CHAPTER I

INTRODUCTION

The vitreous body is an extracellular matrix that is highly hydrated and relatively

acellular except in the periphery where hyalocytes r8eside in the vitreous cortex. Vitreous

consists of 98% water and macromolecules, the most important being collagens and

hyaluronan, organized in an exquisitely clear gel. Floaters arise from molecular changes

within the vitreous body and at the vitreo-retinal interface that occur throughout life and

ultimately attain sufficient prominence to alter vitreous structure.Structural changes within

the vitreous body can result from inflammation, vitreoretinal dystrophies, myopic and

diabetic vitreopathy, but most commonly stem from aging. In addition to altering the internal

structure of the vitreous body, aging also weakens vitreoretinal adhesion1

The strength of attachment of the vitreous body to the retina depends upon the

topographical location. The strongest zone of vitreous attachment is at the vitreous base

where there is a relatively higher concentration of collagen and lower concentration of

hyaluronan, resulting in a more condensed and solid vitreous configuration. The densely

packed basal collagen fibrils align perpendicular to the retina and insert through

discontinuities in the inner limiting membrane (ILM) to anchor on muellerian glia and

astroglia, forming an unbreakable adhesion. In other regions of the vitreo-retinal interface,

collagen fibrils are orientated parallel to the ILM. Although the mechanism of attachment

here is not completely understood, it is thought to result from interface macromolecules

including laminin, fibronectin, chondroitin, and heparin sulphate proteoglycans, forming a

glue-like adhesion. The presence of different types of collagen may also contribute to this

attachment. Vitreoretinal adhesion has been found to be stronger over areas where the ILM is

thinner, including the margin of the optic disc (where the inner limiting membrane of

1
Elschnig may be supported by few astrocytes) over retinal blood vessels, and in a 500 to

1500m disc-shaped zone surrounding the fovea. The strength of vitreo-retinal adhesion may

also relate to the thickness of the posterior vitreous cortex, in particular over retinal blood

vessels and at the macula where there is a thinner vitreous cortex related to the rarefaction of

the collagen fibrils2

At birth the human vitreous body is a colloidal gel; however, with aging, liquefaction

occurs within the vitreous body that can subsequently coalesce into pockets, called lacunae or

cisterns. Recent swept source OCT imaging of posterior vitreous structure in young

individuals has confirmed the presence of the to result from aging. Vitreous gel liquefaction

likely results from dissociation of hyaluronan from its association with collagen, allowing

cross-linking and aggregation of collagen fibrils into macroscopic fibers that scatter incident

light. Lacunae, on the other hand, are regions devoid of collagen fibrils, owing either to

aggregation and displacement of collagen to the periphery of the lacuna, or possibly

enzymatic destruction of collagen, transforming the gel vitreous to a liquid consistency,

facilitating collapse. Lacunae increase vitreous heterogeneity, scatter light (especially at gel-

liquid interfaces) and can disturb vision, if severe. Vitreous gel liquefaction increases with

age, being first evidentat the age of four years3

Posterior vitreous detachment (PVD) occurs as a separation of the posterior vitreous

cortex from the ILM of the retina, that begins posteriorly and progresses up to the posterior

border of the vitreous base. Johnson describes perifoveal PVD as a slow insidious process

until vitreo-papillary separation. PVD is a common age-related process caused by a

combination of vitreous liquefaction and vitreo-retinal dehiscence allowing liquid vitreous to

enter through a cortical defect into the retro-cortical (pre-retinal) space 25, triggering a so-

called rhegmatogenous PVD. PVD is more common with increasing age and in post-mortem

2
studies is reported at an incidence of 63% by the eighth decade. There is also purported to be

a higher incidence of PVD in older women, which may relate to differences in biochemical

composition of vitreous from hormonal changes at menopause. Risk factors for earlier PVD

include myopia and collagen disorders such as Marfan and Stickler syndrome. PVD at

younger ages not only induces the phenomenon of floaters, but also, as the result of firm

vitreo-retinal adhesion to an irregular posterior vitreous base, results in retinal tears and

rhegmatogenous retinal detachment11

3
 CHAPTER II

LITERATURE REVIEW

2.1. DEFINITION OF FLOATERS

Floaters are opacities in the vitreous body which cast shadows onto the retina. Patients

see them as small moving spots orspecs 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 move-ments precisely.2 When attempted to look directly at them,

thefloaters seem to move away, while blinking does not get rid ofthem. They are mostly seen

when looking at something bright likewhite paper, plain white wall or blue sky. The

perception of floatersis known as myodaeopsia (muscae volitantes in Latin). Floaters usually

begin to appear as few small spots, becomingmuch dense upon time. In most cases, vitreous

opacities occur asa result of degenerative changes in the vitreous body.4

Figure 1. Slit lamp imaging of floaters in the vitreous body

4
2.2 ETIOLOGY OF VITREOUS FLOATERS

Floaters, previously called myodesopsia (Greek) and muscae volitantes (Latin), are

visual phenomena caused by vitreous opacities that produce linear grey shadows with focal

dark spots or nodules.5 Related to inertia of the vitreous body and intravitreal currents,

floaters move with eye and head movements. The vitreous body and its internal structures

move with characteristic damping due to viscous drag. 6Floaters are more visible when a

viewed against a bright background such as a sunny sky because the dark shadows created by

the vitreous opacities appear accentuated5. Floaters can arise from changes in structures

endogenous to the vitreous body, as well as from exogenous sources (amyloid, asteroid

bodies, macrophages of Whipple disease, blood (called synchisis scintillans, when chronic),

lymphocytes, opercula, medulloepithelioma, endophytic retinoblastoma, dexamethasone and

other implants, foreign bodies, parasites).7

A. Primary Vitreous Floaters

Primary vitreous floaters are defined as those arising from structures that are

endogenous to the vitreous body. Packed bundles of collagen fibrils form visible fibers that

first appear in the central vitreous where they have a linear configuration. They become more

numerous, thickened and irregular with increasing age and are common at young ages with

axial myopia. With advancingage, the vitreous body liquefies and forms lacunae, the walls of

which interfere with photon transmission to the retina, contributing to the sensation of

floaters. Primary vitreous floaters cause disruption and scattering of light and are appreciated

as mobile dark lines and spots or nodules within the visual field. Some linear floaters have a

translucent "glass noodle" appearance, others are described as spider-web like. The

origin(s) of these different appearances is not known, although it is conceivable that the

translucent tubular structures are remnants of the embryonic hyaloid vasculature, while the

5
dark linear opacities are collagen aggregates. Vitreoretinal disorders such as Stickler

syndrome and Wagner disease may be responsible for increase and variation in primary

vitreous floaters. The clinical manifestations of these conditions are variable depending on

the specific genotype. For example, collagen gene mutations may determine a more

membranous appearance in Stickler type 1 (COL2A1) as opposed to fibrils and beading

described in Stickler type 2 (COL11A1)83. Stickler type 1 will also exhibit a folded

membrane present behind the lens. Floaters are most noticeable when situated in the visual

axis. With increasing size and number,floaters can be considerably symptomatic. PVD causes

the sudden onset of primary floaters as a result of the collapse of the vitreous body and

separation at the vitreo-retinal interface with anterior displacement of the posterior vitreous

cortex. The posterior vitreous cortex scatters incident photons because of the high density of

collagen fibrils . A notable type of floater resulting from PVD is a Weiss ring, the remnant of

vitreo-papillary attachment and peripapillary glial tissue at the optic disc, outlining the area of

Martegiani and often including the septum interpapillo maculare. A Weiss ring can be

visualized by ophthalmoscopy or biomicroscopy as an annular structure adjacent and anterior

to the optic disc. This ring can cast a prominent shadow onto the retina, which patients often

describe as circular or semicircular in appearance, particularly when it is only a few

millimeters anterior to the retina.8

B. Secondary Vitreous Floaters

Secondary floaters are opacities in the vitreous body whose origin is exogenous to the

vitreous body, generally consisting of proteins, amyloid, or cell . The most common cause of

secondary vitreous floaters is pre-retinal or vitreous hemorrhage, which induces the sudden

onset of floaters and hazy vision.

6
 Vitreous hemorrhage can be related to an acute PVD with traction on retinal blood

vessels, retinal tears involving retinal blood vessels, ischemic conditions leading to

retinal or optic disc neovascularization, retino-vascular abnormalities, trauma,

neoplasms, and to some rare abnormalities which include vitreoretinal dystrophies,

i.e. x-linked schisis, FEVR, Stickler syndrome. Retinal detachments can be associated

with vitreous hemorrhage as well as the release of retinal pigment epithelial cells into

the vitreous body, producing symptomatic floaters in addition to the curtain effect of

the detached retina.

Avulsed retinal tissue (operculum) may also induce the symptom of a floater

following anomalous PVD with a retinal break but no retinal detachment. Vitrectomy

to repair a retinal detachment removes these floaters and opercula as an important

beneficial side effect, and can thus be considered one of the first surgical procedures

to remove floaters.
Asteroid hyalosis is a benign accumulation of calcium pyrophosphate spheres within

the vitreous body that usually causes minimal disturbance of vision.

Inflammatory conditions (infectious or non-infectious), or malignant neoplasms, such

as lymphoma, lead to increased vitreous cells, with the potential to cause symptomatic

vitreous floaters if sufficiently numerous.

Secondary vitreous floaters may also occur following intraocular injections. After

vitreo-retinal surgery there can be remnant perfluorocarbon or silicone oil bubbles.

Intraocular injections for anti- VEGF treatment may contain air bubbles that usually

resorb in days, but the injected agents themselves may complex with vitreous

macromolecules and alter vitreous structure.11

2.3 PATHOGENESIS OF FLOATERS

Degenerative changes in the vitreous body start at an early age.Vitreous liquefaction

which destabilizes collagen fibrils has beendetected at age 4 years and 12.5% of the vitreous

7
is liquefied atage of 18. The most common etiologiccauses of floaters are age-related and

myopia-induced liquefactionof the vitreous gel . This liquefaction inducescollagen

aggregation into visible fibrils and, at a later stage, leads to collapse of the vitreous body

.Anatomically and biochemically, the human vitreous body is acomplex structure 6 . At least

98% of its contentis water and only 0.1% is made up from macromolecules . The most

important macromolecules are collagens II andIX, glycosaminoglycans (GAGs) like

hyaluronic acid (hyaluronan,HA), proteoglycans (PGs), and also non-collagenous

glycoproteins(Ponsioen et al., 2010) (Fig. 2).9 Water binds to HA. The ageingprocess leads to

two structural changes: depolymerization of HA,which causes release of water and loss of

collagen IX. Absence ofcollagen IX provokes aggregation of collagen II fibrils

(syneresis)which leads to formation of fluid filled lacunae (synchisis) (Fig. 2). Collagen

filaments aggregation and conden-sation results in formation of larger fibrils, which float in

lacunasof 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 andHA-collagen interaction . In patients older than 70 years of age, at least

50% of the vitreous is liquefied . Interference of the floaters with the visual axis pro-duces

patient discomfort. The number of floaters may increase withage, 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, includ-ing diabetic retinopathy, sickle cell,

venous occlusion, Eales disease as well as, myopia intraocular inflammation , trauma,

cataract surgery and asteroid hyalosis10.

8
2.3.1 Vitreous molecules involved in the pathogenesis of floaters15

The vitreous is the largest structure (80% of the volume) in theeye that consists of

hyalocytes, collagens (type II, IX, V/XI and VI col-lagens), GAGs (hyaluronan, chondroitin

and heparin sulfate), PGsand some other extracellular matrix molecules (fibrillin,

opticin,VIT-1). Collagen molecules are coiledby three alpha polypeptide chains coiled into

left-hand helix. Thethree chains are then wrapped around each other into a right-handed triple

helix providing a rope like network. Every thirdamino acid is a glycine residue that creates

Glycine-X-Yn aminoacid repeats . The X and Y repeatscan be any amino acids, but often X is

alanine or proline and Yis hydroxyproline. Collagens are also rich in lysine. All

collagenshave non-triple-helical regions at the ends of the molecule. Thehydroxyproline

forms hydrogen bonds and stabilizes the structureof the collagen triple helix. The lysine and

hydroxylysine residuesare necessary for the formation of intramolecular cross-links,

whichstabilize the collagen fibrils. Hydroxylysines also provide poten-tial sites for post-

translational glycosylation modifications. To date about 30 different types of collagen

9
molecules from more than 40genes have been characterized . Interest-ingly, vitreous

collagens resemble cartilage collagen fibrils.

A. Type II Collagen

Collagen type II belongs to the subfamily of fibrillar colla-gens that accounts for 70

80% of this molecule in the vitreous. Each type II collagen consists of three

identicalpolypeptide chains, alpha1(II) 3 chains. Type II collagen moleculesare secreted into

the extracellular environment, as a soluble typeIIA (the long form) and IIB (the short form)

procollagens thathave terminal extensions called N- and C-propeptides . In the extracellular

environment, terminalextensions are cleaved by N-proteinase and C-proteinase leavingsmall

non-collagenous telopeptides at each end of the triple-helicalregion. This process reduces the

solubility of the collagen moleculesand allows them to participate in fibril formation.

Alternative splic-ing of exon 2 of the collagen type II pre-mRNA results in twoforms of

expressed collagen chains that affects different functionalproperties of type II collagen. These

two forms may be associatedwith vitreous pathologies such as those observed in Sticklers

syn-drome (STL), Wagner syndrome and Kniest dysplasia . Thus, vitreous anomaly is one of

the clin-ical signs of these syndromes and dysplasia. Wagner disease isassociated with the

extracellular matrix component gene versican. It has phenotypic overlap with STL and,

insome cases, distinguishing Wagner syndrome from the ocular-onlyvariant of STL1 may be

difficult.

B. Type IX Collagen

Type IX collagen has been estimated to represent up to 25% ofthe collagens in the

vitreous . It binds covalentlyto the surface of heterotypic fibrils in a d-period distribution,

butit cannot form fibrils in isolation and it does not undergo extra-cellular proteolytic

cleavage. Type IX collagen is a heterotrimerconsisting of alpha 1(IX), alpha 2 (IX) and alpha

10
3 (IX) chains thatjoin to produce three collagenous domains (COL1, COL2, and

COL3)interspersed between noncollagenous domains (NC1, NC2, NC3,and NC4) . In the

vitreous, type IX collagenpossesses chondroitin sulphate (CS) chain attached to the alpha

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

C. Type V/XI Collagen

The fibrillar type V/XI collagen represents 10% of the collagensin vitreous . It can

bind with type II collagenand form the core of the heterotypic fibrils. Vitreous contains a het-

erotrimer alpha 1(XI) and alpha 2(V) in two chains, while the thirdchain is not known

.Therefore, the molecule is referred to as type V/XI collagen. The N-terminal domain of type

XI collagen is not cleaved that providesregulatory functions to control growth of the fibril.

Type V collagencontrols the initiation of collagen fibril formation . Thus, both of them have

importantfunction in the structure of vitreous collagen fibrils.

D. Type VI Collagen

Type VI collagen is a minor representative of collagens in thehuman vitreous that

binds to fibrillar collagens and HA and formsa stabilizing fine filamentous vitreous network .

Each of the three different chains of theprotein contains a short triple-helical domain, and the

remainderconsists of large N- and C-terminal globular domains . Type VI collagen does not

create fibrils with itself,although it binds to the fibrillar collagens.

E. Glycosaminoglycans And Proteoglycans

GAGs are composed of long chains of repeating disaccha-ride units of which one

residue is N-acetylglucosamine orN-acetylgalactosamine and the other is hexuronic acid or

galac-tose. All GAGs except HA are attached to a protein core formingproteoglycans. The

vitreous is rich in HA and has small amounts ofthe sulphated GAGs, such as CS and heparan

11
sulfate (HS) .HA consists of an unbranched chain of repeating disaccharideunits of d-

glucuronic acid beta-1,3-N-acetylglucosamine-beta1,4. It is a large GAG synthesized atthe

plasma membrane and is rich in mammalian vitreous . Unlike other GAGs, HA is not post-

translationallymodified before being secreted. HA synthesis is regulated byhyaluronan

synthases . Hyaluronan exhibitsunusual physicochemical properties in concentrated solutions:

dueto a combination of its random-coil structure and large size, molec-ular entanglement can

occur, and its capacity to interact withwater molecules change. HA has a large hydrodynamic

volume andforms solutions with high viscosity and elasticity that provide spacefilling,

lubricating, and filtering functions . The highest concentration of HA has been measured in

theposterior vitreous cortex. In adult human vitreous, the HA concen-tration has been

estimated to be between 65 and 400 _g/ml andthe average molecular weight to be 24

million Daltons. HA chainsdo not form stable intermolecular connections, although they

arestabilized by type II and VI collagens .CS proteoglycans are formed by beta14 glucuronic

acidbeta13 N-acetylgalactosamine disaccharide units. The C-4 and/orC-6 of the N-

acetylgalactosamine residues is usually post-translationally modified by sulphation . TheC-2

sulphation of the glucuronic acid occurs less frequently. Thevitreous contain two CS

proteoglycans, type IX collagen and versi-can . Versican is a large proteoglycan with a

centraldomain that carries multiple CS chains. The interaction of versicanand HA is stabilized

by a glycoprotein called link protein, which hasalso been characterized in the vitreous. Gene

polymorphism of ver-sican have been associated with the vitreoretinopathy in

Wagnerssyndrome .

HS is formed by beta14 glucuronic acid alpha14 N-acetylglucosamine disaccharide

units. This sequence is usuallymodified post-translationally . HSproteoglycans are major

components of basement membranes,including the inner limiting lamina on the inner surface

of theretina. HS proteoglycans are present in the vitreous during devel-opment, but the levels

12
are very low in postnatal eyes .Other non-collagenous components in the vitreous are

fibrillin1, opticin and VIT-1. Fibrillin gene defects have been associatedwith Marfan

syndrome. Opticin regulates collagen fibrillogenesis.VIT-1 is a collagen binding molecule

and it is assumed to maintainvitreous gel structure.16

Normal Eye Anatomy, PVD, Retinal Tear, and Retinal Detachsment

13
Area of Peripheral Retina With 2Horseshoe-Shaped Retinal
Tears in an Area of Billowing Retinal Detachment

2.4. FLASHES OF LIGHT (PHOTOPSIAE)

Flashes of light or photopsiae are visual symptoms or sensa-tions of light which occur

in the absence of external light stimuli. Flashes arise by mechanical stimulationof the retinal

cells by vitreoretinal traction. They are less com-mon than floaters and occur in around 50%

of PVD events .16 The most common etiologic factors associatedwith photopsia are: PVD,

migraine with aura and with or withoutheadache, retinal break or detachment, optic neuritis,

hypotension,transient ischemic attack andvitreopapillary traction syndrome .Light flashes are

also reported by most of the astronauts duringspaceflight and patients treated with

radiotherapy for brain tumors,which are induced by cosmic ray .Photopsiae have to be

differentiated from other visual phe-nomenona like palinopsiae, which are a reoccurrence of

visual perception after stimulating object has been removed, and havebeen described in

patients with brain tumors, epilepsy, trauma, sys-temic disease, psychiatric illness and illicit

drug users .17In a study of Goodfellow et al., (2010) out of 77 patients presenting with

symptoms of photopsiae in the eye emergencydepartment, 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 tem-poral were more likely to have RRD. found in the natural

history study of PVD that 6%of patients had photopsiae as presenting symptom of PVD,

14
40%had floaters and 54% reported both. Flashes are a warning signof dynamic traction on the

retina and are much more threateningphenomenon than floaters. The appearance of floaters in

patients under the age of 50 were related to opacities on the plicated membranes in

theposterior portion of the Cloquets canal and to other intravitreousopacities, which is in

contrast to patients aged 50 and older, wherethe main reason for the occurrence of floaters is

PVD.18

2.5 CLINICAL DIAGNOSTICS

A. Presentation and Characterization of Vitreous Floaters22

Floaters arising from intravitreal structural changes, typically related to myopic vitreopathy,

tend to be chronic and progressive, while floaters arising from PVD93 are acute in onset. As

reported by patients,these floaters range in appearance from small dots with linear patterns, to

spider web-like objects that float across the visual field with head or eye movement.Primary

vitreous floaters are increasingly recognized to be more prevalent than previously thought. A

recent electronic survey of 603 self-reporting participants,found that 76% of participants

reported seeing floaters, and 33% reported vision impairment due to their floaters.103 In this

group, myopes were 3.5 times more likely and hyperopes 4.4 times more likely to report

moderate to severe floaters compared to emmetropes. While interpretations from this study

are limited, related to self-reporting and the younger demographic of smartphone users (< 5%

of subjects in this study were older than 50 years of age), it does challenge the perception that

floaters are uncommon. The generally accepted notion that patients will either adapt to

floaters or that floaters will resolve over time is also defied by a study of utility values in 266

patients with floaters where duration of symptoms did not influence the findings, suggesting

that many do not successfully adapt to their symptoms. There is furthermore no data to

support the concept that primary floaters will become less symptomatic as a result of inferior

15
displacement of vitreous structures below the visual axis, although this is often mentioned

anecdotally.

B. Primary Care Evaluation of Patients With Acute-Onset Floaters/Flashes19

Step 1: Elicit the Patients History of Visual Symptoms and Assess for Nonocular

Causes.

Not all floaters and/or flashes represent ocular problems, and non ocular causes can

usually be differentiated by a careful history taking (BOX). By far the most common

condition mimicking PVD is visual aura associated with migraine, or classic migraine. 15

Patients with classic migraine describe an amorphous pattern of lights or jagged lines and

colors marching through the binocular visual field, sometimes surrounding a central area

of visual field loss. Contrary to flashing lights of retinal origin, this phenomenon is

bilateral, involves the sensation of colored lights (vs white lights in PVD), and evolves

over 5 to 30 minutes before resolving with onset of a headache. The visual aura may

occurwithout headache, representing a so-called acephalgic migraine. In these cases, most

patients have a known history of migraine. Patients with visual aura have visual acuity that

is normal (20/20) or unchanged and a normal ocular examination result. Rarely, occipital

lobe disorders such as ischemia or infarction, hemorrhage, arteriovenous malformation,

seizure disorder, and neoplasm may present with migraine-like symptoms, including

headache and/or visual symptoms. However, in these cases there are usually systemic

symptoms and signs or otheratypical features to suggest a neurological etiology. Postural

hypotension can produce brief flashes or dimming of vision in all or part of the binocular

visual field, although the diagnosis should be readily apparent from a history of transient

visual symptoms accompanying lightheadedness or ataxia precipitated by orthostatic

change in posture.

16
Step 2: Perform an Eye Examination.

The physical examination for patients with new-onset floaters and/or flashes begins with

measurement of best corrected visual acuity in each eye separately with a Snellen chart

(corrected with glasses/contact lenses or pinhole if available). This simple assessment is

imperative and often the most informative aspect of the examination because patients with

retinal tear or detachment may have decreased visual acuity in the affected eye. Ideally,

vision is measured with a calibrated distance vision chart, but vision can also be measured

at a reading distance using a near card. If visual acuity is measured at near distance, the

examiner must ensure that the patient is using his/her usual near spectacle correction.

Confrontation visual field testing is another key element of the examination because the

finding of a monocular visual field defect in the affected eye suggests an area of detached

nonseeing retina. To assess for field defects, the examiner has the patient cover one eye

and sits adjacent to the patient, face to face, at approximately 1 arms length away. The

patient is told to focus on the examiners nose, and the examiner holds up fingersin each

quadrant to grossly test the patients visual field in those quadrants using his/her own

visual field as a reference. Next, the pupils should be examined for direct response,

consensual response, and presence of a relative afferent pupillary defect. Slitlamp

biomicroscopy is available in urgent care and emergency department settings and is now

considered a basic competency for emergency physicians. The slitlamp examination may

reveal vitreous pigment or hemorrhage. Vitreous pigment, also knownas tobacco dust,

represents cellular or free melanin in the vitreous, presumably

released from the retinal pigment epithelium in association with a full-thickness retinal

tear. To diagnose vitreous hemorrhage or pigment accurately, the slitlamp beam is focused

behind the crystalline lens into the anterior portion of the vitreous. Having the patient look

17
 up, then immediately down, then immediately straight ahead before focusing the light

beam on the anterior vitreous improves visualization of vitreous hemorrhage or pigment.

Direct ophthalmoscopy after pharmacological pupil dilation can potentially provide

additional information to the generalist physician. There are no absolute contraindications

for generalist physicians to use mydriatic agents in patients with possible retinal tears,

aside from known allergy to a given drop. A common dilating approach is to use 1 drop of

tropicamide, 1.0% (maximum effect in 25 minutes; duration, 3-6 hours) and 1 drop of

phenylephrine, 2.5% (maximum effect in 20 minutes; duration, 3 hours) into each eye and

wait 30 minutes before examination. Dilating the eyes allows for better visualization of the

fundus and may allow a generalist physician to detect an obvious retinal detachment or

vitreous hemorrhage. Measurement of intraocular pressure by the generalist physician is

not necessary in the evaluation of flashes and floaters.

Step 3: Consider Ocular Causes of Floaters/Flashes and Identify High- Risk Features

for Retinal Tear or Detachment.

There are a number of ocular conditions aside from PVD that may present with floaters

and/or flashes (Box). In general, these conditions are benign and are easily differentiated

by history taking (symptoms that occur with oculodigital stimulation or rapid eye

movements), are suggested by the patients ocular history, or are very uncommon. The

bottom line is that from the perspective of the primary care physician, once an ocular

cause of acute onset floaters and/or flashes is suspected, in the absence of symptoms such

as eye pain or photosensitivity to suggest a rare inflammatory ocular condition (eg,

posterior uveitis, which has a prevalence of 0.004%), the presumed diagnosis should be

PVD. A particular concern for generalist physicians is the presence of acute flashes and/or

floaters in patients with diabetes. Advanced proliferative diabetic retinopathy can lead to

18
vitreous hemorrhage and, thus, mimic PVD symptoms of new-onset painless floaters. A

patient with a long-standing history of diabetes and known severe diabetic retinopathy

who reports acute onset of thousands of floaters and monocular vision loss most likely has

vitreous hemorrhage related to bleeding from friable new retinal vessels, though PVD with

retinal tear cannot be excluded. When triaging patients with newonset floaters and/or

flashes and a presumed diagnosis of PVD, primary care physicians must first consider and

rule out an obvious red flag sign of retinal detachment. The main sign to consider is a

progressive monocular visual field defect in the affected eye due to an area of detached

nonseeing retina. Confrontation visual field testing may demonstrate this defect, and direct

ophthalmoscopy through a dilated pupil may reveal a billowing retinal detachment. A

patient with suspected retinal detachment, requires emergent ophthalmologic assessment.

Failure to elicit a visual field defect through confrontation or to see theretinal detachment

with direct ophthalmoscopy does not rule out the process of retinal detachment. Once an

obvious visual field defect is ruled out, the primary care physician must decide on the

urgency of an ophthalmology referral. The role of the ophthalmologist is 2-fold. First, the

ophthalmologist can rule out other ocular causes of floaters and/or flashes. Second, the

ophthalmologist can perform a comprehensive retinal examination to assess for retinal

tears. To help guide primary care physicians in the triaging process, we systematically

reviewed the literature to quantify the importance of symptoms and signs in patients with

floaters and/or flashes and a diagnosis of PVD that might indicate the presence of retinal

tears and increased risk of retinal detachment.

19
Fundus Photograph of Vitreous Hemorrhage

C. Imaging Vitreous Floaters (Ultrasound, SD-OCT, SLO, Dynamic Light

Scattering)13,20

While physical examination with slit lamp biomicroscopy can be used to visualize

central and posterior vitreous structure, it is difficult to visualize the entire vitreous body.

Further, ophthalmoscopy, both direct and indirect, cannot adequately evaluate fine vitreous

structure.

Ultrasound can be used to image opacities within the entire vitreous body based on their

echodensity as well as impedance differences at gel-liquid interfaces. Conventional

diagnostic B-scan ultrasound systems typically assess differences in the sound wave

impedance at interfaces of tissues with different densities, such as the retina and vitreous, but

can also be used to detect interfaces between liquefied and gel vitreous, as well as detect

echoes from vitreous collagen aggregates. Oksala employed ultrasonography to detect echoes

from gel-liquid interfaces in 444 healthy patients and found that the vitreous body was

20
acoustically homogeneous in all individuals under the age of 20 years. Gelliquid interface

echoes were detected in 5% of individuals aged 21 - 40 years, 19% of those aged 41 - 50,

63% aged 51 - 60, and in 80% of individuals older than 60 years of age. Not all of these

interfaces, however, result in symptomatic floaters. Indeed, it is probable that only central

vitreous opacities are likely to be symptomatic. This has been confirmed by Mamou et al.

who found that the vitreous echodensities in the premacular region had the highest correlation

with diminished contrast sensitivity and dissatisfaction with vision as quantified by the N.E.I.

validated Visual Function Questionnaire (VFQ; see below).

Ultrasonography is routinely used to diagnosis PVD, since the dense collagen matrix of the

posteriorvitreous cortex is adequately imaged with conventional B-scan ultrasound once it

separates from the retina. Thus, in the typical evaluation of patients complaining of floaters

ultrasound is usually only used to establish the diagnosis of PVD and rule-out retinal

detachment, although ultrasonography provides real-time imaging of internal and peripheral

vitreous structure. There are recent advances, however, in ultrasonography in the evaluation

of patients with floaters.

Quantitative ultrasonography of vitreous,developed to generate an objective, reproducible,

and quantitative index of vitreous echodensity, provides a useful measure of floater severity.

Such a clinical metric can furnish clinicians with a quantitative assessment of severity based

upon vitreous structure, and theoretically offer a useful adjunct to functional assessments of

vision (see below). Recent studies have indeed demonstrated a positive correlation between

quantitative ultrasonography, contrast sensitivity, and quality of life as quantified by the

N.E.I. VFQ. Such objective metrics for measuring vitreous structure and floater-induced

visual disability as well as assessing quality of life, provide a rational way to gauge clinical

severity and select patients for therapy. These indices can also be used as quantitative

outcome measures to evaluate the effects of vitrectomy, Nd:YAG laser, or pharmacologic

21
vitreolysis. Future developments of superior ultrasound technology such as pulse-encoded

imaging with an annular array probe will likely provide even better techniques with which to

characterize vitreous structure clinically and to evaluate the response to various treatments.

Optical Coherence Tomography (OCT) allows detailed imaging of both the transverse and

coronal (en face) aspects of the vitreo-retinal interface. Recent imaging studies have

combined SD-OCT with scanning laser ophthalmoscopy (SLO) to better evaluate the vitreo

macular interface in various disease states including vitreous floaters (see below); however,

to date, OCT can only image floaters when the vitreous opacities are within a few millimeters

of the retina and therefore it is not an effective technique to identify all vitreous opacities that

are responsible for symptoms. Although it is unlikely that the peripheral vitreous is

responsible for clinically significant floaters, the central and anterior vitreous may be

important but are currently not adequately visualized by OCT. When vitreous floaters are

located posteriorly a floater scotoma" can at times be observed as shadowing on the OCT

image of the retina created by vitreous opacities (see below). There are cases of prefoveal

focal vitreous opacities that cause bothersome floaters that are better on imaged by OCT than

ultrasonography.

Scanning Laser Ophthalmoscopy (SLO) can provide useful evaluation and documentation

of vitreous opacities. both the umbra and penumbra cast by vitreous opacities can be

visualized. It might be useful to perform image analysis of such SLO photos with the aim of

quantifying the umbra and penumbra effects as a way of indexing floater size and density.

Such quantitative measures of vitreous structure could then be used as an index of clinical

severity, as has previously been done with ultrasonographys

22
Dynamic Light Scattering

uses a laser-based nanodetector system for non-invasive in vivo visualization of particles

from 3 nanometers to 3 microns in size within the ocular media including the cornea, lens,

aqueous, and vitreous1. DLS can thus be used to detect morphometric changes in the

constituent molecules of ocular media; for example, the aggregation of lens crystallins in

cataract formation and vitreous collagens as seen in myopic vitreopathy, aging, , and diabetic

vitreopathy. This technique has also been used to evaluate the effects upon

vitreousmacromolecules following pharmacologic vitreolysis with ocriplasmin,

hyaluronidase, and collagenase.

2.6 TREATMENT OF FLOATERS: EVIDENCE FOR SAFETY & EFFICACY

Once diagnosed, patients complaining of floaters are usually managed conservatively with

reassurance and the suggestion that over time they will adapt to the visual symptoms, or that

the floaters will settle inferior to the visual axis. In discussing treatment options, a careful and

thorough history should be taken, including family history of retinal detachment, prematurity,

feeding problems, arthritis, and midline defects. Funduscopic examination should rule-out

vitreous base infiltrates and pars planitis. OCT imaging should be performed to examine for

macular edema and premacular membranes with macular pucker. A thorough examination

may also include fluorescein angiography to detect occult areas of non-perfusion. In myopes,

the palate and hearing could be checked. If posterior capsule opacification, retinal

detachment, macular pucker, and/or cystoid macular edema are found in addition to floaters,

informed consent should emphasize the potentially limited benefit of therapeutic intervention.

This workup should be detailed as patients typically present with relatively good visual

acuity, and there are potential risks to treatment as a result of endophthalmitis,

23
rhegmatogenous retinal detachment, cystoid macular edema, and macular pucker. These must

be clearly identified in a balanced, unpressured explanation of risks and benefits. For patients

with clinically significant and persistent floaters that remain highly symptomatic and impact

on quality of life, our review of the literature indicates that interventional options are

increasingly being considered. These fall into two categories: Floaterectomy by vitrectomy,

particularly sutureless small gauge limited vitrectomy; and Floaterrhexis, via Nd:YAG laser

vitreolysis, or in the future via pharmacologic vitreolysis. Vitrectomy is definitive in that

offending vitreous opacities are permanently removed. In contrast, Nd:YAG laser breaks

large floaters into smaller ones, while pharmacologic vitreolysis can theoretically dissolve

floaters, but this remains to be proven.

A. Vitrectomy for Floaters

Symptomatic floaters can be surgically removed with vitrectomy, and numerous studies have

evaluated the success of vitrectomy for treating vitreous floaters versus the potential risks. To

date, 630 cases have been reported, with information regarding various sized instruments and

different degrees of invasiveness. What all vitrectomies have in common is removal of both

collagen and hyaluronan, which is in contradistinction to Nd:YAG laser treatments. While

initial studies employed 20G instrumentation, current approaches typically employ 25G

vitrectomy instruments. It is not known whether 27G instruments offer any advantage over

25G. Three port entry with operating microscope visualization and endoillumination is the

most commonly employed approach, although Koch in Frankfurt, Germany employs a single

port approach with indirect ophthalmoscopy. Current surgical techniques are sutureless

because highly-shelved small gauge sclerotomies are selfsealing, obviating the need for

sutures. Aspiration settings and cut rates are the same as typically used for vitrectomy, i.e.

between 400 and 600 aspiration and 1800 cuts per minute. The amount of vitreous removed

24
varies from extensive with surgical induction of posterior vitreous detachment (PVD) at some

centers, to limited without PVD induction and with preservation of 3 to 4 mm of retrolental

vitreous. The preservation of retrolental vitreous is thought by some to mitigate cataract

formation post-op, and there is some data to support this contention (see below). The amount

of vitreous removed determines how much balanced salt solution is infused, varying from

more than 10 - 15 ml in extensive vitrectomies to around 5 ml for limited vitrectomies,

although no actual measurements have been performed in any reported studies. Future

surgical techniques might involve robotic surgery as a way to further enhance control over

how much and which parts of the vitreous body are removed.

1. Efficacy

The success rate of vitrectomy for floaters is usually reported to be high. Although visual

acuity is not severely affected by vitreous floaters, several studies did report a small

improvement in acuity ranging from 26 to 50% of participants in cases that were not

confounded by additional procedures of cataract removal. Other measures of vision

improvement included contrast sensitivity and straylight values9. Another measure of success

is symptomatic improvement following surgery, often assessed using a questionnaire. These

questionnaires posed questions relating to ease of daily activities, including reading, using

computers, watching television, and driving as well as overall satisfaction with the results of

the procedure. Studies have used a combination of standardized and non-standardized

questionnaires. Across the various studies, survey results showed the percentage satisfied

ranged from 85% to 100% of participants; however, the subjective basis of this testing makes

it vulnerable to aplacebo effect, found by many studies to be a significant factor in patients

undergoing Nd:YAG laser treatments for floaters (see below).

25
2. Safety

A range of complications is reported among different studies. Peri-operative complications

include intraoperative and post-operative retinal tears, retinal detachment, choroidal

hemorrhage, and proliferative vitreo-retinopathy. The most common complication, however,

is the development of cataracts.

a. Retinal Breaks and Detachments

The reported incidence of retinal breaks varied between 0 and 16.4%, with the larger

sample sizes tending to exhibit higher percentages of retinal breaks and detachments. The

more serious complication of a retinal detachment following vitrectomy has an incidence

between 0% and 10.9%, . More cases of retinal detachment are reported in those studies

with longer follow up periods, often occurring relatively late in these follow up periods.

Thus, it is possible that the short-term studies did not consider a long enough follow-up to

record a valid complication rate, or conversely that the longterm studies may have other

confounding circumstances such as age, natural history of the disease, or subsequent

cataract surgery. It is therefore unclear at what point in time a post-operative retinal

detachment should no longer be considered a complication of floater vitrectomy. The

induction of PVD during surgery may be an important factor in the development of retinal

breaks. In the studies examined, patients who had not already developed a PVD naturally

would often have a PVD induced during the vitrectomy. The risk of iatrogenic tears

associated with vitrectomy may increase with PVD induction during surgery11. Although

one study88 found a nearly 3-fold higher incidence of retinal tears following PVD

induction [30.5% vs. 11.6%; P = 0.019], this association was not always found. Smaller

gauge instrumentation appear to reduce the risk of post-surgical rhegmatogenous

complications. It is also important to consider that the option of not inducing a PVD

during floater vitrectomy so as to avoid the potential complication of retinal breaks may

26
have other long-termconsequences including the recurrence of floaters as a result of

subsequent PVD, a risk of retinal detachment due to future PVD, or the development of

macular pucker as a result of leaving the posterior vitreous cortex on the macula. In our

(JS) experience based upon 120 carefully monitored cases with a mean followup of 21

months, the risk of these events is less than 1%. Thus, in floater patients with an attached

vitreous (typically young myopes) minimally invasive methods involving no PVD

induction or non-surgical approaches such as pharmacologic vitreolysis may be the best

way to minimize these complications. Lastly, some retinal tears may be pre-existing, so a

meticulous pre-operative examination is very important in identifying and treating

peripheral retinal pathology before vitrectomy surgery, so as to mitigate against retinal

detachments following floater vitrectomy.

b. Intraocular Pressure Problems

Changes in intraocular pressure are a complication of vitrectomy that can lead to either

hypotony or ocular hypertension. Hypotony is uncommon, even when using small gauge

instruments and sutureless technique, but can be prevented using air tamponade at the time

of vitrectomy. Acute post- operative ocular hypertension is rare, but can be treated with

IOP lowering medications and generally resolves within 3 weeks of the surgery. Chronic

glaucoma has been described in patients after vitrectomy, potentially occurring many years

later. Introduction of oxygen and toxicity to the trabecular meshwork during the

vitrectomy has been hypothesized as a cause, with increased risk following lens removal.

Other possible contributing mechanisms include surgical inflammation and debris,

increased susceptibilit of the optic disc post vitreous removal and an altered biochemical

environment. Thus, detection of this potential complication needs long-term follow-up;

however glaucoma has not been consistently shown among all studies. Longer term

monitoring of IOP and optic disc morphology may be of value until this risk is further

27
elucidated and potentially minimized with refined vitrectomy procedures. To date,

however, IOP problems have not been encountered to any appreciable degree following

vitrectomy for floaters.

c. Cataracts

Cataracts following vitrectomy in phakic patients are common, occurring in approximately

53% to 76% of cases, depending upon the vitreoretinal pathology that necessitated

vitrectomy and systemic conditions such as diabetes. These studies have shown that

cataracts will develop within two years following the procedure in patients over 50 years

of age. The use of a gas bubble increases the incidence of cataract following a vitrectomy.

One study did report a lower incidence of cataract formation; however, it was unclear how

many of these patients were aphakic in the vitrectomy treatment group. A recent study50

found that cataract surgery was required in only 23% of cases following floater vitrectomy,

with a mean age of 64 years. No patients younger than 53 years of age required cataract

surgery. The authors suggested that this was the result of lower intravitreal oxygen tension

related to not inducing PVD at floater vitrectomy surgery, and protection of the lens

provided by endogenous anti-oxidants in the anterior vitreous that was left intact during

vitrectomy surgery. These findings were confirmed in a more recent study that followed

patients for 2 years comparing the incidence of cataract surgery following extensive

vitrectomy to limited vitrectomy for floaters. The incidence after limited vitrectomy was

half of that following extensive vitrectomy. Targeted floaterectomy may thus preserve a

relatively hypoxic environment and further reduce the incidence of cataracts.14

d. Endophthalmitis

28
 Endophthalmitis is a potential serious complication of any intraocular surgery, including

vitrectomy. Cases of endophthalmitis often have a poor visual outcome. The reported risk

has decreased over time, with more recent reports ranging from 0.018% to 0.04% for post

vitrectomy cases. Of the floater vitrectomy studies available, three cases of

endophthalmitis were reported, consistent with its low incidence.10

B. Nd:YAG Laser Vitreolysis14

Nd:YAG (neodymium-doped yttrium aluminium garnet) lasers are most commonly used for

treating posterior capsule opacification following cataract surgery and opacified anterior

vitreous membranes, as well as for performing peripheral iridotomy; however, Nd:YAG

lasers have also been used to severe collagenous vitreous strands, transvitreal sheets or bands

and most recently to break up vitreous opacities. This is generally performed by focusing the

laser onto vitreous opacities visible at the slit lamp. Typically, only opacities relatively far

from the retina are treated (see below), thus these may represent a subset of floaters that

might be appropriate to treat with Nd:YAG laser, although it is not known whether these

opacities induce enough floaters to be clinically significant. Unlike vitrectomy, the procedure

is closed eye obviating the risk of endophthalmitis and possibly not increasing the risk of

cataract, although if vitreous physiology is altered, there may cataractogenic effects via

increased oxygen levels and altered anti-oxidant activity. As the Nd:YAG laser is focused

upon collagenous vitreous opacities, the hyaluronan component may be minimally affected

by the laser energy. The mechanism of laser vitreolysis may be lysis of fibers and rhexis of

aggregates, followed by displacement out of the visual axis, since nothing is removed from

the vitreous in this closed-eye procedure. Nd:YAG laser vitreolysis thus may be considered

an alternative technique that can be offered to treat symptomatic vitreous floaters; however,

Nd:YAG laser vitreolysis is not currently offered by the overwhelming majority of

29
ophthalmologists as a treatment for symptomatic floaters and, to date, there areonly 91 cases

of Nd:YAG laser vitreolysis of floaters in the literature, compared to 630 floater

vitrectomy cases. However, as a result of marketing and promotion efforts by one laser

manufacturer, the use of this treatment may be expanding.

1. Efficacy

There have been several published studies claiming efficacy of Nd:YAG laser vitreolysis for

floaters, but few case reports are available. These studies are highly variable in design and

treatment protocols, with all having relatively small sample sizes. Assessment of the outcome

and success of the procedure was generally subjective, with none using standardized

questionnaires, and the majority relying on self-reporting of whether there was resolution of

floater symptoms. Most importantly, no objective outcome measures of vision or vitreous

structure were employed in any Nd:YAG laser vitreolysis studies. Using the patients

subjective claim of the resolution of floaters as an outcome measure, the success rates

claimed by existing publications are highly variable, ranging from 0 to 100%. Vandorselaer et

al. suggested that the likelihood of success of the treatment relates to the type of floater with

regards to its suspension characteristics99. They claimed significantly higher success rates in

the treatment of floaters that were suspended by vitreous strands, as opposed to those located

loosely within the vitreous body; however, no objective measures or imaging studies were

performed to support this contention. Although not specified in several of the studies, it

appears that Nd:YAG laser for treating floaters is not necessarily a simple procedure, often

requiring several sessions of treatment. The reported number of required sessions ranged

between one and six. There was also variability in the laser energy used and distance from the

retina of opacities treated, although it is not clear how the distance from the retina was

measured and whether any reproducible objective method was employed. Delaney et al. used

2 mm as a threshold distance with only 1.2mJ per pulse. In contrast, Tsai et al. used energy

30
pulses ranging from 5 to 10mJ but kept a minimum distance of 4 mm from the retina. Little

and Jack used energy pulses rangingfrom 4 to 15mJ in their study, and maintained a distance

of 3 mm from the retina. This greater energy requirement may have been used in other parts

of the study such as cutting vitreous bands in the posterior chamber rather than disrupting

vitreous opacities. Such heterogeneity in the study groups diminishes the value of the

reported findings. In addition to the aforementioned published studies, there are non-peer

reviewed reports available online relating to the "success" of laser treatments for floaters2,

41. One website reported 200 patients within a single practice treated with laser for vitreous

floaters with a satisfaction rate of 92% and no complications. The highest success rates, on

the order of 98%, were reported when treating a Weiss ring; however the reported success

rates were significantly less when attempting to treat smaller floaters41. Another websitethat

advocates the use of Nd:YAG laser in treating floaters summarized the experiences of two

clinicians using laser treatments for floaters. Although no formal studies were reported, the

site reports estimated success rates in treating "simple" vitreous opacities of 95 to 98% for

one clinician and 60 to 95% for the other. The methodology supporting these reported success

rates was not explained.

2. Safety

Among the studies reviewed, a minimal complication rate has been consistently reported,

with only one case of uveitis and transient increased IOP across all studies. Nonetheless,

studies have shown that complications can arise when Nd:YAG laser is used within 2 to 4

mm of the retina or the crystalline lens and is more likely in settings of higher energy2. The

position of focus of the laser beam is an important factor, which if miscalculated could result

in problems, as failure to meet these safety requirements may result in destruction of ocular

tissues. Complications reported for the use of Nd:YAG laser in vitreous when treating

31
conditions other than floaters included retinal holes, chorio-retinal bleeding, vitreous

hemorrhage, local retinal swelling, and cystoid macular edema. There have also been cases of

a permanent increase in IOP reported following Nd:YAG laser vitreolysis for floaters, leading

to open-angle glaucoma.21

32
2.7 CONCLUSIONS

Primary vitreous floaters that result from myopia or age-related vitreous degeneration,

and secondary floaters, usually from vitreous hemorrhage or uveitis, are at times highly

symptomatic and can significantly impact on vision and quality of life. The current treatment

options available for vitreous floaters are vitrectomy and Nd:YAG laser. Vitrectomy has a low

risk profile with an excellent success rate, as determined by objective measures of vision and

standardized quantification of patient satisfaction. On the other hand, Nd:YAG laser for

floaters remains an off-label procedure that is not commonly reported in the peer-reviewed

literature. The response rate to laser is highly variable and while the reported complications

are minimal, rigorous study protocols have not been employed. 23

The advantages of Nd:YAG laser is that the eye remains closed and that vitreous

components are torn and severed, but not removed. Centrally suspended, single floaters might

be candidates for laser lysis or displacement, but this remains to be demonstrated.

Management of floaters should be individualized, prepared by good history taking, and

welldocumented by imaging, allowing for more targeted, limited, and focal intervention.
24
Vitrectomy techniques could be refined by removing only floaters without infusion or using

a robot-guided small gauge one or two port high speed vitrectomy that only removes floaters,

filters out the collagen and reinfuses the autologous anoxic hyaluronan, thus possibly

mitigating cataract and glaucoma, although other effects may be induced. Further prospective

studies using objective, quantitative, standardized outcome measures already employed for

the assessment of vitrectomy are required for evidence-based conclusions regarding the

relative efficacy and safety of Nd:YAG laser treatments. Ultimately, the future will most

33
likely see vitrectomy made simpler or replaced by pharmacologic vitreolysis as a less

invasive treatment for patients with floaters.25

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