 4th. Retina 34 (6), genetic defect in the original Wagner syndrome family. Mol. Vis. 12, 350–355. 1055–1061. https://doi.org/10.1097/IAE.0000000000000063. Kobayashi, H., Ogino, N., 1985. Incidence of posterior detachment in healthy eyes with Matsunaga, N., Ozeki, H., Hirabayashi, Y., et al., 2005. Histopathologic evaluation of the age, sex and as variables. Rinsho Ganka 39, 514–515. internal limiting membrane surgically excised from eyes with diabetic maculopathy. Retina 25 (3), 311–316.

37 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Maumenee, I.H., 1979. Vitreoretinal degenerations as a sign of generalized connective Nguyen, J.H., Nguyen-Cuu, J., Mamou, J, Routledge, B, Yee, KMP, Sebag, J., 2020 Sep 17. tissue diseases. Am. J. Ophthalmol. 88, 432–449. Vitreous structure and visual function in myopic vitreopathy causing Vision Mayne, R., Brewton, R.G., Mayne, P.M., et al., 1993. Isolation and characterization of the Degrading Myodesopsia. Am J Ophthalmol.https://doi.org/10.1016/j.ajo.2020.09. chains of type V/type XI collagen present in bovine vitreous. J. Biol. Chem. 268, 017. 9381–9386. Nguyen, J.H., Yee, K.M.P., Nguyen-Cuu, J., Sebag, J., 2019. Structural and functional Mayne, R., Brewerton, R.G., Ren, Z., 1997. Vitreous body and zonular apparatus. In: characteristics of lamellar macular holes. Retina 39 (11), 2084–2089. https://doi. Harding, J. (Ed.), Biochemistry of the Eye. Chapman and Hall, London, pp. 135–143. org/10.1097/IAE.0000000000002275. McLeod, D.S., Hasegawa, T., Baba, T., et al., 2012. From blood islands to blood vessels: Nguyen, J.H., Yee, K.M., Mamou, J., et al., 2019. Real-world assessment of vitreous morphologic observations and expression of key molecules during hyaloid vascular structure and visual function after Nd:YAG laser vitreolysis. Ophthalmology 126 (11), system development. Invest. Ophthalmol. Vis. Sci. 53 (13), 7912–7927. 1517–1526. https://doi.org/10.1016/j.ophtha.2019.06.021. McMenamin, P.G., Djano, J., Wealthall, R., et al., 2002. Characterization of the macro­ Nguyen-Cuu, J., Nguyen, E., Yee, K.M.P., et al., 2017. Self-administered questionnaires phages associated with the tunica vasculosa lentis of the rat eye. Invest. Ophthalmol. correlate with visual function and vitreous structure in patients with vitreous floaters. Vis. Sci. 43 (7), 2076–2082. Invest. Ophthalmol. Vis. Sci. 58 (8), 1346 [ARVO abstract]. Meeson, A., Palmer, M., Calfon, M., et al., 1996. A relationship between apoptosis and Nikopoulos, K., Schrauwen, I., Simon, M., et al., 2011. Autosomal recessive Stickler flow during programmed capillary regression is revealed by vital analysis. syndrome in two families is caused by mutations in the COL9A1 gene. Invest. Development 122 (12), 3929–3938. Ophthalmol. Vis. Sci. 52 (7), 4774–4779. https://doi.org/10.1167/iovs.10-7128. Meng, T., Ren, Q., Wang, J.M., et al., 2016. Association between COL9A2 Gln326Arg Nixon, T.R.W., Alexander, P., Richards, A., et al., 2019. Homozygous Type IX mutations and the development of intervertebral disc disease in a Chinese population. collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler Genet. Mol. Res. 15 (4). https://doi.org/10.4238/gmr15048958. syndrome - expanding the phenotype. Am. J. Med. Genet. 179 (8), 1498–1506. Merl-Pham, J., Basak, T., Knüppel, L., et al., 2019. Quantitative proteomic profiling of https://doi.org/10.1002/ajmg.a.61191. extracellular matrix and site-specific collagen post-translational modifications in an Nomura, Y., Takahashi, H., Tan, X., et al., 2016. Effect of posterior vitreous detachment in vitro model of lung fibrosis. Matrix Biol. 1, 1–28. https://doi.org/10.1016/j. on aqueous humor level of vascular endothelial growth factor in exudative mbplus.2019.04.002. age-related macular degeneration patients. Graefe’s Arch. Clin. Exp. Ophthalmol. 254 Meskauskas, J., Repetto, R., Siggers, J.H., 2012. Shape change of the vitreous chamber (1) 53–7., 2. influences retinal detachment and reattachment processes: is mechanical stress Novack, M., Welch, R., 1984. Complications of acute symptomatic posterior vitreous during eye rotations a factor? Invest. Ophthalmol. Vis. Sci. 53 (10), 6271–6281. detachment. Am. J. Ophthalmol. 97 (3), 308–314. https://doi.org/10.1167/iovs.11-9390. O'Malley, P., 1976. The pattern of vitreous syneresis - a study of 800 autopsy eyes. In: HR Mets, M.B., 1999. and visual loss: an assessment at two institutions Irvine, C O'Malley (Ed.), Advances in Vitreous Surgery. C Thomas, Springfield, IL, pp. including a “new” cause. Trans. Am. Ophthalmol. Soc. 97, 653–696. 17–33. Meuer, S.M., Myers, C.E., Klein, B.E., et al., 2015. The epidemiology of vitreoretinal in­ Oelz, M.L., Mamou, J., 2016. Review of quantitative ultrasound: envelope statistics and terface abnormalities as detected by spectral-domain optical coherence tomography: backscatter coefficient imaging and contributions to diagnostic ultrasound. IEEE the Beaver Dam Eye Study. Ophthalmology 122 (4), 787–795. https://doi.org/10. Trans. Ultrason. Ferroelectrics Freq. Contr. 63 (2), 336–351. https://doi.org/10. 1016/j.ophtha.2014.10.014. 1109/TUFFC.2015.2513958. Meyer, K., Palmer, J.W., 1934. The polysaccharide of vitreous humour. J. Biol. Chem. Öhman, T., Tamene, F., Göös, H., et al., 2018. Systems pathology analysis identifies 107, 629–634 1934. neuro-degenerative nature of age-related vitreo-retinal interface diseases. Aging Cell Milston, R., Madigan, M.C., Sebag, J., 2016. Vitreous floaters: etiology, diagnostics, and 17 (5), e12809. https://doi.org/10.1111/acel.12809. management. Surv. Ophthalmol. 61 (2), 211–227. Oksala, A., 1978. Ultrasonic findings in the vitreous body at various ages. Graefe’s Arch. Missel, P.J., Sarangapani, R., 2019. Physiologically based ocular pharmacokinetic Clin. Exp. Ophthalmol. 207, 275–280. modeling using computational methods. Drug Discov. Today 24 (8), 1551–1563. Palacio, A.C., Gupta, A., Nesmith, B.L.W., et al., 2017. Vitreomacular adhesion evolution https://doi.org/10.1016/j.drudis.2019.05.039. with age in healthy human eyes. Retina 37 (1), 118–123. Mitchell, C.A., Risau, W., Drexler, H.C.A., 1998. Regression of vessels in the tunica vas­ Parel, J.-M., 2014. The history of vitrectomy instrumentation: a personal account of a culosa lentis is initiated by coordinated endothelial apoptosis: a role for vascular transoceanic Australian-USA collaboration. In: Sebag, J. (Ed.), Vitreous – in Health & endothelial growth factor as a survival factor for endothelium. Dev. Dynam. 213 (3), Disease. Springer, New York, pp. 665–692. 322–333. Parel, J.-M., Sebag, J., 2014. Recalling the development of vitreo-retinal therapeutics Miyamoto, T., Inoue, H., Sakamoto, Y., et al., 2005. Identification of a novel splice site from vitrectomy to pharmacologic vitreolysis. Retina 32 (3), 22–26. mutation of the CSPG2 gene in a Japanese family with Wagner syndrome. Invest. Patrick, D.L., 2019. Many ways to skin a cat: psychometric methods options illustrated. J. Ophthalmol. Vis. Sci. 46, 2726–2735. Pat. Rep. Outcomes 3, 48. https://doi.org/10.1186/s41687-019-0133-2. Mizoguchi, T., Tamura, K., Mamou, J., et al., 2019. Comprehensive backscattering Pau, H., 1996. Topography of the "vitreous structures" (tractus; membranelles) with characteristics analysis for quantitative ultrasound with an annular array: a basic respect to the layers of embryonal blood vessels. Graefes Arch. Clin. Exp. Ophthalmol. study on homogeneous scattering phantom. Jape J. Appl. Phys. 58, 1–7. https://doi. 234 (3), 199–204. org/10.7567/1347-4065/ab0df9. Peng, Y., Yu, Y., Lin, L., et al., 2018. Glycosaminoglycans from bovine eye vitreous Mohammadi, A., Hashemi, H., Mirzajani, A., et al., 2018. Comparison of two methods for humour and interaction with collagen type II. Glycoconj. J. 35 (1), 119–128. https:// measuring contrast sensitivity in anisometropic amblyopia. J. Curr. Ophthalmol. 27 doi.org/10.1007/s10719-017-9808-1. (30), 343–347. https://doi.org/10.1016/j.joco.2018.04.002. 4. Peng, M., Wei, Y., Zhang, T., et al., 2019. Increased levels of DKK1 in vitreous fluid of Monroy, G.L., Pande, P., Shelton, R.Y., et al., 2017. Non-invasive optical assessment of patients with pathological myopia and the correlation between DKK1 levels and axial viscosity of middle ear effusions in otitis media. J. Biophot. 10, 394–403.https://doi. length. Aug 13. Curr. Eye Res. 1–7. https://doi.org/10.1080/02713683.2019. org/10.1002/jbio.201500313. 1646772. [E-pub ahead of print]. Montesano, G., Way, C.M., Ometto, G., et al., 2018. Optimizing OCT acquisition para­ Philippakis, E., Couturier, A., Gaucher, D., et al., 2016. Posterior vitreous detachment in meters for assessments of vitreous haze for application in uveitis. Sci. Rep. 8, 1648. highly myopic eyes undergoing vitrectomy. Retina 36 (6), 1070–1075. https://doi. https://doi.org/10.1038/s41598-018-20092-y. org/10.1097/IAE.0000000000000857. Morgan, I.G., Ohno-Matsui, K., Saw, S.-M., 2012. Myopia. Lancet 379 (9287), 1739–1748. Pickett-Seltner, R., Doughty, M., Pasternak, J., Sivak, J., 1992. Proteins of the vitreous Morgan, I.G., French, A.N., Ashby, R.S., et al., 2018. The epidemics of myopia: aetiology humor during experimentally induced myopia. Invest. Ophthalmol. Vis. Sci. 33 (12), and prevention. Prog. Retin. Eye Res. 62, 134–149. https://doi.org/10.1016/j. 3424–3429. preteyeres.2017.09.004. Pircher, N., Pachala, M., Prager, F., et al., 2015. Changes in straylight and densitometry Morozova, S., Muthukumar, M., 2018. Electrostatic effects in collagen fibril formation. J. values after corneal collagen crosslinking. J. Cataract Refract. Surg. 41 (5), Chem. Phys. 28 (16), 163333. https://doi.org/10.1063/1.5036526. 149. 1038–1043. https://doi.org/10.1016/j.jcrs.2014.07.043. Mura, M., Engelbrecht, L.A., de Smet, M.D., et al., 2011. Surgery for floaters. Poinsioen, T.L., van Luyn, M.J., van der Worp, R.J., et al., 2008. Collagen distribution in Ophthalmology 118, 1894. the human vitreoretinal interface. Invest. Ophthalmol. Vis. Sci. 49, 4089–4095. Murali, K., Kang, D., Nazari, H., et al., 2016. Spatial variations in vitreous oxygen Ponsioen, T.L., van Deemter, M., Bank, R.A., et al., 2009. Mature enzymatic collagen consumption. PloS One 11 (3), e0149961. https://doi.org/10.1371/journal.pone. cross-links, hydroxylysylpyridinoline and lysylpyridinoline, in the aging human 0149961. vitreous. Invest. Ophthalmol. Vis. Sci. 50, 1041–1046. https://doi.org/10.1167/iovs. Nagra, M., Gilmartin, B., Thai, N.J., Logan, N.S., 2017. Determination of retinal surface 08-1714. area. J. Anat. 231 (3), 319–324. https://doi.org/10.1111/joa.12641. Ponsioen, T.L., Hooymans, J.M., Los, L.I., 2010. Remodelling of the human vitreous and Naidoo, K.S., Fricke, T.R., Frick, K.D., et al., 2019. Potential lost productivity resulting vitreoretinal interface - a dynamic process. Prog. Retin. Eye Res. 29, 580–595. from the global burden of myopia - systematic review, meta-analysis, and modeling. Pouran, B., Moshtagh, P.R., Arbabi, V., et al., 2018. Non-enzymatic cross-linking of Ophthalmology 126 (3), 338–346. https://doi.org/10.1016/j.ophtha.2018.10.029. collagen type II fibrils is tuned via osmolality switch. J. Orthop. Res. 36 (7), Nakaizumi, A., Fukumoto, M., Kida, T., 2015. Measurement of serum and vitreous 1929–1936. concentrations of anti-type II collagen antibody in diabetic retinopathy. Clin. Ramesh, S., Bonshek, R.E., Bishop, P.N., 2004. Immunolocalisation of opticin in the Ophthalmol. 9, 543–547. https://doi.org/10.2147/OPTH.S7542. human eye. Br. J. Ophthalmol. 88, 697–702. Neal, R.E., Bettelheim, F.A., Lin, C., et al., 2005. Alterations in human vitreous humour Reardon, A., Heinegard, D., McLeod, D., et al., 1998. The large chondroitin sulphate following cataract extraction. Exp. Eye Res. 80, 337–347. proteoglycan versican in mammalian vitreous. Matrix Biol. 17 (5), 325–333. Neargarder, S.A., Stone, E.R., Cronin-Golomb, A., Oross, S., 2003. The impact of acuity on Reardon, A., Sandell, L., Jones, C.J., et al., 2000a. Localization of pN-type IIA procollagen performance of four clinical measures of contrast sensitivity in Alzheimer's disease. J. on adult bovine vitreous collagen fibrils. Matrix Biol. 19 (2), 169–173. Gerontol. B Psychol. Sci. Soc. Sci. 58 (1), 54–62. Reardon, A.J., Le Goff, M., Briggs, M.D., et al., 2000b. Identification in vitreous and Necas, J., Bartosikova, L., Brauner, P., Kolar, J., 2008. Hyaluronic acid (hyaluronan): a molecular cloning of opticin, a novel member of the family of leucine-rich repeat review. Vet. Med. 53, 397–411. proteins of the extracellular matrix. J. Biol. Chem. 275 (3), 2123–2129 2000.

38 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Redslob, E., 1932. Le Corps Vitré. Masson et Cie, Paris, pp. 160–217. Sebag, J., 1991. Age-related differences in the human vitreo-retinal interface. Arch. Retzius, G., 1871. Om membrana limitans retinae interna. Nord Arch 2, 1–34. Ophthalmol. 109, 966–971. Richards, A.J., Martin, S., Yates, J.R.W., et al., 2008. COL2A1 exon 2 mutations: relevance Sebag, J., 1993. Abnormalities of human vitreous structure in diabetes. Graefe’s Arch. to the Stickler and Wagner syndromes. Br. J. Ophthalmol. 84 (4), 364–371. Clin. Exp. Ophthalmol. 231 (5), 257–260. Robison, C., Krebs, I., Binder, S., et al., 2009. Vitreo-macular adhesion in active and end- Sebag, J., 1996. Diabetic vitreopathy. Ophthalmology 103 (2), 205–206. stage age-related macular degeneration. Am. J. Ophthalmol. 148, 79–82. Sebag, J., 1997. Classifying posterior vitreous detachment - a new way to look at the Rohrbach, D., Wodlinger, B., Wen, J., et al., 2018. High-Frequency quantitative invisible (Guest editorial). Br. J. Ophthalmol. 81, 521–522. ultrasound for imaging prostate cancer using a novel micro-ultrasound scanner. Sebag, J., 1998. Pharmacologic vitreolysis (guest editorial). Retina 18, 1–3. Ultrasound Med. Biol. 44 (7), 1341–1354. https://doi.org/10.1016/j.ultrasmedbio. Sebag, J., 2002. Is Pharmacologic Vitreolysis Brewing? (Guest Editorial), vol. 22. pp. 1–3 2018.02.014. Retina. Rosen, S., Khoshnevis, M., Sebag, J., 2020. Vitreous biochemistry and pharmacologic Sebag, J., 2004a. Seeing the invisible - the challenge of imaging vitreous. J. Biomed. vitreolysis. In: Hartnett, M.E. (Ed.), Pediatric Retina, third ed. Wolters Kluwer Health Optic. 9, 38–46. ISBN-10: 1975110714, ISBN-13: 978-1975110710. Sebag, J., 2004b. Anomalous PVD – a unifying concept in vitreo-retinal diseases. Graefe’s Rostami, B., Nguyen-Cuu, J., Brown, G., et al., 2019. Cost-effectiveness of limited Arch. Clin. Exp. Ophthalmol. 242, 690–698. vitrectomy for vision-degrading myodesopsia. Am. J. Ophthalmol. 204, 1–6. Sebag, J., 2005. Molecular biology of pharmacologic vitreolysis. Trans. Am. Ophthalmol. Roth, M., Trittibach, P., Koerner, F., Sarra, G., 2005. Pars plana vitrectomy for idiopathic Soc. 103, 473–494. vitreous floaters. Klin. Monatsbl. Augenheilkd. 222, 728–732. Sebag, J., 2008. Vitreoschisis. Graefe’s Arch. Clin. Exp. Ophthalmol. 246, 329–332. Rothschild, P.R., Burin-des-Roziers, C., Audo, I., et al., 2015. Spectral-Domain optical Sebag, J., 2009a. Vitreous – the resplendent enigma. (Guest editorial). Br. J. Ophthalmol. coherence tomography in wagner syndrome: characterization of vitreoretinal 93, 989–991. interface and foveal changes. Am. J. Ophthalmol. 160 (5), 1065–1072. https://doi. Sebag, J., 2009b. Pharmacologic vitreolysis – premise and promise of the first decade. org/10.1016/j.ajo.2015.08.012. e1. (Guest Editorial). Retina 29, 871–874. Routledge, B., Nguyen-Cuu, J., Yee, K.M.P., Sebag, J., 2019. Posterior vitreous Sebag, J., 2010. Vitreous anatomy, aging, and anomalous posterior vitreous detachment. displacement in supine position. Invest. Ophthalmol. Vis. Sci. 60 (9), 2015. In: In: Dartt, Besharse, Dana (Eds.), Encyclopedia of the Eye, vol. 4. Elsevier, Oxford, Rowan, S., Bejarano, E., Taylor, A., 2018. Mechanistic targeting of advanced glycation pp. 307–315. end-products in age-related diseases. Biochim. Biophys. Acta (BBA) - Mol. Basis Sebag, J., 2011a. Vitreoschisis in diabetic macular edema. Invest. Ophthalmol. Vis. Sci. 52 Dis. 1864 (12), 3631–3643. https://doi.org/10.1016/j.bbadis.2018.08.036. (11), 8455–8456. Rozema, JJ, Van den Berg, TJ, Tassignon, MJ, 2010. Retinal straylight as a function of age Sebag, J., 2011b. Floaters and the quality of life. Am. J. Ophthalmol. 152, 3–4. and ocular biometry in healthy eyes. Invest. Ophthalmo.l Vis. Sci. 51 (5), 2795–2799. Sebag, J., 2014a. Vitreous – in Health & Disease. Springer. (New York). https://doi.org/10.1167/iovs.09-4056. Sebag, J., 2014b. Pathophysiologie der partiellen PVD und vitreomakulären Traktion. In: Russell, S.R., 2012. What we know (and do not know) about vitreo-retinal adhesion. Maier, M. (Ed.), Die Vitreomakuläre Traktion (VMT). Uni-Med, Bremen, pp. 19–32. Retina 32, 181–186 S. Sebag, J., 2015. Vitreous in AMD therapy – the medium is the message (Guest Editorial). Saint-Geniez, D'Amore, P., 2004. Development and pathology of the hyaloid, choroidal Retina 35 (9), 1715–1718. and retinal vasculature. Int. J. Dev. Biol. 48 (8–9), 1045–1058. Sebag, J., 2016. Vitreous – not just through it. Clin. Exp. Ophthalmol. 44, 547–549. Sakamoto, T., Ishibashi, T., 2011. Hyalocytes - essential cells of the vitreous cavity in https://doi.org/10.1111/ceo.12823. vitreoretinal pathophysiology? Retina 31, 222–228. Sebag, J., 2018a. Vitreous & vitreo-retinal interface. In: Schachat, A.P. (Ed.), Ryan's Santos, F.M., Albuquerque, T., Gaspar, L.M., et al., 2019. Refinement of two-dimensional Retina, sixth ed. Elsevier Part 2, Sect 1, Ch 23. electrophoresis for vitreous proteome profiling using an artificial neural network. Sebag, J., 2018b. Posterior vitreous detachment. (Guest commentary). Ophthalmology Anal. Bioanal. Chem. 411 (20), 5115–5126. https://doi.org/10.1007/s00216-019- 125, 1384–1385. https://doi.org/10.1016/j.ophtha.2018.05.018. 01887-y. Sebag, J., 2018c. Methodological and efficacy issues in a randomized clinical trial Sarrafizadeh, R., Hassan, T.S., Ruby, A.J., et al., 2001. Incidence of retinal detachment investigating vitreous floater treatment. JAMA Ophthalmol. 136 (4), 448. https:// and visual outcome in eyes presenting with posterior vitreous separation and dense doi.org/10.1001/jamaophthalmol.2018.0212. 2018. fundus-obscuring vitreous hemorrhage. Ophthalmology 108 (12), 2273–2278. Sebag, J., Balazs, E.A., 1985. Human vitreous fibres and vitreo-retinal disease. Trans. Sato, T., Kinoshita, R., Taguchi, M., et al., 2018. Assessment of diagnostic and therapeutic Ophthalmol. Soc. U. K. 104, 123–128. vitrectomy for vitreous opacity associated with uveitis with various etiologies. Sebag, J., Balazs, E.A., 1989. Morphology and ultrastructure of human vitreous fibers. Medicine (Baltim.) 97 (2), e9491. https://doi.org/10.1097/MD.0000000000009491. Invest. Ophthalmol. Vis. Sci. 30, 1867–1871. Saudek, D.M., Kay, J., 2003. Advanced glycation endproducts and osteoarthritis. Curr. Sebag, J., Hageman, G.S., 2000. Interfaces. (Guest editorial). Eur. J. Ophthalmol. 10, 1–3. Rheumatol. Rep. 5 (1), 33–40. Sebag, J., McMeel, W., 1986. Diabetic retinopathy - pathogenesis and role of retina-de­ Sauvage, F., Fraire, J.C., Remaut, K., et al., 2019. Photoablation of human vitreous rived growth factor in angiogenesis. Surv. Ophthalmol. 30, 377–384. opacities by light-induced vapor nanobubbles. ACS Nano. https://doi.org/10.1021/ Sebag, J., Balazs, E.A., Eakins, K.E., et al., 1981. The effect of Na-hyaluronate on acsnano.9b04050. (in press). prostaglandin synthesis and phagocytosis by mononuclear phagocytes. Invest. Schiff, W.M., Chang, S., Mandava, N., Barile, G.R., 2000. Pars plana vitrectomy for per­ Ophthalmol. Vis. Sci. 20, 33. sistent, visually significant vitreous opacities. Retina 20, 591–596. Sebag, J., Buckingham, B., Charles, M.A., Reiser, K., 1992. Biochemical abnormalities in Schnepf, A., Yappert, M.C., Borchman, D., 2017. Regional distribution of phospholipids in vitreous of humans with proliferative diabetic retinopathy. Arch. Ophthalmol. 110 porcine vitreous humor. Exp. Eye Res. 160, 116–125. https://doi.org/10.1016/j.exer. (10), 1472–1476. 2017.05.009. Sebag, J., Nie, S., Reiser, K., Charles, M.A., Yu, N.T., 1994. Raman spectroscopy of human Schulz-Key, S., Carlsson, J.O., Crafoord, S., 2011. Long-term follow-up of pars plana vi­ vitreous in proliferative diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 35 (7), trectomy for vitreous floaters: complications, outcomes and patient satisfaction. Acta 2976–2980. Ophthalmol. 89 (2), 159–165. Sebag, J., Ansari, R.R., Dunker, S., Suh, S.I., 1999. Dynamic light scattering of diabetic Schulze-Bonsel, K., Feltgen, N., Burau, H., et al., 2006. Visual acuities "hand motion" and vitreopathy. Diabetes Technol. Therapeut. 1, 169–176. "counting fingers" can be quantified with the Freiburg visual acuity test. Invest. Sebag, J., Gupta, P., Rosen, R., et al., 2007a. Macular holes and macular pucker: the role Ophthalmol. Vis. Sci. 47 (3), 1236–1240. of vitreoschisis as imaged by optical coherence tomography/scanning laser oph­ Schumann, R.G., Gandorfer, A., Ziada, J., et al., 2014. Hyalocytes in idiopathic epiretinal thalmoscopy. Trans. Am. Ophthalmol. Soc. 105, 121–131. membranes: a correlative light and electron microscopic study. Graefes Arch. Clin. Sebag, J., Ansari, R.R., Suh, K.I., 2007b. Pharmacologic vitreolysis with microplasmin Exp. Ophthalmol. 252 (12), 1887–1894. https://doi.org/10.1007/s00417-014- increases vitreous diffusion coefficients. Graefe’s Arch. Clin. Exp. Ophthalmol. 245 2841-x. (4), 576–580. Schumann, R.G., Hagenau, F., Guenther, S.R., et al., 2019. Premacular cell proliferation Sebag, J., Wang, M., Nguyen, D., et al., 2009. Vitreo-papillary adhesion in macular profiles in tangential traction vitreo-maculopathies suggest a key role for hyalocytes. diseases. Trans. Am. Ophthalmol. Soc. 107, 35–46. Ophthalmologica 242 (2), 106–112. https://doi.org/10.1159/000495853. Sebag, J., Yee, K.M.P., Huang, L., Wa, C., Sadun, A.A., 2014a. Vitrectomy for floaters – Schwab, C., Ivastinovic, D., Borkenstein, A., et al., 2012. Prevalence of early and late prospective efficacy analyses and retrospective safety profile. Retina 34, 1062–1068. stages of physiologic PVD in emmetropic elderly population. Acta Ophthalmol. 90, Sebag, J., Silverman, R.H., Coleman, D.J., 2014b. To see the invisible - the quest of e179–e184. https://doi.org/10.1111/j.1755-3768.2011.02310.x. imaging vitreous. In: Sebag, J. (Ed.), Vitreous - in Health & Disease. Springer, New Schwartz, S.G., Flynn, H.W., Fisher, Y.L., 2013. "Floater scotoma" demonstrated on York, pp. 193–222. spectral-domain optical coherence tomography and caused by vitreous opacification. Sebag, J., Niemeyer, M., Koss, M.J., 2014c. Anomalous PVD & vitreoschisis. In: Sebag, J. Ophthal. Surg. Lasers Imag. Retina 44 (4), 415–418. https://doi.org/10.3928/ (Ed.), Vitreous - in Health & Disease. Springer, New York, pp. 241–265. 23258160-20130715-14. Sebag, J., Sadun, A.A., Pierce, E.A., 2017. Paradigm shifts in ophthalmic diagnostics. Scott, J.E., 1992. The chemical morphology of the vitreous. Eye 6, 553–555. Trans. Am. Ophthalmol. Soc. 114 WP1 PMID: 28008209 PMCID: PMC5141845. Scott, J.E., Chen, Y., Brass, A., 1992. Secondary and tertiary structures involving chon­ Sebag, J., Yee, K.M.P., Nguyen, J.H., Nguyen-Cuu, J., 2018. Long-term safety and efficacy droitin and chondroitin sulphates in solution, investigated by rotary shadowing/ of vitrectomy for Vision Degrading Vitreopathy from vitreous floaters. Ophthalmol. electron microscopy and computer simulation. Eur. J. Biochem. 209 (2), 675–680. Retina 2, 881–887. Sebag, J., 1985. La structure fibreuse du corps vitré humain. Bull et Mem Soc Française Seltner, R.L., Sivak, J.G., 1987. A role for the vitreous humor in experimentally-induced d'Ophtalmol 96, 395–397. myopia. Am. J. Optom. Physiol. Opt. 64, 953–957. Sebag, J., 1987. Age-related changes in human vitreous structure. Graefe’s Arch. Clin. Serpetopoulos, C.N., Korakitis, R.A., 1998. An optical explanation of the Exp. Ophthalmol. 225, 89–93. of 'clouds' in posterior vitreous detachment. Ophthalmic Physiol. Optic. 18, 446–451. Sebag, J., 1989. Vitreous - Structure, Function, and Pathobiology. Springer, New York Shah, C.P., Heier, J.S., 2017. YAG laser vitreolysis vs sham YAG vitreolysis for 1989. symptomatic vitreous floaters: a randomized clinical trial. JAMA Ophthalmol. 135 (9), 918–923.

39 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Shah, N.S., Beebe, D.C., Lake, S.P., Filas, B.A., 2016. On the spatiotemporal material Tong, C., Liang, H., Liu, X., et al., 2019. The protective effects of exenatide against anisotropy of the vitreous body in tension and compression. Ann. Biomed. Eng. 44 AGEs-induced articular matrix degradation in human primary chondrocytes. Am. J. (10), 3084–3095. https://doi.org/10.1007/s10439-016-1589-3. Transl. Med. 11 (4), 2081–2089. Sharif-Kashani, P., Hubschman, J.-P., Sasson, D., et al., 2011. Rheology of the vitreous Tozer, K., Johnson, M.W., Sebag, J., 2014. Vitreous aging and posterior vitreous gel: effects of macromelocular organization on the viscoelastic properties. J. detachment. In: Sebag, J. (Ed.), Vitreous – in Health & Disease. Springer, New York, Biomech. 44, 419–423. pp. 131–150. Sheehan, J., Atkins, E., Nieduszynski, I., 1975. X-ray diffraction studies on the connective Tram, N.K., Swindle-Reilly, K.E., 2018. Rheological properties and age-related changes of tissue polysaccharides: two-dimensional packing schemes for threefold hyaluronate the human vitreous humor. Front. Bioeng. Biotechnol. 6, 199. https://doi.org/10. chains. J. Mol. Biol. 91 (2), 153–163. 3389/fbioe.2018.00199. Shui, Y.B., Wang, X., Hu, J.S., et al., 2003. Vascular endothelial growth factor expression Trujillo-Sanchez, G.P., Gonzalez-De La Rosa, A., Navarro-Partida, J., et al., 2018. and signaling in the lens. Invest. Ophthalmol. Vis. Sci. 44 (9), 3911–3919. Feasibility and safety of vitrectomy under topical anesthesia in an office-based Silva, A.F., Alves, M.A., Oliveira, M.S.N., 2017. Rheological behavior of vitreous humour. setting. Indian J. Ophthalmol. 66 (8), 1136–1140. https://doi.org/10.4103/ijo.IJO_ Rheol. Acta 56 (4), 377–387. https://doi.org/10.1007/s00397-017-0997-0. 289_18. Silverman, R.H., 2016. Focused ultrasound in ophthalmology. Clin. Ophthalmol. 10, Tsai, W.F., Chen, Y.C., Su, C.Y., 1993. Treatment of vitreous floaters with neodymium 1865–1875 eCollection 2016. YAG laser. Br. J. Ophthalmol. 77 (8), 485–488. Silverman, R.H., Ketterling, J.A., Mamou, J., et al., 2012. Pulse-encoded ultrasound Tsukahara, M., Mori, K., Gehlbach, P.L., et al., 2018. Posterior vitreous detachment as imaging of the vitreous with an annular array. Ophthalmic Surg. Laser. Imag. 43 (1), observed by wide-angle OCT imaging. Ophthalmology 125, 1372–1383. 82–86. https://doi.org/10.3928/15428877-20110901-03. Tůma, K., Stein, J., Průša, V., et al., 2018. Mathematics and computation motion of the Singh, I.P., 2018. Novel OCT Application and optimized YAG laser enable visualization vitreous humour in a deforming eye–fluid-structure interaction between a nonlinear and treatment of mid- to posterior vitreous floaters. Ophthal. Surg. Lasers elastic solid and viscoelastic fluid. Appl. Math. Comput. 335, 50–64. Imag. Retina 49 (10), 806–811. https://doi.org/10.3928/23258160-20181002-10. Uchino, E., Uemura, A., Ohba, N., 2001. Initial stages of posterior vitreous detachment in Skeie, J.M., Roybal, C.N., Mahajan, V.B., 2015. Proteomic insight into the molecular healthy eyes of older persons evaluated by optical coherence tomography. Arch. function of the vitreous. PloS One 10 (5), e0127567 10.1371/. Ophthalmol. 119 (10), 1475–1479. Smith, S.M., Birk, D.E., 2012. Focus on molecules: collagens V and XI. Exp. Eye Res. 98, Urs, R., Ketterling, J.A., Silverman, R.H., 2016. Ultrafast ultrasound imaging of ocular 105–106. anatomy and blood flow. Invest. Ophthalmol. Vis. Sci. 57 (8), 3810–3816. https:// Smith, J.N., Walker, H.M., Thompson, H., et al., 2018. Lens-regulated retinoic acid doi.org/10.1167/iovs.16-19538. signalling controls expansion of the developing eye. Development 145 (19). https:// National Research Council (US), 2011. Committee on A Framework for developing a new doi.org/10.1242/dev.167171. pii: dev167171. taxonomy of disease. In: Toward Precision Medicine: Building a Knowledge Network Snead, M.P., Richards, A.J., 2014. Hereditary vitreo-retinopathies. In: Sebag, J. (Ed.), for Biomedical Research and a New Taxonomy of Disease. National Academies Press Vitreous - in Health & Disease. Springer, New York, pp. 21–40. (US), Washington, DC. Sonoda, K.H., Sakamoto, T., Qiao, H., et al., 2005. The analysis of systemic tolerance Van Alphen, G., 1990. Emmetropization in the primate eye. In: Boch, G., Widdows, K. elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated (Eds.), Myopia and the Control of Eye Growth. Wiley, New York pg. 115. immune deviation. Immunology 116, 390–399 2005. van de Wouw, D.S., van der Meulen, I.J., van Vliet, J.M., Lapid-Gortzak, R., et al., 2016. Spielberger, C.D., Gorsuch, R.L., Lushene, R., et al., 1983. Manual for the State-Trait Increased straylight in patients with sicca. Cornea 35 (6), Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. 749–753. https://doi.org/10.1097/ICO.0000000000000828. Stanga, P.E., Sala-Puigdollers, A., Caputo, S., et al., 2014. In vivo imaging of cortical van Deemter, M., Ponsioen, T., Bank, R., et al., 2009a. Pentosidine accumulates in the vitreous using 1050-nm swept-source deep range imaging optical coherence aging vitreous: a gender effect. Exp. Eye Res. 88 (6), 1043–1050. tomography. Am. J. Ophthalmol. 157, 397–404. van Deemter, M., Pas, H.H., Kuijer, R., et al., 2009b. Enzymatic breakdown of type II Stefánsson, E., 2009. Physiology of vitreous surgery. Graefes Arch. Clin. Exp. Ophthalmol. collagen in the human vitreous. Invest. Ophthalmol. Vis. Sci. 50 (10), 4552–4560. 247 (2), 147–163. https://doi.org/10.1007/s00417-008-0980-7. https://doi.org/10.1167/iovs.08-3125. Stefánsson, E., 2014. Vitreous physiology. In: Sebag, J. (Ed.), Vitreous - in Health & van Deemter, M., Kuijer, R., Harm Pas, H., et al., 2013. Trypsin-mediated enzymatic Disease. Springer, New York, pp. 437–458. degradation of type II collagen in the human vitreous. Mol. Vis. 19, 1591–1599. Stefánsson, E., Geirsdóttir, A., Sigurdsson, H., 2011. Metabolic physiology in age related van Deemter, M., Bank, R.A., Vehof, J., et al., 2017. Factors associated with pentosidine macular degeneration. Prog. Retin. Eye Res. 30 (1), 72–80. https://doi.org/10.1016/ accumulation in the human vitreous. Retina 37 (4), 770–777. https://doi.org/10. j.preteyeres.2010.09.003. 1097/IAE.0000000000001219. Stitt, A.W., Moore, J.E., Sharkey, J.A., et al., 1998. Advanced glycation end products in van den Berg, T.J., Franssen, L., Kruijt, B., Coppens, J.E., 2013. History of ocular vitreous: structural and functional implications for diabetic vitreopathy. Invest. straylight measurement: a review. Z. Med. Phys. 23 (1), 6–20. Ophthalmol. Vis. Sci. 39, 2517–2523. van der Meulen, I.J., Gjertsen, J., Kruijt, B., et al., 2012. Straylight measurements as an Stitt, A.W., Lois, N., Medina, R.J., et al., 2013. Advances in our understanding of diabetic indication for cataract surgery. J. Cataract Refract. Surg. 38 (5), 840–848. https:// retinopathy. Clin. Sci. (Lond.) 125, 1e17. doi.org/10.1016/j.jcrs.2011.11.048. Stitt, A.W., Curtis, T.M., Chen, M., et al., 2016. The progress in understanding and Vandorselaer, T., Van De Velde, F., Tassignon, M.J., 2001. Eligibility criteria for Nd-YAG treatment of diabetic retinopathy. Prog. Retin. Eye Res. 51, 156–186. laser treatment of highly symptomatic vitreous floaters. Bull. Soc. Belge Ophtalmol. Sun, X., Tian, J., Wang, J., et al., 2019. Nd:YAG laser vitreolysis for symptomatic vitreous 280, 15–19. floaters: application of infrared fundus photography in assessing the treatment Vaz-Pereira, S., Dansingani, K.K., Chen, K.C., et al., 2017. Tomographic relationships efficacy. J. Ophthalmol. https://doi.org/10.1155/2019/8956952.eCollection.2019. between retinal neovascularization and the posterior vitreous in proliferative diabetic 2019:8956952. retinopathy. Retina 37 (7), 1287–1296. https://doi.org/10.1097/IAE. Swann, D.A., 1980. Chemistry and biology of the vitreous body. Int. Rev. Exp. Pathol. 22, 0000000000001336. 1–64. Velez, G., Tang, P.H., Cabral, T., et al., 2018. Personalized proteomics for precision Swann, D.A., Caulfield, J.B., Broadhurst, J.B., 1976. The altered fibrous form of vitreous health: identifying biomarkers of vitreoretinal disease. Transl. Vis. Sci. Technol. 26 collagen following solubilization with pepsin. Biochem. Biophys. Acta 427 (1), (5), 7. https://doi.org/10.1167/tvst.7.5.12. 12. 365–370. Vlassara, H., Uribarri, J., 2014. Advanced glycation end products (age) and diabetes: Szent-Gyorgi, A., 1917. Untersuchungen über die struktur des glaskörpers des menschen. cause, effect, or both? Curr. Diabetes Rep. 14 (1), 453. https://doi.org/10.1007/ Arch. Mikrosk. Anat. 89, 324–386. s11892-013-0453-1. Takahashi, H., Tanaka, N., Shinohara, K., et al., 2019. Ultra-widefield optical coherence Vogel, A., Noack, J., Nahen, K., et al., 1999. Energy balance of optical breakdown in tomographic imaging of posterior vitreous in eyes with high myopia. Am. J. water at nanosecond to femtosecond time scales. Appl. Phys. B 68, 271–280. Ophthalmol. 206, 102–112. Wagle, A.M., Lim, W.Y., Yap, T.P., et al., 2011. Utility values associated with vitreous Tan, H.S., Mura, M., Lesnik Oberstein, S.Y., Bijl, H.M., 2011. Safety of vitrectomy for floaters. Am. J. Ophthalmol. 152 (1), 60–65. floaters. Am. J. Ophthalmol. 151 (6), 995–998. Walton, K.A., Meyer, C.H., Harkrider, C.J., et al., 2002. Age-related changes in vitreous Tang, P.H., Velez, G., Tsang, S.H., et al., 2019. VCAN canonical splice site mutation is mobility as measured by video B scan ultrasound. Exp. Eye Res. 74 (2), 173–180. associated with vitreoretinal degeneration and disrupts an MMP proteolytic site. Wang, J., McLeod, D., Henson, D.B., et al., 2003. Age-dependent changes in the basal Invest. Ophthalmol. Vis. Sci. 60 (1), 282–293. https://doi.org/10.1167/iovs.18- retino-vitreous adhesion. Invest. Ophthalmol. Vis. Sci. 44 (5), 1793–1800. 25624. Wang, M.Y., Nguyen, D., Hindoyan, N., Sadun, A.A., Sebag, J., 2009. Vitreo-papillary Tavassoli, T., Latham, K., Bach, M., et al., 2011. Psychophysical measures of visual acuity adhesion in macular hole and macular pucker. Retina 29, 644–650. in autism spectrum conditions. Vis. Res. 51 (15), 1778–1780. https://doi.org/10. Wang, S., Zaitoun, I.S., Johnson, R.P., et al., 2017. Bim expression in endothelial cells and 1016/j.visres.2011.06.004. pericytes is essential for regression of the fetal ocular vasculature. PloS One 12 (5), Theocaris, A.D., 2008. Versican in health and disease. Connect. Tissue Res. 49 (3), e0178198. https://doi.org/10.1371/journal.pone.0178198.eCollection.2017. 230–234. https://doi.org/10.1080/03008200802147571. Webb, B.F., Webb, J.R., Schroeder, M.C., North, C.S., 2013. Prevalence of vitreous floaters Theocharis, A.D., Papageorgakopoulou, N., Feretis, E., et al., 2002. Occurrence and in a community sample of smartphone users. Int. J. Ophthalmol. 6 (3), 402–405. structural characterization of versican-like proteoglycan in human vitreous. https://doi.org/10.3980/j.issn.2222-3959.2013.03.27. Biochimie 84 (12), 1237–1243. Wei, Q., Jiang, C., Ye, X., et al., 2019. Vitreous proteomics provides new insights Tokita, M., Fujiya, Y., Hikichi, K., 1984. Dynamic viscoelasticity of bovine vitreous body. into antivascular endothelial growth factor therapy for pathologic myopia choroid Biorheology 21, 751–756. neovascularization. J. Interferon Cytokine Res. 39 (12), 786–796. https://doi.org/10. Toledo, D.M.S., Dietrich, C.P., 1977. Tissue specific distribution of sulfated 1089/jir.2019.0030. mucopolysaccharides in mammals. Biochem. Biophys. Acta 498, 114. Wenstrup, R.J., Florer, J.B., Brunskill, E.W., et al., 2004. Type V collagen controls the initiation of collagen fibril assembly. J. Biol. Chem. 279 (51), 53331–53337.

40 J. Sebag Progress in Retinal and Eye Research 79 (2020) 100847

Wert, K.J., Velez, G., Cross, M.R., Wagner, B.A., et al., 2018. Extracellular superoxide Yu, F.-J., Lam, T.C., Liu, L.-Q., et al., 2017. Isotope-coded protein label based quantitative dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface. Free Radic. proteomic analysis reveals significant upregulation of apolipoprotein A1 and Biol. Med. 124, 408–419. https://doi.org/10.1016/j.freeradbiomed.2018.06.024. ovotransferrin in the myopic chick vitreous. Sci. Rep. 7, 12649. https://doi.org/10. White, H.E., Levitan, P., 1962. Floaters in the eye. Sci. Am. 206, 119–127. 1038/s41598-017-12650-7. Wojciechowski, R., Ching-Yu Cheng, C.-Y., 2018. Involvement of multiple molecular Zaida, J., Hagenau, F., Compera, D., et al., 2018. Vitrectomy for intermediate age-related pathways in the genetics of ocular refraction and myopia. Retina 38 (1), 91–101. macular degeneration associated with tangential vitreomacular traction: a https://doi.org/10.1097/IAE.0000000000001518. clinico-pathologic correlation. Retina 38 (3), 531–540. https://doi.org/10.1097/iae. Worst, J.G.F., 1977. Cisternal systems of the fully developed vitreous body in the young 0000000000001573. adult. Trans. Ophthalmol. Soc. U. K. 97, 550–554. Zeisberg, M., Kalluri, R., 2013. Cellular mechanisms of tissue fibrosis. 1. Common and Worst, J.G.F., Los, L.I., 1995. Cisternal Anatomy of the Vitreous. Kugler Publ pg 34. organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Wu, H., Wang, S., Chen, W., et al., 2018. Collagen IX gene polymorphisms and lumbar Physiol. 304 (3), C216–C225. disc degeneration: a systematic review and meta-analysis. J. Orthop. Surg. Res. 13 Zhang, C., Gehlbach, P., Gongora, C., et al., 2005. A potential role for beta- and gamma- (1), 47. https://doi.org/10.1186/s13018-018-0750-0. crystallins in the vascular remodeling of the eye. Dev. Dynam. 234 (1), 36–47. Wullink, B., Pas, H.H., Van der Worp, R.J., et al., 2015. Type VII collagen expression in Zhang, C., Asanaghia, L., Gongora, C., et al., 2011. A developmental defect in astrocytes the human vitreoretinal interface, corpora amylacea and inner retinal layers. PloS inhibits programmed regression of the hyaloid vasculature in the mammalian eye. One 10 (12), e0145502. https://doi.org/10.1371/journal.pone.0145502. Eur. J. Cell Biol. 90 (5), 440–448. https://doi.org/10.1016/j.ejcb.2011.01.003. Wynn, T.A., Ramalingam, T.R., 2012. Mechanisms of fibrosis: therapeutic translation for Zhang, Q., Filas, B.A., Roth, R., et al., 2014. Preservation of the structure of enzymatically- fibrotic disease. Nat. Med. 18 (7), 1028–1040. degraded bovine vitreous using synthetic proteoglycan mimics. Invest. Ophthalmol. Xu, Q., Boylan, N.J., Suk, J.S., et al., 2013. Nanoparticle diffusion in, and microrheology Vis. Sci. 23 (12), 8153–8162. https://doi.org/10.1167/iovs.14-14366. 55. of, the bovine vitreous ex vivo. J. Contr. Release 167 (1), 76–84. Zhao, F., Gandorfer, A., Haritoglou, C., et al., 2013. Epiretinal cell proliferation in Yamashita, T., Uemura, A., Sakamoto, T., 2008. Intraoperative characteristics of macular pucker and vitreomacular traction syndrome: analysis of flat mounted the posterior vitreous cortex in patients with epiretinal membrane. Graefes Arch. internal limiting membrane specimens. Retina 33 (1), 77–88. Clin. Exp. Ophthalmol. 246 (3), 333–337. https://doi.org/10.1007/s00417-007- Zhidkova, N.I., Justice, S.K., Mayne, R., 1995. Alternative mRNA processing occurs in the 0745-8. variable region of the pro-alpha 1(XI) and pro-alpha 2(XI) collagen chains. J. Biol. Yee, K.M.P., Feener, E., Gao, B., et al., 2014. Vitreous cytokines and regression of the fetal Chem. 270 (16), 9486–9493. hyaloid vasculature. In: Sebag, J. (Ed.), Vitreous - in Health & Disease. Springer, New Zhu, Y., Oganesian, A., Keene, D.R., Sandell, L.J., 1999. Type IIA procollagen containing York, pp. 41–56. the cysteine-rich amino propeptide is deposited in the extracellular matrix of Yee, K.M.P., Feener, E.P., Madigan, M., Jackson, N.J., et al., 2015. Proteomic analysis prechondrogenic tissue and binds to TGF-beta1 and BMP-2. J. Cell Biol. 144 (5), of embryonic and young human vitreous. Invest. Ophthalmol. Vis. Sci. 56, 1069–1080. 7036–7042. Zhu, M., Madigan, M.C., van Driel, D., et al., 2000. The human hyaloid system: cell death Yee, K.M.P., Tan, S., Lesnik Oberstein, S.Y., et al., 2017. Incidence of cataract surgery and vascular regression. Exp. Eye Res. 70 (6), 767–776. after vitrectomy for vitreous opacities. Ophthalmol. Retina 1 (2), 154–157. Ziegler, J.S., Valpala, M., Shang, P., et al., 2016. βA3/A1-crystallin and persistent fetal Yonemoto, J., Ideta, H., Sasaki, K., et al., 1994. The age of onset of posterior vitreous vasculature (PFV) disease of the eye. Biochim. Biophys. Acta 287–298 1860,(1, Pt B). detachment. Graefes Arch. Clin. Exp. Ophthalmol. 232 (2), 67–70. Zimmerman, RL, 1980. In vivo measurements of the viscoelasticity of the human vitreous. Yoshikawa, Y., Yamada, T., Tai-Nagara, I., et al., 2016. Developmental regression of humor. Biophys 29, 539–544. hyaloid vasculature is triggered by neurons. J. Exp. Med. 213, 1175–1183. Zou, H., Liu, H., Xu, X., Zhang, X., 2013. The impact of persistent visually disabling Youngblood, H., Robinson, R., Sharma, A., Sharma, S., 2019. Proteomic biomarkers of vitreous floaters on health status utility values. Qual. Life Res. (6), 1507–1514. retinal inflammation in diabetic retinopathy. Int. J. Mol. Sci. 20, 4755. https://doi. https://doi.org/10.1007/s11136-012-0256-x. org/10.3390/ijms20194755.

41