Individualized and Inspiring - The Ophthalmologist
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MAY 2016 Upfront Quest for an anti-VEGF alternative 09 In Practice e usual keratectasia suspects 30 – 33 NextGen Telemedicine brings ROP into the digital era 36 – 38 Profession Getting the most out of the mentor-mentee relationship 42 – 44 # 30 www.theophthalmologist.com Individualized and Inspiring Unraveling the mysteries of aqueous outflow with aqueous angiography, could help surgeons customize glaucoma surgery and maximize its effectiveness 20 – 27
Transcript of Individualized and Inspiring - The Ophthalmologist
MAY 2016
Upfront Quest for an anti-VEGF alternative 09
In PracticeThe usual keratectasia suspects
30 – 33
NextGenTelemedicine brings ROP into the digital era
36 – 38
ProfessionGetting the most out of the mentor-mentee relationship
42 – 44
# 30
www.theophthalmologist.com
Individualized and InspiringUnraveling the mysteries of aqueous outflow with aqueous angiography, could help surgeons customize glaucoma surgery and maximize its effectiveness20 – 27
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The Ophthalmologist Smartfield Perimeter 210x266 e 04.16.indd 1 27.04.2016 13:47:31
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
Last Month’s Top TweetsIowa Eye Alumni @IowaEyeAlumniCongrats, Dr. Ed Stone, on making the @OphthoMag Top 100 #powerlist! http://buff.ly/1TuCw0Z3:21 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 #KeyOpinionLeaders12:55 PM - 21 Apr 2016
Fight for Sight @fightforsightUK#FightforSight Ambassador Prof Marshall recognised 4 his #EyeResearch @OphthoMag #PowerList http://bit.ly/210iZZA8:00 AM - 25 Apr 2016
Online this Month
FacebookCentre for Excellence In Eye Care22 April at 07:05
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!
Power List2016
www.theophthalmologist.com
Feature
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.
03 Online this Month
07 Editorial Help the Heroes, by Mark Hillen
08 Contributors
On The Cover
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
MAY 2016
Upfront Quest for an anti-VEGF alternative 09
In PracticeThe usual keratectasia suspects
30 – 33
NextGenTelemedicine brings ROP into the digital era
36 – 38
ProfessionGetting the most out of the mentor-mentee relationship
42 – 44
# 30
www.theophthalmologist.com
Individualized and InspiringUnraveling the mysteries of aqueous outflow with aqueous angiography, could help surgeons customize glaucoma surgery and maximize its effectiveness20 – 27
Contents
NASA satellite image of the Sundarbans relates nicely to the intricate network of aqueous outflow pathways discussed in this month‘s cover feature.
20
10
Profession
42 Looking After Your Pupils Andreas Lauer explains how to get the most out of mentor- mentee 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.
ISSUE 30 - MAY 2016
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Sitting Down With
50 George Spaeth, Louis J. Esposito Research Professor, and Director Emeritus, Glaucoma Service, Wills Eye Hospital, Philadelphia, Pennsylvania, USA.
45
www.theophthalmologist.com
’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 HillenEditor
Editor ia l
Help the HeroesThose 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?
References1. 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/
Contr ibutors
Alex HuangAlex 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 SaadAlong 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 ChiangMichael 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 KeenanTiarnan 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.
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UpfrontReporting 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]
Upfront10
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
References1. 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.
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 IL-1β 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).
He believes that future clinical studies in patients would be essential to assess the role of inhibitors of IL-1β 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
References1. 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
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).
Upfront 11
Upfront12
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.
Cur ious to know how p l a s t i c 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
Reference1. 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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Upfront14
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 NMDA-induced 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.”
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
References1. RN Weinreb et al., “The pathophysiology and treatment of glaucoma: a review”, JAMA, 14,
1901–1911 (2014). PMID: 24825645.2. HO Ikeda et al., “Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa”, Sci Rep, 6, 5970 (2014). PMID: 25096051.3. N Nakano et al., “Neuroprotective effects of VCP modulators in mouse models of glaucoma”, Heliyon, 2, e00096 (2016). 4. 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: 15034582.5. JO Johnson et al., “Exome sequencing reveals VCP mutations as a cause of familial ALS”, Neuron, 9, 857–864 (2010). PMID: 21145000.6. 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.
Retinal flatmount images of control and KUS-treated mice (12 months). Scale bar, 1000 µm.
Structures of KUS121 and KUS187, the KUSs used by Ikeda and her team (3).
KUS121 KUS187
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Upfront16
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n=23
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Pachymetry
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
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
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
References1. 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.
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TheOphthalmologist_2016_halfPage.indd 2 27.04.2016 10:31:43
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.
Reference1. 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.
Upfront18
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
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 morphologic 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
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
References1. 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].
CATT
Ranibizumab Bevacizumab
Exams Treatments2 years
5 years
CATT Follow-up
Letters lost
Stroke/Myocardial infarction
p=0.008-12.7 -8.8
7.6% 4.5%
At 5 years:
Mean number of
25.3 15.4
were treated at least once with a drug
other than their CATT-assigned drug
50% had VA 20/40 or better20% had VA 20/200 or worse
SD-OCT (n=555)Retinal thickness at the foveal center:
Baseline Year 2 Year 5
61% intraretinal
>212 µm 120–212 µm <120 µm
83% of patients had �uid on OCT
36% sub-RPE
38% subretinal
since CATT
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.
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.
Feature 21
Aqueous angiography promises a revelation in aqueous humor outflow understanding – and could transform MIGS outcomes
By Alex Huang
Individualized. and Inspiring.
www.theophthalmologist.com
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?
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
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.
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).
a.
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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 aldehyde-mediated 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
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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.
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).
a. b.
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Feature24
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.
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).
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).
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).
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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.
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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.
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
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.
Reference1. S Saraswathy et al.,“Aqueous angiography: real-time and physiologic aqueous humor outflow imaging”, PLoS One, 11, e0147176 (2016). PMID: 26807586.
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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).
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
Video
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a b
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30–33The Usual SuspectsSuspicious corneas? Alain Saad discusses the ‘hows’ of predicting and defining which patients will develop keratectasia.
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The Usual SuspectsHow 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,
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 Pract ice30
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 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.
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.
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
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
In Pract ice 31
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.
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 modelsTo 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
analysis (that combines these parameters together) can be a big advantage.
Combination is keySo 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 Pract ice32
Figure 5. SCORE analyzer results from a patient with clear keratoconus (as described by a SCORE of 20.2).
In Pract ice 33
Figure 6. Results from a patient with progressive keratoconus – note the increasing SCORE values over the period between 2007 to 2011.
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.
References1. 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).
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36–38ROP in the Digital EraMichael F. Chiang talks about the everyday challenges faced when caring for babies with ROP – and how telemedicine might change things.
ROP in the Digital EraIndirect 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 hand-drawn 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
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 under-served 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
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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
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.
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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 worldThere 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
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 non-physician 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
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.
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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 remainThe 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.
References1. 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.
Photograph of an ophthalmologist performing an ROP examination at the bedside.
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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.
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Looking After Your PupilsHow 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
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 stagesMentorship 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
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
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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
“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.”
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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
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/
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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 boundariesThere 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 meet ings s tar 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 trustThe 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 itThe 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 forEducation, Kenneth C. Swan Professorof Ophthalmology, and Chief of theVitreoretinal Division at Casey EyeInstitute, Oregon Health SciencesUniversity, Portland, USA.
Reference1. 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.
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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).
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
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
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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
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
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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.
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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.
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 interval provided some interesting insights in this respect, showing that additional diagnoses of sleep apnea were generated in the short-
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, inc luding 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 s tud i e s d id examine po ten t i a l 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 u r f i n d i n g s h a ve i m p o r t a n t 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
“Around one in five adults has OSA,but over 85 percent of individuals with clinically significant OSA have never been diagnosed.”
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 ly, while val idated 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
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.
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 anti-VEGF 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
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“Apart from anything else, picking up and
treating sleep apnea may mean fewer
injections and more money saved for
macular services.”
An ultra-widefield image of a retina with wet AMD.
Imag
e Cre
dit:
Tim
Steff
ens,
CRA,
OCT
-C, F
OPS
money saved for macular services (which are stretched in the UK).
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.
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. Ultimately, the most important question we need to answer is whether treatment of sleep apnea
reduces the excess risk of neovascular AMD that we have discovered.
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.
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.
References1. 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.
www.theophthalmologist.com
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,
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.
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/
Sitt ing Down With 51
“I originally wanted to be a poet or a
composer, but I didn’t have enough courage
to pursue it.”
• Powerful IOP lowering reductions of up to 40% vs baseline1
• Low level of hyperaemia (7%)2
• One preservative- free drop once-daily2
THE NEXT STEP FOR PRESERVATIVE-FREE POWER
NEW in Glaucoma
Product Name: TAPTIQOM® 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container. Composition: One drop (about 30 μl) contains about 0.45 micrograms of tafluprost and 0.15 mg of 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 block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock. Warnings and Precautions: Before initiating treatment, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation related to tafluprost. These changes may be permanent, and lead to differences in appearance between the eyes if only one eye is treated. Similar cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration. Caution should be exercised when prescribing TAPTIQOM® to patients with cardiac or severe peripheral vascular disorders eg Raynaud’s disease or syndrome. Use with caution in patients with mild/moderate COPD and in patients subject to spontaneous hypoglycaemia or labile diabetes. Beta-blockers may mask signs of hyperthyroidism 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 reactive to repeated challenge with such allergens and be unresponsive 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 beta-blockers 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 breast-feed if treatment with TAPTIQOM® is required. Driving and using 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).
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: 932-9442.Taptiqom SPC, available at http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1418969000862.pdf, accessed 11.08.15
TAPTIQOM is a registered trademark of Santen Pharmaceuticals Co., Ltd.
Job code: STN 0817 TAP 00018 (EU) Date of preparation: April 2016
