For ophthalmologists, increasing the knowledge base about uveitis is important for several reasons. According to Dr Jennifer E. Thorne, epidemiological studies of uveitis justify the need for uveitis specialists and training programmes by defining the scope and burden of the disease. Dr Thorne is director of the Division of Ocular Immunology and Uveitis and cross family professor of ophthalmology and epidemiology, Wilmer Eye Institute, Johns Hopkins University of Medicine and Public Health in Baltimore, Maryland, United States.

Published population-based studies detail the burden of visual morbidity, including blindness, societal cost and loss of quality of life. During the past six decades, four major epidemiological studies have revealed the incidence and prevalence of uveitis in the US, one in Rochester, Minnesota (1962); one in the Northwest Veterans Affairs (VA) Centers in Oregon and Washington (2008); and two by Kaiser Permanente in California (2004) and Hawaii (2013).

Moreover, Dr Thorne said she believes that the growth of large insurance databases and the IRIS database will result in additional studies. In the four studies, the incidence rates of uveitis increased with age in each of the studies per 100,000 person-years and ranged from 17.4 in Minnesota, 24.9 in Hawaii, 25.6 in the Northwest VA study and 52.4 in California.

The active prevalence of uveitis in the US per 100,000 persons also increased with age, except in the Northwest VA study. The prevalence rates were 57.5 and 58 in Hawaiian studies (2006 and 2007), 69 in the Northwest VA study and 114.5 in California. Uveitis rates vary considerably outside the United States; the highest rates were seen in India (730 per 100,000 person years) and the lowest in Italy (11.4 per 100,00 person years).

Dr Thorne said uveitis is a leading cause of visual impairment. “In the US, the disease is estimated to be the fifth- or sixth-leading cause of blindness, accounting for 10% to 15% of cases of blindness,” she said.

Studies of uveitis in the Netherlands and India report visual impairment in at least one eye in about one-third of cases; in the Aravind group in India, about one in five affected eyes was blinded by uveitis, but none was affected bilaterally.

The actual rates of blindness and visual impairment may be underestimated because the World Health Organization does not use uveitis as a cause of visual loss, Dr Thorne pointed out. Analysis of the anatomic location of uveitis showed that worsening visual outcomes were seen when the posterior segment was involved. “Since patients with noninfectious intermediate, posterior and panuveitis can require chronic regional and systemic treatment compared with only topical drops, much of the morbidity and cost of the uveitis may be attributed to these patients,” she said.

When it comes to cost and care, a 2011 study reported that uveitis has a high socioeconomic impact that is comparable to diabetic retinopathy in cost. Patients with uveitis, on average, are younger than those with diabetic retinopathy, and the lifetime direct and indirect costs would be expected to be higher among patients with uveitis.

Dr Thorne and colleagues conducted a study

 in which they retrospectively analysed the insurance claims of employees in the US. They considered the uveitis-associated direct costs, defined as inpatient stays, emergency department visits, outpatient visits and prescriptions, in patients with noninfectious intermediate, posterior and panuveitis, and reported that those patients had twice the number of visits compared with controls, which translated to direct costs of $12,940 compared with $3,730.

Analysis of the indirect costs, defined as absenteeism from work and disability, indicated that patients with uveitis had 10.3 days of disability compared with 4.6 days for controls and 18.7 days lost from work compared with 8.4 days for controls, which translated to a cost of $3,144 compared with $1,378.

The caveat regarding the results is that cases of anterior uveitis were not included in the analyses, nor were patients with uveitis who were unemployed or who had insurance through Medicaid or Medicare, for example. Dr Thorne concluded that population-based studies show varied estimates of the incidence and prevalence rates of uveitis in the US and internationally.

“Uveitis appears to increase with increasing age in most studies,” she said. “Visual morbidity is significant in patients with uveitis but may be underreported because uveitis is often not listed as a cause of visual loss in global assessments of blindness.”


Dr Thorne has no financial interest in this subject matter.

De Smet MD, Taylor SRJ, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res. 2011;30:452-470.

Thorne JE, Skup M, Tundia N, et al. Direct and indirect resource use, healthcare costs and work force absence in patients with non-infectious intermediate, posterior or panuveitis. Acta Ophthalmol. 2016;94:e331-e339.

Articles

Ophthalmologists are seeking improved treatment options for uveitis as epidemiological studies demonstrate the scope and sight-stealing burden of the disease.

Uveitis: A leading and underestimated cause of visual morbidity in patients

I spoke to Dr Anthony Khawaja of University College London and Moorfields Hospital, London, UK, about the exciting realm of precision medicine in glaucoma.

How do you define ‘precision management’?

In looking after our patients, most of us review the evidence in the literature. For example, when considering glaucoma patients, I might look at the UK glaucoma treatment study (UKGTS),

 a randomised controlled trial that showed that patients treated with a prostaglandin analogue do better on average than those who are not treated.

Evidence-based medicine tells us how best to treat people on average, but everyone is different. Not everybody in the UKGTS who received latanoprost necessarily benefited from it; in fact, 15% of such patients progressed over 2 years, so they were under-treated. Yet three-quarters of the placebo group did not progress, so some may have been over-treated.

Precision management is about going beyond simply what is best for the average group of patients and instead being able to predict, the first time you see a patient, their risk of worsening, and then titrating their treatment accordingly — maybe starting off more intensively in some high-risk patients so that you do not have to observe further vision loss before stepping up treatment. And it is it about choosing no treatment at all for other patients.

This means resources and treatments can be directed only to the people who will benefit, thus sparing the costs and side effects of treatments that will not work. The key here is understanding that one size does not fit all.

Could you expand on what this would look like for glaucoma?

One example of where precision glaucoma management could be useful is trying, the first time you see the patient, to make an assessment about whether they need treatment or not. Take the patient who has high ocular pressure but not glaucoma as of yet. We know from the Ocular Hypertension Treatment Study (OHTS)

 that if you treat such patients, they will do better on average than people who do not receive treatment: fewer of them will convert to glaucoma. But we also know that most of the group that is not treated do not develop glaucoma, so some are being treated unnecessarily.

An OHTS calculator that predicts the risk of conversion to glaucoma already exists,

 which takes into account the age of the patient, baseline pressure, corneal thickness, visual field mean deviation and cup-disc ratio. Unfortunately, this calculator, while helpful, does not really go far enough.

And so what we are looking to do is bring in other new technologies using genetic information or perhaps artificial intelligence (AI) assessments of images to help decide whether a patient will very likely benefit from treatment or, actually, are at such low risk that we can save the costs and the hassle of treatment. This will in turn also free up health service resources so that we can focus on the patients at highest risk.

You can apply this to other aspects of glaucoma care. For somebody with established glaucoma, do you treat or not, and how aggressively do you treat?

Another area which in my opinion can really benefit from the precision management approach in glaucoma is choosing the right treatment. There are so many different types of treatments available, including four major classes of drug, selective laser trabeculoplasty for open angle disease, and a whole spectrum of surgery from the minimally invasive glaucoma surgeries to the traditional incisional surgeries such as trabeculectomy and tube implants.

And if we are honest with ourselves, we do not know who is going to do well with each treatment. As mentioned, some people respond very well to latanoprost, but others do not respond at all and some experience side effects.

In recent years, we have really started to understand what causes glaucoma. In fact, glaucoma is one of the most hereditary of the common diseases in humans; it is about 70% heritable.

This means, in part, that some glaucoma is inherited through generations in an autosomal dominant fashion due to just a single mutation, most commonly in the myocilin gene. But this comprises only about 4% of primary open angle glaucoma (POAG).

The majority of cases are more complex because they are due to a lot of genetic effects, each one small and insufficient in causing glaucoma on its own but when put together cumulatively reach a threshold that causes disease. For years we were unable to identify these small effects, but recently, with large studies, we have been able to identify many more.

For example, 2 years ago, by looking at the pressure in the eyes of around 140,000 people, we identified over 100 points in the genetic code that underlie some people developing high pressure and then glaucoma.

 And what is exciting is that, when you combine the genetic information at all of these points, you can start to predict who is going to get glaucoma, even from the point of birth because our genetic code does not change after that.

Given that it has got such a genetic basis, what we can start to do next is pick out different types of glaucoma, for example, which are currently indistinguishable. So, POAG to us looks pretty uniform. However, genetically speaking there is a subgroup that seems to have a problem particularly located in Schlemm’s canal and collector channels; for another group the problem seems to particularly affect the trabecular meshwork.

If we could work out which of these patients had primarily a trabecular meshwork problem then we would know that treatment targeted to the trabecular meshwork, such as selective laser trabeculoplasty, or the iStent Inject (Glaukos) and trabecular bypass procedures with microstents (Hydrus), is more likely to work.

Conversely, if the issue is predominantly due to a problem with a patient’s collector channels and Schlemm’s canal, then maybe you are better off not targeting the trabecular meshwork. In that way, we can start to use genetic risk scores to be able not only to tell us about the risk of disease progression but also to predict response to treatment.

How exactly would artificial intelligence assist?

Well, in terms of personalising care, there is an awful lot of information that we collect as glaucoma specialists: images that provide detailed information and potential patterns that we recognise. We learned through our training that we can sometimes look at an optic nerve and see when there is a lot of damage and when a person is at high risk, meaning we need to treat them aggressively.

But there are other times where we just get it wrong and do not predict at baseline that somebody is at high risk of getting worse, and they worsen despite our best efforts. Conversely, we might treat other people that are at low risk and we can never know whether they needed that treatment.

The real power of AI in medicine so far is the ability to classify images, which it can do better than any single human grader. AI has the potential to see patterns in an image that no human being, no matter how expert they are, can see: an interesting study that supports this concept is one from the Google Brain group.

They trained an AI algorithm to look at photos of the retina of healthy participants in a couple of studies, including the UK Biobank study, and to predict sex. The algorithm is 97% accurate in identifying whether a fundus photo is from a man or a woman. Is there is one glaucoma specialist or retinal specialist or human in the world who can do that?

The enticing thought is that if AI can see patterns beyond what humans can appreciate currently, it can predict the future. I can definitely see AI working together with genomics in the future, providing much more individualised care.

I have set my research group an ambitious target: by 4 years’ time we will have developed proven algorithms that can predict the risk of glaucoma progression and response to two different treatments. Once we have got this tool, we need to make it easily accessible and understandable to general glaucoma doctors and physicians, and even patients.

We will need to test it prospectively to see whether it does improve decision making. Glaucoma trials can take quite a long time—at least 2 years—and so I think we are looking at an estimated 5 years to get the proof of principle and a pilot tool that will then need to be proven over a few years before something can be rolled out.

In parallel to this, we need genetic data to be available. Currently, most of our patients do not come with genetic data, although increasing numbers of people are obtaining it from direct-to-consumer genetic tests. There are already platforms where healthcare services can interact with genetic databases to pull out the information they need, with the patient’s consent. So, this is one possibility.

This type of testing can cost less than £50 and when done on scale might be nearer to £20 per person, which is excellent value. And if that one £20 test can tell you whether you should be screened for glaucoma, which treatment you should have and whether you need treatment at all, it could provide a similar picture for other diseases.

For example, it could also tell you, say, whether you should take statins if you have got high lipid levels. Should you be screened for breast cancer or should it be delayed? And for prostate cancer? This is just scratching the surface.

The £20 test can inform a whole gamut of health-related decisions. It will really become a question of 

 you test and obtaining genetic information for all people who interact with healthcare services will become routine.

The people in the aforementioned study were all of European descent and we can predict with a certain degree of accuracy someone’s risk of glaucoma if they are European. This prediction works quite well for Asian people too, but not so well for people of African descent.

If we are to develop a new, better way of managing glaucoma, which means that people get the best treatment for them from the get go and that we spare people who do not need treatment, can we really offer it if it only works in people of certain ethnicities? And I think we all know the answer to that is no.

So, one of the challenges is the need to make sure that we are getting enough data and information on people of all ethnicities. And this is why, having started the Moorfields Glaucoma BioResource, I am pleased to be able to recruit patients from all backgrounds due to London’s very diverse population.

The other challenge is to come up with a better way of managing glaucoma so that expertise is widely distributed and not clustered in certain centres of excellence where there are genetics experts. Such care needs to be delivered by any doctor and to an extent that even patients can understand.

It needs to be accessible and rolled out everywhere, equitably, to people of all ethnicities and backgrounds. And that is the key: we need to make this an equitable innovation.

Anthony Khawaja, MA (Cantab), PhD, FRCOphth

Dr Khawaja is associate professor at UCL Institute of Ophthalmology and honorary consultant ophthalmic surgeon at Moorfields Eye Hospital NHS Foundation Trust, London, UK. He reports acting as consultant to Aerie, Allergan, Google Health, Novartis, Reichert and Santen and has received lecturing fees from Grafton Optical and travel support from Thea.

Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. 

Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. 

Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension.

Khawaja AP, Cooke Bailey JN, Wareham NJ, et al. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. 

Poplin R, Varadarajan A V., Blumer K, et al. Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning. 

Artificial intelligence and genetic testing are expected to facilitate choosing the best treatment for each unique glaucoma patient within the next decade. This will not only lead to the best outcomes for individuals but will also spare them the costs and side effects of suboptimal treatments.

Precision management to revolutionise glaucoma diagnosis and treatment

En-face optical coherence tomography (OCT) is an effective tool that is providing insights into macular anatomy and various macular disorders, according to Dr David Sarraf, who discussed the topic at the American Academy of Ophthalmology 2020 virtual meeting. Dr Sarraf is a clinical professor of ophthalmology at the Stein Eye Institute at the University of California in Los Angeles, United States.

He reviewed the principles of en-face OCT and how this imaging modality has led to an increased understanding of macular anatomy and disease. He described various studies that have applied en-face OCT to gain insight into the pathoanatomy of the fovea and to more precisely characterise various macular disorders, including dissociated optic nerve fibre layer (DONFL), paracentral acute middle maculopathy (PAMM), multiple evanescent white dot syndrome (MEWDS), type 1 macular neovascularisation and geographic atrophy.

According to Dr Sarraf, en-face OCT acquires a dense volume of cross-sectional B scan data projected onto an en-face (coronal) plane. It can display binary reflectivity over a flat fundus view and is capable of providing segmentation at a given level.

“There are many advantages of en-face OCT because it can display the interrelationship and pattern of hyper- and hyporeflective OCT lesions over a fundus view with depth-resolved segmentation capability,” he said.

Compared with cross-sectional OCT, the en face technique greatly enables detection of superficial hyperreflective dots within the fovea. Dr Sarraf and his colleagues took advantage of this capability to quantify these dots in a cohort of eyes and found an age-related increase in their number.

“We believe that these hyperreflective dots may represent the same entity as the white dot fovea seminally described in 1997 by Yokotsuka, Kishi et al. using scanning electronic microscopy,” he said. “These dots are believed to represent activated Müller glial cells breaking through the inner limiting membrane.”

En-face OCT has also been used to characterise the inner retinal dimples of DONFL. A paper authored by Navajas et al. described this application in eyes that had undergone epiretinal membrane peeling and reported that the dimples increased progressively in number 1 month after the surgery and reached a plateau at 6 months.

“The findings are consistent with the idea that peeling of the inner limiting membrane avulses Müller cell endfeet,” Dr Sarraf said. “Because of postoperative oedema in the nerve fibre layer, however, the dimples are not fully appreciated for several months after the surgery until there is resolution of the oedema and nerve fibre layer thickening.”

Insight into the varying patterns of PAMM lesions is another benefit of the application of en face OCT. “PAMM is defined by hyperreflective bands in the middle retina that may represent infarction of the inner nuclear layer,” Dr Sarraf said. “With en-face OCT, we can appreciate different patterns of PAMM lesions that may reflect the progression of ischaemic severity referred to as the ischaemic cascade.”

Illustrating his point, Dr Sarraf showed en-face OCT images from an eye with cilioretinal artery occlusion that displayed a perivenular pattern of PAMM that were remarkable for the presence of fern-like, hyperreflective lesions precisely colocalising with the veins but sparing arteries. Then he presented a sequence of images from the same patient obtained over a 12-hour period that showed progression from the perivenular fern-like pattern to a diffuse globular PAMM pattern, indicating progression of the infarction typical of the ischaemic cascade.

Serial imaging with en-face OCT in eyes with MEWDS has also demonstrated temporal changes in the spots and dots characteristic of this entity. With en-face OCT, the smaller hyperreflective dots in the outer nuclear layer align with and overlie the larger hyporeflective spots that correspond to loss of the ellipsoid zone. Successive images from an eye with MEWDS showed that the spots resolve first and the dots second, Dr Sarraf said.

Another area where en-face OCT may be a useful clinical tool is with identifying and monitoring progression of geographic atrophy in eyes with dry age-related macular degeneration (AMD) and in eyes with type 1 neovascularisation. Representative en-face OCT images from a patient with type 1 neovascularisation and AMD showed a progressive area of atrophy colocalised outside the area of neovascularisation, which was identified with OCT angiography.

“These findings have been attributed to recapitulation of the choriocapillaris by the type 1 neovascular lesion that may sustain the retinal pigment epithelium and photoreceptors and protect these layers from atrophy,” Dr Sarraf concluded.


Dr Sarraf receives research funding from Heidelberg Engineering, Optovue and Topcon Medical Systems, and is a consultant to and speaker for Optovue.

En-face OCT has advantages that make it very useful for characterising macular anatomy and pathologic features of various macular disorders.

Visualisation with en-face OCT offers value for ophthalmologists

Ang-2/VEGF-A Inhibition Synergistic Effect in DME and AMD 

Angiogenesis 2021 Virtual Symposium Takeaways & Final Thoughts 

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Anat Loewenstein, MD, MHA, discusses data from the Angiogenesis, Exudation, and Degeneration 2021 Virtual Symposium on angiopoietin-2/VEGF-A dual inhibition in the management of diabetic macular edema and exudative age-related macular degeneration.

Rapid Readout: Angiopoietin-2 (Ang2) Inhibition in the Treatment of Diabetic Macular Edema and Exudative AMD.

A post hoc analysis of data from Diabetic Retinopathy Clinical Research (DRCR) Retina Network Protocol V clinical trial provides insight on outcomes when eyes with centre-involving diabetic macular oedema (CI-DMO) and good visual acuity are managed with initial observation and treated with anti-vascular endothelial growth factor (anti-VEGF) therapy only if vision worsens. The findings were reported in a paper published in JAMA Ophthalmology

 and reviewed by Dr Carl W. Baker at the American Academy of Ophthalmology’s 2020 virtual meeting.

Protocol V randomly assigned eyes with CI-DMO and visual acuity (VA) 20/25 to initial management with intravitreal aflibercept (Eylea, Regeneron), focal grid laser or observation. Eyes in the laser and observation arms were to receive aflibercept only if they had a decrease in VA meeting protocol-specified criteria.

At the end of the 2-year study, mean VA was 20/20 in the three randomly assigned arms. Among the 236 eyes initially randomly assigned to observation, two-thirds did not require anti-VEGF therapy. Within the latter subgroup, median VA at 2 years was also 20/20 and 31% had spontaneous resolution of their DMO. Eyes in the observation group requiring aflibercept still achieved good vision at 2 years.

Analyses done to identify baseline characteristics associated with receipt of treatment for DMO after initial observation identified three factors that related to DMO severity in the study eye, retinopathy severity in the study eye and need for treatment of DMO in the fellow eye.

“Based on the primary endpoint results from Protocol V that showed no difference in vision outcomes between eyes treated initially with aflibercept and those with treatment withheld until vision worsened, many clinicians and patients might choose initial observation for eyes with CI-DMO and good visual acuity,” said Dr Baker, who is in private practice at the Hilton Head Retina Institute in Hilton Head, South Carolina, United States.

Dr Baker said the post hoc analysis provides more practical guidance for clinicians. “The three risk-related baseline factors identified by this analysis—higher levels of retinopathy, DMO requiring treatment in the fellow eye and greater OCT [optical coherence tomography] thickness—are associated with a potential need for injections,” he pointed out. “It can be useful when clinicians are deciding what treatment strategy may be the best option for their DMO patients with good vision.”

Follow-up in Protocol V for eyes in the observation arm began with visits at 8 and 16 weeks and continued at 16-week intervals unless VA declined. Treatment with aflibercept was initiated if electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) VA decreased by ≥10 letters from baseline at any visit or by 5–9 letters at two consecutive visits 4 weeks apart.

For eyes showing a 5–9-letter loss at one visit that was not sustained at the follow-up visit, the follow-up interval was decreased to every 8 weeks if central subfield thickness (CST) worsened by ≥10% from the preceding visit or exceeded 400 µm. If the eye still did not meet the VA criteria for initiating aflibercept, the follow-up interval was doubled to the previous schedule if CST was stable or improved and halved again if the CST had worsened.

Dr Baker reported that after following this DRCR algorithm, two-thirds of the observation group did not require injections over 2 years and the mean vision was the same as that of eyes that were initially treated with aflibercept.

“Even in the eyes that had worsening vision to the point of requiring aflibercept injections, the median visual acuity was 20/25 at the 2-year end point of the study,” Dr Baker said. “These eyes required fewer injections over the 2-year course of the study than the group initially randomised to aflibercept.”

Dr Baker added that it is not fair to compare VA in the subgroups of eyes in the observation group that did and did not receive aflibercept because the eyes that were treated needed to have vision loss to qualify for aflibercept. An analysis to identify predictors of receiving aflibercept among eyes managed initially with observation looked at nine baseline variables, of which three were found to be significant.

The strongest risk factor was having a non-study eye that was receiving or was planned to receive treatment for DMO within 4 months of study enrollment. A total of 92 eyes were in this subgroup and they had a 2.55-fold greater likelihood of needing aflibercept in the study eye compared with eyes that were not receiving binocular treatment for DMO (P <0.001).

Eyes with a baseline diabetic retinopathy severity score ≥47 (moderate severe nonproliferative diabetic retinopathy or worse; n=80) had a 2.22-fold increased risk of receiving aflibercept compared with eyes entering the study with less severe diabetic retinopathy (P <0.001).

An analysis of the impact of baseline CST showed that eyes with a Zeiss-Stratus equivalent ≥300 µm were approximately twice as likely as eyes with less thickening to need aflibercept (P <0.003). Baseline factors not associated with receipt of aflibercept among the eyes initially managed with observation were gender, age, race/ethnicity, glycated haemoglobin A1C (HbA1c) and VA prior to DMO treatment.

Dr Baker outlined several limitations of the analyses. He noted that because they were conducted post hoc and multiple characteristics were evaluated, some of the associations between baseline features and receipt of aflibercept could have been identified due to chance.

In addition, treatment decisions were guided by VA obtained from E-ETDRS testing following protocol refraction, which could differ from VA measurements taken in clinical settings. Finally, the analyses did not provide information on the group initially treated with laser.


Dr Baker receives grants for clinical research from Regeneron Pharmaceuticals, Inc, and other companies marketing products for treatment of DMO.

Glassman AR, Baker CW, Beaulieu WT, et al. Assessment of the DRCR Retina Network approach to management with initial observation for eyes with center-involved diabetic macular edema and good visual acuity: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2020;138:341-349.

In the DRCR Retina Network Protocol V, which studied management strategies for eyes with centre-involving DMO and good visual acuity, the majority of eyes randomly assigned to initial observation completed the 2-year study without needing anti-VEGF therapy for vision loss and nearly one-third had spontaneous resolution of DMO.

Study targets strategies for CI-DMO

Myopia is a recognised global epidemic expected to affect almost half of the world’s population by 2050. The currently widely used methods of myopia treatment and correction—glasses, contacts or laser vision correction—are not ideal for treating patients with thin or abnormal corneas, contact lens intolerance or anisometropia, according to Dr Gregory D. Parkhurst, the CEO of Parkhurst NuVision in San Antonio, Texas, United States. Those who are not candidates for laser vision correction may benefit most from implantation of a phakic IOL.

Dr Parkhurst and colleagues conducted a retrospective study

 of phakic IOL implantation in military personnel who received the Visian Implantable Collamer Lens (ICL; STAAR Surgical), and in whom laser vision correction was not ideal because of abnormal topography, thin predicted residual bed and/or dry eye disease. In these patients, refractive predictability within 0.5 D with the ICL was seen in 90% of eyes and 96% achieved 20/20 uncorrected vision, he reported.

The objective results are good in a population with abnormal corneas, so the obvious next question is whether this technology should be limited to individuals who are not considered candidates for laser vision correction. One study

 supported the idea that phakic IOLs provide the best quality-of-life scores compared with other refractive surgeries such as laser vision correction. In addition, Dr Parkhurst reported results that showed night vision was superior in patients with phakic IOLs compared with those who underwent wavefront-optimised LASIK even for moderate levels of myopia.

One advantage associated with phakic IOLs is the relatively small learning curve to overcome for experienced anterior segment lens surgeons and the fact that the surgical technology is less expensive to access than laser equipment, which can cost several hundred thousand dollars to acquire. All a surgeon really needs is an operating microscope, a basic cataract set and a few special forceps to get started. In addition, the postoperative care is very similar to that associated with cataract and refractive lens surgery with the important addition of monitoring the vault of the phakic IOL, Dr Parkhurst pointed out.

As with any surgical procedure (or nonsurgical treatment of myopia), there are risks associated with phakic IOL implantation. Endophthalmitis is associated with the performance of any intraocular procedure and the rate associated with phakic IOL implantation is 0.017% (1 in 6,000 cases). Postoperative intraocular pressure (IOP) spikes that require intervention occur in 3.2% and the risk of pupillary block after implantation of the ICL is 0.7%, Dr Parkhurst noted.

Development of cataracts is another risk associated with implantation of phakic IOLs. Seven reports of 3 to 7 years of follow-up after phakic IOL implantation noted clinically relevant cataracts with incidence rates of less than 2%; one report cited a much higher risk of cataracts in patients with very high myopia and older age. In contrast, endothelial cell loss over time has not been a clinically significant problem with the ICL.

The future of phakic IOLs may include further improvements in safety resulting from better ways to size the ICL, Dr Parkhurst said, as well as minor design modifications, diagnostics and improvements in the sizing nomograms. “The sulcus distance is highly variable in eyes; accommodation plays a role as do the shape and anterior lens rise of the human crystalline lens,” he said.

Future developments in the ICL platform include the availability of presbyopia-correcting models. In addition, development of a lens with a central fenestration that was used in Europe resulted in fewer IOP spikes and no cataract development, possibly due to increased flow of aqueous over the anterior lens epithelial cells.

An important consideration for Dr Parkhurst, considering the good safety profile of the Visian ICL and the demand for refractive surgery, is use of a phakic IOL to preserve the cornea and lens for the future. When the cornea is borderline, he explained, the question that must be asked by surgeons is whether they would rather implant a phakic IOL and leave open all options for presbyopia and cataract correction, or potentially risk the integrity of the cornea with the associated risk of corneal transplantation or need for cross-linking. He often opts to implant a phakic IOL.

“As surgeons we must help our patients balance the risks, benefits and alternatives of all options to treat myopia,” Dr Parkhurst concluded. “Modern phakic IOLs offer high-quality vision, a low-risk profile and preserve the cornea and lens for the future, and can be an important tool for the comprehensive refractive surgeon.”


Dr Parkhurst is a consultant to STAAR Surgical.

Parkhurst GD, Psolka M, Kezirian GM. Phakic intraocular lens implantation in United States military warfighters: a retrospective analysis of early clinical outcomes of the Visian ICL. J Refract Surg. 2011;27:473-481.

Leong A, Hau SCH, Rubin GS, Allan, BDS. Quality of life in high myopia before and after implantable Collamer lens implantation. 2010;117:2295-2300.

Parkhurst GD. A prospective comparison of phakic collamer lenses and wavefront optimized laser-assisted in situ keratomileusis for correction of myopia. Clin Ophthalmol. 2016;10:1209-1215.

Phakic IOL implantation offers a number of benefits for patients with myopia who are not candidates for laser vision correction.

When to implant phakic IOLs 

Although the exact relationship between vitamin D and glaucoma remains uncertain, it has increasingly become apparent that low systemic levels of the vitamin may be a risk factor for primary open angle glaucoma (POAG).

 Studies to date have not demonstrated a direct link between vitamin D deficiency and POAG, with many interacting phenotypic, genetic, epigenetic and environmental factors likely to be involved. However, they have lent significant weight to the pursual of further studies in the area.

When examining the link between vitamin D and glaucoma, it is helpful to consider the fact that the retinal ganglion cell (RGC) degeneration that occurs in the inner retina in POAG has been proposed to result from both direct and indirect damage from oxidative stress. Various reviews have explored oxidative stress and its contribution to the pathogenesis of glaucoma.

Hypotheses for the benefits of vitamin D in glaucoma include its role as an antioxidant

 and in suppression of genes involved in the determination of intraocular pressure.

 Vitamin D has also been shown to regulate the functions of neuroprotection in the central nervous system, including the optic nerve.

Treatment with the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3, was found to ameliorate the effects of oxidative stress in human retinal pigment epithelium cells in one study.

 The compound led to suppression of oxidative damage and inflammation through antioxidant signalling pathways and reduced the generation of reactive oxygen species (ROS). Human retinal pigment epithelium cells also had greater survival rates and there was a reduction in the secretion of cytokines and vascular endothelial growth factor.

Ultimately, the multiple complex pathways leading to RGC damage under oxidative stress are likely varied and overlapping. The apoptotic process itself generates ROS and the overall effect is a positive feedback cycle whereby excess ROS produce oxidative stress that eventually yields more ROS.

The relationship between vitamin D and glaucoma may also be a consequence of altered vitamin D metabolism in affected individuals, or due to low vitamin D levels. Observational studies that assessed the relationship between low levels of the vitamin and POAG found a significant association between them. Serum 25(OH)D

 levels were significantly lower in POAG patients than in controls, and specific metabolic processes involving vitamin D were able to differentiate cases from controls.

Although the cross-sectional and case control studies all found POAG to be significantly associated with low vitamin D status, no causal relationship could be established between glaucoma and low vitamin D

 found no significant difference in serum vitamin D levels between POAG patients and controls.

Nevertheless, there was significant between-study heterogeneity: one study was cross-sectional whereas the other two were case-control studies. There were also significant differences in sample size and vitamin D measurements, and Lv et al.’s study

 measured serum calcitriol levels as opposed to serum 25(OH)D.

Some interventional trials have shown promise

 Early interventional studies found a reduction in IOP with intramuscular administration of vitamin D

Treatment of non-human primates with topical vitamin D resulted in a 20% reduction in IOP in both eyes without nasolacrimal duct occlusion, a dose-dependent unilateral IOP response with nasolacrimal duct occlusion, and depressed expression of several genes associated with IOP regulation, though the mechanism for this was unclear.

In one study, no difference in IOP was found with oral supplementation (20,000 IU twice per week); however, it was noted that most participants had IOP within the normal range.

 Accordingly, it may be beneficial for future interventional clinical trials to investigate the link between low vitamin D and glaucoma using alternative supplementation methods such as intramuscular or topical application.

Furthermore, recent genome-wide association studies (GWAS) for vitamin D levels

 or exfoliation glaucoma have been completed.

 GWAS could be used for Mendelian randomisation to explore a causal effect of vitamin D levels in POAG or other types of glaucoma.

Greater sunshine exposure and lower ambient temperatures have been found to increase the likelihood of exfoliation syndrome, an extracellular deposit disorder that is the most common cause of secondary open-angle glaucoma.

 However, there have been no studies to our knowledge investigating the relationship between sun exposure and POAG. Prospective cohort studies would be beneficial to further elucidate this area.

Overall, establishing the relationship between vitamin D and POAG might not only alter the way that we manage glaucoma but also help prevent this sight-threatening disease. Discovering other modifiable risk factors, particularly those that can be inexpensively treated, will have substantial outcomes.

Dr Huynh is based at Westmead Hospital, Sydney, Australia. 

Peter Shah, BSc (Hons), MB ChB, FRCOphth, FRCP Edin, MA (Distinction)

Prof. Shah is consultant ophthalmic surgeon at the University Hospitals Birmingham (UHB) NHS Foundation Trust, as well as co-director of the Birmingham Institute for Glaucoma Research, visiting professor at University College London and honorary professor of glaucoma at the Centre for Health & Social Care Improvement, University of Wolverhampton, UK.

Dr Sii works at the University Hospital Birmingham NHS Foundation Trust and Birmingham Institute for Glaucoma Research, Birmingham, UK.

Dr Hunter is based at the Centre for Vision Research, Westmead Institute for Medical Research, Sydney, Australia and the University of Sydney’s Faculty of Medicine and Health.

Dr Carnt works at the Westmead Institute for Medical Research, Sydney, Australia.

Andrew White, BMedSci (Hons), MBBS, PhD, FRANZCO

Dr White is co-chair of the Agency for Clinical Innovation: Ophthalmology Network Governing Body and head of the Department of Ophthalmology, Westmead Hospital as well as being director of the Community Eye Care Centre, Western Sydney and conjoint associate professor of the School of Optometry and Vision Sciences, UNSW.

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article and the research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Evidence for a connection between low vitamin D levels and glaucoma is increasing but the link remains speculative and no causal connection has been demonstrated. 

Is low vitamin D a risk factor for primary open angle glaucoma?

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