Studies on real world visual field data in glaucoma

(1)

Saunders, L. J. (2015). Studies on real world visual field data in glaucoma. (Unpublished Doctoral thesis, City, University of London)

City Research Online

Original citation: Saunders, L. J. (2015). Studies on real world visual field data in glaucoma. (Unpublished Doctoral thesis, City, University of London)

Permanent City Research Online URL: http://openaccess.city.ac.uk/16170/

Copyright & reuse

City University London has developed City Research Online so that its users may access the research outputs of City University London's staff. Copyright © and Moral Rights for this paper are retained by the individual author(s) and/ or other copyright holders. All material in City Research Online is checked for eligibility for copyright before being made available in the live archive. URLs from City Research Online may be freely distributed and linked to from other web pages.

Versions of research

The version in City Research Online may differ from the final published version. Users are advised to check the Permanent City Research Online URL above for the status of the paper.

Enquiries

If you have any enquiries about any aspect of City Research Online, or if you wish to make contact with the author(s) of this paper, please email the team at [email protected].

(2)

1

Studies on r eal wor ld

visual field data in

glaucoma

Luke John Saunders

A thesis submitted for the degree of Doctor of

Philosophy

School of Health Sciences

February 2015

(3)

City, University of London Northampton Square London EC1V 0HB United Kingdom T +44 (0)20 7040 5060

www.city.ac.uk Academic excellence for business and the professions

THE FOLLOWING PART OF THIS THESIS HAS BEEN PUBLISHED:

Work in Chapter 4 has been published as the following article:

Saunders, L.J., Russell, R.A. and Crabb, D.P., (2015). Measurement

Precision in a Series of Visual Fields Acquired by the Standard and Fast

Versions of the Swedish Interactive Thresholding Algorithm: Analysis of

Large-Scale Data From Clinics, JAMA Ophthalmology, 133(1): 74-80.

doi:10.1001/jamaophthalmol.2014.4237

(4)

2

List of Tables

Table 1.1 – M et hods of det ect ing glaucom at ous progression. ... 54

Table 2.1 - Pat ient inform at ion and M ean Deviat ions (M Ds) of t he cohor t . ... 78

Table 3.1 - The dem ographics of pat ient s analysed in t he st udy. ... 92

Table 3.2 - The pr oport ion of pat ient s likely t o suffer visual field im pairm ent in t he course of t heir lifet im e ... 94

Table 4.1 – Charact erist ics of St udy Sam ple ... 109

Table 4.2 - Tim e t o det ect pr ogression at p < 0.01 for SITA St andard and Fast using

sim ulations of 100,000 progressing t hresholds ... 112

Table 5.1 - A com parison of t he dem ographics of dat aset s ut ilised in t he De M oraes st udy and t he sam ple used for t his project ... 132

(9)

7

List of Figur es

Figure 1.1 – Global causes of blindness due t o eye disease; glaucom a is t he second leading cause of blindness w orldw ide. The figure w as reproduced from

ht t p:/ / w w w .w ho.int / w hr2001/ 2001/ archives/ 2000/ en/ pdf/ St at ist icalAnnex.pdf accessed in June 2014. ... 19

Figure 1.2 – A flow -chart show ing t he prevalence of different classificat ions of glaucom a. Pseudoexfoliative and pigm ent ary glaucom a are classed as secondary glaucom as. Diagram recreat ed based on figure 7.1 from Henson 2000 ... 21

Figure 1.3 - The fluid pat hw ay in t he eye. Glaucom a is oft en relat ed t o t he par t ial or com plet e blockage of t he out flow of aqueous fluid t hr ough t he t rabecular m eshw ork (labelled “ m eshw ork” ). The “ angle” refers t o t he angle bet w een t he iris and cornea. In open-angle glaucom a t his is w ide, w hereas in angle-closure glaucom a t his is narrow such t hat t he iris presses against t he cornea. Im age t aken from t he Nat ional Eye Inst it ut e: ht t p:/ / w w w .nei.nih.gov/ healt h/ glaucom a/ glaucom a_fact s.asp accessed in June 2014. . ... 22

Figure 1.4 – Out put from an OCT show ing t he Ret inal Nerve Fibre Layer of m y ow n right eye. ... 27

Figure 1.5 – A colleague performing St andard Aut om at ed Perim et ry on an Oct opus Visual Field device ... 30

Figure 1.6 – Out put from a Visual Field (VF) exam ination from a pat ient ’s right eye. The left grid show s t he m easured t hreshold sensit ivities at 52 locat ions (excluding t he blind spot ), w hereas t he right grid is a greyscale w it h darker areas represent ing less sensit ive part s of t he VF. ... 31

Figure 1.7 – The m ean sensit ivities for Full t hreshold, SITA St andard and SITA Fast t est s t aken on t he sam e pat ient s in a st udy by Art es et al. 2002. SITA Fast and St andard t est s t ended t o yield higher, m ore opt im ist ic t hresholds t han full t hreshold t est ing. Im age t aken from Art es et al. 2002. ... 34

Figure 1.8 – The t est -ret est variabilit y about full-t hreshold m easured t hresholds using Full t hreshold, SITA St andard and SITA Fast VF t est ing. The variabilit y is great er for SITA Fast t han Full t hreshold, but SITA St andard perform s relat ively w ell by com parison. This im age is t aken from Art es et al. 2002... 35

Figure 1.9 – A range of analyt ical t ools available for use in clinical pract ice a) St at pac 2’s Glaucom a Probabilit y Analysis for t he HFA, b) Eyesuit e Analysis soft w are for t he Oct opus perim et er, c) Progressor and d) Peridat a’s boxplot t rend analysis ... 39

(10)

8

Figure 1.11 - The above dist ribut ion represent s t he variat ion in t he t ot al deviat ion value (TD) of a given point in a m onocular VF. If a m easured TD value falls w it hin t he green area (i.e. below t he fift h percent ile), t hen t here is a significant probabilit y of dam age and t he locat ion w ill be flagged in t he TD plot . This figure w as previous published in t he European Opht halm ic Review (Saunders et al. 2013). ... 42

Figure 1.12 – Tot al and Pat t ern Deviat ion plot s. The t op grids show t he num ber of decibels t hat each t hreshold deviat es from t he expect ed t hreshold, w hereas t he bot t om grids show t he percent iles of t he est im at ed dist ribut ion of a norm al populat ion t he t hresholds reside below . Pat t ern deviat ion plot s correct for diffuse loss in t he eye t hat oft en result s from cat aract ; a com mon co-m orbidit y in old age... 43

Figure 1.13 - A dem onst rat ion of t he differences bet w een (a) event and (b) t rend based analyses for one point in consecut ive visual fields (VF). ... 51

Figure 1.14 – An illust rat ion of how variabilit y changes w it h sensit ivit y levels in various clinical st udies. This figure w as t aken from Russell et al. 2012a. ... 56

Figure 1.15 – Based on Table 2 in t he paper by Chauhan et al. 2008b, t his graph show s an est im at e of t he num ber of visual fields per year required t o have an 80% probabilit y of successfully det ect ing a progressive change in m ean deviat ion in a given num ber of years. This figure w as first published in t he European Opht halmic Review (Saunders et al. 2013).58

Figure 1.16 – The print -out from an Est erm an Test t aken from Visw anat han et al. 1999. .. 62

Figure 1.17 - This figure illust rat es how t he int egrat ed visual field (IVF) is calculat ed. Corresponding point s in t he left and right visual fields (VF) are com pared and t he one w it h t he higher sensit ivit y is chosen t o represent t he IVF for t hat point . The nasal st eps are unique t o each eye so t hese are not used in t he IVF. ... 64

Figure 1.18 – Findings t aken from t he M urat a et al. 2013 st udy show ing t he different part s of t he visual field (VF) im port ant in A) Reading, B) Walking, C) Dining and D) Going out . Im age w as t aken from M urat a et al. 2013. ... 69

Figure 1.19 – An illust rat ion of t he conundrum associat ed w it h m onit oring visual field loss over t im e. The aim of glaucom a m anagement is t o pr event pat ient s from reaching a st at e of severe visual im pairm ent w it hin t heir lifet im e, yet it is not clear w hen pat ient s have progressed t o blindness. This figure is based on an im age from t he European Glaucom a Societ y Guidelines ... 71

Figure 1.20 - The locat ions of t he f our clinical cent res in England w here visual fields used in t his t hesis w ere collect ed ... 73

(11)

9

Figure 2.1 - A receiver operat ing charact erist ic (ROC) plot for using different sum m ary m easures for predict ing t he IVF surrogat e m easure of legal fit ness t o drive. ... 79

Figure 2.2 - A schem at ic show ing t he relat ionship bet w een defect levels (bet t er eye m ean deviat ion) and t he probabilit y of failure of t he surrogat e Est erm an t est w it h 95%

confidence int ervals (CI). ... 80

Figure 2.3 - Exam ples of ‘t rue-posit ive’ (A), ‘t r ue-negat ive’ (B), posit ive’ (C) and ‘false-negat ive’ (D) pat ient s ... 82

Figure 3.1 - A schem at ic illust rat ing t he analysis conduct ed in t his st udy. Visual field (VF) series from t he left and right eyes of a pat ient w ere used t o est im at e a linear rat e of loss in each eye (dB/ y). The pat ient ’s m edian life expect ancy w as obt ained from t he UK Office of Nat ional St at ist ics and w as used t o predict t he m ean deviat ion (M D) of each eye at

expect ed t im e of deat h. ... 89

Figure 3.2 (A) Dist ribut ion of residual life expect ancies for all 3790 pat ient s included in t he st udy and (B) t he rat e of progression of M ean Deviat ion (decibels per year) from all 7149 eyes ... 93

Figure 3.3 - A series of scat t erplot s show ing M ean Deviat ion (M D) in vert ical (Y-axis) and horizont al (X-axis) eyes at baseline, at t he end of follow -up and, t hrough ext rapolat ing current rat es of M D det eriorat ion, aft er 10, 20 and 30 years follow-up and at t he end of expect ed lifet im e. Bot h eyes in t he plot had t o fulfil t he original inclusion crit eria. ... 96

Figure 4.1 - Back-t o-back hist ogram s show ing dist ribut ions of t he frequency densit y of raw residuals generat ed t hrough linear m odelling of each t est locat ion at rounded fit t ed values of 0, 10, 15, 20 and 30dB for SITA St andard (grey) and SITA Fast (red). ... 110

Figure 4.2 - Variabilit y across sensit ivities for SITA St andard (grey) and Fast (red)... 111

Figure 4.3 - Sim ulat ed greyscales produced from a baseline real life visual field of t he sam e eye, but t he variabilit y from SITA St andard and Fast using R st at ist ical soft w are. Each t est locat ion w as sim ulat ed t o progress at 2dB per year w it h noise added from t he dist ribut ions of residuals for each fit t ed sensit ivit y. ... 113

Figure 5.1 – An opt ic nerve – t he solid and dashed lines show t he locat ions of t he alpha and Bet a-zones respect ively. Dam age t o ret inal pigm ent epit helial cells in t his area is defined as Bet a-zone parapapillary at rophy. This im age has been t aken from Teng et al. 2010. . 125

Figure 5.2 – This Bland-Alt m an plot displays t he differences bet w een observed and

predict ed rat es of loss in t he validat ion dat aset t aken f rom De M oraes et al. 2012 ... 130

Figure 5.3 - A hist ogram show ing t he dist ribut ion of adjust ed R2 values from 100,000 sim ulat ed reference m odels.. ... 133

(12)

10

Figure 5.4 – A hist ogram show ing t he dist ribut ion of adjust ed R2 values from 100,000 sim ulat ed reference m odels fit t ed t o sim ulat ed validation dat aset s.. ... 134

Figure 5.5 - A plot of t he est im at ed progression rat e of pat ient s in t he select ed reference dat aset against t heir “ t rue” rat e of pr ogression ... 135

Figure 5.6 - A Bland-Alt m an plotcom paring t he progression rat es of a select ed validat ion dat aset t o t he rat es est im at ed in t he m odel show n in figure 5.5. ... 136

Figure 6.1 - A m ap displaying each t est locat ion in t he binocular IVF ranked by R2 st at ist ics in t he Reading st udy discussed in sect ion 6.3.1 Figure t aken from Burt on et al. 2015. ... 145

Figure 6.2 – A t ool developed by Wesselink et al. 2011 t o illust rat e t he risk of pat ient s progressing t o blindness from baseline for m en (w om en have longer life-expect ancies). This figure w as t aken from Wesselink & Jansonius 2014. ... 149

(13)

11

Acknowledgements

First and most import ant ly of all, I w ould like t o t hank my supervisors Professor David Crabb and Dr Richard Russell for all t heir support over t he last t hree years, not least for t heir involvement in all of t he project s cont ained w it hin t his t hesis. David’s ideas, ambit ion and encouragement have been invaluable in my progression as a researcher, w hilst Richard has been as much an invaluable friend as w ell as a supervisor and has alw ays been around w hen I have needed guidance and advice. I am so grat eful and indebt ed t o t hem bot h.

I am also much obliged for t he support t hat I have received from M oorfields Eye Hospit al and for all t he clinical dat a used in t he st udy. In part icular, I w ould like t o t hank Ted Garw ay-Heat h an am hugely grat eful for t he opport unit y t o present my research at M oorfields Glaucoma Seminars. Andrew M cNaught (Depart ment of Opht halmology, Gloucest ershire Hospit als NHS Foundat ion Trust , Chelt enham and Cranfield Universit y, Bedford), James Kirw an (Depart ment of Opht halmology, Queen Alexandra Hospit al, Port smout h) and Nit in Anand (Calderdale and Huddersfield NHS Foundat ion Trust ) furt her deserve acknow ledgement for providing access t o visual field dat a from t heir respect ive hospit als.

This t hesis w ould not have been possible w it hout t he funding I have received from my Cit y Universit y of London st udent ship, w hich has also been co-funded by an unrest rict ed grant from Allergan Inc. I am also highly grat eful t o t he Universit y for giving me so many opport unit ies t o present my research and allow ing me t o receive feedback t hat has great ly enhanced my present at ion skills.

It is finally import ant t o acknow ledge all t he people w ho have support ed me over t he past t hree years, especially all my colleagues in t he Crabb Lab. It has been a massive pleasure w orking alongside t hem and t hey have provided me w it h friendship, encouragement , comment s, suggest ions and useful advice. I am m uch obliged t o Angharad Hobby, in part icular, w ho helped proof t he background sect ions of my t hesis t o ensure accuracy from a clinical perspect ive. I w ould furt her like t o t hank my w ife, Diana, my mot her and my sist er for aiding me in t he

(14)

12

proof reading of my w ork and for generally being an amazing support for me t hrough t he ups and dow ns of my t hree years at Cit y Universit y. I w ould like t o also ment ion how grat eful I am t o my parent s and grandparent s for t he financial support and encouragement for init ially re-t raining in St at ist ics. Wit hout t his, t here is no chance I w ould have even made it t o Cit y Universit y t o w rit e t his t hesis, so I am incredibly fort unat e t o even have t his opport unit y. Finally, a massive t hanks all my family, my amazing friends at t he Journey church and beyond and, most of all, t o God. I am so blessed by you all.

(15)

13

Declar ation

The w ork cont ained in t his t hesis w as complet ed by t he candidat e, Luke John Saunders. It has not been submit t ed for any ot her degrees, eit her now or in t he past .

Where w ork cont ained w it hin it has been previously published, t his has been st at ed in t he t ext . All sources of informat ion have been acknow ledged and references have been given.

The Universit y Librarian of Cit y Universit y London is permit t ed t o allow t he t hesis t o be copied in w hole or in part w it hout furt her reference t o t he aut hor. This permission covers only single copies made for st udy purposes, subject t o normal condit ions of acknow ledgement .

(16)

14

Abstr act

Glaucoma is a leading cause of blindness. As a progressive condit ion, it is import ant t o monit or how t he visual field (VF) changes over t ime w it h perimet ry in prevent ing vision from det eriorat ing t o a st age w here qualit y of life is affect ed. How ever, t here is lit t le evidence of how clinical measurement s correlat e w it h meaningful qualit y of life landmarks for t he pat ient or, by ext ension, t he proport ion of pat ient s in danger of progressing t o t hese landmarks. Furt her, measurement variabilit y associat ed w it h visual fields make it difficult t o monit or t rue change over t ime. The purpose of t his t hesis w as t o use large-scale clinical dat a (alm ost 500,000 VFs) t o address some of t hese issues.

The first st udy at t empt ed t o relat e clinical measurement s of glaucoma severit y t o UK legal fit ness t o drive st at us. Legal fit ness t o drive (LFTD) w as est imat ed using t he int egrat ed visual field as a surrogat e of t he Est erman t est , w hich is t he approved met hod by t he UK DVLA of defining LFTD, w hile t he mean deviat ion (M D) w as used t o represent defect severit y. An M D of -14dB or w orse in t he bet t er eye w as found t o be associat ed w it h a 92% (95% Confidence Int erval [CI]: 87-95%) probabilit y of being legally unfit t o drive.

The second st udy used a st at ist ical model t o est imat e t he number of pat ient s progressing at rat es t hat could lead t o t his landmark of significant visual impairment or blindness in t heir predict ed remaining lifet ime. A significant minorit y of pat ient s w ere progressing at rat es t hat could lead t o st at ut ory blindness, as defined by t he US Social Securit y Administ rat ion, in t heir predict ed remaining lifet ime (5.2% [CI: 4.5-6.0%]) w it h a furt her 10% in danger of becoming legally unfit t o drive (10.4% [CI: 9.4-11.4%]). M ore t han 90% (CI: 85.7-94.3%) of pat ient s predict ed t o progress t o st at ut ory blindness had an M D w orse t han -6dB in at least one eye at present at ion, suggest ing an associat ion bet w een baseline VF damage and risk of fut ure impairment .

The next sect ion invest igat ed w het her choice of t est ing algorit hm, SITA St andard or SITA Fast , affect ed t he t ime t aken t o det ect progression in VF follow-up. The precision of t he t est s w as measured using linear modelling t echniques and t he impact of t hese differences w as analysed using simulat ions. Though SITA Fast w as found t o be slight ly less precise, no evidence w as found t o suggest t hat t his result ed in progression being det ect ed lat er.

The final st udy evaluat ed a validat ed and published risk calculat or, w hich ut ilised baseline risk fact ors t o profile risk of fast progression. A simpler m odel using baseline VF dat a w as developed t o have similar st at ist ical propert ies for comparison (including equivalent R2 st at ist ics). The result s suggested t hat risk calculat ors w it h low R2 st at ist ics had lit t le ut ilit y for predict ing fut ure progression rat e in clinical pract ice.

Toget her t hese result s cont ribut e a variet y of novel findings and demonst rat e t he benefit of using large quant it ies of dat a collect ed from t he everyday clinical milieu t o ext end clinical know ledge.

(17)

15

List of Abbr eviations and Ter ms

ACG Angle closure glaucoma

ADREV Assessment of Disabilit y Relat ed t o Vision

AGIS Advanced Glaucoma Int ervent ion St udy

AIGS Advanced Imaging in Glaucoma St udy

ANSWERS Analysis w it h Non-St at ionary Weibull Error Regression w it h spat ial

enhancement

AUC Area Under t he curve

Bet a-PPA Bet a-zone Parapapillary At rophy

BEM D Bet t er Eye M ean Deviat ion

CCT Cent ral Corneal Thickness

CGS Canadian Glaucoma St udy

CI Confidence Int erval

CIGTS Collaborat ive Init ial Glaucoma Treat ment St udy

CNTGS Collaborat ive Normal Tension Glaucoma St udy

CPSD Correct ed Pat t ern St andard Deviat ion

DH Disc Haemorrhage

DVLA Driving and Vehicle Licensing Agency

EM GT Early M anifest Glaucoma Trial

ERF Error Relat ed Fact or

FDP Frequency Doubling Perimet ry

FDT Frequency Doubling Technology

FL Fixat ion losses

FN False negat ive

FP False posit ive

GCP Glaucoma Change Probabilit y

GSS Glaucoma St aging Syst em

(18)

16

HFA Humphrey Field Analyzer

IOP Int raocular Pressure

IVF Int egrat ed Visual Field

IQR Int erquart ile Range

LFTD Legal Fit ness t o Drive

LFTDP Legally Fit t o Drive Pat ient s

LUTDP Legally Unfit t o Drive Pat ient s

M D M ean Deviat ion

NICE Nat ional Inst it ut e for Healt h and Clinical Excellence

NPV Negat ive Predict ive Value

NTG Normal Tension Glaucoma

NY-GAPS New York Glaucoma Progression St udy

OHT Ocular Hypert ension

OHTS Ocular Hypert ension Treat ment St udy

OLSR Ordinary Least Squares Regression

ONH Opt ic Nerve Head

ONS Office of Nat ional St at ist ics

OPP Ocular Perfusion Pressure

PoF Probabilit y of failure (t he posit ive predict ive value)

PD Pat t ern deviat ion

PLR Point w ise Linear Regression

POAG Primary open angle glaucoma

PSD Pat t ern St andard deviat ion

POAG Primary Open Angle Glaucoma

PROM Pat ient Report ed Out come M easure

QoL Qualit y of Life

ROC Receiver Operat ing Charact erist ic

(19)

17

SITA Sw edish Int eract ive Thresholding Algorit hm

SSI Severely Sight Impaired

SWAP Short -w avelengt h aut omat ed perimet ry

TD Tot al deviat ion

UKGTS Unit ed Kingdom Glaucoma Treat ment St udy

USP-GVFSS Universit y of Sao Paulo Glaucoma Visual Field Staging Syst em

VF Visual Field

VFI Visual Field Index

WEM D Worse Eye M ean Deviat ion

(20)

18

Chapter One:

Backgr ound and Aims

This int roduct ory chapt er set s out t o briefly go over t he import ant background informat ion underpinning my t opic and defining t he research quest ions t hat I have set out t o answer in t his t hesis. It begins by briefly describing w hat glaucoma is, t he risk fact ors associat ed w it h it s incidence and progression and t he w ay t hat a pat ient visual field (VF; t his refers t o t he full ext ent of w hat an eye can see) is measured. The import ance of monit oring loss effect ively over t ime, t he means of doing so and t he problems associat ed w it h t his VF loss w ill also be looked at , t hus, set t ing t he groundw ork necessary t o int roduce how t he w ork in t his t hesis cont ribut es t o current clinical underst anding.

1.1 Glaucoma

Glaucoma is a group of opt ic neuropat hies in w hich t he opt ic nerve head and ret inal ganglion cells are damaged pot ent ially causing blindness. The eye disease is t he second leading cause of blindness globally (Figure 1.1) and t he leading cause of irreversible blindness w orldw ide affect ing an est imat ed 60.5 million people w orldw ide w it h 8.4 million blind from t he disease (Quigley & Broman 2006, World Healt h Organisat ion 2007, Nat ional Eye Inst it ut e 2010). In t he UK, glaucoma is t he main at t ribut ed cause of 10% of t he cases of blindness (Nat ional Inst it ut e for Healt h and Clinical Excellence 2009). Treat ment and monit oring of t he condit ion is behind over one million hospit al visit s each year (Nat ional Inst it ut e for Healt h and Clinical Excellence 2009) and, due t o t he fact t hat t he condit ion becomes more prevalent in elderly populat ions (Khaw aja et al. 2013), it represent s an even larger challenge t o resources and healt hcare in t he fut ure as global life expect ancies increase (Quigley & Broman 2006, Nat ional Eye Inst it ut e 2010).

(21)

19

Figure 1.1 – Global causes of blindness due to eye disease; glaucoma is the second leading cause of blindness w orldw ide. The figure w as reproduced from

http:/ / w w w .w ho.int/ whr2001/ 2001/ archives/ 2000/ en/ pdf/ StatisticalAnnex.pdf

accessed in June 2014.

There are various t ypes of glaucoma (Figure 1.2), generally classified according t o

feat ures of t he disease, alt hough increased int raocular pressure (IOP) is a common charact erist ic in most t ypes. Glaucoma is comm only referred t o as eit her primary or secondary; t his refers t o nat urally occurring disease and disease caused by or t hrough t reat ing anot her exist ing condit ion. Primary glaucoma is furt her sub-classified t hrough checking t he angle formed bet w een t he iris and cornea of t he eye using a met hod called gonioscopy (Nat ional Inst it ut e for Healt h and Clinical Excellence 2009). Angle closure glaucoma (ACG) is associat ed w it h a narrow angle bet w een t he iris and t he cornea. When t he angle is closed, t he iris can block t he t rabecular meshw ork, blocking t he drainage canals and causing a build-up of fluid inside t he eye, increasing t he IOP (Figure 1.3). The onset can be quick and painful,

(22)

20

as in acut e ACG, or it can be slow and asympt omat ic as chronic ACG usually is. How ever, t he most common form of glaucoma is w hen t he angle t o be w ide, as in primary open angle glaucoma (POAG), w hich is t hought t o arise due t o impeded aqueous out flow t hrough t he t rabecular meshw ork, causing a rise in IOP. Open angle glaucoma is an incurable progressive condit ion t hat requires cont inual monit oring aft er diagnosis and is managed t hrough various medical int ervent ions such as eye-drops or surgery t o reduce t he IOP. The progression of POAG t ends t o be gradual and sympt omless in it s early st ages. Though most glaucoma is associat ed w it h increased IOP, glaucoma can occur w hen pressures inside t he eye are at populat ion normal levels (normal t ension glaucoma; NTG). Anot her primary glaucoma is congenit al glaucoma, a life-long condit ion cont ract ed from birt h. How ever, as t his form of glaucoma is relat ively rare, congenit al glaucoma w ill not be a focus of t he t hesis. Common variet ies of less prevalent secondary glaucoma include pseudoexfoliat ive and pigment ary glaucoma. Pseudoexfoliat ive glaucoma can be seen in eyes w it h pseudoexfoliat ion syndrome, w hich is charact erised by deposit ion of m icroscopic granular prot ein fibers (w hich are like dandruff) in t he ant erior segment (t he area bet w een t he cornea and iris) of t he eye. Glaucoma occurs in t his case w here t his pseudoexfoliat ive mat erial blocks t he drainage canals. Pigment ary glaucoma can occur in individuals w it h pigment dispersion syndrome in w hich pigment is shed from t he back of t he iris, w hich can t hen block drainage canals for ocular aqueous hum our.

(23)

21

Figure 1.2 – A flow -chart show ing the prevalence of different classifications of glaucoma. Pseudoexfoliative and pigmentary glaucoma are classed as secondary glaucomas. Diagram recreated based on figure 7.1 from Henson 2000

Regardless of t he mechanisms behind t he condit ion, and much remains unknow n about t he cause of glaucomat ous sympt oms, t he product of t he condit ion is invariably t he deat h of ganglion cell axons in t he ret ina at t he back of t he eye. Wit h t he deat h of t hese cells, t he signal from phot osensit ive rod and cone cells on t he back of t he eye cannot be t ransmit t ed along t he opt ic nerve t o t he brain. This result s in pat ches in t he field of view w here vision is im paired ot herw ise know n as scot omas. The rat e at w hich vision is lost as a result is know n as t he rat e of progression of t he disease. Due t o t he fact t hat t he brain t ends t o fill in informat ion based upon t he surrounding st imuli, pat ient s oft en do not not ice t heir scot omat a unt il lat er st ages of disease (Crabb et al. 2013). Added t o t he fact t hat glaucoma is usually charact erised by gradual progression (Heijl et al. 2012a), does not t end t o affect cent ral vision lat er st ages of t he disease and t he fields from bot h eyes cover t he same cent ral area (binocular summat ion) pat ient s oft en do not not ice t hey are losing t heir vision unt il lat e in t he disease (Shaw 2005). As a result , pat ient s can be diagnosed w it h visual impairment t hat can seriously underm ine t heir qualit y of life (Ang & Eke 2007, Kot echa et al. 2012a), hence t he condit ion’s nickname as “ t he silent t hief of sight ” . The severit y of t his condit ion, as w ell as t he

(24)

22

fact t hat t here is not yet any cure for t he blindness caused by it , makes finding w ays of det ect ing and prevent ing t he disease progression im perat ive.

Figure 1.3 - The fluid pathway in the eye. Glaucoma is often related to the partial or complete blockage of the outflow of aqueous fluid through the trabecular meshw ork (labelled “meshw ork”). The “angle” refers to the angle betw een the iris and cornea. In open-angle glaucoma this is w ide, w hereas in angle-closure glaucoma this is narrow such that the iris presses against the cornea. Image taken from the National Eye Institute: http:/ / w w w .nei.nih.gov/ health/ glaucoma/ glaucoma_facts.asp accessed in June 2014.

1.1.1 Risk factor s in glaucoma

There are various risk fact ors in glaucoma, yet t he only modifiable one of t hese is an eye’s IOP. Alt hough not all individuals w it h high IOP have glaucoma (individuals w it h IOP over 21 mm Hg but no ot her signs of glaucoma are diagnosed as having ocular hypert ension [OHT]) and not all glaucoma pat ient s have high IOP (as is t he

(25)

23

case in pat ient s w it h NTG), it has been show n repeat edly t o not only be a major risk fact or for glaucomat ous disease incidence and progression (Sommer et al. 1991, Gordon et al. 2002, Chauhan et al. 2008a, Kim et al. 2011, Jiang et al. 2012), but also a fact or in t he rat e of progression of t he disease (Heijl et al. 2012a, M edeiros et al. 2012, Chauhan et al. 2014). Large fluct uat ions in IOP have also been demonst rat ed t o be a risk fact or for glaucoma (Asrani et al. 2000, De M oraes et al. 2011a). How pressure relat es t o t he deat h of ganglion cells is not fully underst ood, but it s effect s, along w it h t he fact it can be changed, makes it an essent ial risk fact or t o consider.

There are various ot her fact ors associat ed w it h glaucoma t hat can be used t o help ident ify at risk groups of t he disease. Old age is very consist ent ly linked w it h developing glaucoma, w it h over 50s a part icularly at risk group (M ukesh et al. 2002, Gordon et al. 2002, Leske et al. 2007, Chauhan et al. 2008a, Nat ional Eye Inst it ut e 2010). Sim ilarly, ot her non-modifiable risk fact ors such as family hist ory of glaucoma (Leske et al. 2008) and et hnicit y (Nat ional Eye Inst it ut e 2010) are also oft en found t o be risk fact ors in disease incidence, w it h individuals of African descent part icularly vulnerable. For inst ance, w hile populat ion st udies est imat e incidences of definit e OAG at around 0.1% per year in largely Caucasian Europe (de Voogd et al. 2005) and Aust ralia (M ukesh et al. 2002) populat ions, t hese est imat es w ere as high as 0.6% in t he predominant ly Afro-Caribbean Barbados Eye St udy (Leske et al. 2001). Feat ures of t he eye such as exfoliat ion syndrome (Heijl et al. 2009) are also linked t o development of glaucoma. Finally, t here are various st ruct ural feat ures of t he eye t hat have oft en been linked t o glaucoma, such as t hin cent ral corneal t hickness (CCT) (Gordon et al. 2002, M edeiros et al. 2003, European Glaucoma Prevent ion St udy Group 2007, De M oraes et al. 2011a, M edieros et al. 2012) and large axial lengt h (w hich causes myopia or short -sight edness) (Jiang et al. 2012, M arcus et al. 2011) t hough t he lat t er fact or has not consist ent ly been show n t o be a reliable risk fact or (Sohn et al. 2010). Int erest ingly, despit e st udies show ing t hat individuals w it h OHT t end t o have high CCT compared t o t hose w it h glaucoma (Sobot t ka Vent ura et al. 2001), at t empt s t o correct IOP for CCT in predict ion models have not yet been found t o have great ut ilit y (Brandt et al. 2012). One possible

(26)

24

explanat ion is dow n t o t he fact t hat t hicker corneas t end t o give higher IOP readings using t onomet ry t han individuals w it h t hinner corneas.

There are various ot her suspect ed fact ors t hat are not universally acknow ledged as risk fact ors for disease. For inst ance, increased syst olic blood pressure has been linked t o disease incidence (Jiang et al. 2012) w hilst ot her morbidit ies such as diabet es (M it chell et al. 1997, Gordon et al. 2002), vasospast ic disease (Broadw ay & Drance 1998) and even sleep apnoea (M ojon et al. 2000) have all previously been linked, alt hough t heir relat ionships w it h t he disease is by no means proven (Chauhan et al. 2008a, European Glaucoma Prevent ion St udy Group 2007). Ocular perfusion pressure (OPP) is anot her clinical charact erist ic t hat has previously been linked t o developing glaucoma (Leske et al. 2008, Zheng et al. 2010), largely in an at t empt t o explain w hy not every glaucoma pat ient has high IOP. How ever, ocular blood flow is difficult t o measure and has largely been est imat ed using a funct ion of t he blood pressure and IOP. Unfort unat ely, t his measurement does not give any more informat ion t han blood pressure w here IOP is also being account ed for (Khaw aja et al. 2013). As a result , t he st at us of OPP as an independent risk fact or is st ill quest ionable.

1.1.2 Diagnosis of glaucoma

Glaucoma is diagnosed t hrough using a bat t ery of different t est s: Nat ional Inst it ut e for Healt h and Clinical Excellence (NICE) Guidelines st ipulat e t hat all people suspect ed of having POAG or w ho even have OHT should have Goldmann applanat ion t onomet ry performed, CCT measured using pachymet ry, gonioscopy performed, VF measurement s using st andard aut omat ed perimet ry (SAP) and opt ic nerve head (ONH) assessment using st ereoscopic slit lamp biomicroscopy (Nat ional Inst it ut e for Healt h and Clinical Excellence 2009).

Tonomet ry is t he met hod used in measuring t he main risk-fact or of glaucoma, t he IOP, so is underst andably import ant in det ermining pressure t arget s for t reat ment . Though not necessarily direct ly relat ed t o glaucoma it self, in conjunct ion w it h high IOP, t hin CCT can be linked t o great er likelihood and speed of progression in glaucoma and is t herefore required t o be t aken int o account w hen det erm ining

(27)

25

t reat ment severit y (Nat ional Inst it ut e for Healt h and Clinical Excellence 2009). The ONH assessment allow s clinicians t o look at t he healt h of t he opt ic nerve, but SAP is t he only means of direct ly invest igat ing t he act ual visual healt h in t erms of it s impact on t he pat ient . Due t o it s import ance in assessing disease st at us and it s relevance t o t he pat ient , it is measurement s from SAP t hat w ill be predom inant ly looked at over t he course of t his t hesis.

1.1.3 Tr eatment for glaucoma

Whilst , t hese risk fact ors are all relat ed t o glaucoma and could be useful for considerat ion in screening purposes, cont rolling t he IOP remains t he only means of t reat ing t he disease. Various clinical t rials, including t he Ocular Hypert ension Treat ment st udy (OHTS) (Gordon et al. 2002), t he Early M anifest Glaucoma Trial (EM GT) (Heijl et al. 2002, Leske et al. 2003) and t he Canadian Glaucoma St udy (CGS) (Chauhan et al. 2010) have all demonst rat ed t he ut ilit y of low ering t he IOP t o reduce t he incidence and progression of glaucom a.

M anagement of IOP is performed eit her t hrough medicat ion (normally eye drops), laser t reat ment or surgery. Eye drops are cert ainly preferable, but can have various side-effect s ranging from eye irrit at ion t o nausea. Non-adherence t o t reat ment is a large issue in glaucoma (Gurw it z et al. 1993, Shaw 2005) for various reasons, including t he fact t hat pat ient s do not realise t heir vision is get t ing w orse and t herefore t he import ance of adherence. In addit ion, t reat ment s can also be difficult t o administ er, part icularly for elderly pat ient s, w ho are unfort unat ely also t he main dem ographic affect ed by glaucoma.

It is import ant t o ensure t hat pat ient vision does not det eriorat e t o blindness or even visual disabilit y w it hin t heir remaining lifet ime, so it is import ant not t o under-t reaunder-t paunder-t ienunder-t s. How ever, under-t here is a significanunder-t risk of overunder-t reaunder-t menunder-t in glaucoma t oo, w hich w ast es limit ed clinical resources; a part icularly pert inent issue given t hat t he grow ing numbers of pat ient s w ill increasingly st ret ch nat ional healt h resources (Tuulonen 2013) and t hat t he condit ion may not necessarily lead t o visual impairment (Heijl et al. 2009). In addit ion, alt hough pat ient s w ould rat her have

(28)

26

surgery t han lose vision (Bhargava et al. 2006), it must be t aken int o considerat ion t hat t reat ment t ends t o become more unpleasant as severit y increases. For inst ance, t rabeculect omy can pot ent ially result in increased risk of cat aract , infect ion, blurred vision, bleeding, sudden, permanent loss of cent ral vision and even secondary glaucoma if fluid drainage is prevent ed by scarring.

1.2 Monitor ing glaucomatous vision loss

It is clearly highly import ant t o monit or pat ient visual det eriorat ion over t ime in order t o evaluat e w het her or not t reat ment is required or needs t o be escalat ed (Heijl 2013). The next sect ion w ill briefly look at w ays of doing so in clinical pract ice.

1.2.1 Str uctur al measur ements

One met hod of monit oring loss is t o measure t he changing st ruct ural charact erist ics of t he eye as t hey change w it h disease. For example, examinat ion of t he opt ic disc and measurement of ret inal nerve fibre layer t hickness can be used. New , high-resolut ion imaging inst rument s such as Spect ral-Domain Opt ical Coherence Tomography are st art ing t o emerge from research laborat ories in t he hope of more accurat ely ident ifying disease progression (Figure 1.4). The ult imat e advant age of st ruct ural met hods is t hat t hey are object ive, as t hey are not reliant on pat ient response. How ever, current imaging devices, t hough useful, are not a replacement for funct ional measurement s in measuring glaucomat ous progression (St rout hidis & Garw ay-Heat h 2008, Gabriele et al. 2011). The largest issue is t hat it is difficult t o reconcile st ruct ural measures t o clinical out comes t hat are meaningful t o t he pat ient , as t hey do not port ray w hat t he pat ient can act ually see and t herefore t he impact of t he disease. M oreover, t here can be large discrepancies bet w een st ruct ural and funct ional measurement s of progression in glaucoma t o t he point of being largely independent of one anot her (Art es & Chauhan 2005). In addit ion, despit e appearing precise, st ruct ural measurem ent s are st ill subject t o variabilit y (Ow en et al. 2006). St ruct ural measurement s are not present ly accept able for t he evaluat ion of medical product s for t he t reat ment of glaucoma (Weinreb & Kaufman

(29)

27

2011). They are, nonet heless, useful t ools in glaucoma diagnosis and monit oring w hen used alongside more funct ional means of measuring glaucomat ous loss. How ever, t his t hesis w ill not focus on t he use of t hese measurement s.

Figure 1.4 – Output from an OCT show ing the Retinal Nerve Fibre Layer of my ow n right eye.

1.2.2 Per imetr y

M easuring t he funct ional progression of t he glaucoma (t hat is, w hat t he pat ient can act ually see) is import ant in diagnosing glaucom a and m onit oring it s progression. Perimet ry is t he means by w hich t he VF; of a pat ient is mapped (Henson 2000), and t he only means of measuring funct ional progression. Ot her t han reduct ion in IOP (w hich is t he basis by w hich most new t herapies are evaluat ed), VF measurement s are t he only accept ed endpoint s in t he evaluat ion of new t reat ment s for glaucoma; t he Advanced Glaucoma Int ervent ion St udy (AGIS), Collaborat ive Init ial Glaucoma Treat ment St udy (CIGTS) and EM GT being examples of major t rials in w hich VF progression w as t he chief endpoint .

M easuring an individual’s VF is simple in principle; t he subject must first fix t heir eyes on a part icular point and light st imuli of varying int ensit ies are t hen displayed around t he individual’s field of vision. The subject must t hen communicat e t o t he examiner w het her t hey can see t he light or not . Tradit ionally, manual met hods of

(30)

28

doing t his w ere performed including t he Goldmann perimet er, but t hese approaches have largely been superseded by aut omat ed perimet ry due t o t he fact t hat Goldmann perimet ry is highly dependent on t he examiner in t erms of accuracy and bias. Given Goldman perimet ry involves a moving st imulus, pat ient s undert aking t his t est t end t o lose fixat ion t o a great er ext ent t han t hose using aut omat ed perimet ry w here t he pseudo-random ised locat ion of t he st imulus is less predict able (Heijl & Krakau 1977). Thus, st at ic aut omat ed perimet ry is a clinical gold st andard in clinical pract ice as t he more reliable and more reproducible opt ion (Fankhauser et al. 1977), alt hough Goldmann perimet ry can somet imes st ill be used in cases w here pat ient s st ruggle t o int erface w it h aut omat ed perimet ry.

1.3 Standar d Automated Per imetr y

There are various aut omat ed perimet ric met hods, but of t hese st andard aut omat ed perimet ry (SAP) is most comm only used in clinical pract ice and regarded as t he clinical st andard. SAP uses w hit e light s as st imuli present ed on a w hit e background. Test s t ypically use st at ic st imuli, w hich are flashed sequent ially in a pre-defined grid of locat ions. The dist ribut ion of t est locat ions can vary, but t he t w o common VF t est ing pat t erns are at 6-degree even int ervals in a 30-2 pat t ern (w it h 38 point s in each hemisphere spanning t he cent ral 30 degrees) or a 24-2 pat t ern (27 point s in each hemisphere spanning t he cent ral 24 degrees). The durat ion and size of st imulus is also fixed in st at ic perimet ry (commonly at 0.2

seconds and 0.43

˚ of visual angle in diameter [Goldmann Size III]

respect ively).

How ever, t hough SAP has been available from t he 1970s, t here have nonet heless been a number of ot her aut omat ed perimet ry met hods t hat have been developed, including Short Wavelengt h Aut omat ed Perim et ry (SWAP), Pulsar (or Flicker Perimet ry) and Frequency Doubling Perimet ry (FDP or FDT) (Giangiacomo et al. 2006, Turalba & Grosskreut z 2010). How ever, research is st ill ongoing on t he ut ilit y of t hese new er t echniques so, for t he moment , SAP remains t he primary met hod for det ect ing VF progression and is hence t he subject of t his research. As w it h st ruct ural met hods, alt ernat ive funct ional met hods may possibly be helpful alongside rat her t han inst ead of SAP (Chauhan et al. 2008b).

(31)

29

There are t hree main machines used for SAP in t he UK at present : t he Humphrey Visual Field Analyzer (HFA; Carl Zeiss M edit ec, Dublin, CA), t he Oct opus (Haag-St reit , Köniz, Sw it zerland) and t he Henson (Elekt ron t echnology, Cambridge, UK). These t hree devices produce slight ly different out put s, but generally perform t he same funct ion, t o similar st andards. The HFA is most commonly used in many large clinical cent res in t he UK, especially in a t ert iary or referral set t ing w here t he goal is t o monit or VFs in pat ient s w it h glaucoma or w ho are at risk of developing glaucoma.

1.3.1 Measur ing the Visual Field using Standar d Automated Per imetr y

SAP derives an est imat e of t he ret inal sensit ivit y at various equally-spaced point locat ions in a pat ient ’s VF. There are t w o comm on t ypes of t est ing: t hreshold and supra-t hreshold t est ing. In case-finding, supra-t hreshold t est ing is oft en used because it is quick; t his mode of t est ing uses one or more light int ensit ies and simply t est s w het her t hese st imuli can be seen in each t est locat ion. How ever, in glaucoma monit oring, w here measuring changes in severit y at each locat ion is import ant , t hreshold t est ing is more commonly used. The aim of t hreshold t est ing is t o t ry and find, for each t est ed locat ion, t he low est level of light t hat it is possible for a pat ient t o ident ify. In order t o det ermine t he t hresholds of each t est locat ion, it is im port ant t o t est at each locat ion repeat edly.

(32)

30

Figure 1.5 – A colleague performing Standard Automated Perimetry on an Octopus Visual Field device

In SAP, t he subject fixat es on a cent ral st imulus and indicat es w het her or not t hey are able t o see ot her light s flashed in randomised locat ions around t heir gaze at varying int ensit ies by pressing a but t on (Figure 1.5). The result is a series of measurement s at each t est ed locat ion called sensit ivit ies (or t hresholds), measured in decibels, an inverse measure of t he st rengt h of t he st imulus (measured in

candelas per met res2). The VF t hreshold measurement ranges from 50 t o 0dB w it h

0 dB represent ing perimet ric blindness in t hat part icular point of t he eye (around 30dB is usually considered healt hy). Generally, t he result s w ill be out put in t he form of a grid of numbers and a greyscale represent ing w hat part s of t he VF are missing in black (Figure 1.6).

(33)

31

Figure 1.6 – Output from a Visual Field (VF) examination from a patient’s right eye. The left grid show s the measured threshold sensitivities at 52 locations (excluding the blind spot), w hereas the right grid is a greyscale w ith darker areas representing less sensitive parts of the VF.

In t heory, pat ient s w ill alw ays see st imuli bright er t han a t est locat ion’s t hreshold, but fail t o see a st imulus dimmer t han a locat ion’s t hreshold. How ever, in realit y, w hen a light bright ness is present ed at a level close t o an individual’s t rue t hreshold, t here is a chance t he pat ient may not respond as expect ed. In ot her w ords, t here is a probabilit y of a pat ient failing t o regist er t he st imulus even if it is visible t o det ect . The probabilit y of a pat ient seeing or not seeing a given st imulus is t herefore somet imes referred t o as t he frequency of seeing. The aim of t est ing is t o t ry and find a light t hreshold at w hich a st imulus is seen 50% of t he t ime.

1.3.2 Per imetr ic Testing algor ithms

There are different met hods for est ablishing VF sensit ivit ies at each locat ion. The earliest t o be w idely used in perimet ry w as full-t hreshold t est ing. In t his met hod, an init ial st imulus is present ed at a t est locat ion. If a pat ient sees t his present at ion, t he st imulus bright ness is decreased by 4dB, w hereas if it cannot be seen t hen t he bright ness is increased by t he same amount . This cont inues unt il t he st at us of w het her t he point can or cannot be seen changes (t he first reversal). The st imulus

(34)

32

int ensit y is t hen decreased or increased back in st eps of 2dB unt il t he pat ient response changes once more (t he second reversal). An average of t he final and penult imat e t est sensit ivit ies is recorded as t he t hreshold for t hat t est locat ion. The order of t he VF locat ions t est ed is randomised aut omat ically in order t o aid fixat ion (Heijl & Krakau 1975). Ult imat ely, t his met hod is t horough, but it can also t ake a relat ively long t ime t o complet e (about 10 t o 15 minut es for each eye for a 24-2 t est pat t ern) (Bengt sson & Heijl 1998a, Bengt sson & Heijl 1998b, Nordmann et al. 1998, W ild et al. 1999) during w hich it can be difficult for t he pat ient t o maint ain t heir at t ent ion. As a result , it is not suit able for all pat ient s.

Though, in t heory, t he increased amount of t est ing is supposed t o improve t est precision, some researchers speculat e t hat t he result ing fat igue from t he lengt h of a full t hreshold t est ing could exaggerat e defect s or even result in t he finding of defect s t hat do not exist (Bengt sson & Heijl 1998b, Turpin & M cKendrick 2011). Thus, fast er met hods have been devised in order t o reduce t est t ime. The most successful and most w idely adopt ed of t hese t echniques is know n as t he Sw edish Int eract ive Thresholding Algorit hm (or SITA as it is commonly know n) for t he HFA. This Bayesian t echnique relies on a sim ilar principle t o t he full t hreshold met hods, but seeks t o cut out t he unnecessary t est ing t ime by reducing t he num ber of present at ions (Bengt sson et al. 1997a).

SITA St andard begins w it h prior informat ion about t he sensit ivit y of each locat ion before t he t est st art s, using age-correct ed normal values, ant icipat ed frequency-of-seeing curves and correlat ions bet w een sensit ivit ies at each t est locat ion (Bengt sson et al. 1997a). How ever, t he t est begins present ing st imuli in t he same w ay as full t hreshold t est ing, measuring t he first four “ primary” point s (or seed point s) in a st epw ise manner; one in each quadrant of t he VF 9 degrees aw ay from fixat ion in bot h axes. As w it h full t hreshold t est ing, aft er present ing an init ial st imulus t he t est simply seeks t he t hreshold sensit ivit y of each t est locat ion in t he eye t hrough increasing or decreasing t he light sensit ivit y present ed in st eps of 4dB unt il t he pat ient response changes. Once t he first four point s are est imat ed, t he sensit ivit ies of t he ot her t est locat ions can be est imat ed and t hese est imat ions are amended as t he t est ing proceeds. In ot her w ords, t he t hreshold of one point act s

(35)

33

t o “ predict ” t he probabilit y of seeing a t hreshold for t he ot hers, so each t est is act ively changing t he predict ed t hreshold of t he ot her point s. A second reversal only occurs if t he difference bet w een adjacent point t hresholds is larger t han a pre-calculat ed value based on t he pat ient ’s demographic know n as t he error relat ed fact or (ERF) (Bengt sson et al. 1997a). The exact det ails of how t he ERF is calculat ed have not been disclosed, but it is calculat ed aut omat ically by most perimet ry machines. During t he t est , response t imes are cont inually recorded and used t o adjust t he durat ion of t est present at ions. At t he end of t he t est , t hresholds may be adjust ed slight ly in post -processing according t o t hresholds of adjacent t est locat ions and changes in react ion t imes during t he t est .

The large advant age of t he SITA St andard is t hat it can halve t he durat ion of t est ing for many pat ient s (Bengt sson & Heijl 1998a, Nordmann et al. 1998, W ild et al. 1999). How ever, t here is a consist ent discrepancy bet w een t he SITA St andard and full t hreshold met hods in t hat t he former algorit hm is consist ent ly more opt imist ic in t erms of t hreshold measurement by around 1dB (Figure 1.7) (Art es et al. 2002, Bengt sson & Heijl 1999). As a result of t he t ime saved using it and t he fact t hat it has similar repeat abilit y t o full t hreshold t est ing (Art es et al. 2002, Bengt sson & Heijl 1999), SITA St andard is now t he most commonly used t hreshold det ect ion met hod.

(36)

34

Figure 1.7 – The mean sensitivities for Full threshold, SITA Standard and SITA Fast tests taken on the same patients in a study by Artes et al. 2002. SITA Fast and Standard tests tended to yield higher, more optimistic thresholds than full threshold testing. Image taken from Artes et al. 2002.

Ot her even fast er met hods have been devised by researchers in order t o enhance t he speed of t est ing furt her. SITA Fast , in part icular, is commonly report ed t o reduce t est ing t imes t o below 5 minut es (Bengt sson & Heijl 1998b, Nordmann et al. 1998, W ild et al. 1999, Pierre-Filho et al. 2006), w hich could pot ent ially have clinical ut ilit y in t erms of saving t ime in clinical pract ice. SITA Fast w as designed t o be equivalent in t erms of accuracy t o Fast -t hreshold st rat egies, such as Fast pac (Glass et al. 1995), w hich uses 3dB st eps and one reversal inst ead of t w o reversals in full t hreshold t est ing, but it is significant ly fast er (Bengt sson & Heijl 1998b). How ever, t he t est algorit hm it self is similar t o SITA St andard, t he main difference being few er reversals. Only one reversal is used (as opposed t o t w o) unless t he difference bet w een t he est imat ed and expect ed t hresholds is great er t han more t han 12dB. In addit ion, t he algorit hm can t erminat e t est ing of any t est locat ion even earlier provided t here is at least one posit ive response at a t est locat ion and t he measurement error is below t he ERF (Bengt sson & Heijl 1998b). Unsurprisingly given t he nat ure of it s design, t here is a suspicion t hat SITA Fast may have less

(37)

35

sensit ivit y in ident ifying VF defect s t han full t hreshold t est ing and SITA St andard and t here is some evidence t hat t he result s from t his t est are less repeat able (Art es et al. 2002) (Figure 1.8). It is uncert ain w het her t he pot ent ial for increased t est ing and t he impact on fat igue com pensat e for t he nat ural reduct ion in precision as a result of less t est ing.

Figure 1.8 – The test-retest variability about full-threshold measured thresholds using Full threshold, SITA Standard and SITA Fast VF testing. The variability is greater for SITA Fast than Full threshold, but SITA Standard performs relatively w ell by comparison. This image is taken from Artes et al. 2002.

1.3.3 Reliability Indices

In an ideal w orld, perimet ry should produce accurat e result s on every occasion, but result s t hat are not reflect ive of a pat ient ’s act ual VF can be produced, due t o loss of at t ent iveness, inexperience, overent husiasm or not fixat ing on t he cent ral point w ell enough. It is t herefore import ant t o evaluat e t he reliabilit y of t he VFs measured before using t hem t o inform clinical decision making.

Every t est ing algorit hm described above have met hods of evaluat ing t he reliabilit y of t he t est it self t hrough looking for false negat ives (FN), false posit ives (FP) and

(38)

36

fixat ion losses (FL). False posit ives are a measure of how ‘t rigger-happy’ t he pat ient is, measuring how likely t hey are t o indicat e observat ion of a st imulus w it hout seeing it . In full t hreshold t est ing t hey are t est ed t hrough simply having occasions w here t he device pret ends t o change t he st imulus locat ion, but show s no light . To cut t est ing t imes, t he SITA algorit hms do not use cat ch t rials, but judge false posit ives by t he react ion speed of t he pat ient s, such as w hen a subject responds before t hey have had t ime t o see and react t o t he st imulus. False negat ives are a measure of inat t ent iveness of t he pat ient – t he devices show a light in an area w here t est ing has already confirmed t he t hreshold and give a bright ness t hat t he pat ient should be able t o det ect . Fixat ion losses meanw hile t est how accurat ely t he subject is fixat ing at t he fixat ion t arget by present ing st imuli at t he locat ion of t heir physiological blindspot ; t his is t he area corresponding t o t heir opt ic disc, w hich has no phot orecept ors.

The major clinical t rials, such as AGIS, CIGTS and EM GT have used all t hese measures t o assess field reliabilit y (The Advanced Glaucoma Int ervent ion St udy Invest igat ors 1994, Gillespie et al. 2003, Heijl et al. 2008), yet t he crit eria applied t o t hem remain arbit rary and vary bet w een t rials. For inst ance, for t he AGIS and CIGTS t rials, a scoring syst em w as used w hich meant t hat pat ient s could t heoret ically pass w it h false posit ive or negat ive rat es in excess of 33% (The Advanced Glaucoma Int ervent ion St udy Invest igat ors 1994, Gillespie et al. 2003), w hilst EM GT t rials did not look at t he FN rat e at all (Heijl, Bengt sson et al. 2008). In addit ion, ot her reliabilit y crit eria such as t he t ot al num ber of quest ions asked (The Advanced Glaucoma Int ervent ion St udy Invest igat ors 1994) (longer t est s imply great er uncert aint y in measuring t he t hreshold) and short t erm fluct uat ion values have been used (The Advanced Glaucoma Int ervent ion St udy Invest igat ors 1994, Gillespie et al. 2003).

There is evidence t o suggest t hat none of t he reliabilit y indices provide an accurat e insight int o a pat ient ’s performance. For inst ance, Bengt sson found t hat none of t he main t hree met rics for reliabilit y cont ribut ed significant ly more informat ion t o t est reproducibilit y t han t he level of VF loss it self (see Sect ion 1.3.4). The only met ric t hat linked t o t est reproducibilit y at all w ere FNs (Bengt sson 2000).

(39)

37

How ever, t here w ere indicat ions in t he same st udy t hat t his relat ionship w as most likely t o be due t o a significant associat ion bet w een FNs and VF loss (Bengt sson 2000). Similarly, Shao et al. found FNs t o be t he best index for predict ing t est reproducibilit y account ing for severit y of VF loss, but also found t hat none of t he reliabilit y indices are good predict ors of overall t est -ret est variabilit y (Shao et al. 2011). M ont olio et al. meanw hile, found false posit ives t o be t he most crucial index, w it h each 10% increase in FPs being est imat ed t o increase t hreshold est imat es by 1dB (Junoy M ont olio et al. 2012). Fixat ion losses have been show n t o cont ribut e t o t est variabilit y w it hout being a major cont ribut or (Henson et al. 1996, Junoy M ont olio et al. 2012).

Overall, t here is likely no single “ best ” reliabilit y index in assessing progression; if a VF is unreliable in any w ay t hen t his has t he pot ent ial of hindering t he abilit y t o det ect progression, w het her it gives t he impression t hat t he pat ient ’s VF is bet t er or w orse t han in realit y, t hereby leading t o impaired clinical judgement . For t his reason, clinicians should be aw are reliabilit y indices w hen t aking VFs. Addit ionally, t he inst ruct ions given t o t he pat ient , t he correct ion of spherical ammet ropia and pat ient at t ent ion may also have a significant bearing on t he result and t hese indices should not be relied upon exclusively (Chauhan et al. 2008b).

1.3.4. Pr oblems in monitor ing Visual Field deter ior ation in per imetr y

The out put produced from SAP can be confusing as it cont ains a huge amount of dat a and informat ion, and it is not alw ays part icularly obvious how large changes are from one VF assessment t o t he next . In spit e of all t he effort s in perimet ry t o accurat ely det ect t he t hreshold of a pat ient accurat ely, t here is st ill a lot of “ noise” in t he measurement s of t hresholds, w hich is w hat makes measuring t he rat e of progression non-t rivial, part icularly in areas of t he VF w here vision is w orse and t his variabilit y is great er (Henson et al. 2000, Art es et al. 2002, Russell et al. 2012a). As a result , t here exist s t est re-t est variabilit y bet w een VF t est s t hat needs t o be t aken int o account w hen analysing result s.

(40)

38

M easuring a t hreshold w here a pat ient can only see 50% of present at ions can oft en be hard t o find explicit ly. Using a t echnique called met hod of const ant st imuli t o measure st imuli accurat ely (Laming & Laming 1992), Gardiner and colleagues found t hat some locat ions w it h measured t hresholds using SAP did not have a st imulus int ensit y associat ed w it h t hem t hat could be seen 50% of t he t ime, w hich led t hem t o conclude t he probabilit y of seeing a st imulus did not increase appreciably regardless of how bright t he st imulus w as at measured ‘t hresholds’ of below 19dB (Gardiner et al. 2014). In ot her w ords, t hey concluded t hat t he likelihood of response at 19dB or bright er is governed by chance rat her t han giving any informat ion on t he ret inal sensit ivit y at t hat locat ion. If t his is t rue, t hen perhaps t here is an argument for incorporat ing a new low er limit for sensit ivit ies in VF t est ing (e.g. set t ing 20dB as t he low est possible measurement ), w hich w ould perhaps reduce variabilit y in t he calculat ion of progression indices. In t he st udies included in t his t hesis, how ever, it is assumed t hat t here is st ill some informat ion t o be gained from low er t hreshold values in VF t est ing.

Furt hermore, t he psychophysical nat ure of t he t est s means t hat learning effect s need t o be t aken int o considerat ion, as pat ient s oft en improve in t heir abilit y t o part icipat e in perimet ric t est ing w it h experience (Wild et al. 1989, Heijl et al. 1989, Heijl & Bengt sson 1996). As a result , measured t hresholds t end t o increase over t ime, somet imes persist ing long aft er t he first t hree t est s (Wild et al. 1989). As t he first t est is oft en part icularly deflat ed (one previous st udy report ed an average increase of as much as 2.6dB in M D bet w een t he first t w o t est s in perimet ry naïve glaucoma pat ient s [Heijl & Bengt sson 1996]), discount ing t he first VFs remains good pract ice w hen assessing glaucoma progression.

In spit e of all t he problems associat ed w it h judging progression, many clinicians nonet heless assess progression ‘manually’ using t heir experience t hrough comparing SAP print out s. How ever, decision-making, even among expert clinicians, can be inconsist ent (Visw anat han et al. 2003, Tanna et al. 2011) and concordance bet w een clinicians has been shown t o increase subst ant ially w hen Progressor soft w are is used (Visw anat han et al. 2003). As a result , it is clear t hat clinical decision-making in evaluat ing progression st at us can be improved w it h t he