Glaucoma

"DuchampDictionary",collage
fromThomasGirst'sbook
Petteri Teikari, PhD
http://petteri-teikari.com/
version Sun 28 May 2017
Glaucoma
Engineering perspective for
diagnosis and disease
management

Introduction
In future we will see how ‘big data’ and multimodal inference is
making ophthalmologic diagnostics, disease management and
personalized treatment more objective and of higher quality.
The highly complex and nonlinear interactions between
measurable variables will eventually replace strict diagnosis
codes and ‘hero researcher’ single metrics with automated analysis
pipelines.
Successful clinicians will embrace machine learning augmented
workflows and healthcare will follow other professions in this “AI
transition”

Glaucoma Overview of the pathology
Symptoms ofglaucoma
Glaucoma doesn't usually have any
symptoms to begin with and is often
only picked up during a routine eye
test.
Many people don't realise they
have it because it develops slowly
over many years and tends to cause a
loss of peripheral vision (the edge of
your vision) at first. Without
treatment, it can eventually lead to
blindness
In glaucoma the vascularization of the
optic nerve head is greatly attenuated.
This is not readily visible from the fundus
photograph (left), whereas the OCT
angiography is a lot more expressive in
terms of distinguishing diseased retina
(PPG) from normal healthy retina
Jia et al. (2012).PPG-Pre-perimetricglaucoma
GlaucomaStatistics
UK
In England, about 480,000
people have chronic open-angle
glaucoma. [NERC]
USA
Over 4 million Americans have
glaucoma but only half of those
know they have it. [GRF]
WORLD
As the second most common cause of
blindness worldwide, Quigley and Broman
estimate that by 2020, 79.6 million people will
be inflicted with glaucoma worldwide, of
which 11.2 million will be predicted to be blind
bilaterally.2 There is no cost-effective
population-based screening program
available at present for detection of
glaucoma.1,4
GlaucomaCosts
UK
In 2008 sight loss cost at least £6.5 billion
[RNIB]
Eye health now accounts for 4.5m GP
consultations and costs the UK economy
£22bneach year. [gponline]
The mean cost of glaucoma treatment
over the lifetime of the patients was
£3001, with an annual mean cost per
patient of£475.[Rahmanet al. 2013]
USA
Glaucoma accounts for over 7 million
visitstophysicianseach year.
The cost to the U.S. government is
estimated to be over $1.5 billion annually.
[GRF]
In the USA, there is a fourfold increase in
average direct costs per patient (pp), with
the earliest stage of glaucoma costing US
$623pp (AUD $667/€482) and end stage
glaucoma/blindness costing US $2511pp
(AUD $2410/€1740). [Scheetz et al. 2016]

Glaucoma highlights summarized
www.nice.org.uk
Venturini,2016

Glaucoma early detection is the key
This study highlights the importance of regular screenings for those over the age of
40. Identifying those at risk for glaucoma could potentially lead to earlier detection
and prevent the associated irreversible vision loss.
"The best available data support an ophthalmologist's examination as the most
accurate way to detect glaucoma," says Dr. Sharma. "This is why it is so important
that family doctors refer their patients over the age of 40 for screening." http://dx.doi.org/10.1016/bs.pbr.2015.03.001

Glaucoma
Pathophysiology
Weinreb et al. (2014) http://dx.doi.org/10.1001/jama.2014.3192, Cited by 219articles
The biological basis of glaucoma is poorly understood and the factors contributing to its
progression have not been fully characterized (Nickellsetal. 2012). Although the pathogenesis of glaucoma
is not fully understood, the level of intraocular pressure is related to retinal ganglion cell death. The
balance between secretion of aqueous humor by the ciliary body and its drainage through 2 independent
pathways—the trabecular meshwork and uveoscleral outflow pathway—determines the intraocular
pressure. In patients with open-angle glaucoma, there is increased resistance to aqueous outflow
through the trabecular meshwork. In contrast, the access to the drainage pathways is obstructed typically
bythe irisin patientswith angle-closure glaucoma(Figure1,nextslide).
Intraocular pressure can cause mechanical stress and strain on the posterior structures of the eye,
notably the lamina cribrosa and adjacent tissues (Figure 2, next slide).The sclera is perforated at the lamina
where the optic nerve fibers (retinal ganglion cell axons) exit the eye. The lamina is the weakest point in
the wall of the pressurized eye. Intraocular pressure–induced stress and strain may result in compression,
deformation, and remodeling of the lamina cribrosa with consequent mechanical axonal damage and
disruption of axonal transport that interrupts retrograde delivery of essential trophic factors to retinal
ganglion cellsfrom their brainstem target (relayneuronsof the lateralgeniculatenucleus).
Population-level surveys suggest that only 10% to 50% of people with glaucoma are aware they have it.
Glaucomas can be classified into 2 broad categories: open-angle glaucoma and angle-closure
glaucoma. In the United States, more than 80% cases are open-angle glaucoma; however, angle-
closureglaucomaisresponsible for adisproportionatenumber ofpatientswith severe vision loss.
Although elevated intraocular pressure is a very consistent risk factor for the presence of glaucoma,
several population-based studies found intraocular pressure was lower than 22 mm Hg in 25% to 50% of
individuals with glaucoma. (Weinreb and Khaw, 2004; Fechtner and Weinreb 1994) Despite the strong
association between elevated intraocular pressure and glaucoma, substantial numbers of people with
elevated intraocular pressure never develop glaucoma even during lengthy follow-up. (
Weinreb and Khaw, 2004)
Because there is no single perfect reference standard for establishing the diagnosis
of glaucoma, early diagnosis can be challenging. Although examination of the optic
nerve head can reveal signs of neuronal loss, wide variability of its appearance in the healthy
population makes identification of early damage challenging. Presence of characteristic
visual field defects can confirm the diagnosis, but asmany as 30% to 50% of retinal ganglion
cells may be lost before defects are detectable by standard visual field testing. (
Quigleyet al.1981; Harwerthetal.2010) Longitudinal evaluation and documentation of
structural damage to the optic nerve is, therefore, a critical component of the
diagnosis of thedisease.(Medeirosetal.2009)
However, subjective identificationof optic disc damage from glaucoma can be challenging,
with large disagreement in grading observed even among glaucoma
specialists.(Jampeletal. 2009)
Slowing disease progression and preservation of quality of life are the main goals for
glaucoma treatment. The decrease in quality of life associated with glaucoma may occur
earlier than previously thought, underscoring the importance of early diagnosis and
treatment. (McKean-Cowdin etal.2008) Reduction of intraocular pressure isthe only
proven method to treat glaucoma. (Bolandet al.2013) Results from several multicenter
clinical trials have demonstrated the benefit of lowering intraocular pressure in preventing
thedevelopmentandslowingthedisease’sprogression.
Considerable efforts have been made to develop neuroprotective glaucoma
treatments that prevent optic nerve damage. Unfortunately, no good evidence exists that
theseagentscan preventdiseaseprogression in patientswithglaucoma

Weinrebetal.(2014)
http://dx.doi.org/10.1001/jama.2014.3192
Citedby219articles

GlaucomaTypes
Open-AngleGlaucoma(OAG)the“silentkiller”
Whatabout primary angle-closure glaucoma(PACG) and normal-tensionglaucoma (NTG)
2016/17 ICD-10-CM Diagnosis Codes > Diseases of the eye
and adnexa H00-H59 > Glaucoma H40-H42 >
http://www.icd10data.com/ICD10CM/Codes/H00-H59/H40-H42/H40-
http://dx.doi.org/10.1016/j.preteyeres.2016.12.003
...the higher prevalence of PACG among Eskimos, Chinese and Mongolians has
long been acknowledged. In 1971, Clemmesen and Alsbirk reported high rates of
PACG in Greenlandic Inuit (Clemmesen and Alsbirk, 1971).
In chronic PACG, the iris slowly
covers the trabecular meshwork
portion by portion, leading to
peripheral anterior synechiae
(PAS). The PAS may be discrete
or multi-centered at the
beginning, then gradually expand
and fuse together
With the development of
imaging devices for the anterior
segment of the eye, some causes
of angle closure, such as lens
subluxation, spherical lens, and
ciliary cysts could be detected
and differentiated from
conventional PACG. The
definition and classification of
PACG may become more
concise as we get to know more
about the pathogenesis of angle
occlusion.
Schematic illustration for proposed PACG pathogenesis. AC: anterior chamber;
AL: axial length; ACW: anterior chamber width; CP: ciliary process.
A schematic drawing and representative gonioscopic images to show
the different shapes of PAS and angle closure in chronic PACG. Most
grading systems that are used clinically appear to simply judge
approximate angle opening in degrees or in Grades 1–4 in four cardinal
positions which gives limited information. The use of a schematic
diagram with essentially three concentric rings describing
Schwalbe's line, scleral spur and iris insertion with the contact between
iris and corneoscleral junction in the black hash line giving a nice
descriptive record of the state of the angle. It may also include a
description of the iris configuration, i.e. whether there is bombe
present, a straight insertion, a plateau iris or a concave iris.
Important parameters relevant
to PACG. A schematic drawing
to show some critical
parameters including ocular
rigidity, volume distributions
and aqueous and blood flow
in the normal eye.
OCT-Angiography images of the peripapillary area in normal eyes (A),
acute attack of PACG (B) and POAG (C).

GlaucomaTypes
Open-AngleGlaucoma(OAG)the“silentkiller”
Whatabout angle-closureglaucoma (ACG) and normal-tension glaucoma (NTG)
http://dx.doi.org/10.1097/APO.0000000000000177
2016/17 ICD-10-CM Diagnosis Codes > Diseases of the eye
and adnexa H00-H59 > Glaucoma H40-H42 >
http://www.icd10data.com/ICD10CM/Codes/H00-H59/H40-H42/H40-
One cause of glaucomatous optic neuropathy is an unstable oxygen supply. Blood flow is unstable
if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the
autoregulation of blood flow disturbed. A common cause for a disturbed ocular blood flow (OBF)
autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension
glaucoma patients. An unstable blood flow leads to recurrent mild reperfusion injury (chronic
oxidative stress) affecting particularly the mitochondria of the optic nerve head. OBF regulation
can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase
inhibitors.
http://dx.doi.org/10.1016/j.coph.2012.10.001

Glaucoma
Ganglioncellloss
http://dx.doi.org/10.1016/j.preteyeres.2011.11.002 http://dx.doi.org/10.1167/iovs.16-19997
Axonal transport failure leading to deficits in neurotrophic factor supply has been proposed to contribute to RGC death in glaucoma.
Neurons that successfully obtain optimal amounts of essential neurotrophic factors will survive, whereas damaged RGCs that are
disconnected fromtheirtargets and undergo obstructionof axonal transport will experience neurotrophic deprivationand die.
At the molecular level, some patients might experience compromised retrograde axonal transport along the
optic nerve and target-derived neurotrophin deprivation, while others might suffer from increased oxidative or
excitotoxic stress. An in-depth understanding of the molecular changesat differentstagesof glaucoma progression is
essential for the development of therapies that are highly specificand minimize adversesideeffects. Theavailability of
biomarkers for glaucoma diagnostic and follow-up (Golubnitschaja and Flammer, 2007; Grusetal., 2008;
Joachimetal.,2007a) should help identify molecular alterations in individual patients and, in the future, may allow the
developmentofpersonalized interventionsfor neuroprotection inglaucoma
Conclusions: This is the first
report illustrating histologic
evidence for reduced mRGC
density in the ganglion cell
layer of retinas with severely
staged glaucoma compared
with age-matched controls.
This result proposes
evaluation of mRGCs
integrity as a basis for
assessing the
pathophysiologic disease
progression of glaucoma.
For examplebyusing
post-illuminationpersistent
response(PIPR; Adhikarietal. 2016)
inpupillarylightreflex astheindication
of glaucoma progression.

Glaucoma
Mitochondria
* Professor ofOcular Neurobiology, Nuffield Dept.Clinical Neurosciences, Oxford University
http://dx.doi.org/10.1016/j.mito.2016.11.009
Glaucoma is an age-related disease and
it is known that transmission of visible
light onto the retina is significantly
reduced in older lenses, especially for the
blue region of the spectrum.
Nevertheless, it is worth recognising that
people are now exposedtomore blue
light (310–450 nm) than ever before.
Such blue light is derived from the sun,
digital screens (from TVs, computers,
laptops, smart phones and tablets),
electronic devices, and from fluorescent
and LED lighting.
Petteri:Notethat 315-400nm is
defined as theUV-A range rather than
visible bluelight. Seee.g.
http://www.skincancer.org/prevention
/uva-and-uvb
Figure 2 summarises the hypothesis that retinal ganglion cell (RGC) mitochondria and glial cells
(astrocytes, microglial and Müller cells) are affected by altered blood delivery characteristics to
initiate primary open-angle glaucoma (POAG). Importantly, the hypothesis suggests RGC
mitochondria are negatively affected by POAG initiation, resulting in oxidative stress. Retinal
ganglion cells are consequently “weakened”, but remain functionally normal but more prone to
insults than they would be otherwise. Thus, once glaucoma is initiated, RGCs remain functional
but exist in amore fragilestate probably similar to advanced-aged neurones.

Glaucoma
Geneticphenotype
Venturini, C; (2016) Doctoral thesis, UCL (University College
London).http://discovery.ucl.ac.uk/1474473/
Weinreb et al.(2014): Several genes—including myocilin (MYOC, GLC1A)
(CCDS1297.1), optineurin (OPTN, GLC1E) (CCDS7094.1) and WD repeat domain
(GLC1G) (CCDS4102.1) —are associated with a monogenic, autosomal dominant trait;
however, these genes account for less than 10% of all glaucoma cases. (
Kwon etal.2009) A growing number of studies use genome-wide scans to look for
glaucoma susceptibility loci. The CAV1/CAV2 (HGNC:1527/HGNC: 1528) locus on
7q34 may be associated with primary open-angle glaucoma in European-derived
populations. This finding has been replicated by independent studies. These genes
encode proteins (caveolins) involved in the generation and function of caveola, which
are invaginations of the cell membrane involved in cell signaling and endocytosis. The
CDKN2BAS(HGNC:34341)locus on 9p21was shown toberelatedtoglaucomariskin
multiplecohorts. (Wiggsetal.2012)
Retinal nerve fibre layer (RNFL)evaluation is a useful tool in early glaucoma diagnosis. Family history of
glaucoma is a risk factor for thinner RNFL. RNFL thickness has also been investigated as a possible bio-
marker in variousneurological conditions.
Interestingly, visual impairment is one of the earliest complaints in AD (Alzheimer’s Disease)
patients (Valenti 2010). Visual functions such as contrast sensitivity in lower spatial frequency, motion
perception, visual field and colour discrimination decreased in AD, showing a similarity with the visual deficits
in glaucoma. Patients with AD and glaucoma show a more rapid and aggressive glaucomatous visual field
loss (Bayer & Ferrari 2002). Both AD and glaucoma affect the visual pathway, but start in different
region along the neural pathway. AD might start in the visual association area (McKee et al. 2006) whereas
glaucoma has its initial damage in the optic nerve. In addition, AD treatments have been shown to have
animpact on glaucoma.
ChEI (cholinesterase inhibitors) treatment, commonly prescribed for AD, lowers IOP and seems to be
protective for retinal ganglion cells (Estermann et al. 20066). Memantine is a neuroprotective drug for AD
and also have implications for the visual system. Memantine has been investigated also for the treatment of
glaucoma and in monkeys with glaucoma and it slows down the progression of cell loss in lateral geniculate
nucleus(LGN)compared withthose animalsnot treated (Yücel et al. 2006).
Epidemiological studies have shown the link between the two diseases. Two groups whose 112 with AD
and 774 without have been compared and 25.9% of the people with AD developed also glaucoma, but only
5.2% of the group without AD (Bayer et al. 2002). Loss of nerve fibre layer tissue in the retina and optic nerve
may be an early biomarker for AD and may appear even before any hippocampus damage, which
isthe brainstructurethat impacts memory(Valenti2011).
A study funded by the National Eye Institute (NEI) has discovered 3
more genes associated with primary open-angle glaucoma (POAG),
the most common type of glaucoma and a leading cause of blindness
worldwide (Bailey JC et al. Nature Gen. doi:10.1038/ng.3482
[published online January 11, 2016]). Previously, 12 genes have been
linked to glaucoma, which damages the optic nerve due to the
buildup of fluid and pressure in the eye.

Glaucoma
Fromgeneticsto proteomics
Published Online:December 15, 2016- http://dx.doi.org/10.1016/j.cels.2016.11.006
Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD
phenotypes This multi-network analysis reveals protein- and disease-specific pathways
involved in theetiology, initiation, and progression of AD.
SembaandEnghild(2014): “In the post-genomic era, recent advances in protein chemistry,
mass spectrometry, and bioinformatics are bringing a rapid and fundamental transformation to
biological and medical research. In humans, 20,000 protein-coding genes give rise to∼
100,000proteinsandanestimated1million differentprotein modifiedforms(∼ Hood etal.2012).
The proteome, which consists of all proteins expressed in a cell, tissue, or organism, is the
basic link between thegenomeandphenotypesofhealthanddisease. “
Human ProteomeProject with high-quality analyses of the proteomes of these
compartments of the human eye: retina, iris, ciliary body, retinal pigment
epithelium/choroid, retrobulbar optic nerve, and sclera, with 3436, 2929, 2867, 2755, 2711, and
1945 proteins, respectively. These proteomics resources represent a useful starting point for a
broad range of research aimed at developing preventive and therapeutic interventions for the
variouscausesofblindness.
Proteomics studies toward molecular mechanisms and biomarkers of glaucoma. A number of studies of human
glaucoma and in vitro and in vivo experimental models have used proteomics analysis techniques. Distinct proteomics
techniques have been applied to analyze diverse sample types, including optic nerve, retina, sclera, trabecular
meshwork, aqueous humor, pseudoexfoliative material, tear, and blood. Ocular samples included tissue lysates unless
indicated otherwise, such as cell cultures or enriched samples of RGCs or astrocytes. Blood samples included whole
serum, IgG elutes, or isolated leukocytes. *indicates the studies including human samples. Proteomics analysis of
glaucoma has resulted in the lists of differentially expressed proteins and contributed to current understanding of
molecular mechanisms and biomarkers of glaucoma.

Glaucoma
DataminingElectronicMedicalRecords(EMR)
http://dx.doi.org/10.1371/journal.pone.0127817
Here we develop and deploy an algorithm utilizing data mining techniques to identify
primary open-angle glaucoma (POAG) in African Americans from EAGLE BioVU for genetic
association studies. The algorithm described here was designed using a combination of
diagnostic codes, current procedural terminology billing codes, and free text searches to
identify POAG status in situations where gold-standard digital photography cannot be
accessed. The case algorithm identified 267 potential POAG subjects but underperformed
after manual review with a positive predictive value of 51.6% and an accuracy of
76.3%. The control algorithm identified controls with a negative predictive value of 98.3%.
Although the case algorithm requires more downstream manual review for use in large-
scale studies, it provides a basis by which to extract a specific clinical subtype of glaucoma
from EMRs in the absence of digital photographs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001772/
The Precision Medicine Initiative (PMI)(1) promises resources and much needed
epidemiologic and clinical data designed to provide a better understanding of the factors
underlying the known inter-individual differences in susceptibility, onset, prognosis, and
treatment of disease(2).
Published index variants for the CDKN2B-AS1 region associated with POAG or POAG
associated trait and availability of these variants on the Metabochip.
The increasing cost of health care has motivated the drive towards preventive medicine,
where the primary concern is recognizing disease risk and taking action at the earliest stage.
We present an application of deep learning to derive robust patient representations from the
electronic health records and to predict future diseases. Experiments showed promising
results in different clinical domains, with the best performances for liver cancer, diabetes, and
heart failure.
http://dx.doi.org/10.1007/978-3-319-30671-1_66

Glaucoma
Modeling
http://dx.doi.org/10.1159/000448480
http://dx.doi.org/10.1007/s13721-016-0136-3
In this study, RGC death pathway of glaucoma was modeled to
predict the response of the protein receptor, ligand, inhibitor and other
regulatory units, which are involved in RGC death pathway in glaucoma. In
the pathway modeling six aspects were considered, namely extrinsic
pathway, intrinsic pathway, endoplasmic reticulum stress, neurotrophins
signaling response, oxidative stress response and calpain activation
induced RGCdegeneration.
In vitro models will never substitute animal studies, but they are important
tools in preclinical studies in the field of glaucoma. Though much less
complex than animal models, in vitro models of EHP offer the advantage
of having controlled experimental conditions, clarifying individual cell
responses to stress and allowing preliminary targeting of a specific cell
type or pathway involved in the progression of glaucoma. There is no
doubt that more studies are needed in this important research field, which
will allow the development of new relevant models to study RGC
neurodegeneration and neuroprotection in the context of
glaucoma.

Glaucoma
Autoimmuneinvolvement
http://dx.doi.org/10.1016/j.coph.2012.09.005 http://dx.doi.org/10.1016/j.ejphar.2016.04.031
Alterations of natural autoantibody patterns in sera and aqueous humor of glaucoma patients
strongly indicate an involvement of autoimmune components in the pathogenesis of glaucoma
(Wax2011; Grusand Sun2008). … Glaucoma patients show alterations of their individual
autoantibody profiles. Typically, upregulated antibodies are explained as an initiation of
autoaggressive sequenceswhichlead topathologic conditions.
A misbalance in the physiological equilibrium may shift from regulatory immunity into a
neuroinflammatory degenerative process, what may lead to a predisposition to glaucoma.
However, the protective nature of autoantibodies and the molecular mechanisms underlying the very
sensitive equilibrium of natural autoimmunity between autoaggression and neuroprotection offer
promising target sitesfor new therapeutic approaches. Finally, the changes in antibody profiles
represent anew opportunityashighlysensitive and specific biomarkersfor diagnosticspurposes.
Sensitivity and specificity of autoantibody
patterns for diagnosis. We compared
autoantibody reactivities in serum samples of
primary open-angle glaucoma patients (POAG)
and non-glaucomatous controls using specific
antigen microarrays in combination with an
artificial neural network (X-axis: 1-specificity,
Y-axis: sensitivity, R= 0.93). The sensitivity and
specificity for a discrimination of prospective
glaucoma and control subjects was 93% depicted
as Receiver operating characteristic. (POAG: n =
20; non-glaucomatous controls: n = 13).
(Boehm et al., 2012).
Shows the proteins significantly changes
in the cells incubated with POAG serum
and belonging to the intrinsic apoptotic
pathway. The Proteins (red =
upregulated; green = downregulated) are
changed in a pro-apoptotic manner.
Furthermore the cut surface between the
other demonstrated studies are shown.
Changes in the levels of caspase 3 were
found in the retinae of immunized
animals. Changes in proteins in an anti-
apoptotic manner, also belonging to this
pathway, were found in cells incubated
with 14-3-3 Ab in comparison to cells
without 14-3-3 Ab. The pathway was
performed by Ingenuity Pathway Analysis
(IPA; Ingenuity Systems Inc., USA,
https://www.analysis.ingenuity.com).

Glaucoma
Amyloid-binvolvementandconnectiontootherneurodegenerativediseases#1
http://dx.doi.org/10.1007/s00018-016-2348-1
http://dx.doi.org/10.1007/s00018-016-2295-x
The retina arises as a neuro-ectodermal derivative of the forebrain duringdevelopment
and delineates several physiological, cellular and biochemical similarities with the brain
tissue. With the advancement in technology, subtle changes in both human and animal
retinas can be directly imaged and assessed in vivo and as such the retina is being
increasingly used as a model to study the neurodegenerative disorders of brain
particularly Alzheimer’s disease (AD, Guptaet al. 2016). Additionally, retinal
disorders such as age-related macular degeneration (AMD) and glaucoma
are chronic neurodegenerative conditions that affect various retinal neurons and lead
toprogressive and irreversible lossofthe vision.
All three diseases are multifactorial with distinct pathological and clinical
manifestations even though age remains the common primary risk factor and
people with family history are at higher risk. Although AMD and glaucoma are not
classified as amyloidogenic diseases, the last decade has seen many animal and
human studies featuring evidence of progressive accumulation of amyloid beta
fragments in the retina (Guptaet al. 2014). Therefore, retinal Ab accumulation can be
regarded asacommon feature ofthese three separatedisorders
Analysing Ab characteristics including fragment size, oligomerisation and anatomical distribution within the retina holds ‘‘reasonable promise’’ to
provide unique retinal signatures and differentiate between various Ab associated disease conditions. For instance, AMD-associated Ab
deposition is more restricted to RPE and likely to be identified as complex with drusen (Anderson etal. 2004). In glaucoma, expression of Ab
could be found in the inner retina (Guo etal. 2007; Guptaetal. 2014)[5, 39] along with ON excavation. Retinal Ab deposition in AD is
geographically more wide spread and again associated with degenerative changes in the inner retina and ON (Gupta etal. 2016). Successful
identification of differences and similarities will drive drug development and mechanism based pathophysiological research.Imaging patterns of Ab
deposition in the eye could be of diagnostic and prognostic value when considered with other ocular or biochemical markers and play imperative
role in disease monitoring. Development of newer Ab imaging technologies will greatly accelerate research into mechanism based therapies
for these neurodegenerative disorders. Longitudinal studies in larger cohorts and rescue experiments will support the hypothesis that Ab
deposition does exert neurotoxic effects on the retina. Concluding, the significance of Ab depostion in mechanistic understanding of retinal
pathology, diseasediagnosis, prognosis or as a treatment target is highly relevant considering its known neurotoxic effects and the high incidenceof
thesediseasesinageing populations.
PhD Project: Multi-
spectral imaging for in
vivo imaging of oxygen
tension and β-amyloid
University Eye Clinic Maastricht

Glaucoma
Amyloid-binvolvementandconnectiontootherneurodegenerativediseases#2
http://dx.doi.org/10.1523/JNEUROSCI.3986-15.2016
Recent work supports the idea that neuronal loss in AD and glaucoma is mediated by
common neurodegenerative pathways. For example, A accumulation has been observed in
experimental glaucoma (McKinnon et al., 2002; Goldblum et al., 2007; Kipfer-Kauer et al.,
2010; Ito et al., 2012), and blockade of the A pathway reduced RGC loss (Guo et al., 2007;
Salt et al., 2014). It is increasingly recognized that tau is a key mediator of A toxicity
(Rapoport et al., 2002; Santacruz et al., 2005; Roberson et al., 2007).
In summary, our data demonstrate a number of important alterations
in endogenous tau induced by ocular hypertension, including
phosphorylation, oligomerization, and accumulation in RGC dendrites.
These pathological changes contribute to neurodegeneration because
reducing tau burden promoted substantial protection of RGC somas
and axons from glaucomatous damage. These results reveal that
glaucoma shares key common features with tauopathies, and identify
tau as a novel therapeutic target to potentially counter RGC
neurodegeneration in glaucoma and other optic neuropathies.

Eyeasamarker for neurological and psychiatric diseases
Again thesameframework withproper trainingdata,scalesto diseasethatarevisiblein theretina
http://www.fiercebiotech.com/medical-devices/neurovision-raises-10m-to-advance-re
tinal-diagnostic-for-alzheimer-s
http://dx.doi.org/10.1186/s40478-016-0346-z
Affiliated with: UCL Institute of Ophthalmology, University College London
http://dx.doi.org/10.1016/j.pscychresns.2011.08.011
Koronyo-Hamaoui et al. (2012) Prof Melanie Campbell motherboard.vice.com
University of Minnesota: Center for Drug Design | https://drugdesign.umn.edu/research/alzheimers-disease-research

Glaucoma
Statistics#1
Br JOphthalmol 2006;90:262-267
doi:10.1136/bjo.2005.081224
Citedby3677articles
Number of people with open angle (OAG) and angle closure glaucoma(ACG)
in2010and2020.
In 2010, 2.1 million people were blind, and 4.2 million were visually impaired due to
glaucoma. Glaucoma caused worldwide 6.6% of all blindness in 2010 and 2.2% of all moderate
and severe visual impairment (MSVI). These figures were lower in regions with younger
populations (<5% in South Asia) than in high-income regions with relatively old populations
(>10%). From 1990 to 2010, the number of blind or visually impaired due to glaucoma increased
by 0.8 million or 62% and by 2.3 million or 83%, respectively. Percentage of global blindness
caused by glaucoma increased between 1990 and 2010 from 4.4% to 6.6%. Age-standardized
prevalence of glaucoma related blindness and MSVI did not differ markedly between world
regions nor between women.
http://dx.doi.org/10.1167/tvst.4.2.1
What kind of interventions could massively
improve clinicians' ability to detect early
glaucoma? How could we better monitor
IOP short- and long-term variability in an
inexpensive and safe fashion to determine
treatment efficacy? Could IOP-independent
risk factors be modified to slow progression?
Could improvements in adherence to
therapy lead to better functional outcomes?
Similarly to the measures that helped eradicate
or mitigate the burdens of many diseases in the
past centuries, the key solutions to glaucoma-
related blindness may lie on basic public
health interventions, such as better medical
training and patient education. Also, increased
accessibility to technological advances by eye
care providers may play an important role to
reduce glaucoma morbidity in the next decades.

Glaucoma
Statistics#2
http://dx.doi.org/10.1016/j.ophtha.2014.05.013, Cited by274 articles
http://dx.doi.org/10.1136/bjophthalmol-2014-306102
Conclusions Across the Asian
subregions, there was greater
glaucoma burden in South-
Central and East Asia. Sustainable
public health strategies to combat
glaucoma in Asia are needed.

Glaucoma
Statistics#3
Conclusion: Glaucoma care needs to be
given high priority in Vision 2020
programs in Africa. Many questions
remain unanswered and there is a need
for further research in glaucoma in SSA in
all aspects especially epidemiology and
clinical care and outcomes involving
randomized controlled trials. Genetic and
genome-wide association studies may aid
identification of high-risk groups. Social
sciences and qualitative studies, health
economics and health systems research
will also enhance public health
approaches for the prevention of
blindness due to glaucoma.
http://www.meajo.org/text.asp?2013/20/2/111/110605
Researchers from Prevent Blindness America, and other leading vision and
eye health groups have declared January National Glaucoma Awareness Month
in an effort to educate the public on glaucoma. Noting that symptoms develop
very gradually, glaucoma can damage central vision if left untreated over time.
According to the report, more than 2.7 million Americans age 40 and older
have open-angle glaucoma, an increase of more than 22 percent from 10 years
ago. Risk factors for glaucoma include age, family history, nearsightedness, eye
injury and surgery, use of steroids, and race. Compared with whites, blacks are
five times more likely to have glaucoma and four times more likely to go blind
from it. Compared with other groups, Hispanics are more likely to develop
glaucoma after age 60.
https://medicalxpress.com/news/2013-01-open-angle-glaucoma-percent-years.html

Diagnosis The Past
Heuristicandsubjectivecriteriaforglaucomadiagnosis
http://www.glaucoma-association.com/glaucom
a-focus/glaucoma_guideline.php
Diagnosisguidance
Following testsforClosed-Angle Glaucoma
1) Intraocular pressure(IOP) with
tonometry
2) CentralCorneal Thickness (CCT)
3) Peripheral anteriorchamber with
gonioscopy
4) Visual fieldwith standard perimetry
5) Optic nervewith dilatation
Establishedtests
havelimited performance
in diagnosing glaucoma.
Improvement with OCT
scans though.
“No single screening
parameter is useful for
glaucoma screening”.
Heuristicdecisions
are made either by
optometrist/
ophthalmologistthat
are subjectto biases
and agreement issues.

Glaucoma
Decisiontreeheuristicsasclinicianspreferexplainabilityoveraccuracy

Glaucomadetection current markers
OCTbecomingcommon,seelaterdetailsonbiomarkers
SS-OCTofferfasterscanning(lessmotion
artifacts, andnicerfor thepatient),anddeeper
retinallayerimages(longerwavelengths
attenuateless) -Spaideet al.(2013)
*OCTOpticalCoherenceTomography
*SD-OCT SpectralDomanOCT
*SS-OCTSwept-SourceOCT
See more on the
technology
differences in:
(Slide 12 ->)

Glaucoma detection human performance
Whatperformanceforoptometrists,andforseniorophthalmologistsweneedtoachieve
Sensitivity and specificity plots showing the
performance characteristics of UK 'glaucoma
optometrists'. The blue circle and orange circle
represent the mean performance of
ophthalmologists and optometrists respectively.
Optometrists displayed higher sensitivity but
lower specificity than the EODAT
ophthalmologists.
http://dx.doi.org/10.1111/opo.12066 (2013)
http://dx.doi.org/10.1111/ijcp.12600
“To explore the validity and reliability of eye healthcare
professionals with different levels of training in diagnosing
and/or identifying glaucomatous progression.
The eye health professionals with ophthalmology training
consistently attained the greatest agreement. When allied
health professionals with different levels of training were
compared, those who had completed residency training were
significantly better than those who had not.”

NHSOphthalmology
Provisionandreferralpathways#1
NHSOphthalmologycareprovisionandreferralpathways
Recent guidance to the commissioners of eye care from the Royal College of Ophthalmologists has
outlined the need for improved non-specialist and out of hospital facilities for ophthalmology, as part
of aRight Care/QIPP vision of ‘hospital without walls’for ophthalmic care.1
Eye care flows from primary care (first presentation and basic conditions) to secondary care
(emergency or serious conditions requiring expert care). The primary care to specialist interface is a
keyorganisational taskfor manyhealth care systems.2
In the UK, Primary Care Ophthalmology is largely provided by optometrists 57% and GPs 43%.3 In
addition, the service is supported by GPs with special interest in ophthalmology (GPSI), a few
Ophthalmic Medical Practitioners (OMPs), Nurses and Nurse Practitioners and Orthoptists as well as
Ophthalmologists. Compared with other specialties, more primarycare in ophthalmology happensin
hospital rather than in general practice because of the lack of equipment, particularly slit lamps, and
lackof ophthalmicskillsand knowledge.4,5,6,7
Demand for ophthalmic services is increasing. From 2009 to 2010, there were 1.69 million first
attendances at English NHS ophthalmology departments, representing 28% of the total of 5.95
million ophthalmology attendances. [NHS information centre]. There has been a rise of 25% in
ophthalmology outpatients over 7 years and ophthalmology outpatients constitute 9% of all NHS
outpatientappointments(the second highest demand specialty).
Increasing detection and more expensive treatment of eye disease is stretching the NHS
ophthalmology budget and secondary care capacity is increasingly strained. To deal with this, the
RCO have proposed an emphasis on non-specialist, primary care ophthalmology to manage patient
flow and free capacity in the Hospital EyeService(HES).1,2
1) Stella Hornby.PrimaryCareOphthalmology –theRoyal CollegeofOphthalmologists. June2013.
2) Malik AN, Cassels-Brown A, Wormald R, Gray JM. Better valueeyecareforthe21stcentury: the population
approach. BritishJournal of Ophthalmology. 2013 Jan15:bjophthalmol-2012.
3) Pierscionek TJ, Moore JE, Pierscionek BK. Referralsto ophthalmology: optometric and general practice
comparison. Ophthalmicand Physiological Optics. 2009 Jan1;29(1):32-40.
4) Featherstone PI, James C, Hall MS, Williams A.General practitioners'confidenceindiagnosing and managing
eyeconditions: a surveyin south Devon.BrJGenPractice1992:42:21-
Summaryof reportfindingsfromRoyal Collegeof Ophthalmologists2013:
● Demographic changes and new treatments and investigations have caused
acute pressures and lack of capacity in secondary care (Hospital Eye Service
or HES).
● Managing the flow of new (as yet undiagnosed) patients to a department to
maximise potential to prevent sight loss but also to get maximum value for
money will become increasingly important in terms of the annual report and
budgetallocations.
● Many patients can be seen in the community if the necessary equipment is
available and increased value could be obtained by using community
optometrists to triage and manage GP referrals for external inflammatory
conditions.
● IT investment linking primary ophthalmic care and HES is key to achieving the
bestvaluemodelforophthalmiccare.
● Opportunistic surveillance for eye diseases such as glaucoma by optometrists
will prevent sight loss but the current provision does not provide equitable
access for everyone and poorer communities have lower take up of sight tests
andhigher ratesofvisualimpairment.
5) McDonnell PJ. Howdo general practitionersmanageeyediseaseinthecommunity? Br J Ophthalmol. 1988
Oct;72(10):733-6.
6) Sheldrick JH, Vernon SA, Wilson A, Read SJ. Demand incidenceand episoderatesof ophthalmicdisease in a
defined urban population. BrMedJ. 1992Oct17;305(6859):933-6.
7) Sheldrick JH, Wilson AD, Vernon SA, Sheldrick CM. Managementof ophthalmic diseaseingeneralpractice.. Br J
GenPract.1993 Nov;43(376):459-62.

NHSOphthalmology
Provisionandreferralpathways#2
Table 1. Tiers of eye healthcare, from Royal College
OphthalmologistsOpthalmicServicesGuidance rcophth.ac.uk
FigureshowingserviceredesigninScotland-Borooah et al. (2013)
Our findings are highly relevant as the impact of
improved electronic communication between primary
and secondary ophthalmic care is likely to increase
further in the near future, following the Scottish
government passing a d6.6 million business case to
connect all community optometrists to hospital
ophthalmologydepartmentsin 2010.
The platform will use a ‘virtual private network’ (VPN)
that connectsto a server and willprovidesecure,remote
access to community optometrists. Twelve of the
fourteen Scottish healthboards have already agreed to
connect to the network at present. The results of these
changes will be available in the near future, and may
have implications for other UK regions as well as
international providersof ophthalmichealthcare.

Glaucoma
UKCommissioningGuide
https://www.rcophth.ac.uk/wp-content/upload
s/2016/06/Glaucoma-Commissioning-Guide-Long
-June-2016-Final.pdf

BasicUKReferrals Retinal diseases
TraditionalNHSreferralpathwaysforretinaldiseases
Optician GP→ GP Ophthalmologists→
NHS eyecare services: visiting an
optician
When you visit an optician for an eye test, you'll be examined by an ophthalmic
practitioner or optometrist who is trained to recognise abnormalities and conditions
such as cataracts or glaucoma. Ophthalmic practitioners will prescribe and fit glasses
and contact lenses, and, if necessary, they will refer you to a GP or a hospital eye clinic for
further investigations. Sometimes you'll be referred to a specialist optometrist for a
referralrefinement.
/defaultview.aspx?id=1986http://dx.doi.org/10.1136/bmjopen-2013-002715
http://dx.doi.org/10.1111/opo.12312
“Good evidence exists for cataract, glaucoma and primary eye care EOS that: with appropriate
training, accredited optometrists manage patients commensurate with usual care standards;
genuine partnerships can exist between community and hospital providers for cataract and
glaucoma EOS; patient satisfaction with all three types of service is high; cost-effectiveness of
services is unproven for cataract and primary eye care, while glaucoma EOS cost-effectiveness
dependson service type;contextual factorsmayinfluence servicesuccess.

‘Novel’UKPathways for diagnosis
VirtualClinic New ServiceDeliveryModel High-streetoptician from fundus toOCT
Hospital-based consultants perform
virtual glaucoma reviews
A prototype informatics application for the remote collection of glaucoma
patients’ data to enable it to be viewed by specialists for diagnosis in another
location has been developed by Moorfields Eye Hospital‘s OpenEyes team,
Charing Systems and BlackPear software. Virtual glaucoma clinics which
potentially can save patients’ numerous and often inconvenient trips to
hospitalandfreeupglaucomaspecialiststime
http://www.moorfields.nhs.uk/news/hospital-based-consultants-perform-virtual-glaucoma-re
views
http://dx.doi.org/10.1136/bmjopen-2015-009463
Newmodelsforscreeningophthalmicpatients
http://www.dailymail.co.uk/news/article-3228075/Opti
cian-Britain-charged-negligent-manslaughter-death-ei
ght-year-old-boy.html
“Optometrists are licensed to perform eye exams and vision tests, prescribe and dispense
corrective lenses, detect certain eye abnormalities and prescribe medications for some
eye diseases.They are not opthalmologists, doctors with at least eight years of medical
trainingafter collegewhocanpractisemedicineandsurgery.”
Optician chains have
a pressure to stay
competitive and offer
new services with
more cross-selling
opportunities

Glaucoma Virtual Clinics
Relievingpressurefromophthalmologistsandreducewait timeforpatients
August 16, 2016; http://dx.doi.org/10.4172/2155-9570.1000585
The percentage of overall agreement on recall time (25%) and review place
(45%) was fair and moderate respectively. The overall agreement on treatment
plan was superior (86%). We found significant disagreement between the senior
consultantandthenewlyappointedconsultant.
Our study demonstrates that greater difference in years of experience between
consultants is associated with more disagreement in management
outcomes. Discrepancies on management outcomes impact on uniformity of
care and service delivery of virtual clinic. We believe this uniformity is important
especially in a virtual service where high volume of patients is seen, often by
differentglaucomaspecialists.Disagreementamongstthe specialists may lead
to confusion in the management plan for the patients and potential waste of
resources.
We suggest the need for implementing structured management guidance in
virtualglaucomaclinictoreducediscrepanciesamongstconsultants.
http://dx.doi.org/10.1111/jgh.13371
“Current service delivery models are inadequate in providing compassionate therapy to a large
number of patients. Implementation of a virtual compassionate clinic can streamline delivery of
a compassionate program, reduces administration and nursing resource burden, ensures delivery
of consistent, high quality care, and provides an opportunity to prospectively collect data.”
https://dx.doi.org/10.2147%2FOPTH.S92409
Challenges to implementation of virtual clinic include staffing issues and use of information
technology. Patient journey time within the stable monitoring service (SMS) averaged 51 minutes,
compared with 92 minutes in the glaucoma outpatient department. Patient satisfaction with the
new service was high.
Implementing innovation into existing services of the National Health Service is challenging.
However, the virtual clinic showed an improved patient journey time compared with that
experienced within the general glaucoma outpatient department. There exists a discrepancy
between patient management decisions of reviewers, suggesting that some may be more risk
averse than others when managing patients seen within this model. Future work will assess the
ability to detect progression of disease in this model compared with the general outpatient
model of care.

UKReferralaccuracies
ReferralsfromGPs,trained‘NHS optometrists’andhighstreet opticians
havedifferentaccuracylevels
J PublicHealth (2016)38 (3): 599-606.doi: 10.1093/pubmed/fdv081
Background Referrals to ophthalmology are predominantly made from
general practitioners (GPs) and optometrists. These two groups of referrers
receive differing types and levels of training and are equipped with different
instrumentation. The purpose of this study was to determine whether the
quality of referrals to the hospital eye service (HES) differs between GPs and
optometristsinWalsall.
Results We achieved our target of auditing 1000 records. The false-positive
rate (patients being discharged from HES with a ‘normal vision’ diagnosis)
was 7.7% of referrals from GPs and 6.2% of referrals from optometrists.
Concordance between referred condition and diagnosed condition at HES
between optometrists and ophthalmologists was 76.1%, and between GPs
andophthalmologistswas67.2%.
“Eye healthcare is bad medicine, says Michael Clarke,
because UK law (under section26oftheOpticiansAct, revised in
1989) leads to opticians making too many referrals to
doctors”
http://dx.doi.org/10.1136/bmj.g2084 (Published19 March2014)
http://dx.doi.org/10.1136/bmj.g3040

UKEcosystem Ophthalmology Quality
World-classresearchandpracticeatMoorfieldsEyeHospital
Flashing lights at varying
points of the visual field test
sensitivity (Viewi optical
concept developed by
Cambridge Consultants) –
with the patient pressing a
button each time they see a
light. The novel Viewi
technology performs the
same test but at a fraction of
the cost – around £20
rather than £20,000 for
the clinical device.
Propelling surgical innovation to the next stage,
product design and development firm
CambridgeConsultants is showcasing Axsis –
one of the smallest known robots for surgical use
(e.g. for cataract surgery). With an external body
the size of a drinks can and instruments only 1.8
millimetres in diameter/ Along with cataract
surgery, Axsis demonstrates how the novel
system design could improve the way medical
professionals approach a variety of other
procedures that require a high level of precision
and minimallyinvasive access.
HIGH TECH LOW TECH
The UCL Institute of Ophthalmology work in partnership with Moorfields Eye Hospital
toleadthewayinvisionresearch.http://www.ucl.ac.uk/ioo/
“Moorfields and the UCL Institute of
Ophthalmology (IoO) are recognised as a
world-class centre of excellence. Together,
we form the largest ophthalmology and
vision research partnership in the world,
with access to a sizeable and diverse
patientpopulation.Along with our academic
partners at the UCL Institute of
Ophthalmology, Moorfields is recognised
as a world-class centre of excellence in eye
research.”
http://www.moorfields.nhs.uk/content/our-vision
For 50 years, Cambridge Consultants has led the way in innovative product
development. We are the development partner of choice to many of the world’s leading
blue chips, as well as the virtual development team for ambitious start-up companies.
http://www.cambridgeconsultants.com/

GlaucomaUKHealtheconomics
HowmuchearlydetectioncutsNHS spending,andindirect lossestotheeconomy
Glaucoma Automated Tests Evaluation (GATE): comparative study of new
imagingtechnologiesforthediagnosisof glaucoma
Currently, a definitive glaucoma diagnosis is based on the expertise of an ophthalmologist
interpreting avisualfield test. New imagingtechniques haveemergedandthiswithin-patient,
multi-centre, comparative study compared these new techniques between themselves and
with current practice. We assessed the cost-effectiveness of adopting individual tests or
combination of tests as triage tests compared with the current practice of diagnostic
examination by an ophthalmologistin asecondary caresetting.
OutcomeandTranslation
Considerable NHS resources are required to assess all patients referred to secondary care
eye services with suspected glaucoma. Furthermore, there is considerable strain on
secondary eye care services through the increase in false–positive referrals from
optometrists.
Automated imaging can be effective in aiding glaucoma diagnosis among individuals
referred from the community to HES. A model of care using a triage composite test appears
to be cost-effective. NICE supported its decision to review the glaucoma clinical guidelines
in 2016 based on the evidence provided by this and other studies (see OHTproject).Future
work is needed as there are uncertainties about glaucoma progression under routine care,
and the cost of providing health care. Acceptability of implementinga triagetest needs to be
explored.Click here forfurtherdetailson thisproject
http://www.abdn.ac.uk/heru/research/assessment-of-technologies/projects-based-on-observationa/
glaucoma-automated-tests-evaluation-gate-comparati/
Trials201617:316DOI: 10.1186/s13063-016-1459-1
http://dx.doi.org/10.1093/pubmed/fdv168
Inspiration from
diabetic
retinopathy
screening

Glaucoma Quality of Life
The quality-adjusted life year or quality-adjusted life-
year (QALY) is a generic measure of diseaseburden, including
both the quality and the quantity of life lived.[1][2] It is used in
economic evaluation to assess the value for money of medical
interventions. One QALY equates to one year in perfect health. If
an individual's health is below this maximum, QALYs are accrued
at a rate of less than 1 per year. To be dead is associated with 0
QALYs, and in some circumstances it is possible to accrue
negative QALYs to reflect health states deemed 'worse than
dead'.
The QALY is often used in cost-utilityanalysis in order to estimate the
cost-per-QALY associated with a health care intervention. This
incremental cost-effectivenessratio (ICER) can then be used toallocate
healthcare resources, often using a threshold approach.[3] In the
United Kingdom, the , which advises on the use of health technologies
within the National Health Service, has since at least 2013 used "£ per
QALY"toevaluate their utility.[4][5]
https://en.wikipedia.org/wiki/Quality-adjusted_life_year
http://dx.doi.org/10.1167/iovs.07-0559
Assessments of quality of life using different methodologies have been shown to produce different outcomes with low
intercorrelations between them. Only aminorityof patientswere prepared to trade time for areturn to normal vision. Conjoint
analysisshowed twosubgroupswith different priorities. Severityofglaucomainfluenced the relative importance of priorities.
http://dx.doi.org/10.1007/s12325-016-0333-6
The ultimate goal of glaucoma management is the preservation of patients’ visual function and quality of life
(QoL). The disease itself as well as the medical or surgical treatment can have an enormous impact on a
patient’s QoL. A better understanding of patient-reported QoL can improve patient–physician
interaction and enhance treatment adherence by customizing treatment options based on individual
patientprofile,thusoptimizing long-termprognosis.
Assessment of QoL with a questionnaire has several limitations. QoL assessment is subjective: patients with
similar disability may rate their QoL differently. An inherent limitation of QoL assessment is that self-reported
visual ability evaluated by any questionnaire can be impaired, at least to some extent, by other visual and
systemic morbidity or psychosocial constraints. Conceivably, even when perimetric indices such as MD are
comparable, different determinants such as spatial distribution and depth of VF scotomas or speed of
perimetricdeteriorationmayaffectpatientswithdissimilarlifestylesandexpectations

Glaucoma Health Economics UK#1
http://dx.doi.org/10.1136/bjo.87.10.1201
http://dx.doi.org/10.1038/eye.2015.288
The proportion of certificates without a single main cause has fallen slightly (16.6 to 14%). The proportion of
certificates with a main cause of degeneration of the macula and posterior pole (mostly age-related macular
degeneration (AMD)) decreased from 58.6 to 50% SSI and from 57.2 to 52.5% SI. Glaucoma remains the
second most common cause (11% SSI; 7.6% SI) but hereditary retinal disorders overtook diabetes as third
leading cause of SSI.

Glaucoma Health Economics UK#2
http://dx.doi.org/10.1186/s12913-016-1849-9
An incremental cost-effectiveness ratio (ICER) of £21,392 per quality
adjusted life year (QALY) was derived for proposed practice improving to a
value of £11,382 once savings for prevented visual impairment was added
to the model. Proposed practice was more cost-effective in younger
patients. Proposed practice for patients with advanced disease at diagnosis
generated ICERs > £60,000 per QALY; these cases would likely be on the
most intensive treatment pathway making clinical information on speed of
VF loss redundant. Sensitivity analysis indicated results to be robust in
relation to hypothetical willingness to pay threshold identified by national
guidelines, although greatest uncertainty was allied to estimates of
implementation and visual impairment costs.

Glaucoma Health Economics Intro #1
MichelsonandGroh(2001)
DennyJohn(2011),M.Sc.thesis

Glaucoma Health Economics USA#1b
Arch Ophthalmol. 2006;124(1):12-19. doi: 10.1001/archopht.124.1.12 | Cited by 153
*The mean difference (MD) between the normal sensitivity (corrected for age) and
the retinal sensitivity for the subject (calculated from all the points tested). Mean
defect or mean deviation increases with the following: media opacities or diffuse
loss or severe localized loss. A retinal sensitivity value worse than normal is indicated
by a negative symbol in Humphrey perimeters (mean deviation) and a positive
symbol in Octopus perimeters (mean defect).

Glaucoma Health Economics Intro #2
[Scheetz et al. 2016]: The burden of glaucoma increases as disease severity
worsens; especially the financial burden. In the USA, there is a fourfold
increase in average direct costs per patient (pp), with the earliest stage of
glaucoma costing US $623pp and end stage glaucoma/blindness costing
US $2511pp (Lee et al. 2006). There have been similar findings in Europe with
early stages of glaucoma having direct costs of US $588pp and end stage
costing US $1253 per person per year (Traverso et al. 2005).
The indirect costs of glaucoma can be difficult to quantify. In Australia, the
prevalence of POAG in 2005 was 208,000 and is expected to rise to 379,000
by 2025 (Dirani et al. 2011). This increase will see the total estimated costs of
treating those with POAG (healthcare costs, indirect costs such as loss of
productivity and loss of well-being measured as disability adjusted life years
rise from US $1.77 billion in 2005 to US $4.01 billion in 2025 (
Dirani et al. 2011).
A European study by Poulsen estimates the average cost per person for
community services (including equipment, residential care, household and
guide dogs) to be US $7885 and patient and family (household and
transportation) to be US $11,149 annually (Poulsen et al. 2005).
These increases in prevalence pose a significant burden on eye healthcare
professionals; especially ophthalmologists as a large number of patients are
unable to be discharged as the condition will require lifelong monitoring and
treatment (Spry et al. 1999).

Blindness Health Economics Ireland
http://dx.doi.org/10.1155/2016/4691276
The direct costs of visual impairment and blindness in the Republic of Ireland have
previously been calculated by Deloitte Access Economics (DAE) [3]. It was estimated that in
2010 the total direct costs (hospital, prescription, general ophthalmic services, and capital and
noncapital expenditure costs) of treating visual impairment as a whole were 116,754,168. This
was projected to increase to 127.4 million in 2015 and reach 136.8 million in 2020. The
proportion of these costs that could be attributed specifically to blindness was not analysed.
Sensitivity analysis 2010–
2020. The table illustrates the
upper (+20%) and lower (−20%)
limits around each point
estimate. For informal care
costs, 21.79 (average hourly
wage in 2010) is used as the
higher estimate and 8.65
(minimum hourly wage in 2010)
is used as the lower estimate of
the cost per hour of informal
care provided. The effect of
reducing deadweight welfare
losses to 9% gives the lower
estimate for this parameter. This
table thus provides a range and
a mean or “likely” figure for the
costs associated with blindness.

Glaucoma Health Economics CentralEurope#1
http://dx.doi.org/10.1007/s00417-013-2354-z
Average total annual direct costs per patient for OHT were 226€ (± 117), for early POAG 423€ (± 647),
moderate 493€ (± 385) and advanced POAG 809€ (± 877). Glaucoma-related medications and
hospitalisation represented the two major components of direct costs, increasing with the progression
of glaucoma. Additional treatment changes are major contributing factors to the increased treatment
costs of glaucoma. If intraocular pressure can be controlled over the long term, progression to
moderateandadvancedstatesavoided,and patients remainoninitialtreatments,treatment costs
coulddecline duetoreducedandlessexpensivehealthcareresourceutilisation.
The Salzburg-Moorfields Collaborative Glaucoma Study performed a complete ophthalmologic
examination on a total of 4864 subjects within a study period of approximately 8 years (98
months).
Direct costs per visit were considerably higher than those reported in the Netherlands or the
United Kingdom. If a health care provider decides to perform a glaucoma screening within
this setting, the costs for the detection of a new case are 7250€ for definite POAG. 4250€
for early POAG, 1450€ for POAG suspect, 5600€ for ocular hypertension (OHT), 2100€ for
glaucomaartefact case, and 156€ for anormal case.
Within our screening setting, the total amount of time per individual spent by an
ophthalmologist and two medical assistants (including administrative work) is 3.1 hours at the
initial examination, 0.7 hours for a second check, and 2.4 hours at each follow-up examination.
The direct costs per visit are EUR 123 at the initial examination, EUR 98 for second checks, and
EUR 95 for a follow-up examination. Although the total direct costs for various screening modes
are reported, it is impossible to give a well-founded decision between different screening
modesat this point. A cost-benefit analysis isnecessary to assess the benefit of screening and to
setup aglaucomascreeningprogram with ahigh cost-benefitratio.
https://www.ncbi.nlm.nih.gov/pubmed/16496251

Glaucoma Health Economics CentralEurope#2
These results demonstrate for the first time in Europe that resource utilisation and direct
medical costs of glaucoma management increase with worsening disease severity. Based on
these findings, managing glaucoma and effectively delaying disease progression would be
expected to significantly reduce the economic burden of this disease. These data are
relevant to general practitioners and healthcare administrators who have a direct influence
on the distribution of resources.
http://dx.doi.org/10.1136/bjo.2005.067355

Glaucoma Health Economics Central/NorthernEurope
Conclusions. The most common single cause of blindness was macular
degeneration. Incidence rates of blindness due to such treatable
conditions as glaucoma were also high. This finding suggests that the taking
of measures for secondary prevention (e.g., early detection and optimal
treatment of patients with glaucoma and diabetic retinopathy) should be
intensified.

Glaucoma Health Economics Finland #1
http://dx.doi.org/10.1111/j.1755-3768.2009.01532.x
In the early2000s, cataract surgery and glaucoma care alone were estimated to account for approximately 80%
of the total non-urgent eye healthcare costs in Finland (Brommelset al. 2004). Because Finland has the highest
prevalence of diabetes in the world and new treatments for AMD create major challenges in terms of resource allocation,
diabetic retinopathyand AMD werealsoincluded in thisstudy.
If the workload ofFinnish ophthalmologistswere keptat the 2003level, the graduation rateof new ophthalmologistswould
have to increase by 75% from the current level. If all glaucoma patients were followed in the public sector in future,
even thisincrease in training would notmeet the demand for physician workforce.
Three scenarios of estimated number of glaucoma visits in the public sector. (A) Care practice
before the new legislation of 2005, when 25% of glaucoma patients had access to public care. (B)
A scenario in which the public sector would care for all glaucoma patients after 2005. (C) A
scenario in which the public sector would care for all glaucoma patients and simultaneously the
diagnostic criteria would be tightened in order to better target the treatment to the ‘right’ patients
– i.e. those with manifest glaucoma. The third scenario assumed that the number of treated
glaucoma patients could safely be reduced by 25% because it has been reported that more than
half of glaucoma patients treated in Finland do not have the disease (
Vaahtoranta-Lehtonen et al. 2007).
The relative distribution of costs of four major eye diseases in the current
study and in Australia and the USA (Taylor et al. 2006; Rein et al. 2006).
The distribution of total costs of the four eye diseases in Finland in
2003. The costs of cataract surgery, glaucoma, diabetic retinopathy
and age-related macular degeneration (AMD) were estimated at €89
million in 2003.

Glaucoma Health Economics Finland #2
The incremental cost of 1 year of avoided visual disability by screening was 32,602€. The cost of
one quality-adjusted life years (QALY) gained by screening was 9,023€ with a discount rate of 5%.
During the average 20 year time horizon considered, the cumulative incremental costs of screening
in a population of 1 million people would be 30M€, producing 3360 incremental QALYs and 930
years of avoided visual disability for 701 persons. The results were sensitive to the estimates of
several parameters, especiallyscreeningcost and specificityof screening tests(96-99% specificity
required).
An organized screening programme could be a cost-effective strategy especially in
older age groups, in which screening is clearly more likely to be acceptable to decision makers at
any level in terms of their willingness to pay for a QALY. Modelling includes some uncertainty
especiallyconcerningthe specificityofdiagnostic testsand screeningcost.
http://dx.doi.org/10.1111/j.1600-0420.2007.00947.x
http://dx.doi.org/10.1111/aos.12141
A total of 168 patients were examined, 85 subjects from an area with higher per
patient treatment costs (Oulu) and 83 patients from a region with lower per patient
treatment costs (Turku). All patients had a history of continuous glaucoma
medication use for a period of 11 years. Patients in the Oulu district consumed more
resources, and glaucoma treatment was more expensive than in the Turku area. The
total treatment cost in Oulu and Turku was 6010 € and 4452 €, respectively, for the
whole11-yearperiod.
Major cost source in open-angle glaucoma treatment is medication, up to 74% of
annual costs. In addition, it seems that higher resource consumption and higher
treatment costs do not increase the patients’ health-related quality of life
(HRQoL) as assessed by the health-related quality of life questionnaire (15D)
instrument.
If a shift towards earlier medical interventions is made in glaucoma treatment and
clinicians start treating all ocular hypertension patients pre-emptively, the
total costofeye health care in Finland will increase substantially.Thisisdue tothe fact
that the number of ocular hypertension patients is several times greater than the
number of glaucoma patients. Although the cost per patient would be smaller, the
total costs of eye health care would be substantial. The opposite approach would
be to treat and spend more resources on patients with manifest glaucoma.
Thenthecostperpatientwouldbehigher,butthetotalcoststosocietymightbeless.

Glaucoma Health Economics China#1
Department of Epidemiology and International Eye Health, Institute
of Ophthalmology, University College London
http://dx.doi.org/10.1136/bjo.85.11.1277
However, the authors believe the visual morbidity from
glaucoma in China is considerable. Primary Angle Closure
Glaucoma (PACG) is probably the leading cause of
glaucoma blindness in both eyes, and warrants detailed
investigation of strategies for prevention.
http://dx.doi.org/10.1097/IJG.0b013e318064c818
The daily cost of glaucoma medications in China ranged much more wildly than developed countries. These data
may be useful in selecting medications for glaucoma therapy. The ophthalmic solution of prostaglandins is
powerful in reducing intraocular pressure. However, its high price should be considered when selecting glaucoma
medications in China.
“Nowadays, prostaglandins have become a first-line
therapeuticoption in developed countries because of
its effective intraocular pressure-lowering ability,
minimal risk ofsystemic side effects, and once-daily
administration.
https://doi.org/10.2147/DDDT.S80338
http://dx.doi.org/10.1097/IJG.0b013e31824083ca

Glaucoma Health Economics Singapore
Singapore Chinese residents (n = 213) with primary open-angle glaucoma or primary
angle-closure glaucoma were recruited from a single tertiary ophthalmic center.
Standard face-to-face interviews were conducted to ask about utility values (time
trade-off and standard gamble for both death and blindness).
Conclusion: Most Chinese glaucoma patients in Singapore are not willing to trade
time or risk blindness. Patients with worse visual fields in the better-seeing eye are
more willing to trade time; whereas patients who have not seen an ophthalmologist for
at least 15 years or who had no history of a previous trabeculectomy are more willing to
risk blindness.
http://dx.doi.org/10.1111/j.1442-9071.2004.00906.x
Conclusion: Acute primary angle closure glaucoma produces a substantial financial
burden on society as well as on the individuals.
There is a relatively high prevalence of depression (30%) and
anxiety disorders (64%) among glaucoma patients in Singapore.
Female glaucoma patients are more likely to suffer from depression.
Other risk factors for depression include higher cup-disc ratio,
higher logMAR BCVA, lower MD, and a lower mean VFQ25 score.
https://doi.org/10.1097/IJG.0000000000000393

Glaucoma Health Economics India#1
A study of 243 patients in southern India found that education level and family support
contribute to noncompliance. Of the patients on at least one medication, 42% reported one
or more problems in using their medication.
In a similar study of 300 patients comparing regular vs. irregular follow-up, independent
predictors of poor follow-up included lack of formal education, failure to use prescribed
glaucoma medications, and belief that follow-up is less important if one uses glaucoma
medications and has no noticeable visual changes. The most prevalent barriers to follow-up
were belief that there was no problem with one’s eyes and lack of escort to office visits.
http://www.healio.com/ophthalmology/glaucoma/news/print/ocular-surgery-news-asia-pacific-edition/%7B32cda806-5a39-4
5fc-bc8b-11a19ef6dd1f%7D/medication-costs-adherence-complicate-glaucoma-treatment-in-india

Glaucoma Health Economics India#2
56,000 INR - £666(Jan2017 rate, 0.0119)
- £771(Jan 2011 rate,0.0138)
£138
£97
£62
£21
The present study has utilized a simultaneous testing method for screening for measuring the
costs and outcomes of a community screening programme for glaucoma. It would be useful to
study the cost effectiveness and epidemiological impact of using a sequential testing method
for glaucoma screening and comparing the findings with the present study. It will be also
useful to study the cost utility of glaucoma screening by applying Markov model and consider
the whole chain of outcomes from screening to visual disability and the full range of costs
associated with this chain

Glaucoma Health Economics USA#1a
http://dx.doi.org/10.1001/archopht.124.1.12
Average direct cost of treatment ranged from $623 per patient per year for
glaucoma suspects or patients with early-stage disease to $2511 per
patient per year for patients with end-stage disease. Medication costs
composed the largest proportion of total direct cost for all stages of disease
(range,24%-61%).
Glaucoma costs the US health care system an estimated
$2.5 billion annually: $1.9 billion in direct costs and $0.6
billion in indirect costs.3
Several retrospective medical record
reviews have considered the aggregate economic burden
associated with the management of glaucoma.3- 5
However,
few data exist regarding medical resource consumption as a
function of varying disease severity in glaucoma, particularly
in the treatment of end-stage disease and with the advent of
more aggressive treatment patterns and the development of
new treatment classes
nce (MD)
al
ed for age)
sitivity for
ted from
d). Mean
viation
following:
diffuse
zed loss.
value
is
tive
ey
eviation)
bol in
s (mean

Glaucoma Health Economics USA#2
JAMAOphthalmol. 2016;134(4):357-365. doi: 10.1001/jamaophthalmol.2015.5479
In the risk-adjusted model, Medicare beneficiaries with glaucoma incurred
an additional $2903 ($2247-$3558) annual total health care costs and
$2599 ($1985-$3212) higher costsfor non-outpatientservicescompared
withMedicarebeneficiarieswithoutglaucoma.
Glaucoma is associated with greater use of inpatient and home health aide
services and with higher annual total and non-outpatient medical costs.
Perception ofvisionlossamong patientswithglaucomamaybeassociated
with depression, falls, and difficulty walking. Reducing the prevalence and
severity of glaucoma may result in improvements in associated non-
glaucomatous medical conditions and resultant reduction in health care
costs.
“Glaucoma is a leading cause of irreversible visual impairment in the United States and
worldwide and results in progressive structural and functional damage to the optic nerve.
Because the disease affects both central and peripheral vision, patients with glaucoma may
experience disability and loss of independence and require rehabilitation or health care
services in addition to regular ophthalmologic care. Furthermore, because glaucoma is a
diseaseofelderlypersons,itsprevalenceisexpectedtoriseasthepopulationages.
Despite the increasing prevalence of glaucoma, the burden of disease is not well
understood. While several studies have assessed the financial costs associated with
glaucoma, some have methodological limitations regarding the population studied or the
data analyzed. Studies that have investigated a subset of patients with glaucoma (eg, those
withend-stageglaucoma)donotcapturetheentirespectrumofthediseaseburden.
Retrospective medical record reviews may provide details on patient-level
characteristics but lack information on cost. Studies using commercial insurance claims have
limited generalizability because glaucoma is more prevalent among the elderly. Studies using
Medicare claims data are ideal for cost-effective analyses from a single-payer perspective.
However, Medicare claims data alone may not capture the total effect of glaucoma on patient-
reportedoutcomes,healthresourceuse,andtotalhealthcarecosts”

Glaucoma Health Economics USA#3
http://dx.doi.org/10.1097/IJG.0b013e3180575202
The highest category of baseline IOP (>35 mm Hg) was
associated with the highest costs, especially in the United
States [US$11,409 in the United States and 3670€ (US$4341)
inEurope].
Although these studies examined cost by stage of disease,
cost per person-year could be estimated in each country as
follows: France 497€ (US$588), Germany 669€ (US$791),
Italy 417€ (US$493), the UK 660€ (US$781), and the US $1659
(1402€). Although a direct comparison of these estimates to
other published studies is not possible due to methodological
differences, several studies have shown the notable impact that
glaucomamanagementcosthasonhealthcareresources.

Glaucoma Health Economics Developingworld
The aim of the study was to disclose a realistic estimate of primary open-angle glaucoma
treatment, follow-up costs, and patients’ monthly glaucoma-economic burden in an
ophthalmologyhospital in Mexico City.
Patients’ monthly average economic burden in glaucoma treatment: low-income patients=61.5%,
moderate-income patients=19.5%, and high-income patients=7.9%. Therefore, screening
plans for earlier diagnosis, and health policies that lessen the cost of disease management
and increase adherence to treatment, and reduce the prevalence of blindness attributed to
glaucoma are essential. These would improve quality of life, reduce personal and national
expenditure, and help increase national economy.
https://dx.doi.org/10.1097%2FMD.0000000000005341
http://dx.doi.org/10.1186/s12913-016-1528-x
Out of 891 POAG cases seen in 2012,351(39.4 %)attended all the required reviewvisits,but
only 84 (9.4%) had fully and continually adhered to all their treatment regimes. The
total estimated cost for the 84 cases in the year was GH¢ 81,237 ($40,619), comprising
GH¢ 72,193 ($36,097) direct medication cost and GH¢9,045 ($4,523) direct non-
medication cost (surgery and test cost), and an average of GH¢ 967 ($484) for a mean visit
of5.6±1.1 in theyear.
CONCLUSIONS:Cost of managing glaucoma constitutes a substantial financial burden
andinfluencedthepattern ofmedication prescription.
https://dx.doi.org/10.7860%2FJCDR%2F2015%2F12491.5966
To analyse economic impact of three commonly used drug combinations in Ahmedabad, India
(Dorzolamide + Timolol = DT; Brimonidine + Timolol = BT; Latanoprost+Timolol = LT) in
primary openangle glaucoma.
Treatment with DT, BT & LT group consumed 8.6%, 4.6% and 7.7% of the per annum income of the
family, respectively. Treatment with BT was found to be most cost-effective among three
groups. Drug therapy takes substantial amount from per annum income of family and was an
important compliance factor in thetreatment ofPOAG.

Glaucoma Health Economics Nigeria
http://dx.doi.org/10.2147/OPTH.S37145
Primary open angle glaucoma is reported to blind 150,000 people in the Nigerian population and over
7000 in Rivers State, and requires constant follow-up. Compliance is a challenge, given that most
inhabitants live below the poverty line. This study was performed to determine how Nigerian patients
are affected economically bythe disease.
Middle-income earners spent over 50% of their monthly income and low-income earners
spend all their monthly earnings on treatment for glaucoma. This situation often resulted in
noncompliance with treatment and hospital follow-up visits. To reduce the economic burden of
glaucoma, trabeculectomy performed by experienced surgeons should be offered as first-line
treatment for glaucomain thiscountry, rather than medical therapy.
http://dx.doi.org/10.1136/bmjopen-2016-012230

Intraocularpressure (IOP)
Cerebrospinal Fluid Pressure (CSFP)?

IOP
Whatpressuremattersactually?IntraocularPressure(IOP)thestandard#1
Boucard et al. 2016: “The classic view of glaucomab
is that of an eye disease in which elevated intraocular pressure (IOP)
mechanically damages the optic nerve (ON) causing the death of retinal ganglion cells (RGCs). Indeed, in high-pressure glaucoma
(HPG, the most common form of glaucoma), RGC and ON damage are associated with an elevated IOP (>21 mmHg).[1]
However,
this view cannot be complete as glaucoma with normal levels of IOP is commonly reported as well. In such normal-pressure
glaucoma (NPG), damage occurs to the ON without the eye pressure exceeding the normal range. By definition, NPG only differs
from HPG in that the IOP is consistently below 22 mmHG.[1]
Moreover, rather than being a disease restricted to the eye, damage
of the RCGs extends to the axons that form the primary visual pathways.c
https://www.youtube.com/watch?v=sgKeXb3PvBs
https://www.reviewofoptometry.com/article/the-dos-and-donts-of-measuring-iop

Glaucoma
Whatpressuremattersactually?IntraocularPressure(IOP)thestandard#2
http://dx.doi.org/10.1016/S0161-6420(95)31054-8
Systemic blood pressure and hypertension are
associated with IOP and high-tension glaucoma. No
association was found between blood pressure or
hypertension and normal-tension glaucoma.
Nature Genetics 46, 1126–1130
(2014) doi:10.1038/ng.3087
We report the results of a genome-wide association study
meta-analysis of 18 population cohorts from the International
Glaucoma Genetics Consortium (IGGC), comprising 35,296
multi-ancestry participants for IOP. We confirm genetic
association of known loci for IOP and primary open-angle
glaucoma (POAG) and identify four new IOP-associated loci
located on chromosome
https://dx.doi.org/10.2147%2FOPTH.S116859
Short-term IOP fluctuations were found to be associated with long-
term IOP fluctuations. Examination of 24-hour IOP fluctuations with
the Triggerfish® contact lens sensor might be useful for predicting
the long-term IOP fluctuation.
There is very low quality evidence (retrospective studies, patients on
different treatments) for the use of a diurnal tension curve or single
measurements to assess short or long-term IOP fluctuation or mean
as a risk factor for the development or progression of glaucoma. There
is very low quality evidence (expert opinion) whether the use of a
diurnal tension curve is beneficial for glaucoma suspects or
patients with progressive glaucoma, despite normal single office IOP
measurements, and leads to a more effective disease management
strategy.
There was some regularity in the 24-hr IOP pattern in POAG, but
different severities of glaucomatous optic neuropathy (GON) and
different subtypes might present different characteristics. Other
non-IOP factors may lead to pathological IOP fluctuation and could
be correlated with GON.
The significantly higher supine IOP is frequently missed in
routine glaucoma practice. An early morning supine IOP
measurement may reveal a peak IOP hitherto not picked up
during routine office IOP measurements, and may be a useful
measurement in unexplained progressive glaucoma.
First Online: 14 October 2016
http://dx.doi.org/:10.1007/s00417-016-3518-4
Sleeping with the head elevated and avoiding the worst
eye-dependent side during sleep may slightly lower
intraocular pressure and reduce visual field loss. Some
food supplements and moderate aerobic exercise may
also reduce intraocular pressure up to 2.0 and
3.0 mmHg, respectively. Frequency of coffee intake
(coffee elevating IOP) may be associated with disease
progression. Potential negative effects are associated
with weight-lifting and yoga exercises.

Glaucoma
Whatpressuremattersactually?IOP,ICP,TLCPorCSFP?#1
0
In open-angle glaucoma (OAG), but not in angle-
closure glaucoma (ACG), calculated trans-lamina
cribrosa pressure difference (TLCPD) versus
intraocular pressure (IOP) showed a better
association with glaucoma presence and amount of
glaucomatous optic neuropathy. It supports the notion
of a potential role of low Cerebrospinal fluid pressure
(CSFP) in the pathogenesis of OAG.
The present study provides information on the relationship
of translamina pressure difference to the development of
optic nerve damage in what is presently called glaucoma. It
does not provide support of the idea that ocular perfusion
pressure plays a major role in the pathogenesis of optic
neuropathy.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635731/
Scheme Illustrating
the Relationships
between
Cerebrospinal Fluid
Pressure (CSFP),
Intraocular Pressure
(IOP) and Other
Ocular and Systemic
Parameters (Red
arrows: positive
relationship; black
arrows: negative
relationship)

Glaucoma
http://dx.doi.org/10.1016/j.taml.2016.03.002 http://dx.doi.org/10.1097/WNO.0000000000000378
In the course of developing glaucoma, the difference between the
intraocular pressure (IOP) and the intracranial pressure (ICP) plays a key
role. It is this difference that exerts on the primary site of glaucoma—the
lamina cribrosa (LC), then results in the irreversible deformation of LC, and
finally induces the damage of the optic nerves passing through LC, thus
triggers the visual field defect, which is medically considered to be the main
pathological mechanism of glaucoma [2] and [3].
The relations
between IOP and
ICP. Thebroken line
standsfor Eq. (1), the
solid lineexpresses
Eq. (3), and different
figuratepoints
indicate the different
experimental data
from Refs. [6], [7], [8]
and [9].
http://dx.doi.org/10.1097/WNO.0000000000000295
The potential relationship between intracranial pressure (ICP) and glaucoma has
raised more questions to be answered. Published data are very suggestive that low
ICP is a risk factor for glaucoma. This may help explain the higher frequency of
glaucoma seen in older populations. Low ICP may, in part, explain normal tension
glaucoma. Low ICP may be responsible for the increased incidence of glaucoma
observed in patients with Normal pressure hydrocephalus (NPH). High ICP may be
protective in some patients with ocular hypertension. Structural alteration of the
lamina cribrosa (LC), has been documented with changes in the TPG. Distortion
and perhaps instability in LC structure may contribute to the development of
glaucoma. Other possible mechanisms include ICP-related alteration in axoplasm
and blood flow, which hypothetically could be primary or secondary to observed
structural changes. An association between ICP and glaucoma seems likely given
the present data, and further investigation of these associations is expected to
enhance our understanding of the pathophysiology of glaucoma.

Glaucoma
http://dx.doi.org/10.1177/2058460116653630http://dx.doi.org/10.1177/2058460115624275
The subarachnoid space (SAS) of the optic nerve (ON) is contiguous with the SAS of the
brain in a normal population. Growing evidence in the literature provides strong support for
the concept that CSF pressure and composition in the SAS surrounding the ON may have
fundamental significance in the pathogenesis of glaucoma (Berdahl and Allingham 2010; Killer et al. 2012)
. As an
extension of the brain, the ON displays remarkable similarities to the brain in terms of
anatomy and functionality (Wostyn et al. 2015)
. Knowledge obtained from brain research could
therefore lead to new insights into the ON and vice versa.
Recently, the ‘‘glymphatic system’’ of the brain has been discovered in rodents by
Iliff et al. (2012). The authors argued that this system was critical to the efficient clearance
of interstitial solutes, including amyloid-b, from the brain Iliff et al. (2012)
. Their findings
suggested a brain-wide paravascular pathway in which CSF flows from the SAS along the
arteries and arterioles into the paravascular Virchow-Robin spaces (VRSs) to exchange with
interstitial fluid (ISF), and ISF is cleared from the brain into the VRSs surrounding the exiting
veins. As ISF exits the brain through the paravenous route, it travels to the lymphatic
vessels in the neck, and eventually returns its contents to the systemic circulation.
Since the ON is a direct extension of the brain, the question is whether there is also
evidence for the existence of a paravascular transport system in the ON. The observation of
such an anatomically distinct clearing system in the ON could also provide new insights
into the pathogenesis of glaucoma. Indeed, if confirmed, one might expect that a
dysfunctional glymphatic system could ultimately result in reduced neurotoxin clearance in
the ON and lead to glaucomatous neurodegeneration (Wostyn et al. 2015)
.
If dilation of VRSs may result from a disturbed interplay between the vascular and
glymphatic system, then preventing arterial stiffness may protect against glaucoma, at
least in part, by promoting solute clearance via the CSF.

Glaucoma Contact lens IOP measurement
MorereliableIOPmeasurement asIOPitselfhasadiurnalpattern
http://dx.doi.org/10.1155/2016/4727423
This review discusses each intraocular pressure (IOP) measuring strategy and focuses on the recently FDA-
approved contact lens sensor (CLS). Using the CLS, IOP-related parameters have been found to be
associated with the rate of visual field progression in primary open-angle glaucoma, disease progression in
primaryangle-closureglaucoma, and variousclinical variables inocular hypertension. TheCLS has been used to
quantify blink rate and limbal strain and measure the circadian rhythm in a variety of diseasestatesincluding
normal-tensionglaucomaand thyroid eyedisease.
One major limitation of the CLS is that its output cannot be converted to millimeter mercury (mmHg) to allow
for direct clinical interpretation. However, because the ocular pattern recorded by CLS is highly correlated to the
IOP rhythm, the readings obtained from the CLS can be used to guide clinicians to determine the critical
time for IOP measurement during the 24-hour period, as stated by FDA (Mansouri etal. 2014). In addition,
current studies indicate that the IOP- related CLS profile itself can be used as an ocular perimeter for
individualized glaucoma management. More studies are needed to determine which biomechanical
properties determine the CLS output and whether the output is associated with corneoscleral properties, such
ascornealhysteresis.
The patient wears the SENSIMED Triggerfish® system up to 24 hours and assumes
normal activities including sleep periods. The SENSIMED Triggerfish® Sensor is a soft
disposable silicone contact lens embedding amicro-sensor that captures spontaneous
circumferential changes at the corneoscleral area.
http://www.sensimed.ch/
Journal ofGlaucoma. August 22, 2016. doi: 10.1097/IJG.0000000000000517
The range of IOP fluctuation was larger in the eyes with normal-tension glaucoma
(NTG) than in the nonglaucoma eyes. This larger fluctuation might be one of the
reasons underlying the aggravation of the visual field by NTG. Measurements of
24-hour continuous IOP might be one of the useful methods to distinguish NTG
from nonglaucoma eyes.

Functionalresponses
Visual field traditionally

Visualfield Introduction
https://xkcd.com/1080/

Visualfield Measurements
“Patterns of early glaucomatous
visual field loss and their
evolution over time”
http://iovs.arvojournals.org/article.aspx?articleid=23
33021
http://dx.doi.org/10.1016/j.ophtha.2014.08.014
http://dx.doi.org/10.1016/j.ajo.2015.12.006
Humphrey HFA II-i
Field Analyzer
HumphreyFieldAnalyzerII-i SITA
TestingStrategies
SITA Strategiesarenotonly fastandaccurate,butalso
friendlyon thepatient.Usingtiming techniques,SITA
isextraordinarily responsivetopatient reaction times.
Thepatientruns theperimeter, ratherthan thereverse.
SITA testing strategiesavailableon theHFAII-i:
SITA Standard: Athresholdtestingmethodwhich
collects thesameamountofinformation in halfthe
timeastheoriginalHumphrey® FullThreshold
standardalgorithm, withoutcompromisingtest
reproducibility.
SITA Fast: A thresholdtestingmethodthat collects
thesameamountof information inhalfthetimeas
FastPac,withoutcompromising testreproducibility.

Visualfield Microperimetry
Microperimetry|VisualField
Right eye of a 72-year-old man. Native en-face
image (A) and reticular drusen (RDR) area
highlighted (B). Interpolated test results for both
scotopic (C) and photopic (D) microperimetry.
Numerical values for scotopic (E) and photopic
(F) microperimetry. Steinberg et al. (2015)
http://dx.doi.org/10.1167/iovs.08
-2926
http://dx.doi.org/10.
1167/tvst.3.5.3
(Top) Humphrey Field Analyzer (10-2 pattern, SITA Standard) and (bottom)
MP-1 microperimetry (10-2 pattern, 4-2 strategy) results from a normal
individual (age 29).
In summary there is an increasing amount of evidence supporting the
usefulness of microperimetry both as a clinical instrument and as a
research tool. The clinician should however be aware of the differences
between microperimetry and conventional perimetry, differences in the
manufacturer’s design that may affect testing conditions and therefore,
the interpretation of results. The advantages over conventional perimetry
include fundus tracking features and the co-registration of the perimetric
results with fundus imaging.
Can J Ophthalmol. 2013 Oct; 48(5): 358–363.
doi: 10.1016/j.jcjo.2013.03.021

Visualfield andGlaucoma#1
The CochraneEyesandVisionGroup defines glaucoma as 'a
disease characterized by defects in the visual field, damage to
the nerve at the back of the eye, and usually raised pressure
insidetheeye.'
As we now know, this view of glaucoma as an optic neuropathy with
elevated IOP as a modifiable risk factor rather than as the
causative agent for damage is more correct, although it still does not
take into account the characteristic morphological and functional aspects
of the disease. It is important for clinicians and the research community
alike to view glaucoma as an optic neuropathy, especially as we drive
towarddiscovering better therapeuticstrategies,includingpharmacologic
neuroprotection.
http://dx.doi.org/10.1038/sj.eye.6702880
Glaucoma - Basic and Clinical Concepts, Edited by Shimon Rumelt
ISBN 978-953-307-591-4
http://www.ehu.eus/OftalmoBiologiaExperimental/documentos/adaptive-changes-in-the-retina-and-central-visual-areas-in-glaucoma.pdf
In thepathologyoftheglaucoma, visualfield losses first occurinthe
peripheralretinaandprogressivelyleadtothelossofallvisionandcomplete
blindness. Themain therapyforthetreatmentofglaucomahasbeenthereduction of
IOPthat stabilizesthevision loss.However, incertain population, thevisualloss
continuesin spiteofthereductionofIOP.
Recent advanceoffunctionalmagneticresonanceimaging(fMRI)providefunctional
assessmentofvisualchangesinglaucomapatients,whichcorrelated,wellwith the
lossofvisualfieldintheeye(Guptaet al.2006).

Visualfield andGlaucoma#2
Lakkis(2014): “Approximately 40 per cent of ganglion cells
need to be lost before an early glaucomatous threshold
visual field defect is manifested (Quigleyetal.,1989,
Citedby 1096 ), and the typically slow progression in optic
nerve head changes makes structural glaucoma detection
difficultuntilsignificantrimtissueislost.”
Although previous studies have evaluated rates of change in monocular visual fields for monitoring
glaucoma, very little is known about rates of change in binocular visual fields (BVF). Recent
studies have shown that functional losses measured by BVFs show a better relationship with
patient-reported quality of vision compared with losses measured by monocular
fields. Therefore, evaluation of rates of change using BVFs could provide a better method for
assessmentoftherisk of functionalimpairmentin glaucoma.
In conclusion, our results demonstrated that the rate of change in BVFs was significantly faster
than that in the visual fields of the slower-changing eyes and slower than that in the visual fields of the
faster-changing eyes. Weexpect that our findings will have significant implications for studies related to
qualityoflife,monitoringofglaucoma, andprovidingtherapeutic guidance.
A novel approach for simulating VFs is introduced. A better understanding
of VF variability will help clinicians to differentiate real VF progression
from measurement variability. Visual field variability leads to false-positive
diagnoses of progression when patients actually have stable glaucoma, which
may lead to needless treatment changes and costs to both patient and
healthcare provider [32]. Conversely, glaucomatous progression may be
missed if clinicians deem any change is due to inherent measurement noise.
This study highlights that, overall, MD variability increases as the level of
damage increases, but variability is highly dependent on the pattern of VF
damage. Future research, using VF simulations, could be employed to
provide benchmarks for measuring the performance of VF progression
detection algorithms and developing new strategies for measuring VF
progression.

Visualfield andGlaucoma#3: Centralvs.Periphery
Patients with similar central visual field loss can have strikingly different
peripheral visual fields, and therefore measuring the peripheral visual field
may add clinically valuable information.
Relationship between global summary measures of
peripheral visual field (MIR) and central visual field
damage (MD). Each data point shows the mean of
the two repeated tests. The Spearman rank order
correlation coefficient was 0.51 (95% CI: 0.18, 0.74).
Central visual field damage test-retest
differences
Peripheral visual field damage test-retest
differences
Central 24-2 testing generally reflects the extent of damage to the more peripheral VF
in glaucoma, although significant disagreement exists for individual eyes. Further work is
needed to determine whether integration of peripheral test points can improve
detection of true VF loss in early glaucoma or be useful in monitoring progressive
glaucomatous damage to areas of preserved VF in advanced glaucoma.
At more advanced stages of disease, we found that
the percentage of abnormal central points exceeded
the percentage of abnormal peripheral points,
suggesting relativeperipheralsparing.
Several practical limitations remain with regard to evaluation of the
peripheral VF. Normal subjects have greater variability at more
peripheral points, likely reflecting variations in the normal hill of vision, and
pointwise variability in the peripheral VF is believed to be greater in the
superior and nasal quadrants, regions frequently affected by early
glaucoma. Additionally, central 24-2 testing takeslesstime, leading
to decreased patient fatigue, and has been shown to pick up a
reasonable amount of early disease by itself. Finally, more false
positives may occur in testing of the far peripheral VF, leading to more
spurious defects. Ideal algorithms to test the far peripheral VF would
initially test only a few peripheral points in eyes with little or no central
defects and then perform further testing of the peripheral VF if abnormal
points are observed. Considerations should also be given to peripheral
testing in patients with advanced central loss in whom standard 24-2 or
10-2testsareunlikelyto detectfurtherprogression.

Glaucoma

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