A retrospective study including patients with at least 12 months of follow-up care shows that the intravitreal dexamethasone 0.7-mg implant Ozurdex (Allergan) provides safe and durably effective treatment for diabetic macular oedema (DMO) across the spectrum of patients who are seen by physicians in routine clinical practice. Although the research found that treatment-naïve patients generally had greater benefit than those who had a history of having received anti-vascular endothelial growth factor (VEGF) treatments, it also showed that eyes with long-standing, chronic DMO responded to the sustained-release steroid treatment.

In addition, the analyses showed that effectiveness was not related to reinjection interval. “Although evidence from clinical trials shows the safety and efficacy of the dexamethasone implant for treating DMO, it is important to collect data from real-world settings,” said Dr Albert J. Augustin, professor and chairman of the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany, and lead author of the study.

Dr Augustin noted that the results of the study are consistent with prior studies and support the utility of the dexamethasone implant as a treatment for DMO in routine practice. “However, the results are preliminary and further, larger-scale studies are warranted,” he pointed out.

The study identified 141 patients treated at seven hospital-based medical retina centres in Germany (n = 108) and Switzerland (n = 33). Eligible patients had DMO-related visual impairment and at least 12 months of follow-up after the first implant injection. For each patient, data from a single eye was analysed – either the eye that received the most injections or one chosen by the investigator if injection number was the same for both eyes.

The baseline data showed that compared with the Swiss cohort, patients from Germany had a longer history of DMO (106 vs 31 months) and included a greater percentage of anti-VEGF treatment-naïve patients (40.7% vs 3.0%). In addition, considering the subgroup of patients who had received anti-VEGF injections, the mean number of injections was two-fold higher in the German cohort compared with the Swiss patients (63 vs 31). At baseline, the mean best corrected visual acuity (BCVA) for the study eyes was 61.6 letters and mean central retinal thickness (CRT) was 413.3 μm.

According to investigators, changes from baseline to 7 to 12 weeks post injection for both BCVA and CRT were analysed as efficacy end points. Across the entire cohort, the mean number of reinjections was three (range, 1-11) and they were given at a mean interval of 5.7 months (median, 4.6 months). BCVA was relatively stable after each reinjection with a mean change from baseline BCVA of +3.4, +3.7, +3.2 and –1.4 letters at 7 to 12 weeks after the first injection and reinjections one, two and three, respectively.

Relatively greater benefit was seen in the analyses of CRT with changes from baseline of –88.3, –81.6, –102.4, and –124.1 μm at 7 to 12 weeks after the first injection and reinjections one, two and three, respectively. Dr Augustin explained that it is well known that CRT does not necessarily correspond with visual acuity. “In some patients, an increase in visual acuity follows the CRT improvement,” he said. “However, in other patients, it is necessary to evaluate the retinal structure in more detail to understand the phenomenon.”

Dr Augustin noted that this is why investigators have to look at other optical coherence tomography (OCT) results, such as retinal structure, external limiting membrane, ellipsoid zone, etc. “EURETINA [the European Society of Retina Specialists] has published a guideline focusing on such OCT results that helps us to better predict the result of intravitreal treatments in patients with DMO,” he added.

Patients receiving the intravitreal implant as their first treatment for DMO had worse BCVA at baseline than their previously treated counterparts (mean, 57.8 vs 63.4 letters) and “more” DMO (mean CRT, 439.1 vs 400.6 μm). Compared with the patients who had a history of anti-VEGF treatment, the treatment-naïve patients had greater functional improvement, but less change in CRT.

Dr Augustin noted that the mean change in BCVA from baseline after the first injection in the treatment-naïve and previously treated patients was +4.7 vs +3.0 letters, respectively, and was +4.2 vs +3.5 letters, respectively, after the first reinjection. Mean CRT change from baseline in the treatment-naïve and previously treated patients was -74.3 vs -63.8 μm, respectively, after the first injection and -63.8 vs -85.8 μm, respectively. The Spearman correlation coefficient showed there was no statistically significant correlation between reinjection interval and either change from baseline in BCVA or CRT for the overall population or in analyses performed for each country individually, Dr Augustin reported.

Dr Augustin concluded with: “Although there was not a significant correlation between reinjection interval and change from BCVA, the small loss in BCVA that was seen after the third reinjection may be due to the reinjection interval.” Moreover, he noted that treatment with the dexamethasone implant had a favourable safety profile in patients.

Only 18% of patients experienced at least one adverse event, with ocular hypertension being the most common. There was no increase in number of adverse events with increasing number of injections.


This article is based on Dr Augustin’s presentation at the EURETINA 2020 virtual meeting. Dr Augustin has received research support and consulting/advisory fees from Allergan and other companies that market products used for the treatment of DMO.

Articles

In a real-world study of patients with treatment-naïve and previously treated diabetic macular oedema, injection of intravitreal dexamethasone 0.7-mg implant provided effective disease control with initial and repeat injections, regardless of reinjection interval.

DMO study shows robust efficacy of intravitreal dexamethasone implant 

Intravitreal treatments have revolutionised the treatment of retinal diseases, enabling drugs to bypass the many barriers that protect the eye and be delivered where they are needed. We have learned, however, that they come with a significant treatment burden for the patient and potentially also for the patient’s caregivers.

It has been well demonstrated in clinical practice that patients with diabetic macular oedema (DMO) undergo fewer anti-vascular endothelial growth factor (VEGF) injections and exhibit worse visual gains in the real world compared with patients in randomised clinical trials. Over time, some patients become anxious about their injections, which may lead to poor compliance. Others may not have easy access to current treatments because of reimbursement issues, according to the particular healthcare system in their country of residence.

There can also be logistical challenges for patients such as the need to find somebody to drive them to the clinic to have their injections or simply the problem of not being able to afford to take a day off work. All these factors mean that even when patients are vigilant about clinic visits, some do not benefit fully from intravitreal injections and have either ongoing vision loss and/or poor anatomic responses.

An eye drop that could deliver treatment to the posterior segment would be one way to alleviate some of these challenges. This ever-elusive treatment remains the holy grail of ocular drug delivery as the search for less-invasive treatment methods continues. A topical, non-invasive, self-administered treatment would undoubtedly expand the proportion of diagnosed patients we treat as well as the number of ophthalmologists who could provide treatment.

Diabetes and its complication diabetic retinopathy is an ongoing public health issue that shows no sign of abating. There is little debate that intravitreal injections of steroids and anti-VEGF treatments have improved vision and anatomic outcomes for many with DMO.

As clinicians, we tend to observe patients with early disease until clinically significant visual impairment occurs and only then do we restore their vision, often partially, with intravitreal injections. Since these treatments are invasive and not without their own challenges, the benefit/risk ratio may not be justified in earlier stages of the disease.

A topical eye drop may present new possibilities, particularly for patients with recent-onset DMO who still have good vision. Indeed, there is the possibility that by using a topical treatment in lieu of an invasive one, we can start treating patients earlier. The ability to vary the dose by varying the number of drops is an additional benefit.

The reduced treatment burden would be attractive to patients, who would still need to be monitored for disease progression but could look forward to fewer and less painful visits. And topical medications would also reduce negative psychosocial impacts associated with injection fears or phobias.

From the clinician’s point of view, patients would now only need to be requested to refill prescriptions and remember to instill drops, an easier request than asking them to attend clinics for injections. Furthermore, it would reduce the reliance on retina specialists or trained ophthalmologists to administer the treatment.

Since patients would be motivated to reduce their need for intravitreal injections, in addition to preserving and/or improving their vision, a topical treatment for posterior segment diseases should have a much higher compliance and adherence rate than treatment for glaucoma, which is often asymptomatic.

Unfortunately for those with retinal disorders, despite all the obvious benefits of topical treatments, delivery of therapeutics to the posterior segment is still not possible. The obstacles to reaching the retina with a topical treatment are numerous: limited solubility of lipophilic drugs in aqueous eye drops and the tear film, short contact time on the surface, and lipid membrane barriers.

These barriers have not stopped researchers from trying. However, until recently, attempts have been unsuccessful. For example:

In the MAKO Phase 3 trial, topical squalamine (Ohr Pharmaceutical) failed to demonstrate a mean visual acuity gain in patients with age-related macular degeneration when added to ranibizumab (Lucentis, Genentech) injections;

Integrins (and in particular αvβ3) are being evaluated for intravitreal dosing,

 but topical dosing has not moved beyond a Phase 1/2 study;

Lifitegrast (approved as dry eye treatment Xiidra Novartis) showed promise as a treatment for DMO in a rat model

Topical nepafenac 0.1% (Nevanac, Alcon) was found not to have a meaningful effect on optical coherence tomography-measured retinal thickness in a DRCR.net study;

Topical mecamylamine (CoMentis), a nonspecific nicotinic acetylcholine receptor blocker, did not progress beyond a Phase 1/2 study.

Scientists are working on ways to overcome the issues with topical delivery of therapeutics to the posterior segment – and are starting to have some success. One therapeutic in development for DMO, OCS-01 (Oculis), is a high concentration of dexamethasone in a solubilising nanoparticle (SNP) aggregate formulation. Novel SNP-based formulations have been shown to achieve better penetration over longer periods of time by creating smartly crafted drug–cyclodextrin complexes that create a highly concentrated drug suspension that is able to deliver the drug for a prolonged period.

 recently presented positive data from a Phase 2 study that evaluated 144 patients randomised to either OCS-01 or vehicle. Mean central macular thickness (CMT) showed a greater decrease from baseline in the OCS-01 group than the vehicle arm at Week 12 (−53.6 μm vs −16.8 μm, 

 = 0.0115). Mean CMT also showed significant differences between groups in favour of OCS-01 at all visits from Week 2 to Week 12.

Mean change in Early Treatment Diabetic Retinopathy Study letter score from baseline to Week 12 was higher in the OCS-01 group than the vehicle group (+2.62 letters vs 1.04 letters, 

= 0.125). P values met the prespecified criteria in the protocol for statistically significant superiority of OCS-01 versus vehicle and the compound is now moving into Phase 3 studies.

In the case of OCS-01, we know from other commercialised products that dexamethasone is an effective anti-inflammatory agent, so this is a test for the eye drop administration route. Although OCS-01 is the furthest along and shows the most promise (to date) as a topical treatment for DMO, there are also other agents in earlier phases of development that may prove equally efficacious in the future, ranging from topical nonsteroidals and corticosteroids

 and even a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor already approved for the treatment of glaucoma and ocular hypertension.

If any of these topical treatments is successful in later-stage studies, the potential is great. Topical drops may let us delay initiating anti-VEGF injections and/or more invasive treatments or prolong the time to next injection for those already undergoing intravitreal treatment. We may even be able to better co-manage patients with other healthcare providers because there is no need for specialised training beyond proper candidate screening.

I continue to look forward to the day when our armamentarium for posterior segment disorders includes topical treatments that are efficacious and safe, that substantially reduce treatment burden for both the clinician and the patient, and that can be widely adapted across all socioeconomic and geographic boundaries.


Prof. Tadayoni is professor of ophthalmology at Université de Paris, France, and head of department at Lariboisière, Saint Louis and Adolphe de Rothschild Foundation Hospitals Paris. He is a European Society of Retina Specialists (EURETINA) board member, past president of the French-speaking Retina Specialists and the leader of RHU EviRed, a national artificial intelligence project on diabetic retinopathy supported by the French government. Prof. Tadayoni is a consultant to Zeiss, Alcon, Bausch & Lomb, Moria, Allergan, Bayer, Novartis, Roche – Genentech, Thea and Oculis. Writing assistance for this article was provided by Michele Dalton from Dalton and Associates; the funding for this assistance was provided by Oculis.

Robin A, Grover DS. Compliance and adherence in glaucoma management. 

Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? 

Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. 

Ohr Pharmaceutical Inc. Ohr announces efficacy results from the MAKO study in wet-AMD. 5 January 2018. Accessed 10 November 2020. https://www.globenewswire.com/News-Release/2018/01/05/1284092/0/En/Ohr-Pharmaceutical-Announces-Efficacy-Results-from-the-Mako-Study-in-Wet-Amd.html.

Allegro Ophthalmics. Allegro Ophthalmics announces positive topline vision results of phase 2 study evaluating risuteganib in patients with intermediate dry age-related macular degeneration. 4 June 2019. https://www.Allegroeye.Com/Allegro-Ophthalmics-Expands-Its-Anti-Integrin-Portfolio-with-New-Front-of-the-Eye-Drug-Candidate-Alg-1007-for-the-Treatment-of-Dry-Eye-Disease-3-2-2/.

Raab-Westphal S, Marshall JF, Goodman SL. Integrins as therapeutic targets: successes and cancers. 

Wenick AS, Bressler NM. Diabetic macular edema: current and emerging therapies. 

Rao VR, Prescott E, Shelke NB, et al. Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR). 

Friedman SM, Almukhtar TH, Baker CW, et al. Topical nepafenec in eyes with noncentral diabetic macular edema. 

Campochiaro PA, Shah SM, Hafiz G, et al. Topical mecamylamine for diabetic macular edema. 

Loftsson T, Jansook P, Stefánsson E. Topical drug delivery to the eye: dorzolamide. 

Jóhannesson G, Moya-Ortega MD, Ásgrímsdóttir GM, et al. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. 

Dugel P, Group D-S. The Oculis OCS-01 Phase 2 Study: an effective topical therapeutic for DME. Angiogenesis, Exudation, and Degeneration Symposium 2020. Miami, FL: University of Miami Miller School of Medicine, 2020.

Or CM, Gallagher JR, Fang Z, Reinoso M. The use of topical steroids and NSAIDs in the treatment of diabetic macular edema. 

Pescina S, Ostacolo C, Gomez-Monterrey IM, et al. Cell penetrating peptides in ocular drug delivery: state of the art. 

Minami Y, Song YS, Ishibazawa A, et al. Effect of ripasudil on diabetic macular edema. 

Topical eye drop treatments for the posterior segment would offer easier, less invasive options than those currently available. This would reduce the burden on both patients and their caregivers, increasing adherence and improving outcomes.

The quest for topical treatments for the posterior segment

Amblyopia is a visual developmental disorder consisting of a reduced best-corrected visual acuity in one or, rarely, both eyes without the presence of any ocular pathology

. The aetiology is often a high refractive error, anisometropia, strabismus or a combination of these factors.

Neurological research in recent years has led to a better understanding as to the mechanisms underlying the visual loss in this condition1. Specifically, many monocular and binocular visual deficits have been shown to be the consequence of the anomalies in the visual pathway of the amblyopes, mainly in the striate and extra-striate cortex

Amblyopic eyes showed worse neural adaptation in V1, V2, V3, V3a, Vp and V4; decreased neural response assessed by functional magnetic resonance imaging;

 and worse effective connectivity between the implied brain regions

. For this reason, visual training has been investigated in recent years to confirm whether it might be an effective option for restoring vision in amblyopic patients

, including computer-based active visual training, such as the use of perceptual learning environments, dichoptic stimulation and virtual reality (VR)

Several validated video games have been developed that use visual and perceptual tasks, such as orientation discrimination or letter recognition, among others, to cause a response in neuro-modulatory pathways and the enhancement of attentional skills, according to neurophysiological studies

. These options may support and optimise treatments with spectacles, patching and penalisation.

Among the more recent products resulting from the evolution of digital technology, VR has become increasingly entrenched in the field of visual training, emerging as a safe, effective and very attractive tool that promotes treatment compliance

. VR consists of the presentation of computer-generated 3D environments, enabling users to become fully immersed in a simulated world in which they can interact via multiple sensory channels: visual, auditory or haptic

Using VR, visual stimuli can be presented to the user in two ways: on a monitor screen or in a fully immersive environment generated using technological equipment such as head mounted displays (HMDs) and motion capture systems. Treating amblyopia with a combination of different serious games based on perceptual learning environments for distinct VR interfaces has shown to be a useful therapeutic approach for enhancing visual impairments that occur in amblyopia even after the critical period of visual development

. Table 1 summarises key findings from the clinical studies reported to date using this therapeutic approach.

Some of the first authors to explore the use of VR in amblyopia were the I-BiT system group, who developed an interactive VR-based binocular system to treat amblyopia via participation in interactive computer games or viewing 3D DVD footage with 3D shutter glasses. With this system, specially configured software is used to preferentially stimulate the amblyopic eye without compromising the vision of the unaffected (dichoptic stimulation). The potential of this technology to improve visual acuity in amblyopia has been proven in different age rangesboth when the therapy was applied in isolation

A randomised clinical trial was conducted to validate this technology with a sample of 75 amblyopic children aged 4–8 years

, obtaining a visual acuity improvement of the amblyopic eye of approximately 0.07 logMAR at 6 weeks of treatment. These authors confirmed that the treatment did not induce any adverse effects among the participants, so dichoptic stimulation using 3D shutter glasses technology can be considered a safe alternative to provide immersive sensory feedback to amblyopic patients.

In 2017, a pilot study was conducted to evaluate the effectiveness of dichoptic visual training (Diplopia game, Vivid Vision) using a VR HMD (Oculus Rift OC DK2) in a sample of 17 anisometropic amblyopic adults

. Visual acuity and stereopsis changes were evaluated after eight sessions of 40 minutes each, showing a significant visual improvement and change in stereopsis. Specifically, a total of eight patients (47.1%) had unmeasurable stereoacuity before dichoptic treatment, while this only occurred in two patients (11.8%) after training.

Other VR-based systems have been developed to treat amblyopia, but there have been no clinical data reported to date in the peer-reviewed literature. Qiu and colleagues

 proposed a full-field vision system designed to provide interactive VR computer games for binocular treatment of amblyopia, the Viston-VRsystem. This system uses two dissociated optical systems to provide independent displaying contents for each eye, and consequently each eye can be stimulated by viewing different cartoon films or playing interactive VR games by means of specially devised glasses.

An initial evaluation of this system in the Second Affiliated Hospital Zhejiang University School of Medicine, China,revealed that a weekly treatment consisting of watching cartoon films for 10 minutes and playing VR games for 20 minutes daily generated a significant improvement of patients’ visual acuity function, shortening the treatment period compared to the traditional treatment

. Rastegarpour described in 2011 another anaglyphic VR-based system that has the potential of being an option for amblyopia management

. The prototype of the system, the ABG InSight, presents the visual stimuli to the patient by means of a pair of glasses with two colour filters and software for use on a personal computer.

VR-based training with this technology is based on forcing the patient to use both eyes, and specifically the amblyopic eye, while playing computer games.Cepeda-Zapata et al.

 proposed a system for performing conventional visual therapy exercises (Brock cord, approach technique or convergence-divergence stimulation) into VR environments, validating it in a sample of 45 non-amblyopic students who confirmed its simplicity and versatility.

VR dichoptic and perceptual learning training seems to be a useful therapeutic option for achieving a successful visual rehabilitation in amblyopic patients, allowing the clinicians to control changes in interocular suppression, which is considered one the main factors leading to cortical alterations in amblyopia

. The promising results of VR-based training in amblyopia should be confirmed in more studies, including randomised clinical trials.

Specifically, it is necessary to conduct comparative trials to evaluate the potential benefit of VR-based training in amblyopia over conventional approaches, perceptual learning or dichoptic training in non-VR environments. Furthermore, these technologies are mostly well tolerated by users during short time exposures and do not cause significant side-effects, but this should be investigated in the long term.

It should be noted that the use of HMDs has been occasionally associated with problems, ranging from visual disturbances, dizziness and nausea

. Some authors pointed out the vergence-accommodation conflict as the responsible of the visual discomfort associated with the use of VR HMDs.

María B. Coco-Martin, MSc, PhD
Luis Leal-Vega, MS
Carlos J Hernández-Rodríguez, MSc
Ainhoa Molina-Martín, PhD
David P Piñero, PhD
E: 

Dr Piñero and Mr Hernández-Rodríguez are based at the Department of Optics, Pharmacology and Anatomy, University of Alicante, Spain and at the Department of Ophthalmology, Vithas Medimar International Hospital, Alicante. Dr Molina-Martín is based at the Department of Optics, Pharmacology and Anatomy, University of Alicante. Dr Coco-Martin and Mr Leal-Vega are members of the Group of Applied Clinical Neurosciences and Advanced Data Analysis, Neurology Department, University of Valladolid, Spain. The authors have no proprietary or commercial interest in the medical devices described in this manuscript.

Hernández-Rodríguez CJ, Piñero DP, Molina-Martín A, et al. Stimuli characteristics and psychophysical requirements for visual training in amblyopia: a narrative review. 

Körtvélyes J, Bankó EM, Andics A, et al. Visual cortical responses to the input from the amblyopic eye are suppressed during binocular viewing. 

Li X, Coyle D, Maguire L, et al. Long timescale fMRI neuronal adaptation effects in human amblyopic cortex. PLoS One 2011; 6: e26562.

Li X, Mullen KT, Thompson B, Hess RF. Effective connectivity anomalies in human amblyopia. 

Hernández-Rodríguez CJ, Piñero DP. Active vision therapy for anisometropic amblyopia in children: a systematic review. 

Coco-Martin MB, Piñero DP, Leal-Vega L, et al. 

The potential of virtual reality for inducing neuroplasticity in children with amblyopia.

Deutsch J, McCoy SW. Virtual reality and serious games in neurorehabilitation of children and adults: Prevention, plasticity and participation. 

Waddingham PE, Butler TK, Cobb SV, et al. Preliminary results from the use of the novel Interactive binocular treatment (I-BiT) system, in the treatment of strabismic and anisometropic amblyopia. 

Cleary M, Moody AD, Buchanan A, et al. Assessment of a computer-based treatment for older amblyopes: the Glasgow Pilot Study. 

Herbison N, Cobb S, Gregson R, et al. Interactive binocular treatment (I-BiT) for amblyopia: results of a pilot study of 3D shutter glasses system. 

Rajavi Z, Sabbaghi H, Amini Sharifi E, et al. The role of interactive binocular treatment system in amblyopia therapy. 

 A, et al. Randomised controlled trial of video clips and interactive games to improve vision in children with amblyopia using the I-BiT system. 

 J, et al. Amblyopia treatment of adults with dichoptic training using the virtual reality Oculus Rift head mounted display: preliminary results. 

Qiu F, Wang LP, Liu Y, Yu L. Interactive binocular amblyopia treatment system with full-field vision based on virtual reality. 1st International Conference on Bioinformatics and Biomedical Engineering 2007, 1257-1260.

A computer-based anaglyphic system for the treatment of amblyopia.

 VA, et al. Implementation of a virtual reality rendered in portable devices for strabismus treatment based on conventional visual therapy. Conf Proc IEEE Eng Med Biol Soc 2019:7189-7192.

Quantitative measurement of interocular suppression in anisometropic amblyopia: a case-control study.

Hoffman DM, Girshick AR, Akeley K, Banks MS. Vergence–accommodation conflicts hinder visual performance and cause visual fatigue. 

Virtual reality dichoptic and perceptual learning training seem to be a useful therapeutic option for achieving a successful visual rehabilitation in amblyopic patients.

Use of virtual reality training in amblyopia 

There are many conditions that can cause irregular corneal surfaces, one of which is keratoconus. Surgeons looking for new approaches to treat keratoconus and improve patients’ vision should consider topography-guided treatment in combination with crosslinking. This is especially, but not exclusively, effective in the early stages of the condition, where crosslinking might be used to halt its progression before the corneal refractive procedure is applied.

It should be noted that treating patients with keratoconus using laser-vision correction is an off-label procedure that should be approached with caution and only after taking into consideration many factors, discussed as follows.

If a patient is older than 40 years, I do not primarily offer crosslinking because nature itself performs crosslinking once a person reaches a certain age.

 Such patients can undergo photorefractive keratectomy (PRK) or topography-guided PRK without crosslinking to achieve stable results without any progression of keratoconus if they are followed up for 12 months with stable topography.

The refraction will not be fully altered down to zero because the regularity must come before the refraction. In keratoconus patients the refraction is not usually the main problem.

If the cornea is too thin or too steep, for example with a reading of 65 K, topography-guided treatment for the keratoconus procedure is not effective. To be a suitable candidate, a patient must have a calculated corneal thickness of at least 400 µm at the thinnest point after the topography-guided treatment.

For example, if a patient has a corneal thickness of 470 µm and receives the treatment for 70 µm, that leaves another 400µm of residual tissue following the laser treatment. I then feel comfortable with the procedure, safe in the knowledge the patient will be okay postoperatively.

Typically, the early stages of keratoconus are in younger patients and the condition is progressive until the age of 30.

For patients aged between 25 and 30 years, I do a combination topography-guided session, which means I perform a topography-guided treatment followed by crosslinking immediately afterwards.

Patients aged over 40 years can start to experience a decrease in vision because they no longer tolerate contact lenses. In these patients, I am happy to perform topography-guided treatment without crosslinking. However, all these patients must show up for regular follow-up every 6 months and I would perform crosslinking in cases of progression.

A high number of patients with keratoconus also suffer from atopic disease and do not tolerate rigid gas-permeable contact lenses.

Laser vision correction is not an ideal approach for treating keratoconus but might provide an alternative to corneal transplantation. Vision in patients with corneal transplants is limited to irregular astigmatism and they have a lifetime risk for corneal graft rejection in cases of penetrating transplantations.

The main reason I screen patients for topography-guided treatment to treat keratoconus is because they are unhappy with their glasses or do not tolerate their contact lenses. First, I consider the patient’s age. If the patient is young and does not achieve good vision with glasses, I recommend topography-guided treatment in combination with crosslinking.

If the patient is 40 years or older, then I consider corneal thickness, corneal steepening and how happy or unhappy the patient is with his or her visual acuity. If the visual acuity is better than 20/30, I do nothing.

If the visual acuity is less than 20/40, then I move forward with the procedure. The K reading must be 60 D or less and the corneal thickness must be at least 450 µm.

An adult refugee from Iran presented to me with keratoconus. He was referred to me by chance because I am of Iranian origin and can speak Farsi.

He had undergone crosslinking to stop the progression of keratoconus, in Iran, at the age of 32. His preoperative visual acuity was only 20/100 (Figure 1). His vision could not be increased with refraction and he was unable to tolerate contact lenses.

He shared that he could not read and was having trouble learning the German language because the courses he was undertaking were in German and he was unable to see anything. He was the first patient I treated with topography-guided PRK because he had been crosslinked 4 years earlier.

Three months postoperatively, his vision had increased from 20/100 to 20/25 unaided. The difference map on the Pentacam (Oculus) was identical to the calculated ablation pattern (Figure 1). Four months later, I performed the same procedure on his second eye.

For surgeons who are new to topography-guided treatment, I recommend starting with the ‘topo smooth’ software of the CRS-Master (Carl Zeiss Meditec). This has the advantage that you do not need to perform any calculations. It is just ‘one click’.

If the patient is highly myopic, one can just reduce the sphere by 1 to 2 D but should not add astigmatism to the refraction because this can result in a refractive surprise. The optical zone should not be too big because the laser increases the treatment zone up to 9 mm including the transition zone. The optical zone should be 6 to no more than 6.5 mm, depending on how much tissue ablation is needed.

I also use a treatment-planning device (OCT Zeiss Cirrus 5000, Carl Zeiss Meditec) for epithelial mapping to assess how thick the corneal epithelium is. I can receive a calculation for the ablation and add the tissue.

This means if the patient has an epithelial thickness of 45 µm, I can add 45 µm in the calculation. Then I can perform a trans topography-guided PRK with the Mel 90 Excimer laser in one step, which makes it all easier.

All topography-guided PRKs in patients with keratoconus must be performed as transepithelial procedures. One should also never forget to apply 0.02% mitomycin to the treated area for 60–80 seconds to inhibit the development of corneal haze.

Topography-guided PRK can be a reasonable procedure, with or without the addition of corneal crosslinking, to increase visual acuity and quality. The procedure is easy to calculate and to perform.

Prof. Navid Ardjomand is a consultant ophthalmic surgeon specialising in cornea, cataract and refractive surgery, and an associate professor at the Medical University Graz. He is a consultant for Carl Zeiss Meditec.

Khakshoor H, Razavi F, Eslampour A, Omdtabrizi A. Photorefractive keratectomy in mild to moderate keratoconus: outcomes in over 40-year-old patients. 

Fujimoto H, Maeda N, Shintani A, et al. Quantitative evaluation of the natural progression of keratoconus using three-dimensional optical coherence tomography. 

Topography-guided PRK, with or without the addition of corneal crosslinking, can improve visual acuity and quality in patients with keratoconus. 

How to use topography-guided laser procedures to treat keratoconus 

A smartphone direct ophthalmoscope attachment (D-EYE) has proved easy to use and successful in visualising the optic disc compared with the direct ophthalmoscope (DO), according to research presented at the virtual annual meeting of the Canadian Ophthalmological Society. Data from the prospective, randomly assigned, crossover, educational trial involved 44 first-year medical students not familiar with this type of examination, who looked at measurements such as vertical cup-to-disc ratio, fundus matching using an online programme and identifying whether the state of health of the optic nerve was normal or abnormal, according to Dr Rachel Curtis, a fourth-year ophthalmology resident at Queen’s University in Kingston, Ontario, Canada, and the study’s presenting author.

“There is a big push for new technologies and new ways of delivering medical teaching,” Dr Curtis told Ophthalmology Times® during an interview. “The whole concept is finding new technologies to teach medical students [how to examine the optic nerve] and ways to integrate these technologies into practice.”

The smartphone DO attachment lets physicians record the picture or video and show the anatomy, Dr Curtis said. “It can improve continuity of care by documenting serial exams,” she explained. “It also helps students identify what they are seeing on examination. Your student or ophthalmology resident can show it to your preceptor. Another advantage is that the images or a video can be uploaded into an electronic medical record.”

Dr Curtis noted that a competent fundus examination is often part of routine clinical evaluation in family practice, the emergency department and inpatient wards, and is a duty of care in many clinical situations. She added that there has been a decrease in confidence and use of ophthalmoscopy among medical students and physicians.

“It is a difficult skill to use a direct ophthalmoscope and it is generally not well taught in medical schools,” said Dr Curtis. “This [D-EYE] is a fairly intuitive technology.”

In the study, a fundus photo matching programme was utilised to compare the performance of the D-EYE with that of the DO. Students were randomised to initiate the examination with the D-EYE or the DO.

The two cohorts studied over 2 consecutive years—one had 26 students and the other had 18—were similar in terms of mean age and gender distribution. Students were given 10 minutes to examine both eyes of one patient, with one eye dilated and one not dilated. They examined multiple patients during the study.

After the examination, students were asked to match the patient’s optic nerve to the fundus photograph that was found in a 9-photo collage that had been randomly generated. They could make multiple attempts and would receive a message under the image telling them whether their choice was correct or incorrect. If it was incorrect, they would receive a message telling them to try again.

Students were asked to complete a form to indicate their perception of “ease of use” of the device and their confidence in using the device. They were also asked to document the vertical cup-to-disc ratio of each eye and to report whether the disc’s state of health overall was normal or abnormal.

Dr Curtis and colleagues found students using the DO needed more attempts (3.57 vs 2.69, P = 0.010) to match the patient’s fundus to the correct photograph and more time (197.00 vs 168.02 seconds, P = 0.043, t test) to correctly choose the proper fundus photograph, when compared with the D-EYE device. These results were discussed at the Canadian Ophthalmological Society annual meeting as part of a paper abstract presentation, which won a third-prize award.

“The difference was both statistically significant and clinically relevant,” said Dr Curtis. “It took 30 seconds more to identify the correct nerve with the DO. Thirty seconds does not seem like a lot, but in a busy ward or clinic, it does make a difference in efficiency. We found that there was not only less time to match the optic nerve, but it took them less matching [fewer attempts] and there was less guessing involved.”

The investigators observed no statistically significant difference in the accuracy of estimating vertical cup-to-disc ratio in either the right or the left eye, which was the primary outcome of the study, using D-EYE vs DO. Medical students reported greater ease of use with the D-EYE (6.40 vs 4.79, P <0.001) as well as overall confidence in the examination (5.65 vs 4.49, P = 0.003).

The technology facilitates examining the optic nerve and is able to distinguish whether its state of health is grossly normal or grossly abnormal, Dr Curtis emphasised. “That is arguably the most clinically relevant outcome,” she said. “If you are going to send [the patient] off for referral or make an appropriate consult, the thing you need to be able to do is to recognise whether or not this nerve needs to be looked at by an ophthalmologist.”

In the time of the COVID-19 pandemic, the use of the smartphone and DO attachment lets clinicians be more physically distant from a patient when performing the examination and adhere to infection-minded prevention. “With the direct ophthalmoscope, you have to be very close to the patient to get a good view,” Dr Curtis concluded. “In an infection-minded environment, you may want a larger buffer between you and the patient. This [smartphone and direct ophthalmoscope attachment] is a good arm’s-length distance between you and the patient’s eye.”


Dr Curtis has no financial disclosures related to this content.

Mackay DD, Garza PS, Bruce BB, Newman NJ, Biousse V. The demise of direct ophthalmoscopy: a modern clinical challenge. 

Gupta RR, Lam WC. Medical students’ self-confidence in performing direct ophthalmoscopy in clinical training. Can 

A smartphone direct ophthalmoscope attachment makes it possible to examine the optic nerve and distinguish whether its state of health is normal or abnormal.

Smartphone direct ophthalmoscope tech helps visualise optic disc

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.

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.

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.

Understanding the genetics of glaucoma

SMILE procedure offers low enhancement rate after nomogram adjustment

IRISS registry study offers real-world outcomes