MAY 2016
Upfront
Quest for an
anti-VEGF alternative
09
# 30
In Practice
The usual
keratectasia suspects
NextGen
Telemedicine brings ROP
into the digital era
Profession
Getting the most out of the
mentor-mentee relationship
30 – 33
36 – 38
42 – 44
Individualized
and Inspiring
Unraveling the mysteries of aqueous
outflow with aqueous angiography,
could help surgeons customize glaucoma
surgery and maximize its effectiveness
20 – 27
www.theophthalmologist.com
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Online
this
Month
What’s got you talking?
www.theophthalmologist.com
This month, we sat down with George Spaeth, our 2016 Power List #1 and Director
Emeritus of the Wills Eye Hospital Glaucoma Service – an ophthalmologist who
has worked tirelessly to further his field and train the next generation of glaucoma
specialists. The highlights of the interview can be found on page 50, but if you want to
read the rest of the interview, head over to our website: top.txp.to/issues/0516/701
Power List
2016
Facebook
Last Month’s Top Tweets
Centre for Excellence In Eye Care
22 April at 07:05
Iowa Eye Alumni @IowaEyeAlumni
Congrats, Dr. Ed Stone, on making the
@OphthoMag Top 100 #powerlist!
http://buff.ly/1TuCw0Z
3:21 PM - 26 Apr 2016
Julia A. Haller MD @JuliaHallerMD
#1 George Spaeth!!
https://theophthalmologist.com/issues/0416/
welcome-to-the-power-list-2016/
… @Wills_Eye @JeffersonUniv
#KeyOpinionLeaders
12:55 PM - 21 Apr 2016
Fight for Sight @fightforsightUK
#FightforSight Ambassador Prof
Marshall recognised 4 his #EyeResearch
@OphthoMag #PowerList
http://bit.ly/210iZZA
8:00 AM - 25 Apr 2016
We are speechless and BEYOND
PROUD.
Congratulations to our very own
Dr. William Trattler for being
named one of the TOP 100 Most
Powerful people in Ophthalmology
in 2016! This list names some
incredible surgeons and we know our
Dr. Trattler was a big deal…seeing
him on this list makes it known to
the rest of the world!
www.theophthalmologist.com
Contents
10
Feature
20
Online this Month
03
07 Editorial
Help the Heroes,
by Mark Hillen
Contributors
08 On The Cover
MAY 2016
# 30
Upfront
Quest for an
anti-VEGF alternative
In Practice
The usual
keratectasia suspects
NextGen
Telemedicine brings ROP
into the digital era
Profession
Getting the most out of the
mentor-mentee relationship
09
30 – 33
36 – 38
42 – 44
Individualized
and Inspiring
Unraveling the mysteries of aqueous
outflow with aqueous angiography,
could help surgeons customize glaucoma
surgery and maximize its effectiveness
20 – 27
www.theophthalmologist.com
NASA satellite image of the Sundarbans
relates nicely to the intricate network of
aqueous outflow pathways discussed in
this month‘s cover feature.
Upfront
10 Mature iPSCs and
Mitochondrial Mutations
11
Enter the Inflammasome
12
Looking Back, for the Future
14
On the KUSp of
Neuroprotective Medicine
16
Recline for Corneal
Thickness Decline
17
Build a Better Banana
18
CATT: Five Years On
19
Business in Brief
20
Individualized and Inspiring
Alex Huang explains how
aqueous angiography could
unravel each patient’s unique
aqueous humor outflow pathways,
and how it will help avoid MIGS
cases turning into “MEGS” cases.
In Practice
30
The Usual Suspects
Alain Saad asks: how can you
predict which patients will develop
keratectasia, and if they do, how do
you go about defining it?
Next Gen
36
ROP in the Digital Era
What is the future for ROP care?
Michael Chiang discusses the
current challenges, and the benefits
that telemedicine may bring.
ISSUE 30 - MAY 2016
Editor - Mark Hillen
[email protected]
Associate Editor - Roisin McGuigan
[email protected]
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[email protected]
Editorial Director - Fedra Pavlou
[email protected]
Content Director - Rich Whitworth
[email protected]
Publishing Director - Neil Hanley
[email protected]
Senior Designer - Marc Bird
[email protected]
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[email protected]
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[email protected]
Events and Office Administrator
- Alice Daniels-Wright
[email protected]
Financial Controller - Phil Dale
[email protected]
45
Looking After Your Pupils
Andreas Lauer explains how
to get the most out of mentormentee relationships.
45
Would You Let Sleeping
Dogmas Lie?
Tiarnan Keenan discusses recent
findings of a study on the impact
of sleep apnea on ocular health,
and explains why you need to
worry about an AMD association,
not a POAG association.
Chief Operating Officer - Tracey Peers
[email protected]
Change of address
[email protected]
Tracey Nicholls,The Ophthalmologist,Texere
Publishing Limited, Haig House, Haig Road,
Knutsford, Cheshire,WA16 8DX, UK.
Single copy sales £15 (plus postage, cost available
on request [email protected])
Annual subscription for non-qualified recipients £110.
Profession
42
Chief Executive Officer - Andy Davies
[email protected]
Sitting Down With
50
George Spaeth, Louis J.
Esposito Research Professor, and
Director Emeritus, Glaucoma
Service, Wills Eye Hospital,
Philadelphia, Pennsylvania, USA.
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Help the Heroes
Those on our Power List typically credit their achievements to
“being in the right place at the right time” – but what about
those (also doing heroic work) who weren’t?
References
1. M Hillen, R McGuigan, “Celebrate Life!
Sitting Down With... George L. Spaeth”,
The Ophthalmologist, 30, 51–52 (2016).
Available at: top.txp.to/issues/0516/701/
2. M Hillen, “A vision time bomb”, The
Ophthalmologist, 6, 20–25 (2014).
Available at: top.txp.to/issues/0314/301/
Editorial
’ve been fortunate enough to meet with many of the big
names in eyecare, and I’ve either interviewed many of them,
or worked with them to produce some amazing feature
articles. Interviewing this year’s Power List #1 George
Spaeth (1) for this month’s issue was an utter privilege: a humble,
wise, hardworking man, who has lived a great life, and continues
to do so, leading by example.
Every single person on each of our Power Lists has worked
extremely hard to get to where they are, and although everyone
has an ego, you’d be surprised by just how many of them attribute
a large part of their success to luck – I often hear, “Oh, I was just in
the right place at the right time”. I think it’s right and proper that
we celebrate the achievements of people that have done so much
to help people see over their careers, but…
What if they hadn’t been in the right place at the right time?
The researchers that chose a different thread of investigation;
the surgeons who took a different fellowship? The fact is, all
ophthalmologists, “listed” or not, have incredible caseloads, and
many struggle to find time to do anything else other than perform
thousands of sight-restoring procedures. I may have a bee in my
bonnet about aging baby boomers being a vision timebomb (2),
but the message I hear time and time again from whoever I speak
to is that the AMD clinics are at bursting point, the cataract lists
are virtually endless…
So what I’m proposing is this. I am going to speak to the people
on the front line of the battle against vision-robbing disease,
and ask them about the challenges they face, how they address
some of those challenges, and what they think needs to be done
about addressing the rest of them. I believe there’s value in that,
and importantly I hope that this will help give some deserved
exposure to some of the unsung heroes of the wards.
No ranking, just narrative. If you’d like to point me in the right
direction of your unsung heroes, please get in contact – my details
are on the masthead. I want this magazine to be your magazine. I
think we are, but I hope this will make us more so.
Mark Hillen
Editor
www.theophthalmologist.com
Contributor s
Alex Huang
Alex Huang is a glaucoma specialist with clinical and research interests in
minimally invasive glaucoma surgery and native aqueous humor outflow pathway
improvements. As a NIH-supported clinician-scientist, his laboratory explores
post-trabecular meshwork outflow resistance, as well as real-time aqueous outflow
imaging technologies for the development of customized glaucoma surgeries.
On page 20, Alex explains how aqueous angiography is about to revolutionize
our understanding of aqueous humor outflow – and how it might transform
microinvasive glaucoma surgery.
Alain Saad
Along with his colleague Damien Gatinel, Saad developed an artificial intelligence
system for the detection of ectasia-susceptible eyes; the SCORE analyzer. A reviewer
and editor for several ophthalmology journals, he has almost 40 publications to
his name. His research interests include corneal ectasias, corneal topography and
tomography, wavefront biomechanics and new keratoplasty techniques.
Predicting which patients have a high risk of developing post-LASIK keratectasia
is challenging, and on page 30, Alain Saad reviews the steps he takes to predict it,
measure it, and define it.
Michael Chiang
Michael Chiang is the Knowles Professor of Ophthalmology, Medical Informatics,
and Clinical Epidemiology at Oregon Health & Science University, and leads
the Oregon State Elks Center for Ophthalmic Informatics. Chiang’s clinical
practice focuses on pediatric ophthalmology, adult strabismus, and retinopathy of
prematurity, and he leads a group that studies the implementation and evaluation of
information technologies for ophthalmic care.
On page 36 Michael asks: is telemedicine the key to better ROP care, and what
barriers stand in the way?
Tiarnan Keenan
Tiarnan Keenan is an ophthalmologist at the University of Manchester, Manchester
and Royal Bolton Hospital, UK. He has received several awards, including the 2013
Fulbright Fight for Sight Research Award, which allowed him to study the role of
the complement system in AMD using Gregory Hageman’s “unique repository
of 12,000 human eyes”, held at the University of Utah. His work has led to the
discovery of a potential new disease mechanism in AMD.
We interview Tiarnan on his latest research on the potential links between sleep
apnea, AMD and glaucoma on page 45.
It’s all in
your
hands.
Technique is everything. You are
the choices you make, so choose
a partner who empowers the way
you phaco.
How do you phaco?
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10
Upfront
Upfront
Reporting on the
innovations in medicine
and surgery, the research
policies and personalities
that shape ophthalmology
practice.
We welcome suggestions
on anything that’s
impactful on
ophthalmology;
please email
[email protected]
Mature iPSCs and
Mitochondrial
Mutations
iPSCs are routinely derived
from fibroblasts and blood
cells, but does the age of the
donor matter?
In 2006, the amazing discovery
of induced pluripotent stem cells
(iPSCs) (1) opened the floodgates to
personalized regenerative medicine.
Ophthalmology certainly joined the
ensuing tidal wave of research, and
the ability to produce donor-matched
ocular cells – not to mention the option
of reprogramming iPSCs derived from
these cells – have peppered publications
in the years since, with the research
showing no signs of slowing down (2).
But every rose has its thorn, as recent
work from Shoukhrat Mitalipov’s team
demonstrates (3). They have shown that
as people age, they accumulate somatic
mutations in their mitochondrial DNA
(mtDNA), which can then be carried
into iPSC lines. In a panel of subjects
aged between 24 and 72 years, iPSCs
generated from younger donors
had significantly fewer mtDNA
mutations compared with those
generated from elderly donors.
While it isn’t a new idea
that mutations in mtDNA
accumulate with age (4),
this is the first clear evidence
confirming the hypothesis.
So what does this mean for
iPSCs? Usually undetectable in
the parental tissue – a proverbial
needle in a genetic haystack – mtDNA
mutations can become prominent in
iPSC populations, which are cloned
from individual donor cells. These
mtDNA mutations may compromise
cell function and respiration, thereby
interfering with the therapeutic
potential of iPSCs. Mitalipov and
his colleagues demonstrated that
metabolic function (as measured by
respiratory chain complex activity and
oxygen consumption rate) was indeed
diminished in iPSCs harboring specific
mtDNA mutations, compared with
mutation-free controls. Confirming that
the therapeutic benefits of iPSCs may be
limited when the integrity of mtDNA is
compromised. They also demonstrated
that when mutated mtDNA was
replaced with mitochondria obtained
from the donor oocytes – a technique
known as somatic cell nuclear transfer
(SCNT) for which Mitalipov was a
pioneer – normal metabolic function
was restored.
Mitalipov noted, “it is imperative to
produce and screen multiple iPSC lines
for chromosomal, nuclear gene, and
mtDNA defects, and to identify optimal
tissues for iPSC induction.” This would
likely mean producing and screening
multiple iPSC lines per patient to allow
selection of the line with the fewest
mutations – and thus the greatest
therapeutic potential. RS
References
1. K Takahashi,S Yamanaka, “Induction of
pluripotent stem cells from mouse embryonic
and adult fibroblast cultures by defined
factors”, Cell, 126, 663–676 (2006).
PMID: 16904174.
2. XL Guo, JS Chen, “Research on induced
pluripotent stem cells and the application
in ocular tissues”, Int J Ophthalmol, 8,
818–825 (2015). PMID: 26309885.
3. E Kang et al., “Age-Related accumulation of
somatic mitochondrial DNA mutations in
adult-derived human iPSCs”, Cell Stem Cell,
18, 1–12 (2016).
4. NG Larsson, “Somatic mitochondrial DNA
mutations in mammalian aging”, Ann
Rev Biochem, 79, 683–706 (2010).
PMID: 20350166.
Upfront
Enter the
Inflammasome
In the quest to unearth
alternative treatment
strategies that don't rely on
VEGF inhibition, researchers
made some surprising
discoveries...
VEGF is something of a Jekyll and Hyde
molecule, with both physiological as well
as pathological functions (1). Although
critical for vascular development, it’s
also strongly linked to angiogenic retinal
pathologies, such as wet AMD and
diabetic macular edema. Intravitreal
anti-VEGF injections are the gold
standard for treating the choroidal
neovascularization that’s associated with
such diseases, and although they have
transformed patients’ outcomes, they
aren’t a panacea. In many cases, their
efficacy does not last forever, and there
is concern that VEGF inhibition in the
retina may lead to thinning and atrophy
of the choriocapillaris, photoreceptor
degeneration, eventually causing
damage to the retina – the complete
opposite of the intended result.
Accordingly, researchers continue to
seek a better therapy – but finding one
may require a greater understanding
of VEGF’s role in ocular pathologies,
according to Alexander Marneros,
of Massachusetts General Hospital.
Marneros used a genetically modified
mouse model which expresses VEGF-A
at two-to-three times physiological
levels, with VEGF expression found
in the lens, retina and ciliary body,
in order to study the protein’s role in
AMD pathogenesis. “Identifying the
downstream mechanisms by which
VEGF-A influences the development
of these diseases may lead to new
therapies that don’t have the adverse
effects of blocking VEGF-A itself,”
he says.
In his pursuit of new knowledge,
Marneros and his colleagues made
an interesting discovery – as well as
uncovering further evidence of the
role of VEGF-A in both wet and dry
macular degeneration, he discovered
a link to another, incredibly common
ocular pathology: “We found that
increased VEGF-A in the lens is
associated with increased oxidative
stress and cataract formation. This
finding provides the first evidence for
a role of increased VEGF-A in the
development of age-related cataracts.
Notably, we found that VEGF-A is
expressed throughout life in cells of
the lens. Whether VEGF-A plays any
roles in the aging processes of the lens
has been completely unknown, but our
experiments provide the rationale for
future studies into a possible link with
cataract formation.”
Oxidative stress and the production
of reactive oxygen species (ROS)
seem to play a pivotal role in AMD
pathogenesis, and as VEGF-A is known
to induce the production of ROS, it’s
possible that VEGF plays an important
role in this cycle. It is generally thought
that hypoxia and oxidative stress may
drive VEGF production, which in turn
leads to additional oxidative stress,
and eventually to the development
of pathologies such as cataract and
AMD (2).
But how can these findings point
towards potential new therapies?
Tissue damage resulting from oxidative
stress is associated with activation of the
NLRP3 inflammasome, and expression
of the proinflammatory cytokines IL1β and IL-18 (2). One encouraging
finding was that inhibition of either
IL-1β or the NLRP3 inflammasome
may inhibit the pathological effects of
increased VEGF-A, says Marneros (see
Figure 1).
11
Figure 1. Effects of increased NLRP3 in
VEGF-Ahyper mice. a. NLRP3 is expressed in
retinal epithelial cells at the sites of choroidal
neovascularization (CNV) (white arrow) b. A
lack of NLRP3 staining is seen in VEGF‐Ahyper/
Nlrp3−/− mice; c. and d. Complement pathway
activation observed in CNV lesions of VEGF‐
Ahyper mice (white arrow in d., but not in control
mice c.). Choroid shown by yellow arrows.
Adapted from (2).
He believes that future clinical
studies in patients would be essential
to assess the role of inhibitors of IL1β or the NLRP3 inflammasome in
preventing or inhibiting AMD and
senile cataracts, while maintaining
the beneficial effects of normal levels
of VEGF-A, which is required for
the normal function of the retina and
choroidal vasculature. “Our studies also
provide the basis for future experiments
to assess links in the pathogenesis of
AMD and cataracts in patients,” says
Marneros. RM
References
1. M Saint-Geniez, P D’Amore, “VEGF has
physiological as well as pathological functions”,
The Ophthalmologist, 4, 16–21 (2014).
Available at: http://bit.ly/1qLg75Y.
2. AG Marneros, “Increased VEGF-A promotes
multiple distinct aging disease of the eye
through shared pathomechanisms”, EMBO
Mol Med, 8, 208–231 (2016). PMID:
26912740.
www.theophthalmologist.com
12
Upfront
Looking Back,
for the Future
From keratoconic to
embryonic: the eye drop that
promises to reinforce the
cornea by inducing keratocytes
to produce embryonic collagen
The 1985 film Back to the Future
featured the song “Back in Time”
by Huey Lewis and The News. And
progressive eye diseases like keratoconus
make you wish you could do exactly that:
go back in time. For several years, this
is exactly what Trevor Sherwin and his
team at the University of Auckland have
been looking to do to keratocytes, in
order to stabilize the cornea in patients
with keratoconus.
Curious to know how plastic
keratocytes are, they asked whether
keratocytes can “remember” their
developmental origin – the neural
crest. They do. When keratocytes were
exposed to factors which stimulate
neural tissue, they began to express
neuronal-specific proteins (1). This led
the team to ask whether they could also
induce the production of type II collagen
– found in the developing embryonic
cornea – reasoning that “keratocytes
also have a memory of producing this
collagen during eye development which
can be reawakened when provided with
the correct stimulus.”
It appears that the correct stimulus
is their eye drop, which contains a
combination of a steroid and a growth
factor. “So far our results [with the eye
drop] have shown success in producing
type II collagen which both thickens
and stiffens the cornea in human tissue
in vitro, and rodent corneas in vivo,” says
Sherwin, adding, “This naturally led to
our team proposing this as a therapeutic
treatment for keratoconus.”
Their aim is to show that the eye drop
is feasible for treating corneas in living
people with lasting effects. Currently,
their combination eye drop is being tested
in sheep, to demonstrate its short-term
and long-term feasibility in thickening
and stiffening the cornea in a new shape.
“If successful, we envisage that we would
be able to treat keratoconic patients with
the eye drop to thicken and stabilize
the cornea at the same time as reducing
excessive ‘coning’,” says Sherwin.
Data from the sheep trial is expected
in early 2017, and following this,
Sherwin and his team are planning to
seek regulatory approval to commence
clinical trials. “Because the reagents have
been used independently in previous
clinical trials, we do not expect a long
approval process and would hope to be
entering human application relatively
quickly,” he says. Beyond helping
keratoconic patients, Sherwin and his
team’s next research goal will be to
translate the technology to reshape and
stabilize the corneas of myopic eyes:
“Myopes already use shape forming
contact lenses for transient effects –
combining this approach with our
treatment may prove very effective in
correcting myopia.”
So sending corneal keratocytes “back
in time” may form part of the future of
keratoconus and myopia treatment.
Watch this space. RS
Reference
1. CA Greene et al., “Cells from the adult corneal
stroma can be reprogrammed to a neuron-like
cell using exogenous growth factors”, Exp Cell
Res, 322, 122–132 (2014). PMID: 24370575.
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14
Upfront
On the KUSp of
Neuroprotective
Medicine
Novel compounds prevent
disease progression in mouse
models of glaucoma
Are we finally on the cusp of treating
neurodegenerative ocular disease by
neuroprotection? Currently, IOP is the
only modifiable risk factor for glaucoma,
but today’s treatments – despite their
successes in reducing IOP – are not always
effective, as many patients continue to
experience gradual loss in vision (albeit at a
less dramatic pace) with treatment. Whilst
efforts in the glaucoma field have been
focusing on neuroprotective treatments, so
far these have been to little avail (1).
Enter Hanako Ikeda and her team at
Kyoto University. Two years ago, they
published research showing that their
novel neuroprotectant compounds –
termed Kyoto University Substances
(KUSs) – prevented photoreceptor cell
death and preserved visual function in a
mouse model of retinitis pigmentosa (2).
Now they have shown that KUSs can
prevent glaucoma progression and loss of
visual function in three different mouse
models, through suppressing the loss of
retinal ganglion cells (RGCs) and nerve
fibers (3). But what exactly are KUSs and
how do they work?
Based on the structure of a naphthalene
derivative, KUSs target valosin containing
protein (VCP), an intracellular protein
involved in a plethora of cellular processes
(2). Linked to several polyglutamine
neurodegenerative diseases, VCP has
also been identified as the causative gene
in inclusion body myopathy with Paget
disease of bone and frontotemporal
dementia and rare cases of ALS/Lou
Gehrig’s disease (4,5). Interestingly,
mutated VCP proteins exhibit elevated
ATPase activities which correlate with
clinical severity of disease (6). KUSs
inhibit this ATPase activity of VCP and
maintain cellular ATP levels (2,6).
What makes VCP interesting for
ophthalmology is its high expression
in all types of retinal neuronal cells and
especially RGCs – the casualties in
glaucoma. Ikeda’s team have shown that
KUSs exhibit neuroprotective effects on
these cells by preventing ER stress and
cell death, thereby mitigating disease
progression in mouse models of glaucoma.
Ikeda notes that “from our cellular studies,
we expected that KUSs would protect
RGCs to some extent in these glaucoma
models [...] we were pleasantly surprised
that we could confirm their functionality
by electroretinograms”.
The team also showed that NMDAinduced RGC injury in thy1-CFP
transgenic mice – which express cyan
fluorescent protein (CFP) in RGCs
– could be rescued by preceding KUS
treatment. Ikeda comments, “it was a
challenge to accurately measure the
remaining RGC numbers through disease
progression or treatment. To meet this
challenge, we customized our OCT
instrument (for the mouse) to detect
CFP and used thy1-CFP transgenic mice
[…] this approach allowed us to take live
images of fluorescing RGCs and nerve
fibers in our mouse models of glaucoma.
We successfully used this instrument in
our mouse studies to evaluate the extent of
retinal damage, as doctors do for patients.”
Retinal flatmount images of control and KUS-treated mice (12 months). Scale bar, 1000 µm.
KUS121
NH2
F
NN
KUS187
o
NH2
N
SO3Na
NN
CHO
N
SO3Na
Structures of KUS121 and KUS187, the KUSs used by Ikeda and her team (3).
So what are the next steps? Ikeda
says, “we believe that a more convenient
and ideal administration route is via
eye drops. We will modify the dosage
forms of KUSs for eye drops, and we
will then examine their efficacies in
our mouse models of glaucoma and
retinitis pigmentosa.” Ikeda reveals
that they are also planning Phase I/
II clinical trials to test the safety and
efficacy of KUSs administered through
intravitreal injection, but estimates
that it will take at least another three
to five years for glaucoma studies, for
which much longer term safety tests
will be needed. Hopefully glaucoma
treatment is on the cusp of something
exciting. RS
References
1. RN Weinreb et al., “The pathophysiology and
treatment of glaucoma: a review”, JAMA, 14,
2. 3. 4. 5. 6. 1901–1911 (2014). PMID: 24825645.
HO Ikeda et al., “Novel VCP modulators
mitigate major pathologies of rd10, a mouse
model of retinitis pigmentosa”, Sci Rep, 6, 5970
(2014). PMID: 25096051.
N Nakano et al., “Neuroprotective effects of VCP
modulators in mouse models of glaucoma”,
Heliyon, 2, e00096 (2016).
GD Watts et al., “Inclusion body myopathy
associated with Paget disease of bone and frontotemporal dementia is caused by mutant
valosin-containing protein”, Nat Genet, 26,
377–381 (2004). PMID: 15034582.
JO Johnson et al., “Exome sequencing reveals
VCP mutations as a cause of familial ALS”,
Neuron, 9, 857–864 (2010). PMID: 21145000.
A Manno et al., “Enhanced ATPase
activities as a primary defect of mutant
valosin-containing proteins that cause inclusion
body myopathy associated with Paget disease of
bone and frontotemporal dementia”, Genes Cells,
15, 911–922 (2010). PMID: 20604808.
16
Upfront
Recline,
for Corneal
Thickness
Decline
Might increasing periods of
bed rest affect CCT?
It has long been known that corneal
thickness influences intraocular pressure
(IOP) measurements, which may be
underestimated in patients with thinner
Patients with
open-angle
glaucoma
n=23
Healthy
controls
Change in CCT (µm)
from baseline
n=23
Change in CCT (µm)
from baseline
Pachymetry
central corneal thicknesses (CCTs), and
overestimated in those with thicker CCT
(1). This observation forms part of the
reason why most glaucoma specialists add
in a pachymetric assessment in addition
to tonometry when assessing patients.
Glaucoma is an age-related disease, with
prevalence and severity increasing as
patients age. There’s also another factor
that increases with advanced age: the
number of patients that are bedridden.
Might this affect CCT?
Maslin et al. (2) assessed whether lying
supine had an effect on CCT on patients
with open-angle glaucoma (n=23) and
healthy controls (n=23) (below). They
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
-11
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
-11
Baseline
found that CCT is influenced by body
position, that it decreases linearly over a
30 minute period, and at a similar rate in
both open angle glaucoma patients and in
healthy control subjects. MH
References
1. MO Gordon et al., “The ocular hypertension
treatment study: baseline factors that predict
the onset of primary open-angle glaucoma”,
Arch Ophthalmol, 120, 714–720 (2002).
PMID: 1204957.
2. JS Maslin et al., "Effect of supine body
position on central corneal thickness", Clin
Experiment Ophthalmol, Epub Ahead of Print
(2016). PMID: 26991869.
-6.7 µm
p=0.0043
-10.2 µm
p<0.001
-5.2 µm
-6.5 µm
p=0.0043
p<0.001
+10 mins
+30 mins
NANO-LASER
THE ONLY REAL LASER CATARACT SURGERY
Building a Better Banana
Boosting banana carotenoid levels could
reduce vision loss – particularly in Africa and
Southeast Asia
•
•
•
•
•
•
Each year, between 250,000 and 500,000 children go
permanently blind in Africa and Southeast Asia because
of vitamin A deficiency – and worse, half die within a
year of losing their sight.
“Golden Bananas” could offer a solution (1).
Bananas are a dietary staple in these regions, and
boosting their vitamin A content (or that of precursors,
like carotenoids, that are metabolized in the liver to
form vitamin A) would yield a big public health benefit.
In terms of carotenoid content, some bananas are better
than others. Pale bananas such as the “Cavendish”
variety produce less carotenoids than the orange
“Asupina” variety.
Cavendish bananas express more carotenoid cleavage
dioxygenase 4 (CCD4) protein than Asupina, and
the latter, “golden” banana, which stashes its carotenoids
in microscopic sacs during ripening, protecting them
from CC4.
This knowledge should provide opportunities to breed
or fortify bananas in order to make them richer sources
of carotenoids, and help tackle vitamin A deficiency –
food for thought.
Reference
1. S Buah, et al., “The quest for golden bananas: investigating carotenoid
regulation in a fe’i group Musa cultivar”, J Agric Food Chem, [Epub
ahead of print] (2016). PMID: 27041343.
DOC
@
t you erg!
e
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www.arclaser.com
[email protected]
Bessemerstr. 14
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18
Upfront
At 5 years:
CATT
Mean number of
Exams
2 years
Ranibizumab
Bevacizumab
Treatments
since CATT
25.3
-12.7
Baseline
-8.8
>212 µm
CATT Follow-up
5 years
Stroke/Myocardial infarction
7.6%
4.5%
CATT: Five
Years On
The five-year follow-up data
are in. Half of all patients
retain BCVA of 20/40 or better,
irrespective of drug used
At the time of its announcement, the
Comparison of AMD Treatments Trials
(CATT) trial caused quite a stir: it was
a rare case of a large clinical trial funded
not by industry, but by the US National
Institute of Health. Large-scale clinical
trials of anti-VEGF agents for retinal
disease also tend to focus on the first one
to two years – relatively few investigators
have characterized patients’ outcomes
after four or more years.
The CATT investigators have. Even
though the trial ended after two years of
SD-OCT (n=555)
Retinal thickness at the
foveal center:
15.4
Letters lost
p=0.008
50% had VA 20/40 or better
20% had VA 20/200 or worse
were treated at
least once with a drug
other than their
CATT-assigned drug
follow-up (1), all patients that were alive
at the end of the study were targeted for
inclusion in the CATT Follow-up study
(2). Three years after being released from
the CATT trial protocol, patients were
called back for examination. This is what
the investigators found:
No statistically significant differences
in VA or mor phologic outcomes
between drug or regimen groups were
observed after five years, other than one
observation that between two and five
years, the patients originally assigned to
ranibizumab during the two years of the
CATT study lost more letters than the
bevacizumab group (-4 letters, p=0.008).
Regarding safety outcomes, the
original ranibizumab patient group
had a higher incidence of stroke and
heart attack (7.6 percent vs. 4.5 percent;
p=0.04), but for both this difference, and
the difference in letters lost between
years two and five, the results need to
Year 2
Year 5
120–212 µm
<120 µm
83% of patients had fluid on OCT
61%
intraretinal
38%
subretinal
36%
sub-RPE
be interpreted with caution: patients
were able to switch drugs or use other
treatments after two years in the trial.
The good news was that half of all
patients retained a VA of 20/40 or better
(meaning that in the US, they’re not
disqualified from driving cars on the
basis of their vision) – and that one in 10
had 20/20 vision. The bad news is that
two in 10 patients had 20/200 vision or
worse. The hope is that ongoing research
will soon yield therapies that are able to
help them too. MH
References
1. DF Martin et al., “Ranibizumab and
bevacizumab for treatment of neovascular
age-related macular degeneration: two-year
results”, Ophthalmology, 119, 1388–1398 (2012).
2. MG Maguire et al., “Five-year outcomes with
anti-VEGF treatment of neovascular
age-related macular degeneration (AMD)”,
Ophthalmology (2016). [Article in press].
Business in Brief
CXL gets the green light in the USA, Valeant
announces new CEO, and Alcon teams up
with PowerVision
•
•
•
•
•
•
Avedro has finally received the long-awaited FDA
approval for its corneal collagen cross-linking platform.
The KXL System – and Photexra Viscous and Photrexa
photoenhancers for use with the system – are indicated
for the treatment of progressive keratoconus.
Valeant has announced Joseph Papa from OTC pharma
company Perrigo, as its new CEO. Papa is expected to
join the company in early May.
Alcon has entered a strategic alliance with PowerVision
to develop fluid-based accommodating IOLs for
cataract patients who also have presbyopia. The
alliance will fund further clinical development and
trials, and will provide Alcon with the option to
purchase PowerVision.
Nicox has submitted a new drug application to the
FDA for AC-170 – a cetirizine eye drop formulation
for the treatment of ocular itching associated with
allergic conjunctivitis.
The dust is still settling after the Allergan-Pfizer deal
fell through in early April. Whilst rumors are rife that
Allergan may be interested in Bausch+Lomb, there is
no clear answer yet, although industry insiders are
saying that Allergan is not denying that Bausch + Lomb
is not of interest if it is available for the right price.
ArcScan has received FDA 510(k) clearance for its
ArcScan Insight 100 device which is indicated for
refractive surgical planning and evaluation of anterior
segment pathology.
Feature
21
Individualized.
and Inspiring.
Aqueous angiography promises a revelation
in aqueous humor outflow understanding –
and could transform MIGS outcomes
By Alex Huang
Y
ou have all heard of MIGS, but have you heard of
MEGS? It’s a term that was coined, half-jokingly,
by the avant-garde of these new surgical approaches,
including my mentor, Robert Weinreb. Their point
was this: although MIGS approaches were considered to be
“minimally invasive,” they were in fact minimally effective! But
many a truth is told in jest: the efficacy of MIGS approaches can
be highly variable. You put a device in the trabecular meshwork
with the assumption that aqueous humor outflow (AHO) is
the same in all patients, and that when you place that little stent
in Schlemm’s canal, there’s going to be sufficient distal outflow
to lower the intraocular pressure (IOP). But this is simply not
always the case. These devices might be all the rage in glaucoma
at the moment (because of their ease and safety), but we all
know they don’t always work as well as they should – and my
colleagues and I believe that we can show you why.
www.theophthalmologist.com
22
Feature
Back to basics
When we teach medical students about AHO, we start with
a two-dimensional picture, with aqueous humor production
at the ciliary processes, followed by aqueous outflow through
the outflow pathways (see Figure 1a). But if you take this
two-dimensional image, rotate around 360º, and you look at
the eye externally from the front (Figure 1b), you will get the
impression that outflow is 360º uniform, circumferential away
from the limbus.
But there is evidence that instead, outflow may be segmental
in nature; basically, some areas have good outflow, whereas
others do not. It may be segmentally different, say between you
and me, or between your left eye and your right eye (Figure
2). There may also be disease relevance here, where the ocular
hypertensive component of glaucoma may be associated with
the loss of functional segmental outflow units.
As alluded to before, there may also be treatment relevance
with MIGS. We almost universally take a temporal clear
corneal approach and place the device nasal. So the inconsistent
results you read about in the literature – sometimes it works,
sometimes it doesn’t – may have to do with whether or not
we are accessing the correct outflow locations. If you want
to perform a surgical procedure to lower IOP, you want
to understand the patient’s unique outflow anatomy and
physiology and take the right MIGS approach in the optimal
location. So imagine if you could see exactly where aqueous
humor was flowing?
a.
b.
What would it take?
Let’s pause to ask a question: what things do we need for a
clinical imaging technique to be successful?
•
•
•
•
First of all, it’s got to be live – after all, we’re dealing with
live people. You can experimentally trace outflow pathways
with the introduction of labeled beads into the anterior
chamber of the eye and see segmental localization in the
trabecular meshwork, it’s just that you have to perform
histology afterwards to obtain that data. This is of less use in
a clinical setting.
Second of all, we need to get the information back in
real-time, just like the camera app display on your iPhone.
If it isn’t in real-time, it isn’t convenient, and has no hope of
being used peri- or intraoperatively.
Third, it has to be comprehensive in both a linear and a
circumferential sense. Linear, in that that the entirety of
the outflow pathways are included – absolutely nothing is
excluded; circumferential means we get potential
information 360º around the limbus simultaneously.
Lastly, it has to be physiologic: we have to do everything at
Figure 1. Aqueous humor is produced by the ciliary epithelium, drains
through the posterior chamber, through the pupil to the anterior chamber,
then out through the trabecular meshwork to Schlemm’s canal, flowing
through multiple collector channels into the episcleral veins; viewed as a
transverse section (a) and externally, en face (b).
physiological IOP. These patients have glaucoma, after all.
We can currently perform real-time AHO imaging in
enucleated eyes, using 2.5% fluorescein as a tracer molecule
and visualizing its distribution in real-time using SD-OCT
(Spectralis OCT2, Heidelberg Engineering). We call this
aqueous angiography, and it’s the fruit of a collaboration
between UCLA and UCSD.
Feature
a.
23
b.
Figure 2. a. Certain segments of the aqueous humor outflow (AHO) pathway may drain better than others – and the distribution of better- and worse-draining
segments may be different between patients, eyes, and across disease states. b. MIGS devices are almost always implanted nasally via a temporal clear corneal approach.
What does aqueous angiography look like?
Figure 3 shows aqueous angiography in model enucleated pig
eyes. The middle column shows composite images: the images
to the left are pre-injection scanning laser ophthalmoscopy
(SLO), and to the right, the pre-injection fluorescein
background. We have a Lewicky anterior chamber maintainer
coming in at six o’clock in both cases, and we deliver the 2.5%
fluorescein at physiologic pressures. Why 2.5%? Because that
concentration of fluorescein has been described as a capsular
dye (albeit a bad one).
At various positions within the angiographic function,
the arrowheads point out perilimbal segmental regions of
angiographic signal outflow; the arrows denote perilimbal
segmental regions without, and the asterisks are more distal.
Now, you might argue that this is just fluorescein staining of
the surface of the conjunctiva, but as we’re using the Spectralis,
we can perform concurrent anterior segment OCT to
prove otherwise.
In pig eyes (Figure 4), in angiographically positive (but not
negative regions), we see intrascleral lumens, reminiscent of
outflow pathways.
Still not convinced? I can do a different experiment,
using fixable fluorescent dextrans (FFDs). FFDs are an
extremely useful imaging technique: the dextran tracer can
be conjugated to surrounding biomolecules by aldehydemediated fixation, meaning it can be detected with
subsequent immunohistochemical and ultrastructural
imaging techniques. So what Figure 5 shows is that in
angiographically positive regions (the green lines), we see
Figure 3. Aqueous angiography shows segmental patterns.
Images from nine cardinal positions were taken on a representative pig
eye demonstrating segmental and differentially emphasized angiographic
patterns. Arrowheads denote regions of perilimbal proximal signal and
asterisks highlight regions of distal signal (episcleral). Arrows show areas of
relatively low perilimbal signal. The central image was a composite image of
cSLO infrared (left side) and pre-injection background (right side) images.
Note that the pre-injection background was even less intense than that
of the stained styrofoam (polygonal background pattern) that the eye was
attached to. Sup = superior; temp = temporal, nas = nasal; inf = inferior..
Scale bar = 1 cm. Adapted from (1).
www.theophthalmologist.com
Feature
24
a
b
c
d
e
f
g
h
i
j
Figure 4. Aqueous angiography (pig eyes) conducted in parallel with
anterior segment OCT. (a/g) Angiographically positive areas (arrowheads)
correlated with (b/h) intrascleral lumens on OCT (arrows). (c/i) In contrast,
angiographically lacking areas (arrowheads) were (d/j) devoid of intrascleral
lumens on OCT (arrows). (e) Angiographically positive areas could be
associated with a classical “side-ways Y” aqueous vein (asterisk). Adapted
from (1).
trapping of the dextran – and therefore labeling of the outflow
pathways – in panels b and e, but not in angiographically
negative regions as in the red lines as illustrated in panels c
and f.
Exploring the potential
The most wonderful thing about having a real-time imaging
method that works, is that we can start making observations,
and start asking questions. We took 36 eyes, evenly divided
10:30 mmHg, right eye, left eye, and performed aqueous
angiography – and saw all sorts of patterns.
To look at this quantitatively, we would make angiographic
rings of data by removing anything within the anterior
chamber and beyond the globe horizon.
With time, the angiographic intensity increases then starts
to plateau. Now this isn’t entirely unsurprising, because these
eyes are enucleated – their episcleral veins are cut and there’s
nowhere for the fluorescein to go. This meant that when we
performed statistical analyses, we chose early time points.
a
d
b
c
e
f
Figure 5. Aqueous angiography localizes to AHO pathways.
Aqueous angiography was conducted with 3 kD fixable fluorescent
dextrans in pig eyes. Two representative eyes (a-c and d-f ) are shown.
Angiographically positive (a/d; green lines) or diminished (a/d; red lines)
regions were identified with aqueous angiography and then sectioned. In
the first eye (a-c), angiographically positive (green line in a corresponds
to panel b) but not angiographically negative (red line in a corresponds to
panel c) regions showed trapping of dextrans within outflow pathways. In
the second eye (d-f ), angiographically positive (green line in d corresponds
to panel e) but not angiographically negative (red line in d corresponds
to panel f ) regions also showed trapping of dextrans within outflow
pathways. Note similar degree of non-specific fluorescence seen in strips
of Descemet Membrane in all cases (asterisks). AP = aqueous plexus,
TM = trabecular meshwork, AC = anterior chamber. Scale bar = 100 µm.
Adapted from (1).
In any event, having these rings enabled us to divide
them into quadrants, and also to divide them into inner
rings and outer rings. So for these 36 eyes, we were able to
stratify the quadrants by relative signal intensity, irrespective
of the locational identity, and you could see that in all the
conditions, the numbers are quite heterogeneous, implying
segmental flow.
We performed a Kruskal-Wallis test, because this is an
ANOVA variant for small sample sizes that looks for an overall
mean difference among the groups. And in every condition,
there was a statistically significant mean difference found,
thereby demonstrating segmental outflow (Figure 6).
You can also stratify the quadrants by location: superior
temporal, superior nasal, and now you see that the numbers
are more homogeneous and there was no case where overall
statistical significance (found by Kruskal-Wallis testing) was
achieved, implying that here, there was no single automatic
best or worst quadrant (Figure 7).
Feature
25
Figure 6. Ranking of outflow by quadrant (highest to lowest). The Kruskal-Wallis (which tests for an overall mean difference between groups) was
performed. A significant mean difference was found between the groups, thus demonstrating segmental outflow.
www.theophthalmologist.com
26
Feature
Figure 7. Illustration of AHO outflow by quadrant location (ST, superior temporal; SN, superior nasal; IT, inferior temporal; IN, inferior nasal). The
Kruskal-Wallis test was insignificant in every case: there was no best or worse quadrant.
Feature
a
b
c
d
e
f
Figure 8. Aqueous angiography in enucleated human eyes.
Aqueous angiography was performed on enucleated eyes from two female
subjects (not known to have glaucoma) at 10 mmHg (subject 1 = (a-c) and
subject 2 = (d-f )). Both right and left eyes from each subject were investigated
and shown at 10–25 seconds. (a/d) Composite cSLO infrared (left side) and
pre-injection background images (right side) are shown from the right eyes
of these two subjects. S = superior; T = temporal, N = nasal; I = inferior. AC =
anterior chamber, TM = trabecular meshwork, SC = Schlemm’s Canal.
Scale bars = 1 cm. Adapted from (1).
Aqueous angiography in humans
We can also perform aqueous angiography in enucleated
human eyes. Figure 8 shows a pair of eyes from 79 and 83 year
old females – both died of cardiac issues. So you can see that
with these two women the patterns are different; between the
women, and between the two eyes of each individual woman.
For instance, take a look at panels e and f on Figure 8 (the
83-year-old female). At first glance, it might appear that the
angiographic signal is all on the left, but remember this is her
right eye and left eye, so in one case it’s nasal and in the other
case it’s temporal.
So at this point with aqueous angiography, what we have is a
method that ticks all of the boxes of an ideal imaging modality
– apart from one; it isn’t yet live – but that’s about to change.
We’re working on that in live animal studies, and will do so in
live humans (we have an IRB). It’s going be fascinating.
Hopefully when recapitulated in live individuals or animals,
we’ll continue to see segmental patterns. But in any event, we will
almost certainly gain a better understanding of AHO – and study
the differences in anatomy between regions of greater outflow
and lesser outflow, and try to understand the reasons why.
What this means for the future of
glaucoma treatment
The clinical implications are clear: if aqueous angiography works
27
in clinical practice, it gives us a means to improve glaucoma
surgery outcomes through customizing our strategy to the
patients’ outflow anatomy. Experiments are already underway in
model eyes, in order to assess where trabecular bypass surgeries
are best conducted. As aqueous angiography is performed
on an increasing number of people, we’ll begin to see if there
are differences in outflow between people with and without
glaucoma, and how various treatments can help them.
Consider this. Today, this technique is at a preclinical stage.
But if you think about cataract surgery a few decades ago, all we
had was axial length and refractive correction – and we selected
intraocular lenses based only on that. Today, pre-cataract surgery
ocular biometry has become far more refined, and the hope
is that technology like aqueous angiography will mean that
glaucoma surgery will become very much like cataract surgery:
each individual patient will have their outflow pathways
mapped and the surgeon will select the right device and location
based on the patient’s own outflow anatomy to safely maximize
effectiveness and IOP reduction. Imagine that!
Alex Huang is an Assistant Professor, Ophthalmology at the
Doheny Eye Centers of Pasadena and the Department of
Ophthalmology, Stein and Doheny Eye Institutes, David Geffen
School of Medicine, UCLA, Los Angeles, California.
Reference
1. S Saraswathy et al.,“Aqueous angiography: real-time and physiologic
aqueous humor outflow imaging”, PLoS One, 11, e0147176 (2016).
PMID: 26807586.
Video
Video. This is an eye from 81-year-old male who died of leukemia.
The anterior chamber maintainer comes at 6 o’clock; nasal was 9 o’clock and
temporal was 3 o’clock. At first, the signal appears superior, then superior nasal, nasal,
inferior nasal, and inferior temporal – and no signal appeared superior temporally.
View the video online at: top.txp.to/issues/0516/301
www.theophthalmologist.com
When you see more
happy patients.
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In
Practice
Surgical Procedures
Diagnosis
New Drugs
30–33
The Usual Suspects
Suspicious corneas? Alain Saad
discusses the ‘hows’ of predicting
and defining which patients will
develop keratectasia.
30
In Practice
The Usual
Suspects
How can you predict which
patients will develop
keratectasia, and if they do,
how are you going to define it?
By Alain Saad
Corneal ectasia can be a disaster for
patients. Blurred vision, light sensitivity,
frequent changes in spectacle prescription,
halo, ghosting, headaches, eye irritation…
and later corneal scarring and hydrops
– are all potential consequences of the
progressive steepening and thinning of the
cornea, and all can conspire to dramatically
reduce the quality of life of these patients.
Keratectasia can come in a primitive
form, as we see in patients with keratoconus
or pellucid marginal degeneration, or an
iatrogenic form, like we see after refractive
surgery on patients with undiagnosed,
Figure 1. Thanks to the work of Rabinowitz et al., (1) we now have qualitative and quantitative
indices to detect early keratoconus based on Placido topography.
At a Glance
•
•
•
•
Predicting which patients are at a
high risk of developing post-LASIK
keratectasia can be a challenge,
particularly in cases of suspect and
forme fruste keratoconus
A range of parameters can be used
to try to distinguish between normal
and at-risk patients, but none are
perfect; the challenge is finding the
right combination
Clear terminology, effective
statistical analysis and a useful
clinical model all help when
developing an artificial intelligence
tool to assess a patient’s risk
A comprehensive statistical analysis
combining a number of parameters
can differentiate normal and
abnormal corneas with a high rate
of success
Figure 2. Some Placido and tomographical indices were significantly different between the two groups.
We observed differences in posterior elevation, thinnest point, decentration of the thinnest point,
difference between central and thinnest pachymetry, 3 mm zone irregularity, and between inferior and
superior keratometry (I-S). When using just one of these parameters alone – for example a 3 mm zone
irregularity or the thinnest pachymetry – it’s not possible to separate between the groups; there is a lot
of overlap as seen on the scattergrams.
subclinical keratoconus. Clearly, anything
that’s iatrogenic is something we need
to minimize the occurrence of. So how
can we detect the earliest manifestations
of keratectasia so that we can avoid
performing laser refractive surgery on
these patients? And what terminology
do we use to label these corneas?
Understanding exactly how to assess and
diagnose these cases is key to making the
right treatment decisions. Often, this isn’t
a simple process.
In Practice
Figure 3. Normal cornea, with a SCORE of -2.2. The most important parameters are displayed on a
radar map with a color scale: Green areas are normal, yellow is suspicious, and red is abnormal.
Figure 4. Forme fruste keratoconus, with a SCORE of +1.7. The SCORE is negative when the cornea
is classified as normal and positive (>0) when the cornea is classified as presenting characteristics of
keratoconus. A SCORE between zero and 2 point on a subclinical keratoconus.
To give us the best chance of detecting
corneas that are susceptible to keratectasia,
we need to do three things: clarify
our terminology, develop appropriate
statistical methods, and use an applicable
clinical model.
What’s in a name?
First, there’s terminology. For example,
is your subclinical keratoconus better
described as forme fruste, or suspect?
The term “keratoconus suspect ”
describes corneas that show anterior
31
topographically detectable features that
are evocative of subclinical disease. These
features were first described qualitatively
by Rabinowitz and colleagues (1), but
their description was limited by the
smooth transition of topographical
aspects (such as inferior steepening)
from normal to suspect and subsequent
keratoconus. The use of quantitative
videokeratography-derived indices (2)
such as the SRAX (skewed radial axis)
or the I-S (difference between inferior
and superior keratometry measured at
5 mm) represents a more reproducible way
of quantifying keratoconus and its early
phenotypes, and reduces the complexity of
proper classification (Figure 1).
In medicine, “forme fruste” means an
incomplete, abortive, or unusual form of
a disease or syndrome. Stephen Klyce (3),
described forme fruste keratoconus as the
fellow eye of a keratoconic cornea that
has no clinical findings of any sort except
subtle characteristics suggestive of an early
subclinical keratoconus. Essentially, this is
a very low phenotypic expression of the
keratoconus that is below the threshold of
Placido detection.
Smart statistical methods…
With the current, gold-standard,
diagnostic tools, the classification of a
cornea as “normal” doesn’t exclude the
possibility of subclinical keratoconus.
The sensitivity of computer-assisted
Placido-based videokeratotopography
is not sufficient, and an I-S value above
1.4 D or a steep keratometry (>47 D)
may not necessarily be an indicator of
a keratoconic subtype – in other words,
the specificity of Placido topography is
not 100 percent. Ideally, we want a test
that can perfectly separate normal and
abnormal corneas – but such a perfect test
doesn’t exist right now.
To improve the accuracy and precision
of this kind of screening, what we need
to do is combine several of the corneal
parameters obtained from Placido and
32
In Practice
analysis (that combines these parameters
together) can be a big advantage.
Figure 5. SCORE analyzer results from a patient with clear keratoconus (as described by a SCORE of 20.2).
elevation topography together into
a discriminant function (4). Linear
discriminant analysis is a technique that
attempts to model the differences between
different classes of data, by looking for
linear combinations of variables that best
explain the data. For example, combining
I-S indices with the thinnest pachymetry
measurements and posterior elevation data
detects subclinical keratoconus with far
greater accuracy than I-S alone.
… and clever use of clinical models
To fully evaluate and characterize such
an approach, we need a pertinent clinical
model. We know that keratoconus
has a genetic component, and in cases
of unilateral keratoconus, we know
that both eyes have the same genetic
makeup – and that even if one eye looks
normal (based on Placido topography),
it probably represents a false negative.
Damien Gatinel and I studied the
contralateral corneas from cases of
unilateral keratoconus (4), on the
basis that these eyes were giving false
negative results using current diagnostic
methods. First, we performed an
Orbscan (Bausch+Lomb) examination
for cases of “unilateral” keratoconus.
Orbscan provides us with Placido
topography and anterior elevation,
posterior elevation and pachymetric
maps information. We also selected a
group of bilateral normal eyes that had
LASIK and three years of follow-up,
without developing ectasia and those
corneas also benefits from an Orbscan
examination. Then, we compared all the
parameters that we had measured with the
Orbscan between the normal eyes and the
eyes that only appeared to be normal – i.e.
those with forme fruste keratoconus.
The results were interesting – some
corneal indices were significantly different
between the two groups. We observed
differences in posterior elevation, thinnest
point, decentration of the thinnest point,
difference between central and thinnest
pachymetry, 3 mm zone irregularity, and
between inferior and superior keratometry
(I-S) (Figure 2).
But again, when using just one of these
parameters alone – for example a 3 mm
zone irregularity – it’s not possible to
separate between the groups; you get a lot of
overlap (Figure 2). So this is where a good
statistical method like linear discriminant
Combination is key
So it’s clear that combining our parameters
was the most successful way to spot
suspicious corneas, and it’s possible to
automate the process. We developed the
SCORE (Screening for Corneal Objective
Risk of Ectasia) Analyzer, that combines
different significant parameters for the
detection of early keratoconus into a single
number and this artificial intelligence
system can now be used on the Orbscan
II system.
Figure 3 shows a normal cornea, with
a SCORE of -2.2 – the most important
parameters are displayed on a color scale
map (Radar), which includes the thinnest
point, the difference between central
pachymetry and thinnest pachymetry, the
posterior elevation, the 3 mm irregularity,
I-S and the decentration of the thinnest
point. Based on the color map, you can
see that green areas are normal, yellow is
suspicious, and red is abnormal.
A forme fruste keratoconus is shown
in Figure 4, so here the SCORE is
slightly positive at + 1.7. In the radar
map, there is green but also some yellow,
and the pachymetry thinning rate (as first
described by Renato Ambrósio et al (5)) is
at the limit of the normal range.
You don’t really need to use the SCORE
analyzer to detect advanced keratoconus
(Figure 5), but it can be used to objectively
evaluate keratoconus progression, as is
shown clearly in Figure 6: in 2007 (a)
the patient’s score was 11.5, in 2009 (b) it
was 12.1, and in 2011 (c) it had increased
to 16.3.
The same approach can be generalized
to other devices – we are currently
investigating an artificial intelligence
system that uses optical path difference
(OPD) scans that combine higher
order aberration detection with Placido
indices in order to obtain an overall
corneal score.
In Practice
33
Trying to distinguish normal from
early pathological cases is a common
challenge in medicine (6), and diseases
that are multifactorial are the most
challenging of all in terms of designing
appropriately sensitive and specific
tests. Techniques such as linear
discriminant analysis (determining
a linear combination of features that
characterize or separates two or more
disease states) may help to increase the
efficiency of screening tests for early
subclinical keratoconus identification –
helping avoid iatrogenic keratoconus,
and the disastrous consequences it can
have in patients.
Alain Saad is an ophthalmologist in
the Cornea, Cataract and Refractive
Surgery Department (Damien Gatinel
Department) at the Rothschild
Foundation in Paris, France.
Figure 6. Results from a patient with progressive keratoconus – note the increasing SCORE values
over the period between 2007 to 2011.
References
1. YS Rabinowitz, PJ McDonnell, “Computer
assisted corneal topography in keratoconus”,
Refract Corneal Surg, 5, 400–408 (1989).
PMID: 2488838.
2. YS Rabinowitz, K Rasheed, “KISA% index:
a quantitative videokeratography algorithm
embodying minimal topographic criteria for
diagnosing keratoconus”, J Cataract Refract
Surg, 25, 1327–1335 (1999). PMID: 10511930.
3. SD Klyce, “Chasing the suspect: keratoconus”,
Br J Ophthalmol, 93, 845–847 (2009).
PMID: 19553507.
4. A Saad, D Gatinel , “Topographic and
tomographic properties of forme fruste
keratoconus corneas”, Invest Ophthalmol Vis Sci,
51, 5546–5555 (2010). PMID: 20554609.
5. R Ambrósio et al., “Corneal-thickness spatial
profile and corneal-volume distribution:
tomographic indices to detect keratoconus”,
J Cataract Refract Surg, 32, 1851–1859 (2006).
PMID: 17081868.
6. D Gatinel, A Saad, “The challenges of the
detection of subclinical keratoconus at it earliest
stage”, Int J Keratoco Ectatic Corneal Dis, 1,
36–43 2012).
200104-001 INT.AE16 © Heidelberg Engineering GmbH
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36–38
ROP in the Digital Era
Michael F. Chiang talks about the
everyday challenges faced when
caring for babies with ROP –
and how telemedicine might
change things.
36
NextGen
ROP in the
Digital Era
Indirect ophthalmoscopy is the
gold standard for ROP diagnosis,
but it comes with multiple
challenges: logistical difficulties,
legal liability, reproducibility
problems, and a skills gap. Is
telemedicine the answer?
By Michael F. Chiang
When I started practicing in 2001, the
standard of care for the diagnosis of
retinopathy of prematurity (ROP) was
to perform indirect ophthalmoscopy on
premature babies in the neonatal intensive
care unit (NICU), and to use those handdrawn sketches which are familiar to
virtually every ophthalmologist (Figure
1, Figure 2). But there are a number
of challenges with this care paradigm.
Once logistical perspectives have been
taken into consideration (traveling time,
time taken for coordination between
ophthalmologists and neonatologists, and
At a Glance
•
•
•
•
Worldwide, ROP continues to be a
leading cause of childhood blindness,
and the traditional standard of care
is indirect ophthalmoscopy performed
at the bedside
There are multiple challenges
with the current care paradigm for
ROP, including time-intensity of the
exam, logistical challenges, and high
medicolegal liability
As such, the numbers of skilled
ophthalmologists willing to perform
ROP examinations are declining,
and access to ROP care can be limited
Telemedicine may improve standards
of ROP care, but there are still
barriers to overcome
Clock hours
12
12
Zone III
Zone III
Zone II
9
Macula
Zone I
Zone II
Zone I
39
3
Optic nerve
Right eye
6
Ora serrata
6
Left eye
Figure 1. Scheme of the retina of the right and left eyes showing zone borders and clock hours used to
describe the location and extent of ROP.
so on), the fact remains that performing
ophthalmoscopy on wriggling babies in
the NICU is difficult, and hand drawing is
inherently an imprecise art that contains a
large element of subjectivity.
The advances in neonatal care for
premature babies over the last six
decades have been incredible – babies
survive today that are smaller and
sicker than were ever thought viable in
the past, but these advances have also
increased the number of babies at risk
of developing ROP. Unfortunately, the
number of ophthalmologists who are
both trained and willing to assess babies
for ROP is decreasing.
Why? The reasons include time
intensity and the difficulty of the exam,
the lack of available adequate training, the
complexities of scheduling ROP care, and
in the US at least, poor reimbursement.
But the elephant in the room is
medicolegal liability and the associated
high cost of medical indemnity insurance
– as far back as 2006, there were reports
that many US-based ophthalmologists
were considering stopping performing
ROP examinations for precisely this
reason (1). An unsurprising consequence
is the reduced availability of ROP care,
particularly in rural and medically underserved areas. Could telemedicine provide
the much-needed solution?
A telemedicine solution?
In addition to the challenges mentioned
above, the accurate diagnosis of ROP can
be hindered by the significant variability
among different ophthalmologists. In
the US, half of all clinicians performing
ROP exams are general ophthalmologists
without retinal or pediatric specialty
training (2) – but even so, clinically
significant ROP is still being missed
in some cases by retinal specialists and
pediatric ophthalmologists (Figure 3) (3,
4), and it is clear that there are a number of
gaps in the training for and the delivery of
quality ROP care.
Using the telemedicine approach,
NICU staff are trained to image the
retina of at-risk infants using wide-angle
digital retinal photography. Those pictures
are then be sent for remote diagnosis by
experts, and babies who then need a full eye
exam – based on their retinal pictures – can
be referred to experts at a central location.
The potential benefits for ROP care with
this approach are many. Improved quality,
accessibility and cost-effectiveness of
NextGen
Credit: Michael F. Chiang
95
37
100
100
Sensitivity (%)
80
60
Credit: Michael F. Chiang
40
20
Figure 2. Wide-angle retinal photograph (top)
(RetCam; Clarity Medical Systems) of premature
infant with severe retinopathy of prematurity including
plus disease (dilation and tortuosity of posterior retinal
vessels) and traditional hand-drawn retinal sketch
(bottom) documenting the same retinal exam.
ROP care; the captured photographs
should allow ROP diagnosis to be more
objective relative to hand-drawn sketches,
and the approach should also improve the
monitoring of the disease.
In the real world
There are many published ROP
telemedicine studies, and based on
a technology review of 10 of these,
telemedicine demonstrates both a high
sensitivity and a high specificity for
diagnosing clinically significant – that is
treatment-requiring or referral-warranted
– ROP (5). More recently, a large-scale
36
27
Type-2 or worse
Treatment-requiring
Figure 3. Sensitivity of retinal specialists and pediatric ophthalmologists in identifying type-2 or worse
ROP and treatment-requiring ROP (3,4).
trial involving over 1,200 babies has shown
a high sensitivity for diagnosing clinically
significant ROP (NCT01264276). In
this study, premature infants from 13
North American centers were assessed
by both diagnostic examinations from
ophthalmologists, and remotely by nonphysician graders using digital imaging.
The sensitivity of remote grading in
identifying referral-warranted ROP
was 82–90 percent when one eye was
examined and 90 percent when both eyes
were examined (6).
So it seems that a photograph can
feasibly allow a correct diagnosis to be
drawn. But all of these studies were
based on the assumption that indirect
ophthalmoscopy is the gold standard
for ROP diagnosis. This leads us to
question “What is the correct diagnosis
for ROP? And how do we know that
ophthalmoscopy is inherently better than
looking at a photo of the eye?” This is a
difficult question to answer, but we started
by looking at intraphysician agreement by
pediatric ophthalmologists who regularly
performed ophthalmoscopic exams for
ROP diagnosis. Six months after the initial
ophthalmoscopic examination we asked
them to examine retinal photos which had
www.theophthalmologist.com
NextGen
Credit: NEI
38
Photograph of an ophthalmologist performing
an ROP examination at the bedside.
been taken at the time of the examination,
and we found an 86 percent intraphysician
agreement between the ophthalmoscopic
diagnosis and the telemedicine diagnosis.
Despite a high-level of agreement between
the two diagnoses, it still meant that in 14
percent of cases there were discrepancies
in diagnosis by the same person.
What went wrong? It seems that in 32
percent of the cases, the photos showed
something that appeared to have been
missed in the original ophthalmoscopic
exam (in which no disease had been
identified). In 29 percent of these
cases, there were discrepancies about
subtype of disease: zone I disease was
identified by telemedicine and zone II by
ophthalmoscopy, or vice versa. In principle,
telemedicine might allow for a more
accurate diagnosis: images can be closely
scrutinized more effectively as opposed
to doing this discrimination on a wiggling
baby at the bedside.
Telemedicine is already being used in
the real-world. Currently in the US, there
are large-scale real-world telemedicine
programs – some of which have been
operational for almost a decade (7, 8).
India has a well-established telemedicine
program – KIDROP – which has
been operational for over eight years.
Promisingly, the 2013 revision to the
American Academy of Ophthalmology
and American Academy of Pediatrics
(AAO-AAP) joint ROP screening
guidelines acknowledge the use of
telemedicine for ROP diagnosis (9),
and both societies have jointly provided
guidance on the use of telemedicine for
the diagnosis of ROP (10). The use of
telemedicine in a real-world setting might
also support the use of computer-based
image analysis tools, such as ROPtool
and FocusROP, to accurately measure
disease and monitor progression, and we
and others – such as David Wallace – have
done work in this area.
Barriers remain
The fact that there are telemedicine
programs operating now suggests that it is
feasible in the real-world, but a few barriers
remain. We need to develop effective
training programs for NICU nurses and
staff in order to teach them how to take the
pictures and how to interpret them.There is
the issue of workflow – we need to get these
systems to work in the real-world. Reading
software, assignment of individual roles and
responsibilities for ophthalmologists and
neonatologists, criteria for identification
of inadequate images, and transfer
rules all need to be defined. In addition,
policies for licensure, insurance cover and
reimbursement all need to be considered –
particularly in the US. Most importantly,
we need to challenge the perception that
indirect ophthalmoscopy is the gold
standard for ROP diagnosis. Telemedicine
will bring ROP care into the digital area
and improve the standard of ROP care,
but we need to develop large scale solutions
to overcome the remaining barriers for
telemedicine. In some ways, I believe that
overcoming these remaining barriers is
more of a political or economic issue rather
than a medical or technological one.
Michael F. Chiang is Knowles Professor
of Ophthalmology & Medical Informatics
and Clinical Epidemiology at Oregon
Health & Science University (OHSU), is a
Vice-Chair (Research) in the ophthalmology
department, and leads the Oregon State Elks
Center for Ophthalmic Informatics.
References
1. K. Altersitz, “Survey: Physicians being driven
away from ROP treatment”, Ocular Surgery
News U.S. Edition (2006). Accessed April
11, 2016.
2. AR Kemper et al., “Retinopathy of prematurity
care: patterns of care and workforce analysis”, J
AAPOS, 12, 344–348 (2008). PMID: 18440256.
3. RVP Chan et al., “Accuracy of retinopathy of
prematurity diagnosis by retinal fellows”,
Retina, 30, 958–965 (2010). PMID: 20168274.
4. JS Myung et al., “Accuracy of retinopathy of
prematurity image-based diagnosis by pediatric
ophthalmology fellows: implications for
training”, J AAPOS, 15, 573–578 (2011).
PMID: 22153403.
5. MF Chiang et al., “Detection of clinically
significant retinopathy of prematurity using
wide-angle digital retinal photography: a
report by the American Academy of
Ophthalmology”, Ophthalmol, 119, 1272–1280
(2012). PMID: 22541632.
6. GE Quinn et al., “Validity of a telemedicine
system for the evaluation of acute-phase retinopathy
of prematurity”, JAMA Ophthalmol, 132,
1178–1184 (2014). PMID: 24970095.
7. SK Wang et al., “SUNDROP: six years
of screening retinopathy of prematurity with
telemedicine”, Can J Ophthalmol, 50, 101–106
(2015). PMID: 25863848.
8. DT Weaver and TJ Murdock,“Telemedicine
detection of type 1 ROP in a distant neonatal
intensive care unit”, J AAPOS, 16, 229–233
(2012). PMID: 22681938.
9. WM Fierson et al., “Screening examination of
premature infants for retinopathy of
prematurity”, Pediatr, 131, 189–195(2013).
PMID: 23277315.
10. WM Fierson et al “Telemedicine for evaluation for
retinopathy of prematurity”, Pediatr, 135,
e238–254(2015). PMID: 25548330.
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42-44
Looking After Your Pupils
Andreas Lauer reviews the four stages
of mentoring and guides on how to get
the most out of mentorship.
45-49
Would You Let Sleeping Dogmas Lie?
We interview Tiarnan Keenan, lead
author on a new study that’s shown
the striking association between AMD
and sleep apnea.
42
Profession
Looking After
Your Pupils
How to get the most out
of mentorship
By Andreas Lauer
In medicine, mentoring is an essential
part of professional development. With
the advent of the Internet, it’s very
easy for students and young doctors to
find factual information and medical
knowledge online from various sources,
without necessarily needing to be taught
in the same way as they would before.
But there are still some things you can’t
learn that way: how to conduct yourself
professionally; the best way to interact
with patients; and how to succeed in
your field.
In a profession such as ours, there’s
undoubtedly a set of behavioral skills that
need to be transferred to a learner, and it
really takes another individual, or group of
individuals, to transfer that information.
In turn, this motivates learners to develop
to their full potential as physicians and
At a Glance
•
•
•
•
For students and young physicians,
mentorship is an essential component
of professional development
The relationship can take many
forms, including group and peer
learning, or mentorship from afar,
but the traditional one-on-one model
can often have the most impact
Institutions should offer different
options to meet different learning
styles and individual backgrounds
A negative mentoring experience
can be disheartening, but identifying
a good match and building trust can
be a formative experience that lasts
a lifetime
surgeons, and when they look back and
see what they’ve gained, they often want
to pass that knowledge on to future
generations. But not all mentorships are
fruitful – there are considerations to bear
in mind, and pitfalls to avoid…
The four key stages
Mentorship has four defined stages:
1.Initiation
The mentee identifies a suitable
mentor, or vice versa, and the
relationship begins.
2.Cultivation
The mentee is developing with the
help of their mentor, and knowledge
and skills are being transferred.
3.Separation
This phase occurs when it becomes
necessary to end the relationship,
either because it's not working, or
simply because it has run its course.
4.Redefinition
Separation isn’t always the end of
the story – the mentorship may carry
on under another format. However,
for the relationship to be successful,
there needs to be an end, a separation,
and then a redefinition. This is a
common stage for things to go wrong.
For example, instead of separating,
the mentee can become more
dependent: the mentee can’t do
without their mentor, and fails to fly
on their own. Mentor and mentee
can continue to work together, but it’s
important for the relationship to
change in nature and be redefined.
What format is best?
When thinking of mentorship, most
people probably think of the classic
model of one-on-one mentorship, i.e.
a dyad. But there are actually many
types, which may suit different types of
“In a profession
such as ours, there’s
undoubtedly a
set of behavioral
skills that need to
be transferred to
a learner, and it
really takes another
individual, or group
of individuals,
to transfer that
information.”
learners, or people at different stages of
their career.
Peer mentorship is becoming
increasingly popular: a group of
individuals, mostly at the same level in
their careers, get together to learn from
each other. For example, it might mean
students getting together to work on a
topic they have been assigned. Typically
this type of group will contain perhaps
five to 10 people, who may introduce
a guest speaker or another more
experienced person to cover the topic.
They can discuss information together
and share their own experiences.
This is a useful and non-threatening
environment for people with similar
experience levels and concerns to come
together and learn as a group.
Another model is long-distance
mentoring, or “mentorship from afar.” An
Profession
43
Figure 1. The individual and overlapping skills required by mentors and mentees in order to develop a successful mentoring relationship. Design adapted
from The Mentoring Group: http://mentoringgroup.com/
individual may be working in a particular,
specialized area of research, and decide
to reach out to an expert in that field.
The expert is excited to hear from
another individual interested in their
topic, and the two might communicate
electronically, or see each other at
congresses or meetings – they might even
begin a collaboration.
It doesn’t have to be about learning
from someone with similar research
interests. The mentorship can be simply
about education, or the mentee might
have identified someone in their field
they find inspiring. In some ways it’s no
different from people seeing attributes
they admire in celebrities or athletes,
and aspiring to achieve them too. It’s
amazing how long-distance mentors
can inspire young people in the field, and
the relationship can develop from there.
However, there is a saying: “Mentors
are fantastic until you meet them.”
Sometimes, when you meet someone you
greatly admire in person, you might find
him or her to be considerably different
from what you imagined or, in some
instances, somewhat disagreeable!
There’s also team mentorship – this is
distinct from peer mentorship as it brings
together people from different levels in
their career working towards a common
cause. For example, a meeting of a retinal
group at an institution – the whole team,
from junior to senior – are working
towards a common cause and share ideas
and concerns.
Finally, there is classic one-on-one
mentoring: this is probably the most
impactful type of relationship, but it
can be impactful in a positive way, or a
negative one. If it’s a bad match for either
party, it’s important to realize this, so the
mentoring relationship can come to an
end and both of you can move on. So,
what should you look for in a one-on-one
mentor or mentee?
What makes a good mentor?
As a mentee, you need to yourself: what
do you want out of the relationship?
There are a few attributes mentees are
looking for, such as the proper knowledge
and skill set, the right type of professional
behavior, and a mentor with a good track
record, who has trained people who have
gone on to succeed.
Whether it’s a junior surgeon talking to
a senior surgeon in between cases, or after
a clinic where a teacher takes a student
aside to discuss specific cases, or two
people working on a research project or
case report together, these are vital times
www.theophthalmologist.com
44
Profession
during a mentee’s education. It isn’t just
a transfer of knowledge – appropriate
behavior and professional (or surgical)
judgement is being handed down too.
It’s also important to remember that
it’s not just the mentee who benefits
from these relationships – many
mentors find the experience equally
rewarding, and have a sense of leaving
a legacy. They often find their mentees
invigorating – a mentee can be a real
challenge, but it's great to hear fresh
ideas and it keeps you on your toes! Many
academic institutions recognize mentors
in the form of awards, or other forms
of recognition, so it can benefit your
career too.
Barriers and boundaries
There are several reasons why a
mentorship program might not be
successful (1). One simple but perhaps
fairly common problem is that of
scheduling – the mentor is perhaps
incredibly busy, or simply not around
when the mentee has time to see them,
or vice versa. Then there are people who
have difficulty establishing relationships,
and who might find it difficult to open
up in a one-on-one setting, and may be
better suited to joining a group.
It’s also very important to set
boundaries – when a mentor and mentee
meet, it is good to do so in the workplace.
The moment the meetings star t
happening outside of work, you need to
think about what this might mean, and
whether it’s appropriate, say, to have that
person over to your house, or if you’re
moving beyond the scope of the mentor/
mentee dynamic. Keeping the location
neutral is often the most sensible choice.
It’s also important to establish the
goals of the relationship, or you risk
finishing your mentorship without the
desired outcome. For example, if I am
working with a new resident who needs
to learn how to do a retinal exam, I will
state clearly: “During your time with
me, I want you to become increasingly
accurate and efficient at performing a
retinal exam. You’re going to be working
on this for the next 10 weeks, and this is
how I would suggest you go about doing
it.” Setting goals and then assessing
them at the end of the training period
is a great way to reflect on what you are
actually achieving.
When looking at individual mentors
and mentees, there’s also the issue
of differences – be they cultural,
generational or gender-based. In my
experience, there’s a lot of discussion in
academic medicine around how best
to match people of common interests,
backgrounds or experiences in order
to fulfill the institution’s mentorship
mission, and that’s a good thing. For
example, we have a Native American
group at our institution, and this allows
junior individuals to meet and learn from
highly successful people in their field with
a common cultural background. Another
example is our women in medicine group.
Having a portfolio of different mentors
is very important when catering to a
diverse group individuals – one option is
never enough!
Building trust
The final, and possibly one of the most
crucial, parts of successful mentoring is
building trust. In academic medicine,
there are times when you are giving
information and skills to people who
might soon compete with you. This can
be a major disincentive for people to
transfer everything they know, and it’s
something that isn’t often spoken about.
But it all comes down to the relationship
that people form – and building trust is
huge. Mentors may think: “Well, if I give
my time and my knowledge, I expect
some recognition or gratitude for it”,
because it’s generally uncompensated
activity and effort. So when mentees don’t
recognize their mentors, or don’t thank
them, it puts people off. Likewise, when a
mentor takes advantage of their mentees
by not giving them credit for having done
a certain amount of work, it has the same
negative effect.
But when the relationship is built on
mutual trust and respect, the mentee will
know that what they are gaining from
the mentor is absolutely essential for
their formation as a professional. In turn,
the mentor will know that transferring
this information is propagating the
profession, and that the success of their
mentee will also be a demonstration of
their own success as an educator.
It’s worth it
The mentoring skills model (Figure
1) outlines the skills that a mentee
needs, the skills a mentor needs, and
the common set of shared skills that
they both need to build a successful
mentorship relationship. Mentorship
programs are common in the US, and can
be found all over the world – but there
can be hugely different interpersonal
dynamics, depending on the culture
at the institution involved, the needs
of the individuals, and the support the
institution is able to provide. Mentoring
always has been, and always will be, an
essential part of passing down medical
knowledge from one generation to the
next, and when it’s done right, it can be
a hugely positive experience for everyone
involved, junior or senior.
Andreas Lauer is Vice-Chair for
Education, Kenneth C. Swan Professor
of Ophthalmology, and Chief of the
Vitreoretinal Division at Casey Eye
Institute, Oregon Health Sciences
University, Portland, USA.
Reference
1. AR Gagliardi et al., "Exploring mentorship as
a strategy to build capacity for knowledge
translation research and practice: a scoping
systematic review", Implement Sci. 25, 122
(2014). PMID: 25252966.
Profession
45
Would You
Let Sleeping
Dogmas Lie?
A new association is identified
between sleep apnea and AMD,
which could put the OSA and
POAG theory to bed
By Ruth Steer
Rising obesity levels in the general
population have meant that obstructive
sleep apnea (OSA) – a condition where
the upper airway repeatedly collapses
during sleep – is now a common disorder
of the adult population. People with
OSA suffer disrupted sleep, as repeated
interruptions to their breathing results
in neurological arousal and reduced
blood oxygen saturation. Unsurprisingly,
recurrent episodes of hypoxia over time
can have an impact on health, including
increased risk of cardiovascular disease,
metabolic impairment and stroke (1).
At a Glance
• Is there a link between obstructive
sleep apnea (OSA) and primary
open-angle glaucoma (POAG)?
Smaller, prospective studies tend to
suggest yes, but larger retrospective
cohort studies disagree
• A recent record linkage study –
involving over 67,000 patients
with OSA – has revealed no
association
• However, OSA and AMD were
found to be positively associated, and
this association was identified to be
independent of obesity
• This represents a new area of interest
for vision researchers, and may have
important implications for clinical
practice in the future
Over recent years, many have
considered that there may be a link
between OSA and primary open-angle
glaucoma (POAG), rationalized by the
following hypotheses:
•
•
•
Recurrent episodes of hypoxia are
associated with reduced optic nerve
head perfusion
OSA-induced hypoxia leads to
an increased risk or progression in
glaucomatous optic neuropathy, plus
Mechanical factors affecting
intraocular pressure (IOP) may also
be involved.
If a link was established, this would
provide important insights into POAG
pathophysiology, particularly the
contribution of vascular dysfunction,
and a strong rationale for screening
individuals with one condition for the
other. The problem is that it isn’t clear
whether OSA and POAG are linked, as
previous studies have reported conflicting
results: smaller prospective studies tend
to report an association, whereas larger
retrospective cohort studies tend to
find no such association (2). When you
look closer, many of these studies had
significant methodological limitations in
www.theophthalmologist.com
46
Profession
terms of sample size and study design.
Isn’t it time that someone provided
some strong data? That is exactly what
Michael Goldacre and his collaborators
(Tiarnan Keenan and Raph Goldacre)
have delivered in their recently published
paper – although the results may not be
entirely as anticipated by some (3).
In a cohort of over 67,000 patients
with OSA – collated from linked
English hospital episode statistics
(1999–2011) – they observed that there
was no significant increase in the risk of
POAG when compared with a reference
cohort (containing over 2,600,000
people; Figure 1).
For completeness, there was also no
significant risk of OSA in a cohort of
over 87,000 patients with POAG. Not
only did they observe that OSA and
POAG were not positively associated
in these cohorts, the closeness of the
rate ratios to one suggested little, if any,
association, even when subgroups such
as sex and age groups were analyzed.
Interestingly, they also observed that
OSA was significantly associated with
POAG in the first year of admission but
not in subsequent years, suggesting that
additional cases of sleep apnea may have
1.01
OSA
POAG
1.00
POAG
OSA
1.44
OSA
AMD
1.24
AMD
OSA
1.24
Obesity
AMD
1.05
AMD
0.2
0.4
0.6
0.8
1
Subsequent hospital episodes
Patient cohort
been diagnosed in the short-term at the
point of POAG diagnosis (presumably
from referral by ophthalmologists).
Some would argue that Goldacre
and his collaborators have presented
strong evidence that it may be time for
ophthalmologists to consider putting
the hypothesis of a link between POAG
and OSA to bed.
Moving on from POAG, Goldacre
and his collaborators also identified a
novel association between OSA and
age-related macular degeneration
(AMD; Figure 1), and this significantly
increased risk was also observed when
Obesity
1.2
1.4
1.6
1.8
Rate ratio (95% CI)
Figure 1. Associations between OSA, POAG, AMD and obesity. Standardized rate ratios and 95% CIs were obtained from comparing the rates of subsequent
hospital episodes of POAG, OSA, AMD and obesity observed in patient cohorts with those observed in the reference cohort. CI, confidence interval.
Profession
the OSA cohort was analyzed by sex
and age. They also analyzed an obesity
cohort – aware of the knowledge that
obesity has been identified as a risk
factor for both OSA and AMD – and
revealed that the relationship between
obesity and AMD was not as strong as
the observed association between OSA
and AMD, indicating that OSA had a
significantly independent effect.
But what does this all mean?
We spoke with Tiarnan Keenan –
the corresponding author for the
study – for his thoughts on the
findings and where the field may
be headed.
“Around one in five
adults has OSA,
but over 85 percent
of individuals with
clinically significant
OSA have never
been diagnosed.”
What were the driving factors for
this research?
My original motivation was based
more around examining the potential
link between OSA and glaucoma. The
idea of an association between these
two conditions has been generating a
lot of interest in recent years – and has
important implications – but existing
studies in this area have been relatively
small and inconsistent. By using a ‘big
data’ approach through a collaboration
with Michael Goldacre, Professor of
Public Health at the University of
Oxford, we were able to perform the
most highly powered single study to
date to address this question.
But I also have a particular interest in
AMD. So while we were planning the
study, I wanted to see if sleep apnea might
be associated with an increased risk of
AMD. At that time, only one small study
(4) had reported a related finding, that
patients with retinal diseases responding
poorly to anti-VEGF therapy had
higher risk of sleep apnea. We were
extremely well placed to perform this
analysis; we had previously undertaken
some of the largest studies in similar
areas, for example, demonstrating the
absence of any association between
Alzheimer’s disease and AMD (5), and
a small association between arthritis
and AMD (6).
Did the result that OSA was not
associated with POAG surprise you?
I was not particularly surprised by this.
I think that the rhetoric in this area
had rather outstripped the evidence.
While there were plausible biological
reasons to consider a link between sleep
apnea and glaucoma, the published
data so far had been inconsistent. In
particular, previous studies had generally
been relatively small in size and had
methodological limitations.
In fact, I was slightly surprised that
the rate ratios in our analysis were so
precisely and consistently close to 1
(i.e. no increased risk in either temporal
direction). This was despite substantial
interest in this area in recent years,
which could have led to an artefactual
finding of a positive association
(through ophthalmologists referring
many additional glaucoma patients for
sleep studies).
Indeed, our analysis of the association
by time inter val provided some
interesting insights in this respect,
showing that additional diagnoses of
sleep apnea were generated in the short-
47
term following glaucoma diagnoses, but
that these diagnoses were just brought
forward in time rather than representing
a genuinely positive association.
Were you surprised that OSA had a
significantly independent effect on
AMD when compared with obesity?
I was really interested (but not overly
surprised) by this finding. Evidence has
been accumulating that OSA is linked
to a whole host of other conditions,
including cardiovascular disease,
metabolic impairment and stroke. In
addition, we have some evidence that
sleep apnea leads to increased systemic
oxidative stress, inflammation and
VEGF up-regulation, all of which
are strongly implicated in AMD
pathogenesis. It therefore seemed highly
plausible to consider a link between
OSA and AMD.
Previous well-known epidemiological
studies did examine potential
associations between AMD and various
systemic conditions. However OSA was
generally overlooked in these studies.
With the advent of ‘big data’ approaches
such as ours, and increased interest in
the field of OSA, I believe that the time
was ripe for this discovery.
What impact do you expect your
findings to have?
O ur findings have important
implications. For a start, it’s important
to emphasize how common OSA is.
Around one in five adults has OSA,
but over 85 percent of individuals with
clinically significant OSA have never
been diagnosed. This includes the
elderly population, where undiagnosed
OSA is very common but tends to
be overlooked.
In clinical practice, we have often had
a tendency to treat neovascular AMD
in relative isolation from the patient
and any other medical conditions. At its
most extreme, this has meant treating
www.theophthalmologist.com
48
Profession
Image Credit: Tim Steffens, CRA, OCT-C, FOPS
“Apart from anything
else, picking up and
treating sleep apnea
may mean fewer
injections and more
money saved for
macular services.”
have taken a special interest in sleep
apnea. So the precedent exists. It would
seem a good time to enter into talks with
sleep physicians to discuss these ideas
and refine referral pathways.
An ultra-widefield image of a retina with wet AMD.
the optical coherence tomography (OCT)
rather than the individual. With the
knowledge that sleep apnea increases the
risk of neovascular AMD and interferes
with its treatment, we may now need to
probe deeper into our patients’ medical
history to reduce their risk of visual loss. If
more conditions follow, we may be facing
a paradigm shift where our patients’ sleep
and general health are just as important as
their OCT and fundal findings.
As retinal specialists, we certainly
have strong precedents for this in other
conditions that we treat, particularly
diabetic retinopathy and retinal
vascular occlusion.
Do you feel that a questionnaire on
sleep symptoms is going to be enough?
The use of a validated sleep questionnaire
(e.g. the Berlin Questionnaire, with just
10 questions) is definitely a good starting
place – this is ideal as a screening tool.
I believe that we should definitely now
be using these on neovascular AMD
patients labeled as ‘poor responders’ to
anti-VEGF therapy – ideally we should
actually be using them on all neovascular
AMD patients at the point of diagnosis.
Treating sleep apnea at this point would
provide a great opportunity to improve
the visual outcomes with anti-VEGF
therapy, as well as improving patients’
sleep and general health. But our results
in this paper suggest we could be using
questionnaires even earlier. If treating
sleep apnea turns out to reduce the
excess risk of neovascular AMD, we
should be giving sleep questionnaires
to all AMD patients, not just those who
have progressed to neovascular disease.
Clear l y, while validated sleep
questionnaires are ideal as screening
tools, the gold standard for diagnosis is
polysomnography. So patients could be
referred for sleep studies on the basis
of the questionnaire results, in order to
improve detection rates and use services
most efficiently. In fact, this has already
been happening to some extent – with
local variation – in the glaucoma field,
particularly by glaucoma specialists who
What will be the key benefits
for patients?
Those with neovascular AMD will
benefit in two ways. First, those with
undiagnosed sleep apnea should have
better visual outcomes and reduced antiVEGF treatment burden with prompt
therapy for sleep apnea. In addition, they
should have improved sleep and general
health if their sleep condition is picked
up following AMD diagnosis.
How will your findings benefit
ophthalmologists?
Ophthalmologists should benefit in turn.
With anti-VEGF therapy as the current
mainstay for neovascular AMD treatment,
the label of ‘poor responder’ can mean a
frustrating barrier in the ophthalmologist’s
ability to offer sight-saving care. The
recognition of any condition with
implications for neovascular AMD risk
or treatment is of great benefit to the
ophthalmologist. Apart from anything
else, picking up and treating sleep apnea
may mean fewer injections and more
money saved for macular services (which
are stretched in the UK).
reduces the excess risk of neovascular
AMD that we have discovered.
Do you think your findings will benefit
other clinicians?
Sleep physicians and scientists are also
likely to be interested in our findings.
We have discovered another important
condition where OSA increases risk,
which underlines the importance of
their work and research. The advice
given to individuals diagnosed with
sleep apnea should therefore expand,
adding to the motivation for improving
their sleep and using continuous positive
airway pressure where applicable. I
would suggest they are also asked to
consult an optometrist at the point of
OSA diagnosis, and made aware of the
link with AMD.
Where to next?
We are conducting further research into
other systemic conditions of hypoxia.
We are very interested to see whether
there is something unique about OSA, or
whether other hypoxic conditions such as
pulmonary diseases also carry increased
AMD risk. Any expansion to our list
of associated conditions has important
implications for clinical practice.
What will be key to determine in
future research?
First, I would be very interested to
see our novel findings replicated in
another country. Beyond that, an
important question is whether OSA
increases the risk of early AMD and/
or progression to geographic atrophy
(GA), as well as risk of neovascular
AMD. Another vital question is
whether there is any interaction with
the main genetic variants for AMD
– i.e. CFH-CFHR at chromosome 1
and ARMS2/HTRA1 at chromosome
10. For example, sleep apnea might
contribute to both GA and neovascular
AMD but only in those with CFH
risk variants (i.e. complement-driven
AMD). Alternatively, it might increase
risk of progression from early AMD to
neovascular disease in all individuals,
irrespective of genotype. Clearly we
will need to make these important
distinctions in the future, particularly in
the context of increasingly personalized
medicine. U ltimatel y, the most
important question we need to answer
is whether treatment of sleep apnea
Tiarnan Keenan is an ophthalmologist at
the University of Manchester and Royal
Bolton Hospital, UK. Tiarnan is also an
honorary fellow at the University
of Manchester.
References
1. C Gonzaga et al., “Obstructive sleep apnea,
hypertension and cardiovascular diseases”, J
Hum Hypertens, 29, 705–712 (2015).
PMID: 25761667.
2. AA Aref., “What happens to glaucoma patients
during sleep?”, Curr Opin Ophthalmol, 24,
162–166 (2013). PMID: 23262987.
3. TD Keenan et al., “Associations between
obstructive sleep apnoea, primary open angle
glaucoma and age-related macular degeneration:
record linkage study”, Br J Ophthalmol. [Epub
ahead of print]. PMID: 27044342.
4. BL Nesmith et al., “Poor responders to
bevacizumab pharmacotherapy in age-related
macular degeneration and in diabetic macular
edema demonstrate increased risk for obstructive
sleep apnea”, Retina, 34, 2423–2430 (2014).
PMID: 25062438.
5. TD Keenan et al., “Associations between age
related macular degeneration, Alzheimer disease,
and dementia: record linkage study of hospital
admissions”, JAMA Ophthalmol, 132, 63–68
(2014). PMID: 24232933.
6. TD Keenan et al., “Associations between age
related macular degeneration, osteoarthritis
and rheumatoid arthritis: record linkage
study”, Retina, 35, 2613–2618 (2015).
PMID: 25996429.
Celebrate
Life!
Sitting Down With... George L. Spaeth, Louis J. Esposito
Research Professor, and Director Emeritus, Glaucoma Service,
Wills Eye Hospital, Philadelphia, Pennsylvania, USA.
Sitting Down With
How did it feel to be voted number one on
this year’s Power List?
It’s surprising, and also very gratifying. It
suggests, to some extent at least, that what
I’m saying – what I’m trying to get across to
people – is of importance to my colleagues.
To have the respect of the people you work
with is important, and very lovely.
What is the most important thing you’d
like to communicate to your field?
In many ways, there is no principal thing
– in fact, that itself might be the principal
thing! But overall, it’s that every patient
is a unique individual, with a distinct
situation. I think ophthalmologists often
think they know what is best for their
patient, even if the patient doesn’t agree,
like when a patient refuses recommended
glaucoma surgery. This is a constant
dilemma we face in medicine: what we
think is right, versus what the patient
thinks is right, and we have a huge
obligation to understand what is good for
each patient, from their own perspective.
You have a very holistic approach
– is this lacking in ophthalmology?
I think we miss it in our lives, and in
medicine generally. We frequently hear
that the goal of glaucoma specialists is to
control pressure. We could expand on that
a little and say our goal is to preserve vision.
But these are not the primary goals, they
are methods that you use to pursue your
real goal, which is to ask – is this patient
able to celebrate and enjoy their life? And
what can we do to make that as achievable
for them as possible?
What informed your philosophy on
medicine, and how to practice it?
It’s very hard to answer that! I’m sure it’s
got to do with some very fundamental
things about me – my genes, my early
experiences, and my upbringing. I went to
a Quaker school, and I think this was very
instrumental. We were taught that there
is god in each person. I believe that, and
I think every person has a good aspect in
them that you can appeal to.
You have an impressive publishing record.
Why was this such a focus for you?
When I was a resident, Irving Leopold,
who was in many ways a mentor to me,
asked why I wasn’t publishing, and I
replied, “But I’m only a resident!” He
told me, “There’s no reason why you can’t
start right now, there are things that need
to be known.” He was right – publishing
papers isn’t about getting recognized and
promoted. You do it to contribute to your
field, by increasing medical knowledge
and answering important questions.
During my time at the National
Institutes of Health (NIH), I published
quite a few articles on metabolic disease,
among other things. And when I went
into practice, there were some areas that
seemed deficient to me, such as how to
examine the anterior chamber angle.
When I came across gaps, I aimed to study
and publish on them.
Why glaucoma?
I originally wanted to be a poet or a
composer, but I didn’t have enough
courage to pursue it. So I went to medical
school, and I chose ophthalmology partly
because it’s a field with a strong aesthetic
component – the eye is a beautiful thing.
I became involved in glaucoma because
I didn’t want to go to the Korean War. I
don’t think war is a good thing, and I didn’t
want to participate in one. I chose public
health service instead and was assigned to
glaucoma at the NIH – so it wasn’t a field
I chose.
Do you have any advice for teaching fellows?
Three things. First, you have to have
something to teach. Second, you need
to have people who want to contribute.
Finally – and most importantly – who you
are as a person will determine how much
you value learning and being skilled.
Your intent to be helpful, responsible,
51
and to do a good job has to come first, or
nothing else will follow.
Above all, I’d advise people that
mentorship is wonderful. The mentor
always grows as the trainee grows. It’s
one of the loveliest relationships I can
think of. There is a group of people who
trained with me called the International
Society of Spaeth fellows. Recently I’ve
been traveling a lot, and visiting many
of them. There are not many things in
this world nicer than visiting a former
mentee, and seeing the wonderful things
they’ve achieved.
“I originally wanted
to be a poet or a
composer, but I didn’t
have enough courage
to pursue it.”
What motivates you in work and in life?
I believe in living with enthusiasm and
optimism. Having fun is so important,
and you need to try and live in the
moment and enjoy things. I try to live
my life to the fullest extent possible, but
I’m still learning, and I’m sure I could
do better!
As for how I ended up where I am,
doing what I do, it’s hard to say. I think
the simple answer would be fate. I don’t
think I can take any real credit for it. I
was given a lot of gifts: some intelligence,
some curiosity, an excellent education. I
had no control over those things. All you
can do is try and do your best with the
gifts you’re given.
An extended version of this
interview is available online at:
top.txp.to/issues/0516/701/
www.theophthalmologist.com
NEW in Glaucoma
THE NEXT STEP FOR
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• Powerful IOP lowering
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Product Name: TAPTIQOM® 15 micrograms/ml + 5 mg/ml eye drops,
solution in single-dose container. Composition: One drop (about
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timolol. One single-dose container (0.3 ml) of eye drops contains 4.5
micrograms of tafluprost and 1.5 mg of timolol. Please refer to the
Summary of Product Characteristics (SmPC) for a full list of excipients.
Indication: Reduction of intraocular pressure in adult patients with open
angle glaucoma or ocular hypertension who are insufficiently responsive
to topical monotherapy with beta-blockers or prostaglandin analogues
and require a combination therapy, and who would benefit from
preservative free eye drops. Posology and method of administration:
Recommended dose is one drop in the conjunctival sac of the affected
eye(s) once daily. Not to exceed one drop per day in the affected eye.
Not recommended in children or adolescents (under the age of 18).
In renal or hepatic impairment use with caution. To reduce systemic
absorption, patients should be advised to use nasolacrimal occlusion or
close the eyelids for 2 minutes after instillation. Excess solution should
be wiped away to reduce the risk of darkening of eyelid skin. If more
than one ophthalmic product is used, five minutes should separate their
administration. Contact lenses should be removed before instillation.
Contraindications: Hypersensitivity to the active substances or to any
of the excipients. Reactive airway disease including bronchial asthma,
or a history of bronchial asthma, severe chronic obstructive pulmonary
disease. Sinus bradycardia, sick sinus syndrome, including sino-atrial
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of the possibility of eyelash growth, darkening of the eyelid skin and
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Caution should be exercised when prescribing TAPTIQOM® to patients
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and block systemic beta-agonist effects such as those of adrenaline.
Anaesthetists should be informed when a patient is receiving timolol.
Patients with a history of severe anaphylactic reaction may be more
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to the usual doses of adrenaline used to treat anaphylactic reactions.
The known effects of systemic beta blockers may be potentiated when
TAPTIQOM® is given concomitantly. The use of two topical betablockers is not recommended. Patients with corneal disease should
be treated with caution as ophthalmic beta-blockers may induce dry
eyes. When timolol is used to reduce elevated intraocular pressure in
angle-closure glaucoma, always use a miotic. Caution is recommended
when using tafluprost in aphakic patients, pseudophakic patients with
torn posterior lens capsule or anterior chamber lenses, and in patients
with known risk factors for cystoid macular oedema or iritis/uveitis.
Please see the SmPC for further information. Interactions with other
medicinal products: Potential for hypotension / marked bradycardia
when administered with oral calcium channel blockers, beta-adrenergic
blockers, anti-arrhythmics, digitalis glycosides, parasympathomimetics
and guanethedine. Please refer to the SmPC. Pregnancy: Do not use
in women of childbearing age/potential unless adequate contraceptive
measures are in place. Breast-feeding: It is not recommended to
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machines: If transient blurred vision occurs on instillation, the patient
should not drive or use machines until clear vision returns. Undesirable
Effects: Conjunctival/ocular hyperaemia occurred in approximately
7% of patients participating in clinical studies with TAPTIQOM®.
Other common side effects include: eye pruritus, eye pain, change of
eyelashes (increased length, thickness and number of lashes), eyelash
discolouration, eye irritation, foreign body sensation, blurred vision,
photophobia. Adverse reactions that have been seen with either of the
active substances (tafluprost or timolol) and may potentially occur also
with TAPTIQOM® include: increased iris pigmentation, anterior chamber
cells/flare, iritis/uveitis, deepening of eyelid sulcus, hypertrichosis of
eyelid, exacerbation of asthma, dyspnea, allergy, angioedema, urticaria,
anaphylaxis, hypoglycaemia, syncope, ptosis, bradycardia, chest pain,
palpitations, oedema, cardiac arrest, heart block, AV block, cardiac
failure. Please also see the SmPC. Overdose: Treatment should be
symptomatic and supportive. Special Precautions for Storage:
Store in a refrigerator (2°C - 8°C). After opening the foil pouch keep
the single-dose containers in the original pouch and do not store
above 25°C. Discard open single-dose containers with any remaining
solution immediately after use. Package quantities and basic NHS
cost: 30 x 0.3ml single-dose containers £14.50. Product Licence
Holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland (PL
16058/0012) Price: 30 x 0.3ml single-dose containers £14.50. Date
of Authorisation: 30/10/2014 POM Date of Prescribing Information:
31/05/2015
Adverse events should be reported. Reporting forms and
information can be found at www.mhra.gov.uk/yellowcard.
Adverse events should also be reported to Santen UK Limited
(Email [email protected] or telephone: 0845 075 4863).
TAPTIQOM is a registered trademark of Santen Pharmaceuticals Co., Ltd.
References:
1.Holló G et al. Fixed-Dose Combination of Tafluprost and Timolol in
the Treatment of Open-Angle Glaucoma and Ocular Hypertension:
Comparison with Other Fixed-Combination Products. Adv Ther. 2014;
31: 932-944
2.Taptiqom SPC, available at http://www.mhra.gov.uk/home/groups/
spcpil/documents/spcpil/con1418969000862.pdf, accessed 11.08.15
Job code: STN 0817 TAP 00018 (EU) Date of preparation: April 2016