Ageing Research Reviews 21 (2015) 71–77

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Review

Ageing of the vitreous: From acute onset floaters and flashes to retinal detachment Xhevat Lumi a , Marko Hawlina a , Damjan Glavaˇc b , Andrea Facskó c , Morten C. Moe d , Kai Kaarniranta e , Goran Petrovski c,d,∗ a

Eye Hospital, University Medical Centre, Ljubljana, Slovenia Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia c Department of Ophthalmology, Faculty of Medicine, University of Szeged, Hungary d Center for Eye Research, Department of Ophthalmology, Oslo University Hospital and University of Oslo, and Norwegian Center for Stem Cell Research, Norway e Department of Ophthalmology, Institute of Clinical Medicine and Kuopio University Hospital, University of Eastern Finland, Finland b

a r t i c l e

i n f o

Article history: Received 22 November 2014 Received in revised form 23 March 2015 Accepted 30 March 2015 Available online 2 April 2015 Keywords: Ageing of the vitreous Acute-onset floaters Flashes Photopsia Posterior vitreous detachment Retinal detachment

a b s t r a c t Floaters and flashes are most commonly symptoms of age-related degenerative changes in the vitreous body and posterior vitreous detachment. The etiology and pathogenesis of floaters’ formation is still not well understood. Patients with acute-onset floaters, flashes and defects in their visual field, represent a medical emergency with the need for same day referral to an ophthalmologist. Indirect ophthalmoscopy with scleral indentation is needed in order to find possible retinal break(s), on-time treatment and prevention of retinal detachment. The molecular and genetic pathogenesis, as well as the epidemiology of the ageing changes of the vitreous is summarized here, with view on the several treatment modalities in relation to their success rate and side-effects. © 2015 Published by Elsevier B.V.

Contents 1. 2.

3. 4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of floaters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Vitreous molecules involved in the pathogenesis of floaters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Type II collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Type IX collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Type V/XI collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Type VI collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Glycosaminoglycans and proteoglycans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Flashes of light (photopsiae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PVD and RRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Epidemiology of PVD and RRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Genetic risk of RRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Department of Ophthalmology, University of Szeged, Korányi fasor 10-11, 6720 Szeged, Hungary. Tel.: +36 62 544 573; fax: +36 62 545 487. E-mail addresses: [email protected] (X. Lumi), [email protected] (M. Hawlina), [email protected] (D. Glavaˇc), [email protected] (A. Facskó), [email protected] (M.C. Moe), Kai.Kaarniranta@kuh.fi (K. Kaarniranta), [email protected] (G. Petrovski). http://dx.doi.org/10.1016/j.arr.2015.03.006 1568-1637/© 2015 Published by Elsevier B.V.

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1. Introduction Ageing of the vitreous is a complex biochemical and structural process. Floaters are opacities in the vitreous body which cast shadows onto the retina. Patients see them as small moving spots or specs in the visual field. They may appear as lines, circles, dots, cobwebs, clouds, flies or of any other shape (Fig. 1). Floaters move as the eye moves, but do not follow eye movements precisely. When attempted to look directly at them, the floaters seem to move away, while blinking does not get rid of them. They are mostly seen when looking at something bright like white paper, plain white wall or blue sky. The perception of floaters is known as myodaeopsia (muscae volitantes in Latin) (Cline et al., 1997). Floaters usually begin to appear as few small spots, becoming much dense upon time. In most cases, vitreous opacities occur as a result of degenerative changes in the vitreous body. Vitreous liquefaction (synchisis senilis) provokes condensation of the vitreous collagen fibers and posterior vitreous detachment (PVD) (Wagle et al., 2011). More dramatic condition is an acute onset of floaters, the most common cause of which is PVD, having a prevalence of 24% among adults aged 50–59 years and 87% in those over 80 years old (Hikichi et al., 1995). Flashes of light or lightening streaks appear independently or sometimes together with floaters. They are usually noticed in dim light, at night or in a dark room. They can be induced by eye movements. The most common cause of flashes is also PVD (Hikichi et al., 1995). PVD is involved as inciting event in most cases of rhegmatogenous retinal detachment (RRD) (Banker and Freeman, 2001). By

Fig. 1. Slit lamp imaging of floaters in the vitreous body (arrow points at the floater).

definition, RRD is described as separation of the neurosensory retina from the underlying retinal pigment epithelium by an accumulation of fluid (Feltgen and Walter, 2014). This review focuses on the degenerative changes – biochemical and pathological, occurring in the vitreous throughout ageing and the symptoms associated with floaters and flashes of light. In addition, PVD and RRD are discussed here in the context of their role or appearance in acute-onset floaters and flashes. Finally, treatment modalities for managing floaters, PVD and RRD are presented. 2. Pathogenesis of floaters Degenerative changes in the vitreous body start at an early age. Vitreous liquefaction which destabilizes collagen fibrils has been detected at age 4 years and 12.5% of the vitreous is liquefied at age of 18 (Balazs and Denlinger, 1982). The most common etiologic causes of floaters are age-related and myopia-induced liquefaction of the vitreous gel (Sebag et al., 2014). This liquefaction induces collagen aggregation into visible fibrils and, at a later stage, leads to collapse of the vitreous body (Sebag, 1989). Anatomically and biochemically, the human vitreous body is a complex structure (de Nie et al., 2013). At least 98% of its content is water and only 0.1% is made up from macromolecules (Bishop, 2000). The most important macromolecules are collagens II and IX, glycosaminoglycans (GAGs) like hyaluronic acid (hyaluronan, HA), proteoglycans (PGs), and also non-collagenous glycoproteins (Ponsioen et al., 2010) (Fig. 2). Water binds to HA. The ageing process leads to two structural changes: depolymerization of HA, which causes release of water and loss of collagen IX. Absence of collagen IX provokes aggregation of collagen II fibrils (syneresis) which leads to formation of fluid filled lacunae (synchisis) (de Nie et al., 2013) (Fig. 2). Collagen filaments aggregation and condensation results in formation of larger fibrils, which float in lacunas of liquefied vitreous giving the patients the perception of floaters. The speed at which these vitreous changes happen depend on age, environmental factors, exposure to sunlight, oxidative effects and HA-collagen interaction (Roth et al., 2005). In patients older than 70 years of age, at least 50% of the vitreous is liquefied (Foos and Wheeler, 1982). Interference of the floaters with the visual axis produces patient discomfort. The number of floaters may increase with age, which has impact on the quality-of-life as well. There have been many other causes of floaters described before, such as vitreous hemorrhage in proliferative retinopathies, including diabetic retinopathy, sickle cell, venous occlusion, Eales disease (Alan et al., 2009) as well as, myopia (Balazs and Denlinger, 1982),

Fig. 2. Pathogenesis of floaters (Col II, IX: Collagen II, IX; HA: hyaluronic acid, PG: prostaglandins).

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intraocular inflammation (Lai and Pulido, 2002), trauma, cataract surgery and asteroid hyalosis (Alan et al., 2009).

(IX) chain in the NC3 domain, which makes the collagen also a PG (see Section 2.1.5).

2.1. Vitreous molecules involved in the pathogenesis of floaters

2.1.3. Type V/XI collagen The fibrillar type V/XI collagen represents 10% of the collagens in vitreous (Zhidkova et al., 1995). It can bind with type II collagen and form the core of the heterotypic fibrils. Vitreous contains a heterotrimer alpha 1(XI) and alpha 2(V) in two chains, while the third chain is not known (Bishop et al., 1994; Mayne and Brewton, 1993). Therefore, the molecule is referred to as type V/XI collagen. The Nterminal domain of type XI collagen is not cleaved that provides regulatory functions to control growth of the fibril. Type V collagen controls the initiation of collagen fibril formation (Gregory et al., 2000; Wenstrup et al., 2004). Thus, both of them have important function in the structure of vitreous collagen fibrils.

The vitreous is the largest structure (80% of the volume) in the eye that consists of hyalocytes, collagens (type II, IX, V/XI and VI collagens), GAGs (hyaluronan, chondroitin and heparin sulfate), PGs and some other extracellular matrix molecules (fibrillin, opticin, VIT-1) (Le Goff and Bishop, 2008). Collagen molecules are coiled by three alpha polypeptide chains coiled into left-hand helix. The three chains are then wrapped around each other into a righthanded triple helix providing a rope like network. Every third amino acid is a glycine residue that creates Glycine-X-Yn amino acid repeats (Prockop and Kivirikko, 1995). The X and Y repeats can be any amino acids, but often X is alanine or proline and Y is hydroxyproline. Collagens are also rich in lysine. All collagens have non-triple-helical regions at the ends of the molecule. The hydroxyproline forms hydrogen bonds and stabilizes the structure of the collagen triple helix. The lysine and hydroxylysine residues are necessary for the formation of intramolecular cross-links, which stabilize the collagen fibrils. Hydroxylysines also provide potential sites for post-translational glycosylation modifications. To date about 30 different types of collagen molecules from more than 40 genes have been characterized (Gordon and Hahn, 2010). Interestingly, vitreous collagens resemble cartilage collagen fibrils.

2.1.1. Type II collagen Collagen type II belongs to the subfamily of fibrillar collagens that accounts for 70–80% of this molecule in the vitreous (Bishop et al., 1994). Each type II collagen consists of three identical polypeptide chains, alpha1(II) 3 chains. Type II collagen molecules are secreted into the extracellular environment, as a soluble type IIA (the long form) and IIB (the short form) procollagens that have terminal extensions called N- and C-propeptides (Prockop and Kivirikko, 1995). In the extracellular environment, terminal extensions are cleaved by N-proteinase and C-proteinase leaving small non-collagenous telopeptides at each end of the triple-helical region. This process reduces the solubility of the collagen molecules and allows them to participate in fibril formation. Alternative splicing of exon 2 of the collagen type II pre-mRNA results in two forms of expressed collagen chains that affects different functional properties of type II collagen. These two forms may be associated with vitreous pathologies such as those observed in Stickler’s syndrome (STL), Wagner syndrome and Kniest dysplasia (Maumenee and Traboulsi, 1985; Ritvaniemi et al., 1993; Snead and Yates, 1999; Kaarniranta et al., 2006). Thus, vitreous anomaly is one of the clinical signs of these syndromes and dysplasia. Wagner disease is associated with the extracellular matrix component gene versican (Miyamoto et al., 2005). It has phenotypic overlap with STL and, in some cases, distinguishing Wagner syndrome from the ocular-only variant of STL1 may be difficult.

2.1.2. Type IX collagen Type IX collagen has been estimated to represent up to 25% of the collagens in the vitreous (Bishop et al., 1994). It binds covalently to the surface of heterotypic fibrils in a d-period distribution, but it cannot form fibrils in isolation and it does not undergo extracellular proteolytic cleavage. Type IX collagen is a heterotrimer consisting of alpha 1(IX), alpha 2 (IX) and alpha 3 (IX) chains that join to produce three collagenous domains (COL1, COL2, and COL3) interspersed between noncollagenous domains (NC1, NC2, NC3, and NC4) (Nishimura et al., 1989). In the vitreous, type IX collagen possesses chondroitin sulphate (CS) chain attached to the alpha 2

2.1.4. Type VI collagen Type VI collagen is a minor representative of collagens in the human vitreous that binds to fibrillar collagens and HA and forms a stabilizing fine filamentous vitreous network (Marshall, 1987; Fitzgerald et al., 2013). Each of the three different chains of the protein contains a short triple-helical domain, and the remainder consists of large N- and C-terminal globular domains (Prockop and Kivirikko, 1995). Type VI collagen does not create fibrils with itself, although it binds to the fibrillar collagens. 2.1.5. Glycosaminoglycans and proteoglycans GAGs are composed of long chains of repeating disaccharide units of which one residue is N-acetylglucosamine or N-acetylgalactosamine and the other is hexuronic acid or galactose. All GAGs except HA are attached to a protein core forming proteoglycans. The vitreous is rich in HA and has small amounts of the sulphated GAGs, such as CS and heparan sulfate (HS) (Bishop, 2000). HA consists of an unbranched chain of repeating disaccharide units of d-glucuronic acid beta-1,3-N-acetylglucosamine-beta1,4 (Weissmann and Meyer, 1954). It is a large GAG synthesized at the plasma membrane and is rich in mammalian vitreous (Bishop et al., 2002). Unlike other GAGs, HA is not post-translationally modified before being secreted. HA synthesis is regulated by hyaluronan synthases (Tammi et al., 2002). Hyaluronan exhibits unusual physicochemical properties in concentrated solutions: due to a combination of its random-coil structure and large size, molecular entanglement can occur, and its capacity to interact with water molecules change. HA has a large hydrodynamic volume and forms solutions with high viscosity and elasticity that provide space filling, lubricating, and filtering functions (Balazs and Denlinger, 1982). The highest concentration of HA has been measured in the posterior vitreous cortex. In adult human vitreous, the HA concentration has been estimated to be between 65 and 400 ␮g/ml and the average molecular weight to be 2–4 million Daltons. HA chains do not form stable intermolecular connections, although they are stabilized by type II and VI collagens (Balazs and Denlinger, 1982). CS proteoglycans are formed by beta1–4 glucuronic acid beta1–3 N-acetylgalactosamine disaccharide units. The C-4 and/or C-6 of the N-acetylgalactosamine residues is usually posttranslationally modified by sulphation (Bishop et al., 1994). The C-2 sulphation of the glucuronic acid occurs less frequently. The vitreous contain two CS proteoglycans, type IX collagen and versican (Bishop, 2000). Versican is a large proteoglycan with a central domain that carries multiple CS chains. The interaction of versican and HA is stabilized by a glycoprotein called link protein, which has also been characterized in the vitreous. Gene polymorphism of versican have been associated with the vitreoretinopathy in Wagner’s syndrome (Miyamoto et al., 2005).

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HS is formed by beta1–4 glucuronic acid alpha1–4 Nacetylglucosamine disaccharide units. This sequence is usually modified post-translationally (Le Goff and Bishop, 2008). HS proteoglycans are major components of basement membranes, including the inner limiting lamina on the inner surface of the retina. HS proteoglycans are present in the vitreous during development, but the levels are very low in postnatal eyes (Halfter et al., 2005). Other non-collagenous components in the vitreous are fibrillin 1, opticin and VIT-1. Fibrillin gene defects have been associated with Marfan syndrome. Opticin regulates collagen fibrillogenesis. VIT-1 is a collagen binding molecule and it is assumed to maintain vitreous gel structure (Le Goff and Bishop, 2008). 3. Flashes of light (photopsiae) Flashes of light or photopsiae are visual symptoms or sensations of light which occur in the absence of external light stimuli (Kahawita et al., 2014). Flashes arise by mechanical stimulation of the retinal cells by vitreoretinal traction. They are less common than floaters and occur in around 50% of PVD events (Yanoff and Duker, 2004). The most common etiologic factors associated with photopsia are: PVD, migraine with aura and with or without headache, retinal break or detachment, optic neuritis, hypotension, transient ischemic attack (Amos, 1999; Gariano and Kim, 2004) and vitreopapillary traction syndrome (Johnson, 2010). Light flashes are also reported by most of the astronauts during spaceflight and patients treated with radiotherapy for brain tumors, which are induced by cosmic ray traversals (Dieter et al., 2013). Photopsiae have to be differentiated from other visual phenomenona like palinopsiae, which are a reoccurrence of visual perception after stimulating object has been removed, and have been described in patients with brain tumors, epilepsy, trauma, systemic disease, psychiatric illness and illicit drug users (Abert and Ilsen, 2010). In a study of Goodfellow et al., (2010) out of 77 patients presenting with symptoms of photopsiae in the eye emergency department, 27 had PVD alone, 7 had retinal tear and 25 had RRD. Photopsiae were more often located at the temporal quadrants (94%) and oriented vertically (59%). According to their findings, patients with photopsiae located in quadrants other than the temporal were more likely to have RRD (Goodfellow et al., 2010). Byer (1994) found in the natural history study of PVD that 6% of patients had photopsiae as presenting symptom of PVD, 40% had floaters and 54% reported both. Flashes are a warning sign of dynamic traction on the retina and are much more threatening phenomenon than floaters (Kuhn and Aylward, 2014). According to Hikichi et al., the appearance of floaters in patients under the age of 50 were related to opacities on the plicated membranes in the posterior portion of the Cloquet’s canal and to other intravitreous opacities, which is in contrast to patients aged 50 and older, where the main reason for the occurrence of floaters is PVD (Hikichi et al., 1995). 4. PVD and RRD The reason for sudden onset of floaters in patients 50 years or older has been related to PVD in 95% of cases (Murakami et al., 1983). In the pathogenesis of PVD, after vitreous body liquefaction, the second most important event is age-related weakening of the adhesions between the posterior hyaloid membrane and the internal limiting membrane, which leads to separation of these two structures, shrinkage and collapse of the vitreous body (Sebag, 1991). In patients with high myopia, vitreous liquefaction and

floaters related to PVD occur much earlier compared to the same age patients with emmetropia or hyperopia (Balazs and Denlinger, 1982). Early vitreous liquefaction and PVD has been described in conditions fowllowing trauma, aphakia, intraocular inflammation, vitreous hemorrhage and retinal vascular diseases (Johnson, 2010). During ageing, the vitreous body degenerates, collapses and detaches from the retina. The most common complications of agerelated total PVD are retinal tear, vitreous-, retinal- and optic dischemorrhage as well as RRD (Johnson, 2010). In the latter, we have observed pigmented and non-pigmented sphere-like structures which contained cells capable of proliferating and expressed pluripotency markers when cultivated in vitro (Frøen et al., 2013).

4.1. Epidemiology of PVD and RRD In patients with acute onset of floaters and/or flashes as a consequence of PVD, the incidence of retinal tear is 14% (Hollands et al., 2009). Patients initially diagnosed as having uncomplicated PVD have a 3.4% chance of a retinal tear within 6 weeks (Hollands et al., 2009). According to Byer, the prompt and conscientious vitreoretinal examination of each patient older than 45 years of age who experiences vitreous floaters, is the most effective way for preventing RRD (Byer, 1994). In the study of Dayan et al., the incidence of retinal detachment was 16.6% in patients presenting with an isolated PVD. Furthermore, retinal tear was detected in 26.7% of patients with PVD presenting with floaters alone (Dayan et al., 1996). Sharma et al. found floaters to be a presenting symptom of patients with PVD-related retinal tears in 89% of cases, flashes in 62% and both in 51% of cases with duration of less than 1 month from 92.7% of the examined patients (Sharma et al., 2004). In cases where PVD is complicated by vitreous hemorrhage, the incidence of retinal tear was found to be 70% (Byer, 1994). PVD is even more accelerated after cataract surgery. In eyes without preoperative PVD or lattice degeneration, PVD occurred in 75.9% of patients after uncomplicated phacoemulsification in a follow-up period of 5 years (Ripandelli et al., 2007). The incidence of retinal detachment in eyes with post-operative PVD after uneventful phacoemulsification was 21.27% (Ripandelli et al., 2007). Linder reported the preponderance of females over males in their study of PVD, finding a female/male ratio of 73/27% (Linder, 1966). Female gender, myopia and higher intake of vitamin B6 have also been associated with higher incidence of PVD (Chuo et al., 2006). In their meta-analysis of RRD incidence, Mitry et al., found wide geographical variations with incidence ranging between 6.3 and 17.9 per 100 000 subjects. The highest incidence rate between 19 and 27 per 100 000 was found in the 60–69-year old age group (Mitry et al., 2010). Bilateral involvement also varies from study to study, ranging from 3 to 33%, depending on the study duration (Gupta and Benson, 2005). The incidence of RRD in the general population in Europe is 1 in 10 000, with greater incidence in subjects aged 55-70 years; bilateral involvement has been recorded in 9-10% of the subjects within 4 years (Feltgen and Walter, 2014). The incidence increases with age, and is higher in males, following cataract surgery, in myopia with axial length over 26 mm and after trauma (Feltgen and Walter, 2014; Mitry et al., 2010). Eyes after cataract surgery with history of uveitis and glaucoma are also at greater risk for RRD (Banker and Freeman, 2001). Algvere et al. (1999) reported that history of cataract surgery was found in 30.8% of the eyes with RRD in Sweden. Similar findings with around 30% of patients having retinal detachment after cataract surgery were reported by Mitry et al. (2011) The risk of suffering RRD after an uncomplicated cataract operation has been estimated to be approximately 1/1000 (Mitry et al., 2010).

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4.2. Genetic risk of RRD High incidence of RRD with autosomal dominant inheritance is described in syndromic etiologies such as STL, Wagner disease or erosive vitreoretinopathy. There have been genetic mutations described and identified in different types of these syndromes. STL consists of many subtypes. STL1 is the most common cause of inherited RRD and results from altered type II collagen molecules encoded by COL2A1 gene (Richards et al., 2000). In 2005, Go et al. found myopia to be an important risk factor for RRD development and suggested that genetic risk factors for RRD, other than those determining axial length exist, since myopia could not fully explain the increased risk in first-degree relatives in their study (Go et al., 2005). As they reported previously, evidence showed linkage of RRD with a region containing COL2A1 gene in 2 unrelated RRD families and identification of the pathogenic mutation Arg453Ter in 1 family (Go et al., 2003). Yu et al. investigated whether polymorphisms of lysyl oxidase (LOX), which may play an important role in ocular tissue integrity, associates with susceptibility to RRD and PVR. The results of the study suggest a potential correlation between LOX and ocular inflammation (Yu et al., 2013). A polygenic component underlying RRD risk was supported by the study of Kirin et al. (2013). They also found a genome-wide significant association of RRD and the marker rs267738 which is involved in ceramide synthase 2 (CERS2) expression (Kirin et al., 2013). In recent years some additional evidence has been collected on genetic background of proliferative vitreoretinopathy (PVR), which is the main reason for RRD surgery failure. PVR is considered an abnormal wound healing process. Due to impact of the genetic base, growth factors and cytokines accumulated in the vitreous body can orient the healing process through a different route than the normal one, thus leading to formation of PVR. An association between the development of PVR and genetic profile of tumor growth factor beta1 (TGF-␤1) has been detected in the study of Sanabria RuizColmenares et al. (2006). Rojas et al. (2010) provides insight into this question in their candidate gene association study examining inflammatory genetic markers with the occurrence of PVR after primary RD repair and describes strong association of tumor necrosis factor (TNF) locus and PVR. Later, this group found implication of Mothers against decapentaplegic homolog 7 (SMAD7) and TNF locus to the genetic contribution of PVR (Rojas et al., 2013). They identified single nucleotide polymorphisms (SNPs) in the genes SMAD7 and TNF03B1 between subjects who developed PVR and those who did not (Rojas et al., 2013). SMAD7 is an intracellular signaling molecule that results in downstream inhibition of TGF-03B2 – mediated fibrosis. It is noteworthy, that this study could not replicate the previously described TGF-␤ association (Sanabria Ruiz-Colmenares et al., 2006). Pastor-Idoate et al. (2013) found a ‘pro’ version of the p53 codon 72 polymorphism to be associated with a high risk of PVR after retinal detachment. These findings strongly suggest the influence of gene polymorphism in the development of PVR. It is worth noting here the TNF-␣ associations with PVR, since there exist approved drugs which can block the proinflammatory cytokine production and can be administered intraocularly (Stryjewski and Vavvas, 2013).

5. Treatment Floaters can result in intermittent blurred vision, glare and haze attributable to migration of vitreous opacities into the visual axis. This event interferes with important activities of daily life such as reading, driving and performing near work (Yonemoto et al.,

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1994). Wagle et al. (2011) analyzed health-related quality-of-life in patients with floaters and found significant negative impact. Also Sebag et al. (2014) showed that vitreous floaters have impact on vision by markedly lowering contrast sensitivity function up to 67%. In the analysis of quality-of-life of patients with floaters, Mason et al. (2014) found 50% impairment in this parameter due to reading difficulties and 30% impairment due to driving difficulty. According to the findings of Wagle et al. (2011) these patients were willing to take an 11% risk of death and a 7% risk of blindness just to get rid of the bothersome floaters. Several different treatment modalities for floaters have also been described: eye drops, neodymium yttrium aluminium garnet (Nd-YAG) laser, phacoemulsification combined with deep anterior vitrectomy and minimally invasive vitrectomy (Sebag et al., 2014; Delaney et al., 2002; Mossa et al., 2002). There is no scientific evidence of the effectiveness of eye drops in treating vitreous floaters, but there is some evidence of using Nd-YAG lasers. In the study of Tsai et al. (1993) 15 patients were treated and followed-up over 12 months. During the follow-up period, all patients were satisfied with the outcome and no patients showed visual deterioration or recurrence of symptoms. Delaney et al. (2002) compared Nd-YAG vitreolysis and pars plana vitrectomy (PPV) for floaters. In 38% of patients treated with Nd-YAG vitreolysis, there was a moderate improvement in their symptoms. Patients treated by vitrectomy observed complete resolution of symptoms in 93.3% of the treated eyes (Delaney et al., 2002). An earlier study by Little and Jack (1986) found improvement in less than half of the patients treated by Nd-YAG laser, but also complications like focal opacities of the crystalline lens, retinal hemorrhages and retinal breaks with detachment were mentioned. Up to now, Nd-YAG laser vitreolysis has not been accepted as a method of choice in the treatment of vitreous floaters and remains an “off-label” treatment option for selected cases (Sendrowski and Bronstein, 2010). In a different approach called floaterectomy, Mossa et al. (2002) combined phacoemulsification with deep anterior vitrectomy. Out of 10 eyes included in the study, 6 months after the treatment, an improvement was found in 8 eyes. Nevertheless, this approach has also not become widely popular or accepted. Higher success rate in removing floaters was achieved with vitrectomy: the first studies reported a success rate in 88% of the patients treated; however, the intra-operative and post-operative complication rates were also significantly higher. Intra-operative iatrogenic retinal breaks were found in 16.4% of patients and also retinal detachment occurred in 10.9% of cases (de Nie et al., 2013; Tan et al., 2011; Schulz-Key et al., 2011). More favorable surgical outcome and lower complication rates were recently reported by Sebag et al., (2014) and Mason et al. (2014) using sutureless 25-gauge PPV. These authors recommend core vitrectomy without inducing PVD and leaving the anterior vitreous, which in turn reduces the risk of intra-operative retinal tears and post-operative cataract formation (Sebag et al., 2014). RRD can sometimes be prevented. The most effective way is by early examination in patients suffering symptoms suggestive of acute PVD. Detection of retinal tear(s) and management with laser or cryotherapy eliminates the risk for RRD in over 95% of the cases (Smiddy et al., 1991). Patients with high myopia and those who are prone to RRD can be instructed to avoid activities where there is a risk of shock to the head or eyes, like contact sports. Indirect ophthalmoscopy with scleral depression is a standard examination and treatment approach in the management of patients with acute PVD, with re-examination done in 1 month time. In patients with PVD and vitreous hemorrhage, reexamination is necessary every 2–3 weeks until the whole vitreous clears. Patients must be instructed to return immediately in case of increased number of floaters, flashes or visual field defect (Sharma

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et al., 2004). Even patients with uncomplicated PVD can develop subsequent retinal breaks. In a series by Sharma et al. (2004) subsequent retinal tear(s) developed in 12.2% of primary treated patients with retinal breaks. Several different procedures for managing RRD are now available and can be used alone or in combination. They all depend on finding a retinal tear, closing it and relieving vitreo-retinal traction. Three main surgical techniques are in use to manage RRD: pneumatic retinopexy, scleral buckling and PPV with or without scleral buckling. Pneumatic retinopexy is an office based procedure suitable for retinal detachments with single retinal break or with a group of breaks that do not exceed 1 clock hour, and localized at the superior two thirds of the retina. Trans-conjuctival injection of gas bubble intravitreally is performed with a proper head posturing after the procedure. Indications for pneumatic retinopexy are RRDs with a traction that is not too advanced and rather limited syneretic changes in the vitreous body (Kuhn and Aylward, 2014). The chances of new retinal break occurrence during this procedure are up to 30% (Poliner et al., 1987). Scleral buckling technique is performed with the help of scleral sponges as a buckling element which is sutured extrasclerally over the breaks, indenting the eye wall and modifying the direction of the force that is pulling on the edges of the retinal break, thus counter-balancing its strength (Kuhn and Aylward, 2014). Scleral buckling is the most appropriate surgical procedure for uncomplicated RRD with final anatomic success rates of greater than 94% (Sodhi et al., 2008). This technique has several disadvantages and possible postoperative complications. The most common complication is ocular motility disturbance leading to strabismus and diplopia. Pain after surgery is common, long postoperative recovery time and very often induced refractive error due to distortion of the shape of the eye has been documented (Sodhi et al., 2008). Scleral buckling is associated with high rate of anatomic failure and poor visual outcome in RRDs with multiple retinal tears, giant tears, retinal detachments lasting longer than one week, retinal detachments with the macula-off and detachments with poor pre-operative visual acuity (Grizzard et al., 1994). The most common reason for failure of this surgical technique is development of PVR (Asaria and Gregor, 2002). More recently, an alternative to the external buckling has been developed - internal buckling involving injection of modified HA material supra-choroidally, thus tamponading against the retinal tear from the inside of the eye and centripetally (El Rayes and Oshima, 2013). The benefits and side-effects of this procedure remain to be reported and peer reviewed in the near future. Heimann et al. (2007) showed a benefit from the improved visual acuity after scleral buckling surgery in phakic eyes with RRD of medium complexity compared to eyes managed by PPV. They found better anatomical outcome in pseudophakic eyes managed with vitrectomy compared to scleral buckling and no significant difference in the visual function outcome (Heimann et al., 2007). Similar independent study found over 4 times higher rate of recurrent retinal detachment after scleral buckling compared to vitrectomy after more than 1 year of complete reattachment (Bopp and Böhm, 2008). PPV as a primary surgical technique was used in the past mainly for complicated RRDs. With the introduction of transconjuctival suttureless 23 and 25-gauge vitrectomy, the popularity is shifting towards vitrectomy as a first choice technique in managing RRD.

6. Conclusion Floaters and flashes are most commonly symptoms of agerelated degenerative changes in the vitreous body and PVD. Patients with acute-onset floaters, flashes and defects in their visual field,

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