University of Groningen

Population based glaucoma screeningStoutenbeek, Remco

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Chapter 2 Literature review

13

Chapter 2

Whether glaucoma is suitable for population based screening depends on many factors. In 1968, at the World Health Organization conference in Geneva, Wilson and Jungner proposed a set of criteria for assessing whether screening for a particular disease is worthwhile.10 In the course of years, some of the criteria were modified, and - predominantly because of advancements in genetics - additional criteria were appended. Genetic screening for glaucoma is not yet at issue, because genetic mutations known to cause primary open angle glaucoma account for only a small minority of glaucoma cases.11 Therefore, the original criteria are still valid. They will be applied to glaucoma screening, and will serve as a scaffold for the literature review of this thesis. The Wilson & Jungner criteria for appraising the validity of a screening programme are:

1. The condition being screened for should be an important health problem

2. The natural history of the condition should be well understood 3. There should be a detectable early stage 4. Treatment at an early stage should be of more benefit than at a later

stage 5. A suitable test should be devised for the early stage 6. The test should be acceptable 7. Intervals for repeating the test should be determined 8. Adequate health service provision should be made for the extra clinical

workload resulting from screening 9. The risks, both physical and psychological, should be less than the

benefits 10. The costs should be balanced against the benefits

14

Literature review

2.1 The condition being screened for should be an important health problem

Glaucoma is the second leading cause of blindness worldwide; second to cataract in developing countries and second to Macular Degeneration in developed countries. World Health Organization (WHO) definitions for blindness and low vision are shown in table 2.1.1. Visual impairment includes both blindness and low vision. Table 2.1.1 Blindness, low vision, and visual impairment definitions.

BCVA in better eye VF in better eye

max min max min

vis. impaired* <6/18 lp – and/or <20° 0°

low vision* <6/18 1/20 and/or <20° 10°

blindness* <1/20 lp – and/or <10° 0°

blindness# ≤2/20 lp – and/or ≤20° 0° BCVA = Best Corrected Visual Acuity; VF = Visual Field (widest radius with Goldmann III-4 stimulus, measuring from the fixation point); lp – = no light perception * = as defined in the 10th Revision of the WHO International Statistical Classification of Diseases, Injuries and Causes of Death (ICD-10) # = as defined by United States federal legislation Table 2.1.2 shows an estimate of global blindness and visual impairment in 2002 per WHO region. Data were derived from a WHO paper by Resnikoff.2 The number of blind people worldwide was estimated to be 36,9 million. This corresponds to a prevalence of 0.6%. In Western Europe, the prevalence of blindness is 0.2%.

15

Chapter 2

Table 2.1.2 Magnitude of visual impairment worldwide.2

Tota

l

6214

161.

2

124.

3

36.9

100%

100%

Wes

tern

Pa

cific

Re

gion

1718

41.8

32.5

9.3

28%

25%

Sout

h-Ea

st

Asi

a Re

gion

1591

45.1

33.5

11.6

26%

32%

East

ern

Med

iterr

Re

gion

503

16.5

12.4

4.0

8%

11%

Afr

ican

Re

gion

672

26.8

20.0

6.8

11%

18%

Regi

on o

f th

e A

mer

icas

853

15.5

13.1

2.4

14%

7%

East

Eu

rope

an

Regi

on

463

9.1

7.4

1.8

7%

5%

Wes

t Eu

rope

an

Regi

on

415

6.4

5.4

0.9

7%

2%

popu

latio

n (x

mill

ion)

vis.

impa

irmen

t (x

mill

ion)

low

vis

ion

(x m

illio

n)

blin

d (x

mill

ion)

% o

f tot

al

popu

latio

n

% o

f tot

al

blin

dnes

s

16

Literature review

Causes of blindness are shown in figure 2.1.1a (worldwide) en figure 2.1.1b (Western Europe). Blindness due to glaucoma affects 4.5 million people worldwide (12.3% of 36.9 mln) and 170,000 Western Europeans (18% of 0.9 mln).2

glauc 12.3% others

#

*

drp

cataractarmd

Figure 2.1.1a Causes of blindness in 2002 worldwide.2 # = trachoma; * = corneal opacity; drp = diabetic retinopathy; armd = age related macular degeneration; glauc = glaucoma

17

Chapter 2

others glauc

18% *

drp cat

armd

Figure 2.1.1b Causes of blindness in 2002 for Western Europe.2 * = corneal opacity; drp = diabetic retinopathy; armd = age related macular degeneration; cat = cataract; glauc = glaucoma Quigley estimated12 that there would be 60.5 million people with primary glaucoma worldwide in 2010: 44.7 million with open-angle glaucoma (OAG) and 15.7 million with angle-closure glaucoma (ACG). Glaucoma in the European derived region (defined as Europe including the Russian Federation and Ukraine, United States, Bermuda, Canada, Greenland, Australia, New Zealand, and Israel) was estimated to affect 12.1 million people: 10.7 million with OAG and 1.4 million with ACG. The number of people blind from glaucoma worldwide in 2010 was estimated to be 8.4 million: 4.5 from OAG and 3.9 from ACG. This estimate by Quigley, although of somewhat comparable magnitude, is higher than the WHO estimate (4.5 million people blind from glaucoma in 2002, 12.3% of 36.9 million, see above). The two estimates differ, partly because of the increasing world population from 2002 to 2010, but mainly because of methodological issues. Blindness prevalence surveys often assign the most “treatable” disease as the primary cause of blindness. Cataract is considered more treatable than glaucoma, which leads to an underestimation of glaucoma blindness in developing countries in the WHO survey. Projections for 2020 from the same article expect an increase in glaucoma burden of 19.1 million people in one decade, to a total of 79.6 million people with glaucoma worldwide. Glaucoma related blindness will by then affect

18

Literature review

approximately 11.1 million people. The increase in glaucoma burden is the result of predicted population growth and longer life expectancy. Both Resnikoffs and Quigleys estimates are based on glaucoma prevalence and incidence studies. Key characteristics of important epidemiological studies on POAG prevalence and incidence are summarized in table 2.1.3 and 2.1.4 respectively (presented below figure 2.1.2). Reported prevalence rates vary between 0.8% and 8.8%. The pooled prevalence rate from these and several additional minor studies is 2.1%.8 Reported 5-year incidence rates vary between 1.1% and 3.1%. Discrepancies between studies in reported prevalence and incidence rates are predominantly due to differences in ethnicity, age, and glaucoma definition used. The latter is illustrated in figure 2.1.2 (see below). The graph shows the variation in prevalence of glaucoma by age, when glaucoma definitions from other population based studies are applied to data of the Rotterdam study.7

Figure 2.1.2 Variation in prevalence of open angle glaucoma when different criteria for glaucoma are applied to data of the Rotterdam study.7 Reproduction, courtesy of Dr. R.C.W. Wolfs.

19

Chapter 2

Table 2.1.3 POAG prevalence.

study period ethnicity age (years)

N prevalence

USA, Framingham13 1973-1975 Caucasian 52-85 2433 1.4%

Italy, Ponza14 1986 Caucasian ≥40 1034 2.5%

USA, Wisconsin, Beaver Dam15

1988-1990 Caucasian 43-84 4926 2.1%

Australia, Blue Mountains16 1992-1994 Caucasian ≥49 3654 3.0%

Italy, Egna-Neumarkt17 1995 Caucasian ≥40 4297 1.4%

The Netherlands, Rotterdam7

1990-1993 Caucasian ≥55 6281 0.8%

USA, Baltimore18 1985-1988 Caucasian ≥40 2913 1.1%

USA, Baltimore18 1985-1988 African ≥40 2395 4.2%

Caribbean, West Indies19

<1989 African-

Caribbean ≥30 1679 8.8%

Barbados20 1988-1992 African-

Caribbean 40-84 4631 6.7%

Japan, Yokohama21 2000 Asian 6-98 64394 1.2%

20

Literature review

Table 2.1.4 POAG incidence.

study period ethnicity age (years)

N incidence (5 year risk)

Sweden, Dalby22 1977-1986 Caucasian ≥55 1295 1.2%

Sweden, Tierp23 1984/86-1988/91 Caucasian 65-74 413 3.1%

Barbados24 1988/92-1992/97

African ≥40 3427 2.8%

Australia, Melbourne25

1992/94-1997/99 Caucasian ≥40 3257 1.1%

The Netherlands, Rotterdam26

1990/93-1997/99 Caucasian ≥55 3842 1.8%

21

Chapter 2

2.2 The natural history of the condition should be well understood The term “glaucoma” comes from “glaukosis”, which was first described by Hippocrates in his book Concerning Vision of the Corpus Hippocraticum around 400 BC. Glaukosis may have been derived from the Greek word “glaukos”, which means greenish glaze. It probably represented cataract instead of glaucoma.27 POAG is currently defined by the European Glaucoma Society as a chronic progressive optic neuropathy with characteristic morphological changes at the optic nerve head and retinal nerve fibre layer, in the absence of other ocular disease or congenital anomalies. Progressive retinal ganglion cell death and VF loss are associated with these changes.28 The relative risk for POAG rises continuously with the level of IOP. Elevated IOP results from increased resistance to aqueous outflow at the level of the trabecular meshwork.29 Individuals with a statistically normal IOP can also develop POAG, which is then termed Normal Tension Glaucoma, and is not uncommon.30 The pathogenesis of glaucoma remains unclear. Apoptosis of retinal ganglion cells with concurrent demise of their axons is the established final common pathway of glaucomatous optic neuropathy.31 The most likely anatomical location where damage to the optical pathway must take place, can be deduced from knowledge of the progression patterns of VF loss. Scotomas are unlikely to cross the horizontal meridian when their size increases due to glaucoma progression.32 Only at the level of the optic disk can this finding be accounted for, so this is where damage must occur. 33 Morphologic disk changes such as cupping and bowing of the lamina cribrosa support this finding. The underlying mechanisms that take place at the optic disc and lead to apoptosis of ganglion cells, are subject of debate however, and probably multi-factorial. Two popular theories are: mechanical compression of axons at the level of the lamina cribrosa, hampering axonal transport;34;35 and ischemia of the optic nerve head as a result of deficient blood flow autoregulation.31;36 Even though the pathogenesis of glaucoma has not been elucidated, there is a good understanding of its natural history. Important studies that contributed most to the understanding of untreated glaucoma are the Early Manifest Glaucoma Trial (EMGT)3;4 and a study by Wilson et al.37 The EMGT is a clinical trial that evaluated the effectiveness of IOP reduction by randomising newly detected, previously untreated glaucoma patients to either treatment with trabeculoplasty and betaxolol eye drops (n=129) or no treatment (n=126).3;4 An average IOP reduction of 5.1 mmHg was achieved, which constituted a 25% reduction from baseline. The median follow-up period was 6 years (range 51-102 months). Glaucoma progression was considered present when either the visual field worsened, or optic disc cupping increased. Progression was less frequent in the treatment group (58/129=45%) than in the

22

Literature review

non-treatment group (78/126=62%; P=0.002). Interestingly, they also calculated the Mean Deviation (MD) change in dB per month, which was found to be -0.05 dB ±0.07 dB (± Standard Deviation, SD) in the untreated group. These figures can be used to estimate the long term outcome of untreated glaucoma, when we assume that the deterioration is linear. Over the course of 10 years, the MD will progress on average -6 dB. In the very worst case scenario however, reflected by adding twice the SD, the MD progression becomes -22.8 dB in ten years. Since baseline MD in the non-treatment group was -4.4 dB ±3.3 SD, these worst case scenario patients develop end-stage glaucoma in ten years. Moreover, the exclusion of high tension cases (mean IOP >30 mmHg or any IOP >35 mmHg), might have led to an underestimation of the actual progression rate. In 2002, the same year that the EMGT results were published, a study by Wilson et al37 appeared that presented a more direct view of the natural course of glaucoma. Their study took place in St. Lucia, West Indies, where a national survey had been conducted from 1986 to 1987 regarding the prevalence of primary open-angle glaucoma among 1,679 Afro-Caribbean individuals. 147 subjects (8.8%) had been diagnosed with glaucoma, and 217 subjects were diagnosed as glaucoma suspects. Those with severe glaucoma received surgery and those requiring glaucoma medications received them at no charge. However, in 1988 the infrastructure for subsidized glaucoma care changed, so unfortunately only a few cases were actually treated. This was discovered ten years later when Wilson conducted a follow-up study in 1997. It became a unique opportunity to study the natural course of untreated glaucoma. Of the 364 subjects at baseline, 159 were lost to follow up. Of the remaining 205 patients, 59 right and 64 left eyes were excluded. Based on the Advanced Glaucoma Intervention Study (AGIS)38 criteria, 55% of 146 right eyes and 52% of 141 left eyes showed progression of visual field loss. The cumulative probability of reaching end-stage glaucoma (AGIS score ≥18) in ten years in at least one eye was 16%; for bilateral end-stage glaucoma the cumulative probability was 7%. Various glaucoma risk factors have been identified, mainly through population based studies. Important risk factors are: intraocular pressure, 7;26;39 age,7 family history of glaucoma,40 black ethnicity,18 central corneal thickness41, and myopia42.

23

Chapter 2

2.3 There should be a detectable early stage Screening is aimed at detecting a disease before symptoms arise. The purpose is to treat the disease in an earlier stage, which is often beneficial: easier treatment, better prognosis, less health damage. Depicted in figure 2.3.1 is a schematic representation of an individual who becomes ill at a certain point in life.

screening

P Q R

birth

Figure 2.3.1 Disease phases. Adapted from Vandenbroucke JP et al.43 (N)D-PCP = (non)detectable preclinical phase Point P marks the biological onset of disease, but since the disorder is initially very small, detection is not yet possible. From point Q onwards, screening tests are able to detect abnormalities. From point R onwards, the patient becomes symptomatic (manifest disease). Between biological onset and manifest disease lies the preclinical phase. This preclinical phase can be subdivided in a non-detectable preclinical phase (ND-PCP) and a detectable preclinical phase (D-PCP). Cases detected through a screening programme are on average halfway between point Q and point R. Therefore, the gain in time that results from detection through screening is defined as half of the D-PCP, and is known as the “lead time”. As a consequence, the longer the D-PCP is, the longer the lead time, and the more suitable a disease becomes for screening. Glaucoma is characterised by its insidious onset and long D-PCP. Visual field loss goes unnoticed by most individuals, because scotomas are compensated for by the fellow eye, or are being filled in by the brain. Visual acuity typically remains intact until late in the disease process, when extensive optic nerve damage has occurred. In the Netherlands, many cases are presently discovered through case finding by opticians, optometrists, and ophthalmologists, and not as a result of glaucoma related symptoms. Even with case finding, only about half of all people

death

preclinical phase (PCP) manifest disease

ND-PCP D-PCP

24

Literature review

with glaucoma are known (i.e. detected as having glaucoma, and visiting an ophthalmologists regularly).7-9 Quigley et al performed a questionnaire study in 2003 among 308 glaucoma patients (362 eligible, response rate 85%) to determine how glaucoma patients are identified.44 Only 25% of the study subjects reported having eye symptoms at their initial ophthalmologist visit. Moreover, in at least three-quarters of these cases, the reported eye symptoms seemed unrelated to glaucoma.

25

Chapter 2

2.4 Treatment at an early stage should be of more benefit than at a later stage

Glaucomatous damage to the optic nerve is irreversible. Treatment (which consists of lowering of IOP) can slow down the progressive loss of nerve fibres, but can not stop it. In advanced glaucoma, much effort needs to be made to keep the rate of progression to an absolute minimum. A lower target IOP becomes necessary45, which requires stricter monitoring (more frequent visits), more medications, and more often glaucoma surgery. It is not always possible to prevent visual impairment and blindness. Early glaucoma on the other hand permits a more lenient approach regarding both follow-up and treatment, since patients are unlikely to become visually impaired. In the 1990s, two prospective randomised controlled trials were conducted: the Early Manifest Glaucoma Trial (EMGT)4 and the Ocular Hypertension Treatment Study (OHTS)5. Both studies prove that early treatment is beneficial (see below). The EMGT evaluated whether lowering of IOP decreased the progression of glaucomatous damage in early glaucoma patients. The EMGT is discussed in paragraph 2.2. In summary, progression was less frequent in the treatment group (45%) than in the non-treatment group (62%; P=0.002).3 The OHTS evaluated whether lowering of IOP decreased the conversion rate from ocular hypertension (OHT) to glaucoma in subjects with OHT. Participants with no evidence of glaucomatous damage, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye, were randomized to either treatment with topical ocular hypotensive medication (n=702) or observation (n=706). IOP reduction was 22.5% in the medication group versus 4.0% in the observation group. Conversion to glaucoma was considered present when either reproducible visual field abnormalities developed or reproducible optic disc deterioration was found. At 60 months follow-up, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio 0.40; 95% confidence interval 0.27-0.59; P<.0001).6 Several other influential prospective studies also evaluated the effect of IOP reduction on glaucoma progression, but these are not specifically aimed at early glaucoma, the focus of this paragraph. The Collaborative Normal-Tension Glaucoma Study (CNTGS) evaluated 140 patients with normal tension glaucoma. Patients were randomized to either treatment (n=61) or observation (n=79). Glaucoma progression was less frequent in the treatment group (12%) than in the non-treatment group (35%; P=0.002).46 The Advanced Glaucoma Intervention Study (AGIS)38 was designed to compare two surgical treatment strategies for patients with open-angle glaucoma that could no longer be adequately controlled by medications alone. A large

26

Literature review

proportion of the 738 participants had moderate or advanced glaucoma. Data was not only used to decide which surgical treatment strategy was more favourable, but also to examine the relationship between intraocular pressure and progression of visual field damage. For the latter purpose, participants were stratified into subgroups based on their IOP. After seven years of follow-up, eyes with lower IOP showed less glaucomatous visual field progression than eyes with higher IOP (P<0.001).45 In a meta-analysis by Maier et al.,39 data from five OHT treatment studies and two glaucoma treatment studies (the EMGT and the CNTGS) were pooled. Treatment had a significant protective effect on conversion from OHT to glaucoma, as well as on progression of established glaucoma. The hazard ratio for OHT treatment was 0.56 (95% confidence interval 0.39 to 0.81, P=0.01) and for glaucoma treatment 0.65 (95% confidence interval 0.49 to 0.87, P=0.003). Hattenhauer et al. evaluated the probability of blindness from treated OAG and treated OHT in a retrospective, community-based, longitudinal study in Minnesota.47 The United States federal legislation definition of blindness was used (see table 2.1.1). Newly diagnosed OAG and OHT cases identified between 1965 and 1980 were included in the study. The mean follow-up time was 15 years. Kaplan–Meier cumulative probability of bilateral blindness at 20 years was estimated to be 4% for treated OHT patients (n=177), and 22% for treated OAG patients (n=118). Obviously, these rates do not apply to modern glaucoma care, since in 1965 the standards for glaucoma care were different, and options for lowering IOP with medication were limited. Also, the definition of blindness as established by US legislation is fairly liberal, particularly with respect to the visual field criterion (see last row to table 2.1.1), which also contributes to the high rate of blindness. Nevertheless, the large difference in blindness rates between OAG and OHT patients is an indication that treatment at an early stage is preferable to treatment at a later stage. Chen conducted a similar study48, using the same definition for blindness. Patients undergoing glaucoma treatment in 2000 at the Eye Clinic of the University of Washington Medical Center that were newly diagnosed between 1975 and 1998 were eligible. 186 patients were included, their mean follow-up time was 10.2 years. The Kaplan-Meier cumulative probability of bilateral blindness at 15 years was estimated to be 6.4%. The amount of baseline visual field (VF) loss was identified as the most important risk factor for blindness

�(relative risk 1.20/dB deterioration in baseline MD (P<0.001).

27

Chapter 2

2.5 A suitable test should be devised for the early stage The ideal mass screening test should be safe, cheap, fast, easy to perform by both examiner and examinee, and have a high specificity and reasonable sensitivity. Specificity is more important than sensitivity in the setting of mass screening, since it is important to minimise the number of false positive test results. Some sensitivity can be sacrificed in order to maintain high specificity, provided that advanced cases are not missed and can still be treated adequately. Diagnostic testing for glaucoma consists of two modalities: perimetry and imaging. In perimetry, the visual field (VF) is evaluated. Glaucoma is the leading cause of VF loss, but there are many non-glaucomatous causes.49 Perimetry is a subjective test of function, and thus requires cooperation and concentration from the test subject. In glaucoma imaging, the structure of the optic nerve head or its surrounding nerve fibre layer is evaluated. Imaging is an objective test of anatomic proportions, which requires less cooperation, but it yields an indirect measure of function. Anatomical variations of the optic disc, as seen in tilted or myopic discs, present problems for imaging devices, as well as the presence of peripapillary atrophy in otherwise normal discs. Perimetry and imaging are discussed below in paragraph 2.5.1 and 2.5.2. A third category of diagnostic tests is measurement of the IOP. The gold standard for measuring IOP is Goldmann applanation tonometry; most opticians perform non-contact tonometry. Elevated IOP is a risk factor for glaucoma, but does not provide direct information about the presence or absence of glaucoma. A characteristic of glaucoma is its increased fluctuation in IOP throughout the day, hence glaucoma patients with on average elevated IOP may sometimes have normal readings. Moreover, a not insignificant part of glaucoma patients has statistically normal IOP continuously (so called normal tension glaucoma – NTG). As a consequence of these problems, only about half of the glaucoma patients have elevated IOP at a single visit.50 On the whole, tonometry is unsuitable for population based screening, although it most definitely remains useful for case finding, as demonstrated by Peeters et al.51 2.5.1 Perimetry Standard Automated Perimetry (SAP) has become the most commonly used form of perimetry for glaucoma diagnosis and follow-up. Commonly used SAP devices are the Humphrey Field Analyzer (HFA, Carl Zeiss Meditec Inc., Dublin, CA, USA) and the Octopus perimeter (Haag-Streit AG, Koeniz, Switzerland), among others. In SAP, the threshold luminance of every test location in the visual field is determined by a staircase procedure: the stimulus luminance is either increased

28

Literature review

or decreased stepwise until a change occurs in the response of the subject.52;53 This detailed VF information allows for careful monitoring of glaucoma patients during follow-up. For screening purposes however, it is only necessary to differentiate a normal VF from a glaucomatous VF; follow-up is not at issue. Fewer requirements allow for a simpler test. The frequency doubling perimeter (FDT - Carl Zeiss Meditec, Dublin, California, USA; Welch-Allyn, Skaneateles, New York, USA) is particularly suitable for screening. It is an automated static perimeter that uses only 17 test locations in a 24° VF, compared to 52 and 76 test locations for the HFA24-2 and 30-2 respectively. In C20-1 screening mode, the FDT uses a supra-threshold instead of a full threshold algorithm, designed for high specificity. Testing times are typically 40 seconds per eye in case of no VF loss, which can increase to 120 seconds in case of extensive VF loss. Frequency doubling perimetry uses a special stimulus type, specifically a sinusoidal spatial waveform composed of alternative white-and-black stripes that counter-phase flicker at 25 Hz. This creates an optical illusion: the target is perceived to have twice its actual spatial frequency.54-56 Several studies reported on the diagnostic performance of the FDT C20-1. Some of them are shown in table 2.5.1. Classification (glaucoma or no glaucoma) was done on a by-patient basis in the study by Stoutenbeek et al.57 (see chapter three) and on a by-eye basis in the other studies. This difference in methodology explains the higher sensitivity and somewhat lower specificity reported by Stoutenbeek et al., since by-patient testing gives each individual two chances (two eyes) to be classified as abnormal. Table 2.5.1 Diagnostic performance of the Frequency Doubling perimeter in C20-1 screening mode.

study period N sensitivity specif.

glauc. normal early moderat severe

Trible et al.58 2000 125 95 39% 86% 100% 95%

Stouten- beek et al.57 2004 100 108 74% 100% 100% 88%

Ferreras et al.59 2007 110 92 32% 65% 100% 100%

Iwase et al.60 2007 171 5295 41% 88% 93%

early = early glaucoma, defined as HFA mean deviation (MD) > -6 dB; moderate = -6 dB ≥ MD > -12 dB; severe = MD ≤ -12 dB

29

Chapter 2

As can be seen in table 2.5.1, FDT C20-1 has a high specificity. Sensitivity for early glaucoma is limited, however no cases with severe glaucoma (defined as HFA mean deviation ≤ -12 dB) were missed. FDT C20-1 perimetry is therefore appropriate as a diagnostic test for glaucoma screening. Learning effects for FDT in perimetric novices are very small in comparison to test-retest variability and compared to standard automated perimetry (i.e. HFA perimetry).61 2.5.2 Imaging Currently, there are three principal imaging modalities used for analysing the optic nerve head (ONH) and the surrounding retinal nerve fibre layer (RNFL). [1]. The confocal scanning laser ophthalmoscopy (CSLO) uses a laser beam to scan the three dimensional shape of the ONH. [2]. Optical coherence tomography (OCT) measures the thickness of the RNFL based on the coherence of reflected laser light, similar to the physical principals of ultrasound. [3]. Scanning laser polarimetry (SLP) measures the thickness of the RNFL by assessing the retardation that results from the birefringent properties of ganglion cell axons. See table 2.5.2 for an overview. Table 2.5.2 Glaucoma imaging devices.

device modality target dilation

Heidelberg Retina Tomograph (HRT) CSLO ONH no

Stratus Optical Coherence Tomography (OCT) OCT RNFL yes

GDx Nerve Fiber Analyzer (GDx) SLP RNFL no

dilation = pupil dilation required; CSLO = confocal scanning laser ophthalmoscopy; SLP = scanning laser polarimetry; ONH = optic nerve head; RNFL = retinal nerve fibre layer All three devices have similar diagnostic performance.62-65 OCT requires pupil dilation, and is for that reason less interesting for screening purposes (though the latest generation OCT may be able to operate through pupil sizes as small as 3mm). Diagnostic performance of the HRT compared to the GDx is shown in table 2.5.3. Each study determined sensitivity and specificity rates for both the HRT and the GDx within a single group of subjects.

30

Literature review

Table 2.5.3 Diagnostic performance of the Heidelberg Retina Tomograph (HRT) compared to the GDx Nerve Fiber Analyzer (GDx).

study period N sensitivity specif.

glauc. normal HRT GDx both

Medeiros et al.62 2004 107 76 59% 61% 95%

Pueyo et al.63 2007 73 66 85% 48% 95%

Badala et al.65 2007 46 46 70% 78% 95%

Reus et al.66 2007 48 40 85% 92% 95%

Medeiros et al.67 2008 40 42 35% 50% 95%

At 95% specificity, reported sensitivity rates for HRT and GDx vary considerably from 35% to 85% and from 48% to 92% respectively. This is primarily due to differences in average glaucoma severity of enrolled patients. Since structural damage to the optic nerve generally precedes VF loss,6;68-70 most imaging studies focussed on early glaucoma and glaucoma suspects, yielding lower sensitivity. Only a few studies contain stratified data for moderate and severe glaucoma cases, see table 2.5.4. The lower specificity as found by Heeg et al. results from classification on a by-patient basis, analogous to the FDT perimetry study by Stoutenbeek et al. discussed earlier in this paragraph (see paragraph 2.5.1).

31

Chapter 2

Table 2.5.4 Sensitivity to moderate and severe glaucoma for the Heidelberg Retina Tomograph (HRT) and the GDx Nerve Fiber Analyzer (GDx).

study period device N sensitivity specif.

moderat severe moderat severe

Ferreras et al.71 2007 HRT 32 21 94% * 95% * 86%

Reus et al.72 2004 GDx 28 81 93% * 100% # 96%

Heeg et al.73 2005 GDx 329 95% # 78%

* severity of glaucoma rated according to Hodapp–Parrish–Anderson score74 # severity of glaucoma rated conform legend to table 2.5.1 Grading of glaucoma severity based on the Hodapp–Parrish–Anderson score74 (see table 2.5.4) is more complex and more strict than grading based on HFA mean deviation as described in the legend to table 2.5.1. This needs to be taken into account when comparing table 2.5.4 (imaging) to 2.5.1 (perimetry). Both the HRT and GDx seem appropriate diagnostic tests for glaucoma screening, and are on par with perimetry (FDT). The upper limit in test specificity for all glaucoma screening tests (perimetry and imaging) is probably at 95%; higher specificities are currently not feasible since sensitivity for severe glaucoma would fall. These conclusions are in concordance with a recently published meta-analysis on glaucoma screening tests by the United Kingdom Health Technology Assessment programme.75 It is important to keep in mind that the stated specificity of 95% is applicable to the testing of one eye only; specificity will be lower if both eyes are examined. See paragraph 8.1 regarding by-eye versus by-patient specificity for further discussion.

32

Literature review

2.6 The test should be acceptable Glaucoma tests mentioned in paragraph 2.5 (FDT, HRT, GDx) are all non-invasive. No ionizing radiation is used for imaging, and pupil dilation is not necessary (excluding OCT). Testing is not painful, awkward, or time-consuming. Subjects are required to concentrate on their visual task (for FDT), or keep their eyes steady on a point of focus (for imaging). Testing takes less than three minutes per eye. Measurement of intra ocular pressure (IOP) can be performed by non-contact tonometry, which uses a puff of air to applanate the cornea. Topical anaesthesia is not required (as opposed to Goldmann applanation tonometry), and since corneal touch does not occur, chances of microbiological and prion transmission are minimal. Testing takes less than a minute per eye. These glaucoma screening tests place far less of a burden on screened subjects than existing population based screening programmes in the Netherlands (mammography, heel prick test, and Pap smear – see introduction to chapter two).

33

Chapter 2

2.7 Intervals for repeating the test should be determined The optimal time period between two consecutive screening tests is determined by a balance of two opposing main interests. To minimize the chances that an individual reaches end-stage glaucoma between screening visits, the interval should be kept short. However, the length of the inter-test interval has considerable impact on the costs of a screening programme, since it directly determines how many people need to be screened each year. A larger screening interval is more likely to be economically feasible. An acceptable compromise between these conflicting interests depends to some extent on the society’s willingness to pay: how much money is made available for avoiding glaucoma induced blindness. Nevertheless, data on rate of progression of glaucoma can be used to estimate a reasonable screening interval. In the EMGT study, the progression rate of untreated glaucoma was analysed (see paragraph 2.2).3;4 Extrapolating from their results and assuming linear progression, the worst case scenario (97.5th percentile) patient progresses -22.8 dB in ten years, which is equivalent to end-stage glaucoma. A ten year screening interval thus seems unfavourable, even if none of the participants would have any baseline loss. In reality, baseline loss will not be uncommon, because in every screening round quite a few early glaucoma cases will have been missed, the so called false negatives (early glaucoma is defined as HFA MD better than -6 dB; see legend to table 2.5.1). This results from the need for high test specificity in a screening setting (see paragraph 2.8), which implies that some test sensitivity for early glaucoma must be sacrificed to attain high overall specificity. Missed cases in the prior screening round start their successive screening interval with baseline loss. Taking baseline loss into account and choosing a five year screening interval (arbitrarily chosen), the worst case scenario patient would start at -6 dB and progress -11.4 dB to end up at -17.4 dB at the successive screening test. This seems just acceptable. Other studies also provide empirical data concerning glaucoma progression over a period of approximately five years. In the Groningen Longitudinal Glaucoma Study (GLGS), a cohort of patients at risk for developing glaucoma (patients with ocular hypertension or a family history of glaucoma, but without visual field abnormalities at baseline) was followed prospectively in a clinical setting for 4 years with SAP, FDT, and GDx.69;73;76 Of 174 glaucoma suspect patients, 26 had developed reproducible glaucomatous visual field loss on SAP. At the end of follow-up, the HFA MD of the worse eye of the 26 incident glaucoma cases ranged from -7.6 to -0.8 dB, with an average value of -3.6 dB. The Rotterdam Study is a prospective, population-based cohort study of residents aged 55 and older living in a district of Rotterdam.7;26 Participants were examined at baseline and follow-up, 87 of 3842 participants developed incident glaucoma during a

34

Literature review

mean follow-up time of 6.5 years. 78 of 87 incident glaucoma cases were available for analyses, and 45 of these 78 cases had visual field loss on supra-threshold visual field testing (see chapter six; in the remaining 33 incident glaucoma cases, diagnosis was based on progressive optic disc cupping).77 At the 75th percentile, glaucoma progression over 6.5 years was –2.8 dB in the better eye and –9.3 dB in the worse eye. Missed points on Supra-Threshold Perimetry (STP) have been converted into HFA MD scores according to the method described in chapter seven. Both the EMGT, the GLGS, and the Rotterdam Study yield comparable results: during a five year interval, considerable glaucoma progression can take place in unfavourable cases, but even when baseline loss was also present, the resulting amount of glaucomatous damage will fall short of end-stage glaucoma and is amenable to treatment. Recent cost-effectiveness studies also use a five year screening interval for modelling of a screening programme78;79 (see paragraph 2.10).

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2.8 Adequate health service provision should be made for the extra clinical workload resulting from screening

Implementation and upkeep of a population based screening programme requires a great logistical effort and consumes considerable amounts of resources. However, screening is only the first step towards prevention of morbidity. All subjects with a positive screening test will need further evaluation. Some of them will prove to have glaucoma (the true positives) and require follow-up and treatment. Borderline cases will also need follow-up. Unconfirmed cases (the false positives) pose a distinct problem: they may either return to periodic screening or quite the reverse, see paragraph 8.5 (general discussion). For the estimates given below, false positive cases were assumed to return to periodic screening or even opportunistic case finding and to not require ongoing follow-up, as this approach seems most likely to be economically feasible. Effects of accumulation of normal subjects that repeatedly fail their screening test every screening round are ignored since estimates are performed for a single 5 year screening round only. The clinical workload that results from true and false positive screening tests, depends on the prevalence of undetected glaucoma, and on the sensitivity and specificity of the screening test. Prevalence of glaucoma in the Dutch 40+ population is about 2% (see table 2.1.3 – POAG prevalence). At least half of all glaucoma patients are undetected,7-9 so the prevalence of undetected glaucoma is approximately 1%. Since this is a relatively low percentage, the specificity of the screening test will be of far greater importance with respect to ensuing clinical workload than the sensitivity. Based on data from table 2.5.1, 2.5.3, and 2.5.4, sensitivity and specificity for a glaucoma screening test are arbitrarily determined as 75% and 95% respectively. Table 2.8.1 shows the corresponding estimated number of true and false positives.

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Table 2.8.1 Population of the Netherlands for different age groups; rough estimates of clinical workload that results from glaucoma screening.

[ estimated figures ]

age inhabitants (x million)

known glau- coma patients

true positives

false positives

all 16.4

40+ 8.2 66 000 49 000 404 000

45+ 6.9 63 000 47 000 339 000

50+ 5.6 56 000 42 000 277 000

inhabitants = number of Dutch inhabitants on 01-01-2008 according to Statistics Netherlands;80 known glaucoma patients = number of inhabitants with known glaucoma, assuming a prevalence of

1% for age over 50 & 0.5% for age 45 to 50 & 0.25% for age 40 to 45 years; true positives = number of inhabitants with unknown glaucoma that would be discovered by

screening, assuming a test sensitivity of 75% and a prevalence of unknown glaucoma of 1% for age over 50 & 0.5% for age 45 to 50 & 0.25% for age 40 to 45 years;

false positives = number of inhabitants without glaucoma that would have a false positive screening test result, assuming a test specificity of 95% As can be seen in table 2.8.1, the lower age limit of the population to be screened has a profound influence on the number of false positives. Moreover, glaucoma prevalence is very low for subjects aged 40 to 50 years, so screening would yield few cases in this stratum. This is illustrated in figure 2.1.2, where the prevalence of glaucoma in the Rotterdam Study7 drops below 0.1% for subjects under age 55 for most glaucoma definitions. On the other hand, young undetected glaucoma patients run the highest risk of becoming blind, and will on average spend more years being blind, because they have the longest life expectancy. A reasonable compromise is to start glaucoma screening at age 50. The estimated number of true and false positive test subjects would then be 319,000, if everyone would attend for screening. Participation rates for breast cancer screening vary considerably, but 70% is regarded to be achievable.81 When we apply this rate to glaucoma screening, we can expect 223,000 subjects per screening round referred for further evaluation. For a test interval of five years (see paragraph 2.7), this corresponds to a clinical workload of 45,000 subjects with a true or false positive test result each year. In the clinical setting, each subject requires once again perimetry and/or imaging, and at least one or two ophthalmologist visits. About 10,000 glaucoma and borderline cases will need ongoing follow-up. This places a heavy burden on ophthalmologists and technical personnel. Currently there are 557 ophthalmologists registered in the Netherlands, a considerable

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proportion of whom work part time (based on data from the Dutch Ophthalmologic Society, yearbook 2008). At least an additional 15 full time ophthalmologists and 30 technical ophthalmologic assistants are needed initially, and requirements may increase in the course of years.

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Literature review

2.9 The risks, both physical and psychological, should be less than the benefits

As discussed in paragraph 2.6, diagnostics tests for glaucoma are non-invasive and do not use ionizing radiation. Consequently, screening participants are not exposed to any risks whatsoever, only burdened by having to attend the screening. There are no reports regarding the psychological consequences of false positive test results, but inconvenience from necessary follow-up and anxiety to be diagnosed with glaucoma seem likely. Medical treatment for glaucoma initially consisted of IOP lowering eye drops in the form of β-blockers and miotics. Recently, an increasing number of topical agents have become available, including carbonic anhydrase inhibitors, α2-agonists, and prostaglandin analogues. As a result of the broader therapeutic armamentarium at the ophthalmologists’ disposal, operation rates have declined in favour of medical management.82 Conscientiously prescribed medication will have few topical or systemic side effects. Occasionally it takes some trial and error to find the most suitable choice. An increasing number of preparations are also available without preservative, so that patients with allergic reactions to certain preservatives can also be treated. Only a small minority of patients can not be maintained on medication and need surgery. In contrast to medical treatment, glaucoma surgery caries a significant risk of serious ocular complications.83-86 The risk of surgical complications is weighed against the risk of glaucomatous progression due to failure to medically control IOP. In summary, treatment for glaucoma poses little risk to patients, except for difficult cases. Glaucoma has a negative influence on quality of life (QoL) in several ways. The diagnosis in itself causes depression, anxiety, changes in health perception, and worry about blindness. Furthermore, patients dislike having to use medication every day, as it reminds them of their disorder. Instillation of eye drops takes effort, it stings, and drops may have local and systemic side effects. Finally, there is a direct relationship between various QoL measures and both visual acuity and the visual field.87-92 Glaucoma reduces patients’ health-related QoL mainly in advanced stages of the disease, when severe visual field damage has occurred in both eyes.93;94 A considerable proportion of glaucoma patients would not have become blind when left untreated, before deceasing (see chapter six).77 These patients profit little from being detected by screening, but they do bear the disadvantages as mentioned above. However, the small proportion of glaucoma patients for whom screening and earlier treatment prevents visual impairment gain a substantial amount of QoL, since visual impairment has a major impact on QoL.89;90

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Chapter 2

2.10 The costs should be balanced against the benefits Breast cancer screening programmes were initially considered successful at lowering mortality rates associated with breast cancer,95 but later on, initiated by a Swedish epidemiological study in 1999,96 they became controversial.97;98 Once a screening programme has become operational, it is extremely difficult to confirm or invalidate it’s effectiveness. Observational studies that investigate ongoing screening programmes are prone to several types of bias related to screening (see paragraph 8.2 – general discussion). It is therefore crucial to investigate whether a health problem is suitable for screening prior to the introduction of a screening programme. Unambiguous evidence for cost-effectiveness requires a randomized controlled trial (RCT), that compares glaucoma screening to the current practice of opportunistic case finding. A literature review did not identify any RCT’s on glaucoma screening, which is not surprising. Such a trial would need a very large number of participants as well as long-term follow-up. Another approach is to estimate the cost-effectiveness of glaucoma screening by developing an economic model of all major costs and effects involved (see table 2.10.1). A systemic review of all cost-effectiveness studies on glaucoma screening published until December 2005 was performed by Hernandez et al.99 They found four studies that met their inclusion criteria.100-103 These were conducted between 1983 and 1997, the latest of which was based on data from 1995. They reported that all four studies suffered from numerous methodological weaknesses, that the screening tests and treatment protocols have become outdated, that the data was not sufficiently detailed to allow for reinterpretation, and that the outcomes ranged widely between studies. Therefore, they conclude that there is insufficient economic evidence on which to base recommendations regarding screening for OAG. Since then, two additional cost-effectiveness studies have been published which will be discussed below, one conducted by Vaahtoranta-Lehtonen et al. in Finland,78 the other conducted by Hernandez et al. in the United Kingdom.79 Both studies compared population based screening to opportunistic case finding, and both studies used a Markov model for this purpose. A Markov model is suitable for modelling a chronic progressive diseases like glaucoma.104 It uses Markov states to represent all relevant outcomes in the screening and treatment process, in which individuals stay for a period of time called a ‘cycle’. Initial distribution of individuals over the separate Markov states is based on prevalence figures. The flow through the model is determined by using transition probabilities, which reflect the chance of an individual moving from one Markov state to another. Costs and benefits are calculated according to time spent per individual per Markov state.

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Literature review

Table 2.10.1 Costs and benefits of a glaucoma screening programme.

costs

screening personnel (organisation, technicians, clinicians, overhead)

logistics (invitation of participants)

test equipment

premises

clinical diagnostic evaluation (of participants with abnormal test results)

follow-up (of borderline and glaucoma cases)

treatment (drugs; glaucoma surgery; secondary cataract surgery)

societal QoL loss (anxiety in participants with false positive test result; inconvenience)

productivity loss (due to having to attend the screening programme, and possibly needing to visit an ophthalmologist for further evaluation)

transport (travel of participants to the examination centres and back)

benefits

screening [none]

clinical earlier treatment (which means easier treatment, see paragraph 2.4)

societal reduced loss of QoL (in individuals that were successfully identified and treated due to the screening programme)

reduced blindness incurred costs (social services / rehabilitation costs; aids for reading, writing, mobility; disability homes)

reduced productivity loss from blindness (minimal effect, because progression to blindness will almost exclusively occur after retirement)

QoL = Quality of Life

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Chapter 2

In the Finnish study,78 an organized screening programme in a population aged 50-79 years at 5 year intervals was simulated. The examinations carried out in the screening arm were IOP measurement, autorefraction, digital imaging of the fundus, and VF examination. In positive cases the same tests were repeated once. They found that the incremental cost of one Quality Adjusted Life Year (QALY) gained by screening compared to opportunistic case finding was €9023, which makes screening an appealing alternative. Costs per QALY were much higher in the younger age groups, whereas screening became dominant (i.e. both cheaper and more effective) in the eldest cohorts (>70 years). The effects of assumptions and uncertainties in the input data of the model were tested with sensitivity analyses. Diagnostic test specificity and cost per screening were revealed to have the most significant influence on the final cost per QALY in their model. Unfortunately, both of these parameters were chosen optimistically. A test specificity of 98% was assumed, based on combining different diagnostic tests and repeating abnormal test results. 98% is a very high specificity, especially since it applies to by-patient classification. This issue is further discussed in paragraph 8.2. Cost per screening was estimated to be €33, which seems rather inexpensive for a battery of four tests. Moreover, productivity loss due to having to attend screening was not taken into account, and costs for invitation of participants were also missing. Finally, although screening was found to be the most cost-effective in the eldest cohorts, no data indicating correction for the reduced life expectancy of elderly subjects was mentioned,105 and no Markov state “deceased” seemed to be present in the model. Despite these points of criticism, the majority of the study design was thorough, and the authors are lauded for their vast work in this matter. In the UK study,79 multiple simulations were carried out using various combinations of different settings in the input data of their model. These include: cohorts starting at 40, 60 or 75 years of age; screening interval of 3, 5 or 10 years; prevalence of glaucoma from 1 to 10%; test specificity from 80 to 100%; society’s willingness to pay of £10,000, £20,000, £30,000, and £50,000; and several other parameters. Two screening strategies were explored, screening by a technician and screening by a glaucoma-trained optometrist, and both were compared to opportunistic case finding. They concluded that general population screening for glaucoma is unlikely to be cost-effective. Screening at any age was expected to cost more than £30,000 per gained QALY at realistic age adjusted glaucoma prevalence rates (probably about £60,000 per QALY; rough estimate, no exact figures given). Only in certain subgroups of the 40 years old age cohort, specifically participants with a family history of glaucoma and participants of black ethnicity, screening might become cost-effective (defined as cost per QALY <£30,000; see paragraph 8.1 – general discussion) as a result of the increased glaucoma prevalence.

42

Literature review

Both the Finnish and the UK study used Markov models, and in both studies these models were populated with data based on systematic literature reviews when possible. Although the outcome measures of both studies in terms of costs per QALY were in the same order of magnitude, those costs still differed considerably, and in consequence, the authors ended up with opposing conclusions. Sensitivity analyses of both studies confirmed the common sense notion that modelling of so many variables each with its own confidence limits creates a very wide margin of uncertainty in the final output. In any case, the conflicting evidence precludes a definite statement on whether or not population based glaucoma screening should be introduced. This discussion will continue in chapter eight, appended by information from the publications contained in this thesis (chapters three to seven).

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