arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma;...

51
Glaucoma Jost B. Jonas, MD(1), Tin Aung MD(2), Rupert R. Bourne, MD(3), Alain M. Bron, MD(4), Robert Ritch, MD(5), Songhomitra Panda-Jonas, MD(1) (1) Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Germany (2) Singapore Eye Research Institute, Singapore; Singapore National Eye Centre, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (3) Vision & Eye Research Unit, Anglia Ruskin University, Cambridge, UK (4) Department of Ophthalmology, University Hospital, Dijon, France; Eye and Nutrition Research Group, Bourgogne Franche-Comté University, Dijon, France (5) Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA Running title: Glaucoma Key words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Transcript of arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma;...

Page 1: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

Glaucoma

Jost B. Jonas, MD(1), Tin Aung MD(2), Rupert R. Bourne, MD(3), Alain M. Bron, MD(4), Robert

Ritch, MD(5), Songhomitra Panda-Jonas, MD(1)

(1) Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of

Heidelberg, Germany

(2) Singapore Eye Research Institute, Singapore; Singapore National Eye Centre, Singapore;

Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of

Singapore, Singapore

(3) Vision & Eye Research Unit, Anglia Ruskin University, Cambridge, UK

(4) Department of Ophthalmology, University Hospital, Dijon, France; Eye and Nutrition Research

Group, Bourgogne Franche-Comté University, Dijon, France

(5) Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York,

NY 10003, USA

Running title: Glaucoma

Key words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension

glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital glaucoma; Trans-

lamina cribrosa pressure difference; Trans-lamina cribrosa pressure gradient; Intraocular

pressure; Optic nerve head; retinal nerve fiber layer; Optical coherence tomography; Perimetry;

Glaucoma surgery;

Funding: None

Corresponding author: Prof. J. Jonas, Universitäts-Augenklinik, Theodor-Kutzer-Ufer 1-3, 68167

Mannheim, Germany; Phone: **49-6221-3929320; e-mail: [email protected]

1

2

3

4

5

6

7

8

9

1011

12

13

14

15

1617

181920

21

2223

24

25

26

27

28

29

30

3132333435

36

37

Page 2: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

2 Glaucoma

SummaryGlaucoma is a heterogeneous group of diseases with an intraocular pressure (IOP) higher than

the pressure resistance of the optic nerve head. It is characterized by optic nerve head cupping

and visual field damage. It is the most frequent cause of irreversible blindness worldwide with an

age-standardized prevalence of 3% in the population aged 40+ years. Chronic glaucomas are

painless and symptomatic visual field defects occur late. Early detection by ophthalmological

examination is therefore mandatory. The most common risk factors for primary open-angle

glaucoma, the most common form of glaucoma, include elevated IOP, older age, Sub-Saharan

African ethnicity, positive family history and high myopia. Older age, hyperopia and East Asian

ethnicity are main risk factors for primary angle-closure glaucoma. Glaucoma diagnosis is based

on ophthalmoscopy, perimetry and tonometry. Therapy is based on medication to lower IOP,

laser treatment, and surgical intervention if these treatment modalities fail to prevent progression.

38

39

40414243444546474849

Page 3: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

3 Glaucoma

IntroductionRanking above other major eye diseases, such as age-related macular degeneration, diabetic

retinopathy and myopia, glaucoma is the most frequent cause of irreversible blindness

worldwide.1–3 Since chronic open-angle glaucoma is usually painless and can progress unnoticed

by the patient until central visual acuity and reading ability are affected late in the disease, early

detection is important before subjective symptoms develop. The importance of glaucoma as a

public health problem will continue to increase as most glaucomas are age-dependent and the

number of older individuals is increasing worldwide due to demographic trends and longer life

expectancy.3 This article outlines the epidemiology, pathophysiology, symptoms, diagnosis and

therapy, and potential future developments in the field.

TerminologyThe term “glaucoma” includes a panoply of diseases which differ in their etiology, risk factors,

demographics, symptoms, duration, therapy and prognosis. They have in common a

characteristic optic neuropathy underlying irreversible visual loss. The term was used inclusively

prior to the increasing discovery of subdivisions, which are themselves distinct diseases with

different genetic and pathophysiologic risk factors. Depending on the morphology of the anterior

chamber angle (the region between the peripheral cornea and the peripheral iris), glaucoma can

be broadly divided into open-angle glaucoma and angle-closure glaucoma (Fig. 1, 2). In open-

angle glaucoma, the aqueous humour has free access in the anterior chamber angle to the

trabecular meshwork and Schlemm´s canal, through which it leaves the eye. In “secondary”

open-angle glaucomas, the outflow resistance through the trabecular meshwork/Schlemm´s canal

is increased due to a cause visible on eye examination, such as in pigmentary glaucoma and

exfoliative glaucoma.4,5 In primary open-angle glaucoma (POAG) (both “high-tension” and

“normal-tension”), no visible cause is evident on examination, but relatively recent and ongoing

discoveries are elucidating differences in both genetic parameters and systemic risk factors

allowing increasing differentiation of POAG, which was until recently thought of as a single

disease.

In angle-closure, the peripheral iris is in contact with the trabecular meshwork at levels up

to Schwalbe’s line, so that the anterior chamber angle is blocked by iris tissue and the aqueous

humour has no access to the outflow system.6,7 In primary angle-closure (PAC, “push”

mechanism), the iridocorneal contact is caused by a forward bulging of the peripheral iris, due to

an increased pressure difference between the posterior chamber and anterior chamber of the

eye, or due to an anatomical predisposition of the morphology of the anterior chamber angle.

Primary angle-closure glaucoma (PACG) is present when glaucomatous optic nerve and visual

field damage occurs. In secondary angle-closure glaucoma (“pull” mechanism), the iridocorneal

contact is caused by the iris being pulled into the angle by causes such as neovascularization in

50

51

5253545556575859

60

61

62

63646566676869707172737475767778

7980818283848586

Page 4: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

4 Glaucoma

the iris root, usually provoked by ischemic retinopathy (“neovascular glaucoma”), iridocorneal

endothelial syndrome, or peripheral anterior synechiae caused by uveitis.8 In congenital

glaucoma, the trans-trabecular outflow is reduced, often due to a not (yet) fully developed

trabecular meshwork and Schlemm´s canal.9 The increase in intraocular pressure (IOP) in

children younger than 2 years results in an enlargement of the globe, also called buphthalmos.

EpidemiologyAs reported by the Global Burden of Disease Study, 32.4 million individuals worldwide were blind

(defined as visual acuity in the better eye of <3/60) and 191 million individuals were vision

impaired (defined as visual acuity in the better eye of <6/18, ≥3/60) in 2010.10 Glaucoma was the

cause for blindness in 2.1 million (95% uncertainty interval (UI):1.9, 2.6) people and was the

cause for visual impairment in 4.2 million (95% UI:3.7, 5.8). Glaucoma caused 6.6% (95% UI: 5.9,

7.9) of all blindness worldwide in 2010 and 2.2% (95% UI: 2.0, 2.8) of all visual impairment. Due

to its association with older age, glaucoma prevalence was lower in regions with younger

populations than in high-income regions with relatively old populations. From 1990 to 2010, the

number of blind or visually impaired due to glaucoma increased by 0.8 million (95%UI: 0.7, 1.1) or

62% and by 2.3 million (95%UI: 2.1, 3.5) or 83%, respectively. The age-standardized global

prevalence of glaucoma related blindness in adults aged 50+ years decreased from 0.2% (95%

UI: 0.1, 0.2) in 1990 to 0.1% (95% UI: 0.1, 0.2) in 2010. The age-standardized global prevalence

of glaucoma related visual impairment for the same age group increased from 0.2% (95%UI: 0.2,

0.3) to 0.3% (95% UI: 0.2, 0.4). Between 1990 and 2010, the percentage of global blindness and

visual impairment caused by glaucoma increased from 4.4% (4.0, 5.1) to 6.6%, and from 1.2%

(1.1, 1.5) to 2.2% (2.0, 2.8), respectively. Age-standardized prevalence of glaucoma related

blindness and visual impairment did not differ markedly between world regions nor between

women (0.1% (95% UI: 0.1, 0.2) and 0.3% (95% UI: 0.2, 0.4), respectively) and men (0.1% (95%

UI: 0.1, 0.2) and 0.3% (95% UI:0.3, 0.4), respectively).10

In a recent meta-analysis, the global prevalence of glaucoma was 3.54% (95% credible

Intervals (CrI), 2.09-5.82) for the population aged 40-80 years.3 POAG with a pooled global

prevalence of 3.05% was six times more common than PACG with a pooled global prevalence of

0.50%. The prevalence of POAG was highest in Africa (4.20%; 95% CrI, 2.08-7.35), and the

prevalence of PACG was highest in Asia (1.09%; 95% CrI, 0.43-2.32). In 2013, the number of

people aged 40-80 years with glaucoma worldwide was assessed to be 64.3 million, predicted to

increase to 76 million in 2020 and to 112 million in 2040. Men were more likely to have POAG

than women (odds ratio [OR], 1.36; 95% CrI, 1.23-1.52), and people of African ancestry were

more likely to have POAG than people of European ancestry (OR, 2.80; 95% CrI, 1.83-4.06). The

prevalence of glaucoma-related bilateral blindness or unilateral blindness was higher in the

PACG group than in the open-angle glaucoma group, suggesting that PACG has a worse visual

87

88899091

92

93

94

9596979899

100101102103104105106107108109110111112113

114115116117118119120121122123

Page 5: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

5 Glaucoma

outcome and prognosis.

Anatomy and PhysiologyIntraocular pressure (normal range: 10-21 mm Hg) is regulated by a balance between the

secretion of aqueous humour by the ciliary body in the posterior chamber and its drainage from

the anterior chamber angle either through the trabecular meshwork and Schlemm´s canal into the

episcleral veins or via the uveoscleral outflow pathway through the iris root into the uveoscleral

interface (into the ciliary body?) (Fig. 1, 2). The physiological functions of the aqueous humour

include maintaining the IOP to give the eye a constant shape and size (what is of utmost

importance for the optical system of the eye), nutrition of the lens and cornea, and heat

convection in the anterior chamber. Elevated IOP is due to decreased outflow facility of aqueous

humour.

In glaucomatous optic neuropathy, typical morphological changes can be detected with

ophthalmoscopy in the retinal nerve fiber layer and at the optic nerve head (Fig. 3-5).11–13 The

retinal nerve fiber layer inside the eye consists of the retinal ganglion cell (RGC) axons and forms

the inner layer of the retina. It is located between the RGC layer on its outer side and the inner

limiting membrane as the basal membrane of the retinal Müller cells on its inner side.

The optic nerve head (also called optic disc) is the anterior tissue of the optic nerve

located 15° nasal to the fovea (the center of the macula). Its diameter is about 1.5 to 2.0 mm. Its

area, showing an inter-individual variability of about 1:7, is associated with the ethnic background:

Caucasians have on an average smaller optic discs as compared to Chinese, followed by Indians

and Africans or individuals of African descent (Fig. 3).15 Its size is constant after about age 15

years, except for highly myopic eyes, in which the optic disc secondarily enlarges in association

with the axial elongation of the eye. The RGC axons exit the eye at the optic disc and form the

optic nerve posterior to the eye. The optic disc also serves for the exit of the central retinal vein

and for entry of the central retinal artery. The base of the optic nerve head consists of the lamina

cribrosa, a perforated collagenous sieve-like structure through which the optic nerve fibers and

blood vessels take their course, and which is the site at which the damage to the RGC

axons/optic nerve fibers occurs in glaucoma (Fig. 6).16 It is the frontier between the intravitreal

compartment with the IOP and the retro-laminar compartment with the optic nerve tissue pressure

and the retrobulbar cerebrospinal fluid pressure. 17 The trans-lamina cribrosa pressure difference

has been defined as difference between IOP and retrobulbar pressure, mainly the retrobulbar

cerebrospinal fluid pressure. 18 Inside the optic disc, the RGC axons form the neuroretinal rim,

while the disc center is occupied by the optic cup, a nerve fiber free region. Under physiological

conditions, rim size and cup size increase with larger optic disc size. The neuroretinal rim has a

characteristic shape following the so called ISNT (inferior–superior–nasal–temporal) rule; it is

usually widest in the inferior disc region and superior disc region, and it is thinnest in the temporal

124

125

126

127

128129130131132133134135136

137138139140141

142143144145146147148149150151152153154155156157158159160

Page 6: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

6 Glaucoma

disc sector.19 In the retro-laminar region, the RGC axons form the optic nerve, which contains

approximately 1.4 million myelinated axons at birth and physiologically loses about 0.3% of these

axons per year of age.

PathophysiologyIn contrast to a variety of causes for elevated IOP or reasons for increased susceptibility of the

optic nerve head to glaucoma whether or not IOP is elevated, all glaucomas have in common

typical optic nerve damage, or glaucomatous optic neuropathy, a neurodegenerative disorder.

Elevated IOP can be due to specific causes, such as liberation of pigment granules from the iris

pigment epithelium, as is the case in both pigment dispersion syndrome/glaucoma and exfoliation

syndrome/glaucoma.5 Glaucomas in which a definitive cause is recognizable on slit-lamp

examination are termed “secondary” glaucomas.

In pigment dispersion syndrome, which has its onset in the second and third decade, the

peripheral iris is concave and rubs against the zonular apparatus during accommodation and

during pupillary dilation and constriction. It is far more common than previously believed and

often goes undiagnosed because of low suspicion of glaucoma in the younger population. It can

have an autosomal dominant inheritance and leads to glaucoma in about 10% of affected

individuals. Men and women are equally affected but glaucoma is about three times as common

in men. Eighty percent of those manifesting signs of the disorder are myopes and 20%

emmetropes. Its occurrence in hyperopes is extremely rare, but these people serve as carriers of

the gene. The incidence of glaucoma increases in women after menopause. The iridozonular

friction between the posterior surface of the iris and zonule fibers of the lens leads to disruption of

the iris pigment epithelium and the liberated pigment is deposited on structures throughout the

anterior chamber, including the trabecular meshwork, where it may increase aqueous outflow

resistance and lead to elevated IOP.20

Exfoliation syndrome is an age-related disease and is the most common recognizable

cause of open-angle glaucoma worldwide, accounting for the majority of cases in some

countries.4 It is estimated to affect about 80 million people worldwide and is most common in

Caucasians. About 1/3 of affected individuals develop glaucoma, which carries a more severe

prognosis than POAG. It is characterized by the production, deposition, and progressive

accumulation of a white, fibrillar, extracellular material in many ocular tissues, most prominent on

the anterior lens surface and pupillary border and represents a generalized disorder of elastic tissue and

the extracellular matrix (Fig. 7).21 Rubbing of the iris over the lens causes disruption of the deposited

exfoliation material, while the material itself acts like sandpaper, disrupting the iris pigment

epithelium and leading to pigment liberation, both of which are deposited in the trabecular

meshwork, leading to increased outflow resistance and often markedly elevated IOP. Exfoliation

syndrome causes not only open-angle, but also is a prominent cause of angle-closure glaucoma.

161

162163

164

165

166

167168169170171172173

174175176177178179180181182183184185186

187188189190191192193194195196197

Page 7: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

7 Glaucoma

It is not a “type” or “form” of glaucoma, but the glaucoma is an ocular manifestation of a systemic

disorder, and associations with other disorders are being steadily assessed. These disorders

include hearing loss, cerebrovascular and cardiovascular disease, and disorders of elastic tissue,

including pelvic organ prolapse and inguinal hernia. It is considered a conformational disorder of

fibrillin and has been shown to be a disorder of autophagy and mitochondrial dysfunction, similar to

other neurodegenerative diseases.22 Two single nucleotide polymorphisms of the LOXL1 gene are

present in 99% of affected Caucasians, but a large portion of the unaffected populations,

including non-Caucasians, also have these polymorphisms, implying that they are not causative

in themselves.23 An additional 5 genes have recently been described. Environmental factors

appear also to influence the manifestation of the disease.24

In POAG, aqueous humour outflow resistance is increased to yet unknown factors. The

level of IOP varies markedly and reaches down to subnormal values of as low as 10 mmHg. If in

the case of POAG, glaucomatous optic nerve damage developed in the presence of statistically

normal IOP levels, the condition has also been called normal-pressure glaucoma, showing the full

range of POAG. In normal-pressure glaucoma, aqueous outflow resistance is normal or may be

slightly increased.

In primary angle-closure glaucoma, as mentioned, aqueous humour access to the outflow

pathways is blocked by contact with or without adhesions between the peripheral iris and the

anterior trabecular meshwork, where Schwalbe’s line forms the boundary between that structure

and the cornea. Reasons are an increased pressure difference between the posterior chamber

and the anterior chamber due to an increased trans-pupillary flow resistance in association with

anatomic parameters, such as an increased lens vault, an enlarged contact area between the

posterior iris and the lens surface, and an abnormal insertion of the iris root on the ciliary body

(Fig. 1).7 In secondary angle-closure glaucoma, a neovascularization in the anterior chamber has

developed as reaction of an ischemic retinopathy, such as proliferative diabetic retinopathy, with

formation of vascular endothelial growth factor (VEGF).25 The newly formed blood vessels cover

the anterior chamber angle, block the latter by formation of a new basement membrane on the

surface, and finally retract the peripheral iris peripheral cornea, irreversibly blocking the anterior

chamber angle.

The increased IOP, or an IOP higher than the pressure sensitivity of the optic nerve head,

can cause mechanical stress and strain on the lamina cribrosa at the bottom of the optic nerve

head and on adjacent tissues.16 It may result in compression, deformation, and eventual

remodeling of the lamina cribrosa with consequent mechanical axonal damage and disruption of

the orthograde and retrograde axonal transport.11,26,27 Disruption of the retrograde axoplasmic

flow decreases the delivery of trophic factors from the neurons of the lateral geniculate nucleus to

the retinal ganglion cell bodies in the retina.28,29 Animal studies with experimentally induced

ocular hypertension demonstrated a blockade of both orthograde and retrograde axonal transport

198

199200201202203204205206207208

209210211212213214

215216217218219220221222223224225226227

228229230231232233234

Page 8: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

8 Glaucoma

at the level of the lamina cribrosa at an early stage of glaucoma.28,29

A low ocular perfusion pressure, including low systemic blood pressure, has been

reported to be associated with glaucomatous optic neuropathy. 30–33 Blood pressure follows a

diurnal curve distribution, similar to that of IOP, and it is normal for blood pressure to be lower at

night, but overdipping is associated with an increased risk for glaucoma progression, and

perhaps, development. 32,32 We caution general physicians and cardiologists against giving blood

pressure lowering medications at bedtime in patients with glaucoma. It has to be considered that

the strength of IOP as a risk factor for glaucoma may preclude any useful interpretation of ocular

perfusion pressure, defined as difference of diastolic blood pressure minus IOP, in unadjusted

statistical analyses, and that after adjusting for IOP the correlations no longer represent the risk

caused by ocular perfusion pressure. 34 Also, an increase in the central retinal venous pressure in

glaucoma was not taken into account when the ocular perfusion pressure was calculated. 35 It

remains unclear whether the mitochondria located in a high concentration in the pre-laminar

region play a direct role in the pathogenesis of glaucomatous optic neuropathy. 36,37 In a similar

manner, the pathways from gene mutations contributing to glaucoma and the eventual

dysfunction of the encoded proteins have not been fully explored yet. 38,39

Glaucoma-associated loss of neurons is not limited to the RGCs, but extends into the

lateral geniculate nucleus and the visual cortex.40,41 With respect to different classes of RGCs,

clinical studies and histological investigations have suggested that the glaucomatous damage

affects all subsets of RGCs in a similar manner.40,42,43 Studies also showed that the glaucomatous

loss of RGCs and their axons was accompanied by changes in the glial cell population, including

astrocytes and the retinal microglial cells.44,45

Risk Factors The main risk factors for both development and progression of glaucoma are an IOP too high

relative to the pressure sensitivity of the optic nerve head, 46–51 older age, 3,52–55 ethnic

background, 53,56 positive family history for glaucoma, stage of the disease, and high myopia. 57–59

In a recent randomized placebo-controlled trial conducted by Garway-Heath and colleagues,

medical lowering of IOP resulted in preservation of visual field in patients with open-angle

glaucoma. 51 A meta-analysis of population-based studies revealed that the odds ratio of the

prevalence of POAG was 1.73 (95% CrI, 1.63-1.82) for each decade increase in age beyond age

40. 3 Similarly, the prevalence of PACG increases with older age. Across all ethnicities,

individuals of African ancestry had the highest prevalence of glaucoma (6.11%; 95% CrI, 3.83-

9.13) and POAG (5.40%; 95% CrI, 3.17-8.27), while Asians had the highest prevalence of PACG

(1.20%; 95% CrI, 0.46-2.55). 3 Gender has been inconsistently associated with the prevalence of

open-angle glaucoma, yet two meta-analyses of population-based glaucoma studies reported a

higher prevalence of POAG in men than in women with an odds ratio of 1.36 for men. 3,53 High

myopia with a myopic refractive error of more than -6 diopters or more than -8 diopters is another

235

236

237238239240241242243244245246247248249250251

252253254255256

257

258

259

260261262263264265266267268269270271272

Page 9: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

9 Glaucoma

strong risk factor for glaucoma. 57–60 Correspondingly, the Singapore Malay Study Eye showed an

association between moderate or higher myopia (worse than -4D) and higher prevalence of

POAG. 59 Since IOP is often within the normal range and since the myopic appearance of the

optic nerve head makes the detection of glaucomatous changes difficult, the diagnosis of

glaucomatous optic neuropathy can be missed in myopic eyes. Studies have suggested that the

main factor for the myopia-associated increase in glaucoma susceptibility is the myopia

associated enlargement of the optic disc. 60 Secondary stretching and thinning of the lamina

cribrosa in association with an elongation and thinning of the peripapillary scleral flange could

lead to marked changes in the biomechanics of the optic nerve head and an increase in the

glaucoma susceptibility. Another factor may be the biomechanics of the optic nerve dura mater,

which pulls on the peripapillary sclera in eye movements and increases the stress and strain of

the lamina cribrosa. 61

Socioeconomic status has an influence on the rate of early detection of glaucoma and on

the commencement and compliance of therapy.62,63 It is therefore associated with prognosis. It

has remained unclear whether nutritional status and diet have an influence on the prevalence and

incidence of any type of the glaucomas. In a similar manner, the relationship between POAG and

diabetes mellitus,64,65 arterial hypertension,66,67 body mass index,68 obstructive sleep apnea,69 and

oral contraceptive use,70 has remained unclear. Although controversial, low cerebrospinal fluid

pressure 71,72 and low ocular perfusion pressure including a low systemic blood pressure may

potentially play a role in glaucoma. 30–34,73,74

A thinner central cornea has been considered a risk factor for glaucoma, since a thin

cornea leads to falsely low measurements of IOP. 52,75,76 Besides being a diagnostic risk factor for

the underestimation of IOP and thus for the detection of glaucoma, it was reported that a thin

cornea, due to a hypothetical association with a thin lamina cribrosa could additionally be a

structural risk factor. An association between corneal thickness and thickness of the lamina

cribrosa has however, not been shown yet; in contrast, in a histomorphometric study both

parameters were not significantly correlated with each other. 77 Correspondingly, corneal

biomechanical parameters such as corneal hysteresis and corneal resistance factor were not

significantly correlated with the severity of PACG nor was central corneal thickness associated

with glaucoma in an East Asian population. 78,79

The main risk factors for development of PAC are older age, axial hyperopia, East Asian

ethnicity, and female sex. 6,7,80 –83 The main ocular risk factors include a crowded anterior segment

in a small eye, with a smaller width, area and volume of the anterior chamber, a thicker and more

anteriorly positioned lens, thicker irides with greater iris curvature, and a greater lens vault in

association with a short axial length of the eye. 80 –8 3 The lack of space in the anterior chamber

leads to a higher risk of blockage of the angle by peripheral iris. The obstruction of the angle may

occur acutely, leading to acute and painful angle-closure glaucoma, or it may develop chronically,

273

274275276277278279280281282283284285

286287288289290291292293

294295296297298299300301302303

304305306307308309

Page 10: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

10 Glaucoma

associated with painless chronic angle-closure glaucoma. In addition to biometric parameters of

the anterior ocular segment, choroidal expansion has been been reported to be associated with

untreated and treated, acute and chronic primary angle closure. 84 –86 It is unclear, however,

whether this finding was a cause or effect of angle-closure.

GeneticsSporadic POAG has been found by genome wide association studies (GWAS) to be associated

with several genes such as CDKN2B-AS for predominantly normal-pressure glaucoma, CAV1-

CAV2, TMCO1, and ABCA1 for high pressure glaucoma, and AFAP1, GAS7, TXNRD2, ATXN2,

chromosome 8q22 intergenic region, and SIX1/SIX6 for POAG. 87 –94 This spectrum of POAG loci

was unexpectedly broad. Also, GWAS have identified genetic loci associated with quantitative

glaucoma-related traits such as IOP, central corneal thickness and optic disc size. 23,93,95 –105

Unexpectedly, the number of genetic loci shared between IOP and the POAG phenotype was

limited (CAV1-CAV2, TMCO1, ABCA1, and GAS7), suggesting that the genetic susceptibility to

POAG was not solely explained by elevated IOP alone. The genetic associations of glaucoma

vary according to the ethnic group. Common glaucoma susceptibility alleles that are seen in

Caucasians at the genome-wide level (CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22

intergenic region, and SIX1/SIX6) appear to have weaker associations with POAG in African-

Americans.

Thus far, genome wide association studies on PACG implicate 8 genetic loci that showed

strong association with disease.38,90 These loci suggest the involvement of cell-cell adhesion

(PLEKHA7, FERMT2, and EPDR1), collagen metabolism (COL11A1), type 2 diabetes-related

pathway (GLIS3), and acetylcholine-mediated signaling (CHAT) as important in the PACG

disease process.

Fitting with the results of genetic studies, assessment of family history of glaucoma is

clinically important. Having a first-degree relative with glaucoma has been consistently

associated with an increased risk for POAG and PACG in prevalence surveys. Siblings of

affected individuals have nearly an 8-fold risk of POAG and 5-times risk of angle closure when

compared to siblings of unaffected individuals. The risk for POAG may be stronger when the

affected relative is a sibling rather than a parent or child.

Family linkage studies on patients with a strongly positive family history of glaucoma have

implicated broad chromosomal regions showing significant linkage with POAG and congenital

glaucoma, many genes of which (such as CYP1B1) show very strong disease penetrance.

Genes such as myocilin (MYOC, GLC1A) (CCDS1297.1), optineurin (OPTN, GLC1E)

(CCDS7094.1) and WD repeat domain (GLC1G) (CCDS4102.1) are associated with a

monogenic, autosomal dominant inheritance.87,88 These genes, however, explain the

development of the disease in only less than 10% of all glaucoma patients. To cite an example,

310

311312313

314

315

316

317318319320321322323324325326327328329

330331332333334

335336337338339340

341342343344345346

Page 11: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

11 Glaucoma

the MYOC gene at the GLC1A locus encodes the protein myocilin, mutations of which are

generally found in the juvenile or early adult form of POAG with a high IOP. The penetrance for

carriers of disease-associated mutations is approximately 90%. In adult patients with POAG

without a strong family history however, the prevalence of myocilin mutations varies from 3% to

5%. Glaucoma patients with the OPTN (optineurin) gene mutations have POAG with normal IOP.

Optineurin may have a neuroprotective role by reducing the susceptibility of RGCs to apoptotic

stimuli.

Although a number of genes have been found to be associated with glaucoma, the

connection between the gene mutation, the secondary change in the shape of the encoded

protein and the tertiary alteration in the function of this protein have remained unclear. The

genetic findings therefore have not yet markedly contributed to elucidate the pathogenesis of the

glaucomas.

Screening for glaucomaA large proportion of glaucoma patients remain undiagnosed in developed, developing, and

underdeveloped regions (50-90%).63,106 Although screening for glaucoma in the entire population

would be an option, it is not considered logistically feasible. In particular, due to a relatively low

prevalence of about 3% in the population aged 40+years, and since diagnostic measures with

sufficient diagnostic precision are not yet available, general screening for glaucoma would result

in an unacceptable high number of false positive diagnoses. Using a health economic model,

Burr and colleagues compared opportunistic case finding to two proposed screening strategies

for glaucoma in the United Kingdom.107 They found that general population screening was not

cost-effective at the given prevalence rate and that targeted screening of specific subgroups

aligned with the established risk factors would be needed in order to achieve cost-effectiveness.

It holds true also for genetic screening for glaucoma. It is therefore important to select

participants at substantial risk in order for screening programs to be effective. If only one

screening technique can be applied, imaging of the optic nerve and retinal nerve fiber layer is

currently thought to be the best. A single measurement of IOP has a low sensitivity to detect

glaucoma under screening conditions.

DiagnosisSince the chronic glaucomas are painless and measurable visual field defects do not develop at

an early stage of glaucoma, and since defects often do not occur at homonymous locations in

both visual fields, self-detection of glaucoma by affected patients usually occurs at a late stage of

the disease. The mainstay of the detection of glaucoma is the examination of the optic nerve

head and retinal nerve fiber layer. 107 –114 Glaucomatous changes of the optic nerve head include

loss of neuroretinal rim, leading to enlargement of the optic cup (found otherwise only in eyes

347

348349350351352353354

355356357358

359

360

361

362363364365366367368369370371372373374375

376

377

378

379380381382383

Page 12: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

12 Glaucoma

after arteritic anterior ischemic optic neuropathy and in few patients with brain tumors close to the

inner aperture of the optic nerve canal), deepening of the optic cup (partially reversible if the

trans-lamina cribrosa pressure difference reduced to normal or subnormal levels), development

and enlargement of parapapillary beta zone, thinning of the retinal nerve fiber layer, and optic

disc hemorrhages as signs of progression of the disease. These changes can be assessed by

simple ophthalmoscopy or by using imaging techniques such as spectral-domain optical

coherence tomography. The latter is particularly useful for follow-up examinations, since by

electronically comparing digitized images it can detect glaucoma progression.115,116

Tonometry is an essential part of the diagnosis and follow-up of glaucoma although a

relatively large group of patents may have statistically normal IOP measurements.117 The

dependence of the tonometric measurements on the central corneal thickness and curvature has

to be taken into account.118 In eyes with abnormally thick corneas, tonometry gives falsely high

readings, potentially leading to overdiagnosis, and in eyes with abnormally thin corneas, the

tonometric measurements are falsely low, with the risk of underdiagnosis of glaucoma. Central

corneal thickness and corneal curvature should therefore be measured once, so that the

tonometric readings can be corrected accordingly.

Perimetric visual field examination is the second pillar in the diagnosis and follow-up of

glaucomatous optic nerve damage. 46–48 Since a substantial number of optic nerve fibers can be

lost before perimetric defects are detected, the diagnostic precision of perimetry increases with

the stage of glaucoma.119 The advantage of perimetry is that it describes the subjective

psychophysical defect as experienced by the patient. Its disadvantage is a relatively high inter-

visit variability so that at least three perimetric examinations may be necessary to reliably detect

visual field deterioration. Other psychophysical tests, including assessment of glaucoma-related

acquired dyschromatopsis or color vision deficiency, decreased dark adaptation, increased

photophobia and decreased contrast sensitivity are of importance for the quality of vision of the

patient. These modalities however, are not routinely measured due to a high inter-individual and

intra-individual variability.

A potential future development is the application of the newly developed optical

coherence tomography angiography to visualize the superficial and deep retinal vascular network

and in particular the peripapillary radial vascular network.120 Assessment of the latter may be of

diagnostic help in the detection and follow-up of glaucomatous optic neuropathy in highly myopic

eyes in which most other diagnostic methods fail.

Open-angle glaucoma is distinguished from angle-closure glaucoma by gonioscopic

examination of the anterior chamber angle. The main characteristic of PACG compared to open-

angle glaucoma is that the anterior chamber angle is obstructed by apposition of the iris. Like

open-angle glaucoma, angle-closure glaucoma in patients of East Asian ethnicity is

predominantly an asymptomatic disease with individuals often unaware they have the disorder

384

385386387388389390391392

393394395396397398399400

401402403404405406407408409410411

412413414415416

417418419420

Page 13: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

13 Glaucoma

until advanced visual loss has occurred. In Caucasian populations, acute angle-closure

glaucoma caused by relative pupillary block is more common. It is characterized by an inflamed

eye with a pronounced marked hyperemia of the conjunctiva, corneal edema, a mid-dilated

unreactive pupil, a shallow anterior chamber, and high IOP. It is usually accompanied by severe

ocular pain with blurring of vision with haloes noticed around lights, nausea and vomiting.

Therapy Open-angle glaucoma

The only proven and generally accepted therapy to reduce the risk of further progression of

glaucomatous optic neuropathy is to lower IOP.49,51,121 IOP reduction is achieved by medical

therapy, laser treatment or surgery. The goal is to lower the IOP toward a target level at which

further progression of glaucomatous optic nerve damage is unlikely. The target IOP for a

particular eye is estimated on the pretreatment IOP, the severity of damage, presence of risk

factors for progression, life expectancy, and potential for adverse effects from treatment. One

usually aims for an IOP reduction of 20% to 50%. The target pressure is set lower the greater the

pre-existing optic nerve damage and the more risk factors present. The target IOP should be

estimated on an individual basis and should periodically be re-analyzed by assessing whether the

optic nerve damage is stable or progressed. Several categories of topical IOP-lowering drugs are

available. The choice of medication is influenced by cost, adverse effects, and dosing schedules.

In general, prostaglandin analogues are first-line medical therapy which, delivered once in the

evening, lower IOP by improving uveoscleral outflow. Local side effects include elongation and

darkening of eyelashes, loss of orbital fat (so-called prostaglandin-associated periorbitopathy)

with resulting enophthalmos, iris darkening in eyes with greenish-brown iris color, and periocular

skin pigmentation. An alternative to prostaglandins are β-adrenergic blockers, which reduce IOP

by decreasing aqueous humour production. Applied once (in the morning) or twice (morning and

evening) daily, they can result in systemic side effects including bradycardia, arrhythmias, drop in

blood pressure, reduced libido, and increased obstructive bronchial problems that can lead to an

asthmatic attack. Beta-blockers are contraindicated in patients with a history of chronic

pulmonary obstructive disease, asthma, or bradycardia. Other groups of drugs include topical

carbonic anhydrase inhibitors, that reduce aqueous humour production, and α-adrenergic

agonists (brimonidine), which decrease aqueous humour production and increase uveoscleral

outflow. Miotics, such as pilocarpine, have the longest history of application and reduce IOP by

improving the trans-trabecular outflow. Local side-effects are a varying degree of annoying

involuntary accommodation in patients younger than 40 years and pupillary constriction. The

latter is inconvenient at night and can reduce visual acuity in eyes with cataract, increases

however the depth of focus due to the stenopeic effect. Miotics can therefore be useful in eyes

with artificial intraocular lenses after cataract surgery. Miotics do not have major systemic side

421

422423424425

426

427

428

429

430431432433434435436437438439440441442443444445446447448449450451452453454455456457

Page 14: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

14 Glaucoma

effects. Prostaglandin analogues, carbonic anhydrase inhibitors and miotics reduce IOP during

both day and night, while β-adrenergic blockers and α-adrenergic agonists are effective mostly

during daytime. Most drug groups can be combined with each other.

A new class of topically applied drugs are rho-kinase inhibitors which have finished a

phase 3 trial and are expected to be approved in 2016. 122 – 124 They reduce IOP by increasing the

trans-trabecular outflow, and potentially by additionally decreasing the production of aqueous

humour.

To decrease the systemic side effects of topically applied eye drops, it is recommended

to use gentle occlusion of the lower lacrimal duct or just to close the eyes for a few minutes.

These measures markedly reduce the amount of drug passing through the lacrimal drainage

system onto the mucosa of the oropharynx where the drugs are easily absorbed and, by avoiding

breakdown by the hepatic system, can lead to systemic side-effects. Non-ophthalmic doctors

should take into account the possibility of systemic side effects of topically applied ophthalmic

drugs, in particular of topical β-blockers, and may encourage the patients to take the drugs and

increase their adherence.

In eyes with an open anterior chamber angle, medical therapy may be augmented by, or

in some cases replaced by, laser therapy (laser trabeculoplasty) to the trabecular meshwork, in

particular if the target IOP is not achieved by medical therapy. It holds true in particular in poorly

compliant patients. Independently of a concurrent medical therapy, this laser intervention can

reduce the IOP by few additional mmHg. The excellent safety profile of the laser therapy is

combined with a relatively low efficacy. If the IOP lowering effect is not sufficient, incisional

glaucoma surgery has to be performed, usually under local or occasionally under topical

anesthesia. In patients with poor compliance or those intolerant to medical therapy, incisional

surgery can also be performed as the first step in the glaucoma therapy. A whole panoply of

surgical anti-glaucomatous procedures has been developed in the last decade. Creating an

additional outflow pathway for the aqueous humour out of the eye, all these surgical techniques

such as trabeculectomy risk reduced long-term success secondary to fibrosis around the exit

point of the fistula. During and after surgery, anti-metabolites are applied to the surgical site to

decrease the fibrotic response and to keep the fistula site open. Glaucoma implant drainage

devices are another surgical option and act by channeling the aqueous humour through a tube

out of the eye into the subconjunctival space. These devices are similarly effective in lowering

IOP to trabeculectomy.125 More recently, so-called minimally invasive glaucoma surgeries (MIGS)

show, as compared with standard trabeculectomy, a combination of fewer side effects but lower

efficacy. 126 In general, these minimally invasive glaucoma surgeries have not the same IOP–

lowering efficacy and a lower risk profile as compared with trabeculectomy. In a similar manner,

trabeculectomy as compared with non-penetrating surgeries (deep sclerectomy,

458

459460461

462463464465

466467468469470471472473

474475476477478479480481482483484485486487488489490491492493

Page 15: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

15 Glaucoma

viscocanalostomy, and canaloplasty) was more effective in reducing the IOP and carried a higher

risk of complications.126,127

Primary angle-closure glaucoma

The therapy of acute angle closure differs profoundly from the therapeutic regime in open-angle

glaucoma. In acute angle closure, acutely elevated IOP is classically first lowered by medication,

including miotics as first-line drugs (repeatedly instilled in short intervals) and other drugs used in

chronic open-angle glaucoma. The aim is open up the angle by inducing a miosis and pulling the

peripheral iris tissue out of the angle. An alternative may be immediate laser iridoplasty.128 As

definitive treatment, laser peripheral iridotomy, which creates a pathway for aqueous flow

between the posterior chamber and anterior chamber by creating a small hole in the peripheral

iris is mandatory for all patients with angle-closure. It reduces the pressure differences between

both chambers, so that the peripheral iris can flatten and can be retracted out of the anterior

chamber angle. If performed at an early stage, a single procedure can result in lifelong cure. If

the procedure is delayed, peripheral anterior synechiae may form, and if not released by a

surgical intervention within few days to weeks, further circumferential adhesions occur resulting in

an irreversible block of the anterior chamber angle and the outflow system. In some cases in

which mechanisms other than pupillary block are present (plateau iris syndrome, phacomorphic

angle-closure), continued appositional closure of the angle is common. In these cases, laser

peripheral iridoplasty can succeed in opening the angle. It does not break peripheral anterior

synechiae, which may progress if appositional closure is not relieved.129 Non-pupillary block

mechanisms, such as plateau iris, may cause a considerable proportion of angle closure in East

Asians, an ethnic group which has a higher propensity for angle-closure glaucoma.

Post-iridotomy procedures to further lower IOP are similar to those performed for the

therapy of open-angle glaucoma. Since the risk of acute angle closure is usually similar between

both eyes, laser peripheral iridotomy should be performed prophylactically in the contralateral eye

of a patient presenting with unilateral angle closure. There is currently increased interest in clear

corneal cataract extraction for primary angle-closure, particularly in areas of East Asia where

adequate diagnostic gonioscopy and laser treatment are not readily available. 130 If laser

periphery iridotomy fails to normalize the IOP, in particular due to persisting peripheral anterior

synechiae between iris and cornea, combined cataract surgery and goniosynechialysis, a

procedure to free the angle of peripheral anterior synechiae and expose the trabecular meshwork

to aqueous humour in the anterior chamber, can be successful if the peripheral anterior

synechiae are less than about 1 year old.131 If the IOP is not sufficiently lowered, topical anti-

glaucomatous medication can be applied and incisional anti-glaucoma surgery, including

trabeculectomy or lens extraction with implantation of glaucoma drainage implants, can be carried

out.

494

495

496

497

498

499500501502503504505506507508509510511512513514515516517

518519520521522523524525526527528529530

Page 16: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

16 Glaucoma

Congenital glaucoma

Therapy of congenital glaucomas is primarily surgical by procedures such as goniotomy or

trabeculotomy, in which the inner wall of Schlemm´s canal is opened into the anterior chamber.

Future developments: - The observed increase in the prevalence of cataract surgery and the increase in the prevalence

of axial myopia in particular in Asia may decrease the occurrence of angle-closure glaucoma in

the future.132 Studies that investigate the benefits of iridotomy in East Asian patients with angle

closure will hopefully provide guidance on the efficacy of this treatment in these populations

where angle closure is relatively prevalent among adults.133

- As discussed above, topically applied r ho-kinase inhibitors may become an additional pillar in

the medical therapy of glaucoma. 122 – 124 Novel sustained-release delivery systems such as

intracameral injection of slow-release IOP-lowering drug pellets or topically applied cyclodextrins

are being tested in trials. 134 Such systems may reduce the problems associated with poor

adherence and ocular surface damage that may occur with long-term use of topically applied eye

drops.

- Improved understanding of patient-reported experience and outcomes is of great importance

with this disease that is a cause of great anxiety and which consumes enormous resources within

health economies.135

- Better awareness of the disease among the public and healthcare professionals will hopefully

address the large proportion of glaucoma that remains undetected even in high-income

countries.106 Encouragement of adults with a family history of glaucoma to seek an

ophthalmological examination is an important first step in this regard.

- Future research will further refine the morphological diagnosis, in particular the measurement of

the thickness of the retinal nerve fiber layer and the width of the neuroretinal rim to further

improve precision in detecting progression of glaucomatous optic nerve damage. This can be

facilitated by combining structural with functional measurements based on perimetry. Early

recognition of deterioration of the disease can then prompt changes in treatment or efforts to

improve compliance. 111–116

- Since the optic nerve is a fascicle of the brain and thus part of the central nervous system, it is

surrounded by the optic nerve meninges and it is imbedded into cerebrospinal fluid. The orbital

cerebrospinal fluid pressure is thus the retro-ocular counter-pressure to the IOP. 18 Future studies

may assess the hypothesis that in patients with POAG and normal IOP values, the orbital

cerebrospinal fluid could be abnormally low, so that the trans-lamina cribrosa pressure difference

was elevated. 71,72

531

532

533

534

535

536

537

538539540541542

543544545546547548

549550551

552553554555

556557558559560561

562563564565566

Page 17: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

17 Glaucoma

- Future research into the pathogenesis of POAG include exploration of the secondary

involvement of the retinal microglial cells in the process of RGC damage; 136 elucidation of

secondary intracranial changes including cerebral neuroplasticity; 42 examination of the role of

retinal vein pulsations and retinal venous blood pressure in the pathogenesis and diagnosis of

glaucomatous optic neuropathy; 137 assessment of the etiology of parapapillary beta zone; 138

investigations of the reasons for the increased glaucoma susceptibility in high myopia; 57,112

examination of the biomechanics of the optic nerve dura mater and its influence on the optic

nerve head.61,139

- Exfoliation syndrome is a protean disorder and is potentially preventable or reversible. New

research into the genetics, proteomics, molecular biology and cellular processes of this disease

have led to more insight into the cell biology of this disorder may further open novel approaches

to therapy.140

- Possible novel future therapies include induction of a re-sprouting of RGC dendrites to increase

the receptive field of the still existing ganglion cells;141 development of devices (including those

intraocularly implanted) to deliver long-term slow-release of anti-glaucoma medications;14^2 to

develop refinements of the existing surgical technique to reduce the risk of a postoperative

scarification of the filtering bleb leading to a treatment failure; and to further assess the

application of stem cells and gene therapy.

567

568569570571572573574575

576577578579

580581582583584

Page 18: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

18 Glaucoma

Search strategy and selection criteria:

We systematically searched the Cochrane Library (2000-2016), MEDLINE (2000-2016), and

EMBASE (2000-2016) and used the search words of glaucoma, primary open-angle glaucoma,

secondary open-angle glaucoma, angle-closure glaucoma, intraocular pressure, optical

coherence tomography, perimetry, optic disc, optic nerve head, retinal nerve fiber layer,

trabecular meshwork, glaucoma therapy, and glaucoma surgery. We largely selected

publications in the past 5 years, but did not exclude commonly referenced and highly regarded

older publications. We also searched the reference lists of articles identified by this search

strategy and selected those we judged relevant. Review articles and book chapters are cited to

provide readers with more details and more references than this Seminar has room for. Our

reference list was modified on the basis of comments from peer reviewers.”

Competing interest statement- Jost B. Jonas: Consultant for Mundipharma Co. (Cambridge, UK); patent holder with

Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using

encapsulated cells encoding and secreting neuroprotective factor and / or anti-angiogenic factor;

Patent number: 20120263794), and patent application with University of Heidelberg (Heidelberg,

Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or

hyperopia; Europäische Patentanmeldung 15 000 771.4).

- Tin Aung: Alcon: Consultant, Lecture fees/travel, research support; Allergan: Consultant,

Lecture fees/travel, research support; Belkin Lasers: Consultant; Carl Zeiss Meditec: Consultant,

Lecture fees, research support; Ellex: research support; Ocular Therapeutics: Research support;

Pfizer: Consultant, Lecture fees/travel; Roche: Consultant, Lecture fees/travel, research support;

Quark: Consultant, research support; Santen, Inc.: Consultant, Lecture fees/travel, research

support; Tomey: Lecture fees/travel, research support.

- Rupert Bourne: Consultant, Lecture fees/travel, research support: Allergan; Consultant, Lecture

fees/travel: Santen; Consultant, Lecture fees/travel, Research support: Tomey.

- Alain M. Bron: Consultant for Allergan (Irvine, CA, USA), Bausch-Lomb (Montpellier, France),

Théa (Clermont-Ferrand, France). Research grants from Théa and Horus (Nice, France).

- Robert Ritch: Personal fees from Sensimed AG (Lausanne, Switzerland), personal fees from

iSonic Medical, Inc. (Paris, France), personal fees from Aeon Astron Europe B.V. (Leiden

Netherlands), other from Diopsys, Inc. (Pine Brook, NJ, USA), other from GLIA, LLC (Centreville,

MD, USA), other from Guardion Health Sciences (San Diego, CA, USA), other from Mobius

Therapeutics (St. Louis, MO, USA), other from Intelon Optics, Inc. (Fresh Pond, PI, USA),

personal fees f\rom Santen Pharmaceutical Co., Ltd. (Osaka, Japan), personal fees from Ocular

Instruments, Inc. (Bellevue, WA, USA), other from Xoma (US) LLC (Berkely, CA, USA), other

from The International Eye Wellness Institute, Inc. (Hudson, Ohio, USA), personal fees from

585

586

587588589590591592593594595

596

597

598

599600601602603604

605606607608609610

611612

613614

615616617618619620621

Page 19: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

19 Glaucoma

Gerson Lehrman Group (New York, NY, USA), personal fees from Gillis Zago Professional

Corporation (Brampton, ON, Canada), personal fees from Donahey Defossez & Beausay,

personal fees from Tanoury, Nauts, McKinney & Garbarino, PLLC (Columbus, Ohio, USA),

outside the submitted work. In addition, Dr. Ritch has a patent GLAUCOVITE with royalties paid

to The International Eye Wellness Institute, Inc. (Hudson, Ohio, USA).

- Songhomitra Panda-Jonas: Patent holder with Biocompatible UK Ltd. (Title: Treatment of eye

diseases using encapsulated cells encoding and secreting neuroprotective factor and / or anti-

angiogenic factor; Patent number: 20120263794), and patent application with university of

Heidelberg (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or

hyperopia; Europäische Patentanmeldung 15 000 771.4).

622

623624625626627

628629630631

Page 20: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

20 Glaucoma

References1 Bourne RR, Stevens GA, White RA, et al.; on behalf of the Vision Loss Expert Group.

Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health 2013; 1: e339–e49.

2 Stevens G, White R, Flaxman SR, et al. Global prevalence of visual impairment and

blindness: magnitude and temporal trends, 1990-2010. Ophthalmology 2013; 120: 2377–84.

3 Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of

glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-

analysis. Ophthalmology 2014; 121: 2081–90.

4 Ritch R. Exfoliation syndrome: The most common identifiable cause of open-angle

glaucoma. J Glaucoma 1994; 3: 176–8.

5 Moroi SE, Lark KK, Sieving PA, et al. Long anterior zonules and pigment dispersion. Am

J Ophthalmol 2003; 136:1176–8.

6 Congdon NG, Youlin Q, Quigley H, et al. Biometry and primary angle-closure glaucoma

among Chinese, white, and black populations. Ophthalmology 1997;104: 1489–95.

7 Nongpiur ME, He M, Amerasinghe N, et al. Lens vault, thickness, and position in Chinese

subjects with angle closure. Ophthalmology 2011;118: 474–9.

8 Dandona L, Dandona R, Mandal P, et al. Angle-closure glaucoma in an urban population

in southern India. The Andhra Pradesh eye disease study. Ophthalmology 2000;107: 1710–6.

9 Ko F, Papadopoulos M, Khaw PT. Primary congenital glaucoma. Prog Brain Res 2015;

221: 177–89.

10 Bourne RR, Taylor HR, Flaxman SR, et al. Number of people blind or visually impaired

by glaucoma worldwide and in world regions. A meta-analysis. PLoS One 2016; 11: e0162229.

11 Quigley HA, Katz J, Derick RJ, Gilbert D, Sommer A. An evaluation of optic disc and

nerve fiber layer examinations in monitoring progression of early glaucoma damage.

Ophthalmology 1992; 99: 19–28.

12 Schuman JS, Hee MR, Puliafito CA, et al. Quantification of nerve fiber layer thickness in

normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol 1995;

113: 586–96.

13 Zangwill LM, Bowd C, Berry CC, et al. Discriminating between normal and glaucomatous

eyes using the Heidelberg Retina Tomograph, GDx Nerve Fiber Analyzer, and Optical Coherence

Tomograph. Arch Ophthalmol 2001; 119: 985–93.

15 Varma R, Tielsch JM, Quigley HA, et al. Race-, age-, gender-, and refractive error-related

differences in the normal optic disc. Arch Ophthalmol 1994; 112: 1068–76.

16 Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve damage in human

glaucoma, II: the site of injury and susceptibility to damage. Arch Ophthalmol 1981; 99: 635–49.

17 Lockwood H, Reynaud J, Gardiner S, et al. Lamina cribrosa microarchitecture in normal

632

633

634635636

637638

639640641

642643

644645

646647

648649

650651

652653

654655

656657658

659660661

662663664

665666

667668

Page 21: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

21 Glaucoma

monkey eyes part 1: methods and initial results. Invest Ophthalmol Vis Sci 2015; 56: 1618–37.

18 Morgan WH, Yu DY, Balaratnasingam C. The role of cerebrospinal fluid pressure in

glaucoma pathophysiology: the dark side of the optic disc. J Glaucoma 2008; 17: 408–13.

19 Jonas JB, Gusek GC, Naumann GO. Optic disc, cup and neuroretinal rim size,

configuration and correlations in normal eyes. Invest Ophthalmol Vis Sci 1988; 29: 1151–8.

20 Ritch R: Pigment dispersion syndrome – update 2003. In: Grehn F, Stamper R, eds.

Glaucoma. Springer-Verlag, Berlin, 2004:177–92.

21 Ritch R, Schlötzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol 2001; 45: 265–

315.

22 Want A, Gillesie SR, Gordon R, et al. Autophagy and mitochondrial dysfunction in Tenon

fibroblasts from exfoliation glaucoma patients. PLOS One 2016; 11: e0157404.

23 Aung T, Ozaki M, Mizoguchi T, et al. . A common variant mapping to CACNA1A is

associated with susceptibility to exfoliation syndrome. Nat Genet 2015; 47: 387–92.

24 Dewundara S, Pasquale LR. Exfoliation syndrome: a disease with an environmental

component. Curr Opin Ophthalmol. 2015; 26: 78–81.

25 Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of

patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331: 1480–7.

26 Yang H, Ren R, Lockwood H, et al. The Connective Tissue Components of Optic Nerve

Head Cupping in Monkey Experimental Glaucoma Part 1: Global Change. Invest Ophthalmol Vis

Sci 2015; 56: 7661–78.

27 Sigal IA, Yang H, Roberts MD, et al. IOP-induced lamina cribrosa deformation and scleral

canal expansion: independent or related? Invest Ophthalmol Vis Sci 2011; 52: 9023–32.

28 Quigley HA, McKinnon SJ, Zack DJ, et al. Retrograde axonal transport of BDNF in retinal

ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 2000; 41: 3460–66.

29 Abbott CJ, Choe TE, Lusardi TA, Burgoyne CF, Wang L, Fortune B. Evaluation of retinal

nerve fiber layer thickness and axonal transport 1 and 2 weeks after 8 hours of acute intraocular

pressure elevation in rats. Invest Ophthalmol Vis Sci 2014;55: 674–87.

30 Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC. Hypertension, perfusion pressure,

and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol 1995; 113: 216–21.

31 Zheng Y, Wong TY, Mitchell P, Friedman DS, He M, Aung T. Distribution of ocular

perfusion pressure and its relationship with open-angle glaucoma: the Singapore Malay Eye

Study. Invest Ophthalmol Vis Sci 2010; 51: 3399–404.

32 Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension

and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994; 117: 603–

24.

669

670

671672

673674

675676

677678

679680

681682

683684

685686

687688689

690691

692693694

695696697

698699700

701702703

704705

Page 22: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

22 Glaucoma

33 Charlson M, De Moraes CG, Link AR, et al. Nocturnal systemic hypotension increases

the risk of glaucoma progression. Ophthalmology 2014; 121: 2004–12.

34 Khawaja AP, Crabb DP, Jansonius NM. The role of ocular perfusion pressure in

glaucoma cannot be studied with multivariable regression analysis applied to surrogates. Invest

Ophthalmol Vis Sci 2013; 54: 4619–20.

35 Stodtmeister R, Ventzke S, Spoerl E, et al. Enhanced pressure in the central retinal vein

decreases the perfusion pressure in the prelaminar region of the optic nerve head. Invest

Ophthalmol Vis Sci 2013; 54: 4698–704.

36 Osborne NN, Núñez-Álvarez C, Del Olmo-Aguado S. The effect of visual blue light on

mitochondrial function associated with retinal ganglions cells. Exp Eye Res 2014; 128: 8–14.

37 Sanchez MI, Crowston JG, Mackey DA, Trounce IA. Emerging mitochondrial therapeutic

targets in optic neuropathies. Pharmacol Ther 2016; 165: 132–52.

38 Khor CC, Do T, Jia H, et al. Genome-wide association study identifies five new

susceptibility loci for primary angle closure glaucoma. Nat Genet 2016; 48: 556–62.

39 Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies

TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet

2016; 48: 189–94.

40 Yucel YH, Zhang Q, Gupta N, Kaufman PL, Weinreb RN. Loss of neurons in

magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch

Ophthalmol 2000; 118: 378–84.

41 Crawford ML, Harwerth RS, Smith EL 3rd, Mills S, Ewing B. Experimental glaucoma in

primates: changes in cytochrome oxidase blobs in V1 cortex. Invest Ophthalmol Vis Sci 2001; 42: 358–64.

42 Gupta N, Ang LC, Noël de Tilly L, Bidaisee L, Yücel YH. Human glaucoma and neural

degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J

Ophthalmol 2006; 90: 674–8.

43 Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-specific

perimetry for indirect comparison of different ganglion cell populations in glaucoma. Invest

Ophthalmol Vis Sci 2000; 41: 1783–90.

44 Pena JD, Agapova O, Gabelt BT, et al. Increased elastin expression in astrocytes of the

lamina cribrosa in response to elevated intraocular pressure. Invest Ophthalmol Vis Sci 2001; 42: 2303–14.

45 Wang L, Cioffi GA, Cull G, Dong J, Fortune B. Immunohistologic evidence for retinal glial

cell changes in human glaucoma. Invest Ophthalmol Vis Sci 2002; 43: 1088–94.

46 Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study

Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am

J Ophthalmol 2001; 131: 699–708.

706

707708

709710711

712713714

715716

717718

719720

721722723

724725726

727728729

730731732

733734735

736737738

739740

741742

Page 23: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

23 Glaucoma

47 The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The

relationship between control of intraocular pressure and visual field deterioration. The AGIS

Investigators. Am J Ophthalmol 2000; 130: 429–40.

48 Musch DC, Gillespie BW, Lichter PR, Niziol LM, Janz NK; CIGTS Study Investigators.

Visual field progression in the Collaborative Initial Glaucoma Treatment Study the impact of

treatment and other baseline factors. Ophthalmology 2009; 116: 200–7.

49 Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study:

a randomized trial determines that topical ocular hypotensive medication delays or prevents the

onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 701–13.

50 Leske MC, Heijl A, Hyman L, et al; EMGT Group. Predictors of long-term progression in

the early manifest glaucoma trial. Ophthalmology 2007; 114: 1965–72.

51 Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma

(UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet 2015; 385: 1295–304.

52 Heijl A, Bengtsson B, Hyman L, Leske MC; Early Manifest Glaucoma Trial Group. Natural

history of open-angle glaucoma. Ophthalmology 2009; 116: 2271–6.

53 Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in primary open-angle

glaucoma prevalence by age, gender, and race: a Bayesian meta-analysis. Invest Ophthalmol Vis

Sci 2006; 47: 4254–61.

54 Kim M, Kim TW, Park KH, Kim JM. Risk factors for primary open-angle glaucoma in

South Korea: the Namil study. Jpn J Ophthalmol. 2012; 56: 324–9.

55 Kim KE, Kim MJ, Park KH, et al. Prevalence, awareness, and risk factors of primary

open-angle glaucoma: Korea National Health and Nutrition Examination Survey 2008-2011.

Ophthalmology 2016; 123: 532–41.

56 Leske MC, Wu SY, Honkanen R, et al; Barbados Eye Studies Group. Nine-year incidence

of open-angle glaucoma in the Barbados Eye Studies. Ophthalmology 2007; 114: 1058–64.

57 Xu L, Wang Y, Wang S, Wang Y, Jonas JB. High myopia and glaucoma susceptibility the

Beijing Eye Study. Ophthalmology 2007; 114: 216–20.

58 Qiu M, Wang SY, Singh K, Lin SC. Association between myopia and glaucoma in the

United States population. Invest Ophthalmol Vis Sci 2013; 54: 830–35.

59 Perera SA, Wong TY, Tay WT, Foster PJ, Saw SM, Aung T. Refractive error, axial

dimensions and primary open angle glaucoma: The Singapore Malay Eye Study. Arch

Ophthalmol 2010; 128: 900–5.

60 Nagaoka N, Jonas JB, Morohoshi K, et al. Glaucomatous-type optic discs in high myopia.

PLoS One 2015; 10: e0138825.

61 Wang X, Rumpel H, Lim WE, et al. Finite element analysis predicts large optic nerve

head strains during horizontal eye movements. Invest Ophthalmol Vis Sci 2016; 57: 2452–62.

743

744745746

747748749

750751752

753754

755756

757758

759760761

762763

764765766

767768

769770

771772

773774775

776777

778

Page 24: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

24 Glaucoma

62 Zhang X, Beckles GL, Chou CF, et al. Socioeconomic disparity in use of eye care

services among US adults with age-related eye diseases: National Health Interview Survey, 2002

and 2008. JAMA Ophthalmol 2013; 131: 1198–206.

63 Topouzis F, Coleman AL, Harris A, et al. Factors associated with undiagnosed open-

angle glaucoma: the Thessaloniki Eye Study. Am J Ophthalmol 2008; 145: 327–35.

64 Zhao D, Cho J, Kim MH, Friedman DS, Guallar E. Diabetes, fasting glucose, and the risk

of glaucoma: a meta-analysis. Ophthalmology 2015; 122: 72–8.

65 Zhou M, Wang W, Huang W, Zhang X. Diabetes mellitus as a risk factor for open-angle

glaucoma: a systematic review and meta-analysis. PLoS One 2014; 9: e102972.

66 Bae HW, Lee N, Lee HS, Hong S, Seong GJ, Kim CY. Systemic hypertension as a risk

factor for open-angle glaucoma: a meta-analysis of population-based studies. PLoS One 2014; 9: e108226.

67 Zhao D, Cho J, Kim MH, Guallar E. The association of blood pressure and primary open-

angle glaucoma: a meta-analysis. Am J Ophthalmol 2014; 158: 615–27.

68 Kang JH, Loomis SJ, Rosner BA, Wiggs JL, Pasquale LR. Comparison of risk factor

profiles for primary open-angle glaucoma subtypes defined by pattern of visual field loss: A

prospective study. Invest Ophthalmol Vis Sci 2015; 56: 2439–48.

69 Zhao XJ, Yang CC, Zhang JC, Zheng H, Liu PP, Li Q. Obstructive sleep apnea and

retinal nerve fiber layer thickness: A meta-analysis. J Glaucoma 2016; 25: e413–8.

70 Wang YE, Kakigi C, Barbosa D, et al. Oral contraceptive use and prevalence of self-

reported glaucoma or ocular hypertension in the United States. Ophthalmology 2016; 123: 729–

36.

71 Morgan WH, Yu DY, Cooper RL, Alder VA, Cringle SJ, Constable IJ. The influence of

cerebrospinal fluid pressure on the lamina cribrosa tissue pressure gradient. Invest Ophthalmol

Vis Sci 1995; 36: 1163–72.

72 Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary

open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study.

Invest Ophthalmol Vis Sci 2008; 49: 5412–8.

73 De Moraes CG, Liebmann JM, Greenfield DS, et al.; Low-pressure Glaucoma Treatment

Study Group. Risk factors for visual field progression in the low-pressure glaucoma treatment

study. Am J Ophthalmol 2012; 154: 702–11.

74 Topouzis F, Wilson MR, Harris A, et al. Association of open-angle glaucoma with

perfusion pressure status in the Thessaloniki Eye Study. Am J Ophthalmol 2013; 155: 843–51.

75 Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study:

baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol

2002;120: 714–20.

76 Copt RP, Thomas R, Mermoud A. Corneal thickness in ocular hypertension, primary

779

780781782

783784

785786

787788

789790791

792793

794795796

797798

799800801

802803804

805806807

808809810

811812

813814815

Page 25: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

25 Glaucoma

open-angle glaucoma, and normal tension glaucoma. Arch Ophthalmol 1999;117: 14–6.

77 Jonas JB, Holbach L. Central corneal thickness and thickness of the lamina cribrosa in

human eyes. Invest Ophthalmol Vis Sci 2005; 46: 1275–9.

78 Nongpiur ME, Png O, Chiew JW, et al. Lack of association between corneal hysteresis

and corneal resistance factor with glaucoma severity in primary angle closure Glaucoma. Invest

Ophthalmol Vis Sci 2015; 56: 6879–85.

79 Day AC, Machin D, Aung T, et al. Central corneal thickness and glaucoma in East Asian

people. Invest Ophthalmol Vis Sci 2011; 52: 8407–12.

80 Lavanya R, Wong TY, Friedman DS, et al. Determinants of angle closure in older

Singaporeans. Arch Ophthalmol 2008; 126: 686–691.

81 Ozaki M, Nongpiur ME, Aung T, He M, Mizoguchi T. Increased lens vault as a risk factor

for angle closure: confirmation in a Japanese population. Graefes Arch Clin Exp Ophthalmol

2012;250: 1863–8.

82 Foo LL, Nongpiur ME, Allen JC, et al. Determinants of angle width in Chinese

Singaporeans. Ophthalmology 2012;119: 278–82.

83 Moghimi S, Ramezani F, He M, Coleman AL, Lin SC. Comparison of anterior segment-

optical coherence tomography parameters in phacomorphic angle closure and acute angle

closure eyes. Invest Ophthalmol Vis Sci 2015; 56: 7611–7.

84 Arora KS, Jefferys JL, Maul EA, Quigley HA. The choroid is thicker in angle closure than

in open angle and control eyes. Invest Ophthalmol Vis Sci 2012; 53: 7813–8.

85 Zhou M, Wang W, Ding X, et al. Choroidal thickness in fellow eyes of patients with acute

primary angle-closure measured by enhanced depth imaging spectral-domain optical coherence

tomography. Invest Ophthalmol Vis Sci 2013; 54: 1971–8.

86 Huang W, Wang W, Gao X, et al. Choroidal thickness in the subtypes of angle closure: an

EDI-OCT study. Invest Ophthalmol Vis Sci 2013; 54: 7849–53.

87 Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open

angle glaucoma. Science 1997; 275: 668–70.

88 Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused

by mutations in optineurin. Science 2002; 295: 1077–9.

89 Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2

are associated with primary open-angle glaucoma. Nat Genet 2010; 42: 906–9.

90 Vithana EN, Khor CC, Qiao C, et al. Genome-wide association analyses identify three

new susceptibility loci for primary angle closure glaucoma. Nat Genet 2012; 44: 1142–6.

91 Gharahkhani P, Burdon KP, Fogarty R, et al. Common variants near ABCA1, AFAP1 and

GMDS confer risk of primary open-angle glaucoma. Nat Genet 2014; 46: 1120–5.

92 Chen Y, Lin Y, Vithana EN, et al. Common variants near ABCA1 and in PMM2 are

associated with primary open-angle glaucoma. Nat Genet 2014; 46: 1115–9.

816

817

818819

820821822

823824

825826

827828829

830831

832833834

835836

837838839

840841

842843

844845

846847

848849

850851

852

Page 26: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

26 Glaucoma

93 Hysi PG, Cheng CY, Springelkamp H, et al. Genome-wide analysis of multi-ancestry

cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat

Genet 2014; 46: 1126–30.

94 Trikha S, Saffari E, Nongpiur M, et al. A genetic variant in TGFBR3-CDC7 is associated

with visual field progression in primary open-angle glaucoma patients from Singapore.

Ophthalmology 2015; 122: 2416–22.

95 Cornes BK, Khor CC, Nongpiur ME, et al. Identification of four novel variants that

influence central corneal thickness in multi-ethnic Asian populations. Hum Mol Genet 2012;21: 437–45.

96 Ramdas WD, van Koolwijk LM, Ikram MK, et al. A genome-wide association study of optic

disc parameters. PLoS Genet 2010;6: e1000978.

97 Macgregor S, Hewitt AW, Hysi PG, et al. Genome-wide association identifies ATOH7 as a

major gene determining human optic disc size. Hum Mol Genet 2010;19: 2716–24.

98 Philomenadin FS, Asokan R, N V, George R, Lingam V, Sarangapani S. Genetic

association of SNPs near ATOH7, CARD10, CDKN2B, CDC7 and SIX1/SIX6 with the

endophenotypes of primary open angle glaucoma in Indian population. PLoS One 2015; 10: e0119703.

99 Nag A, Venturini C, Small KS; et al. A genome-wide association study of intra-ocular

pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort. Hum Mol

Genet 2014; 23: 3343–8.

100 Springelkamp H, Höhn R, Mishra A, et al. Meta-analysis of genome-wide association

studies identifies novel loci that influence cupping and the glaucomatous process. Nat Commun

2014; 5: 4883.

101 Springelkamp H, Mishra A, Hysi PG, et al. Meta-analysis of genome-wide association

studies identifies novel loci associated with optic disc morphology. Genet Epidemiol 2015;39: 207–16.

102 Li Z, Allingham RR, Nakano M, et al. A common variant near TGFBR3 is associated with

primary open angle glaucoma. Hum Mol Genet 2015; 24: 3880–92.

103 Tham YC, Liao J, Vithana EN, et al. Aggregate effects of intraocular pressure and cup-to-

disc ratio genetic variants on glaucoma in a multiethnic Asian population. Ophthalmology 2015;

122: 1149–57.

104 Springelkamp H, Iglesias AI, Mishra A, et al. New insights into the genetics of primary

open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc

characteristics. Hum Mol Gen 2016; In Print

105 Nongpiur ME, Khor CC, Jia H, et al. ABCC5, a gene that influences the anterior chamber

depth, is associated with primary angle closure glaucoma. PLoS Genet 2014;10: e1004089.

106 Shaikh Y, Yu F, Coleman AL. Burden of undetected and untreated glaucoma in the

853

854855856

857858859

860861862

863864

865866

867868869870

871872873

874875876

877878879

880881

882883884

885886887

888889

Page 27: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

27 Glaucoma

United States. Am J Ophthalmol 2014; 158: 1121–9.

107 Burr JM, Mowatt G, Hernández R, et al. The clinical effectiveness and cost-effectiveness

of screening for open angle glaucoma: a systematic review and economic evaluation. Health

Technol Assess 2007;11: iii-iv, ix-x, 1-190.

108 Lee KY, Tomidokoro A, Sakata R, et al. Cross-sectional anatomic configurations of

peripapillary atrophy evaluated with spectral domain-optical coherence tomography. Invest

Ophthalmol Vis Sci 2010; 51: 666–71.

109 Akagi T, Hangai M, Kimura Y, et al. Peripapillary scleral deformation and retinal nerve

fiber damage in high myopia assessed with swept-source optical coherence tomography. Am J

Ophthalmol 2013; 155: 927–36.

110 Chauhan BC, O'Leary N, Almobarak FA, et al. Enhanced detection of open-angle

glaucoma with an anatomically accurate optical coherence tomography-derived neuroretinal rim

parameter. Ophthalmology 2013; 120: 535–43.

111 Loewen NA, Zhang X, Tan O, et al.; Advanced Imaging for Glaucoma Study Group.

Combining measurements from three anatomical areas for glaucoma diagnosis using Fourier-

domain optical coherence tomography. Br J Ophthalmol 2015; 99: 1224–9.

112 Skaat A, De Moraes CG, Bowd C, et al.; Diagnostic Innovations in Glaucoma Study and

African Descent and Glaucoma Evaluation Study Groups. African Descent and Glaucoma

Evaluation Study (ADAGES): Racial differences in optic disc hemorrhage and beta-zone

parapapillary atrophy. Ophthalmology 2016; 123: 1476–83.

113 Zhang X, Loewen N, Tan O, et al.; Advanced Imaging for Glaucoma Study Group.

Predicting development of glaucomatous visual field conversion using baseline fourier-domain

optical coherence tomography. Am J Ophthalmol 2016; 163: 29–37.

114 Yu M, Lin C, Weinreb RN, Lai G, Chiu V, Leung CK. Risk of visual field progression in

glaucoma patients with progressive retinal nerve fiber layer thinning: A 5-year prospective study.

Ophthalmology 2016; 123: 1201–10.

115 Belghith A, Medeiros FA, Bowd C, et al. Structural change can be detected in advanced-

glaucoma eyes. Invest Ophthalmol Vis Sci 2016;57: OCT511–8.

116 Baril C, Vianna JR, Shuba LM, Rafuse PE, Chauhan BC, Nicolela MT. Rates of

glaucomatous visual field change after trabeculectomy. Br J Ophthalmol. 2016 Nov 3. pii:

bjophthalmol-2016-308948. doi: 10.1136/bjophthalmol-2016-308948. [Epub ahead of print]

117 Iwase A, Suzuki Y, Araie M, et al. The prevalence of primary open-angle glaucoma in

Japanese: the Tajimi Study. Ophthalmology 2004; 111: 1641–8.

118 Whitacre MM, Stein RA, Hassanein K. The effect of corneal thickness on applanation

tonometry. Am J Ophthalmol 1993; 115: 592-6.

890

891

892893894

895896897

898899900

901902903

904905906

907908909910

911912913

914915916

917918

919920921

922923

924

Page 28: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

28 Glaucoma

119 Kerrigan-Baumrind LA, Quigley HA, Pease ME, Kerrigan DF, Mitchell RS. Number of

ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons.

Invest Ophthalmol Vis Sci 2000; 41: 741–8.

120 Akagi T, Iida Y, Nakanishi H, et al. Microvascular density in glaucomatous eyes with

hemifield visual field defects: An optical coherence tomography angiography study. Am J

Ophthalmol 2016; 168: 237–49.

121 Heijl A, Leske MC, Bengtsson B, et al.; Early Manifest Glaucoma Trial Group. Reduction

of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma

Trial. Arch Ophthalmol 2002; 120: 1268–79.

122 Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular pressure-lowering effects of

the rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: A report of 2

randomized clinical trials. JAMA Ophthalmol 2015; 133: 755 – 61.

123 Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD; AR-13324-CS202 Study

Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in

patients with elevated intraocular pressure. Ophthalmology 2015; 122: 302 – 7.

124 Tanihara H, Inoue T, Yamamoto T, et al. One-year clinical evaluation of 0.4% ripasudil

(K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol 2016;

94: e26 – 34.

125 Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus

Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol 2012; 153: 789e2–

803e2.

126 Rulli E, Biagioli E, Riva I, et al. Efficacy and safety of trabeculectomy vs nonpenetrating

surgical procedures: a systematic review and meta-analysis. JAMA Ophthalmol 2013; 131: 1573–

82.

127 Ayyala RS, Chaudhry AL, Okogbaa CB, Zurakowski D. Comparison of surgical outcomes

between canaloplasty and trabeculectomy at 12 months’ follow-up. Ophthalmology 2011; 118: 2427–33.

128 Lam DS, Lai JS, Tham CC, Chua JK, Poon AS. Argon laser peripheral iridoplasty versus

conventional systemic medical therapy in treatment of acute primary angle-closure glaucoma : a

prospective, randomized, controlled trial. Ophthalmology 2002; 109: 1591–6.

129 Ritch R, Tham CC, Lam DS. Long-term success of argon laser peripheral iridoplasty in

the management of plateau iris syndrome. Ophthalmology 2004; 111: 104–8.

130 Azuara-Blanco A, Burr J, Ramsay C, et al. Effectiveness of early lens extraction for the

treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet

2016; 388: 1389–97.

131 Teekhasaenee C, Ritch R. Combined phacoemulsification and goniosynechialysis for

uncontrolled chronic angle-closure glaucoma after acute angle-closure glaucoma. Ophthalmology

925

926927928

929930931

932933934

935936937

938939940

941942943

944945946

947948949

950951952

953954955

956957

958959960

961

Page 29: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

29 Glaucoma

1999;106: 669–75.

132 Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia

and temporal trends from 2000 through 2050. Ophthalmology 2016; 123: 1036–42.

133 Jiang Y, Friedman DS, He M, Huang S, Kong X, Foster PJ. Design and methodology of a

randomized controlled trial of laser iridotomy for the prevention of angle closure in southern

China: the Zhongshan Angle Closure Prevention trial. Ophthalmic Epidemiol 2010; 17: 321–32.

134 Gudmundsdottir BS, Petursdottir D, Asgrimsdottir GM, et al. γ-Cyclodextrin nanoparticle

eye drops with dorzolamide: effect on intraocular pressure in man. J Ocul Pharmacol Ther 2014;

30: 35–41.

135 Somner JE, Sii F, Bourne RR, Cross V, Burr JM, Shah P. Moving from PROMs to POEMs

for glaucoma care – a qualitative scoping exercise. Invest Ophthalmol Vis Sci 2012;53:5940–7.

136 Wang JW, Chen SD, Zhang XL, Jonas JB. Retinal microglia in glaucoma. J Glaucoma

2016;25:459–65.

137 Golzan SM, Morgan WH, Georgevsky D, Graham SL. Correlation of retinal nerve fibre

layer thickness and spontaneous retinal venous pulsations in glaucoma and normal controls.

PLoS One 2015; 10: e0128433.

138 Wang YX, Jiang R, Wang NL, Xu L, Jonas JB. Acute peripapillary retinal pigment

epithelium changes associated with acute intraocular pressure elevation. Ophthalmology 2015;

122: 2022 – 8.

139 Fortune B, Reynaud J, Hardin C, Wang L, Sigal IA, Burgoyne CF. Experimental glaucoma

causes optic nerve head neural rim tissue compression: A potentially important mechanism of

axon injury. Invest Ophthalmol Vis Sci 2016; 57: 4403–11.

140 Wolosin JM, Ritch R, Bernstein AM. Is autophagy dysfunction a key to exfoliation

glaucoma? J Glaucoma 2016;Epub Dec 20

141 Lindsey JD, Duong-Polk KX, Hammond D, Chindasub P, Leung CK, Weinreb RN.

Differential protection of injured retinal ganglion cell dendrites by brimonidine. Invest Ophthalmol

Vis Sci 2015; 56: 1789–804.

142 Perera SA, Ting DS, Nongpiur ME, et al. Feasibility study of sustained-release travoprost

punctum plug for intraocular pressure reduction in an Asian population. Clin Ophthalmol 2016;

10: 757–64.

962

963

964965

966967968

969970971

972973

974975

976977978

979980981

982983984

985986

987988989

990991

Page 30: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

30 Glaucoma

Figures

Fig. 1

Histo-photograph showing the ciliary body (“1”) in the posterior chamber as site of the production

of aqueous humour; “2”: Gap between the iris (“3”) and the lens (“4”) as connecting path for the

aqueous humour to percolate from the posterior chamber into the anterior chamber through the

pupil (“5”). The anterior chamber angle is located between the peripheral cornea (“6”) and the

peripheral iris and contains the trabecular meshwork (“7”) and Schlemm´s canal (“8”) as outflow

system for the aqueous humour (in addition to the uveoscleral outflow).

992

993

994

995996997998999

1000

1001

1002

1003

1004

Page 31: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

31 Glaucoma

Fig. 2

Gonioscopic view on the open anterior chamber angle in an eye with pigment dispersion

syndrome, showing the hyperpigmented Schwalbe´s line (Sampaolesi´s line as the end of

Descemet´s membrane) (black arrows), the hyperpigmented trabecular meshwork (red arrows)

and the scleral spur (blue arrows) as the posterior end of the anterior chamber angle; while arrow:

peripheral iris; green arrow: pupillary margin

1005

1006

1007100810091010

1011

1012

1013

Page 32: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

32 Glaucoma

Fig. 3

Ophthalmoscopic photograph of a small optic disc without cupping (left image) and of primary

macrodisc (right image) with a pseudo-glaucomatous but physiologic macrocup; Note: the

neuroretinal rim has its physiologic shape with the widest part in the inferior disc region (“I”),

followed by the superior disc region (“S”), the nasal disc area (“N”), and finally the temporal disc

region (“T”) (so called ISNT-rule)

10141015

1016

1017101810191020

1021

1022

Page 33: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

33 Glaucoma

1023

1024

Page 34: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

34 Glaucoma

Fig. 4

Series of optic discs from a normal finding (Fig. 4a) to early glaucoma (Fig. 4b), and eventually

end-stage of glaucoma (Fig. 4f)

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

Page 35: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

35 Glaucoma

Fig. 5a, b

Fig. 5a: Ophthalmoscopic photograph of the retinal nerve fiber layer of a normal left eye, with the

best visibility (and thickest part) retinal nerve fiber layer in the temporal inferior region, followed by

the temporal superior region, the nasal superior region, and finally the nasal inferior region. Fig.

5b: Ophthalmoscopic photograph of the retinal nerve fiber layer of a glaucomatous eye with

localized defect (between white arrows) and a diffusely decreased visibility (and thickness) of the

retinal nerve fiber layer

1036

1037

10381039104010411042

1043

1044

1045

1046

Page 36: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

36 Glaucoma

Fig. 5b1047

1048

1049

1050

1051

1052

1053

1054

1055

Page 37: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

37 Glaucoma

Fig. 6

Histo-photograph showing a normal optic nerve head with the lamina cribrosa (between green

stars) as the bottom of the optic cup (“A”) and the neuroretinal rim (“B”) containing the retinal

ganglion cell axons; “C” orbital cerebrospinal fluid space between the pia mater of the optic nerve

(“D”) and the dura mater of the optic nerve (“E”)

1056

1057

105810591060

1061

1062

1063

1064

Page 38: arro.anglia.ac.uk  · Web viewKey words: Glaucoma; Open-angle glaucoma; Angle-closure glaucoma; Normal-tension glaucoma; Exfoliation syndrome; Pigment dispersion syndrome; Congenital

38 Glaucoma

Fig. 7

Slit lamp assisted biomicroscopy of the lens surface of an eye with exfoliation syndrome and with

the pupil medically dilated, showing the dandruff material in the central region of the lens surface

(white arrows) and in the peripheral region (red arrows), leaving free an intermediary zone

corresponding to the rubbing of the posterior pupillary margin on the lens surface

1065

1066

106710681069

1070

1071

1072

1073