BIGH3 (transforming growth factor-β-induced Gene Human Clone 30) is a promising serum biomarker for diabetic macular oedema (DMO) in patients with nonproliferative diabetic retinopathy (NPDR), according to Dr Andric Perez-Ortiz, who presented research at the Association for Research in Vision and Ophthalmology 2020 virtual annual conference. Dr Perez-Ortiz and colleagues conducted a case-control study analysing levels of BIGH3, transforming growth factor-β1 (TGF-β1) and transforming growth factor-β2 (TGF-β2) in the aqueous humour and serum of patients with DMO and unaffected controls.

The results showed that BIGH3 was the only cytokine that was present in significantly different concentrations in both fluids in DMO patients compared with controls, and the only cytokine with a positive significant correlation between its level in aqueous humour and serum. None of the three cytokines, however, correlated with macular thickness or optical coherence tomography (OCT) phenotype among patients with DMO.

According to Dr Perez-Ortiz, studies investigating expression and levels of these cytokines have all been performed 

. “The aim of our study was to measure the concentrations of TGF-β1, TGF-β2 and BIGH3 in aqueous humour of patients with NPDR—with and without DMO—and to assess their clinical applicability as serum markers by testing their correlation in aqueous humour and serum, and association with macular thickness and DMO phenotype,” said Dr Perez-Ortiz, an associate professor in the Department of Public Health at Universidad Panamericana in México City, Mexico and research fellow, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States.

“The predictive capacity of BIGH3 certainly warrants further study,” he said. “Especially its sensitivity and specificity and/or predictive use as an early biomarker for DMO development.”

Interest in exploring the potential for TGF-β1, TGF-β2 and BIGH3 to serve as biomarkers for DMO is based on understanding of their role in the pathogenesis of DR and DMO. Dr Perez-Ortiz explained that pericyte dropout and increased inflammation and activation of proinflammatory transcription factors that induce monocyte and macrophage infiltration occur early in the pathogenesis of these diabetic eye diseases. Macrophages predominantly secrete TGF-β1 and TGF-β2 that induce apoptosis of retinal pigment epithelium (RPE) and upregulation of the gene encoding for BIGH3.

BIGH3 is an extracellular matrix protein that can act in an autocrine or paracrine manner to induce apoptosis of RPO cells, pericytes and retinal endothelial cells in a time- and dose-dependent fashion. The presence of BIGH3 has been observed in the histopathologic retinal section of a postmortem globe with documented NPDR deposited predominantly around retinal vessels and occasionally in choroidal vessels. “Hence it has been hypothesised that monocyte/macrophage-induced BIGH3 expression is an important progressive step in the pathophysiology of pericyte loss,” Dr Perez-Ortiz said.

The study investigating levels of the TGF-β cytokines and BIGH3 in patients with NPDR included adults aged 18 years and older with type 2 diabetes mellitus who were undergoing a surgical procedure (initiation of intravitreal injection for DMO patients and cataract surgery for controls). It included 26 patients with DMO and 27 patients without DMO.

Patients were excluded if they had systemic inflammatory disease or a history of any vitreous procedure. The aqueous humour sample of approximately 1 µL was collected in all eyes prior to any surgical intervention, and the cytokine levels in serum and aqueous humour were quantified with cytometric-bead assays.

The two groups were similar in mean age (~ 63 years) and sex distribution, but the average time since diabetes diagnosis was significantly longer in the DMO patients than in the controls. As would be expected, maximum central macular thickness (CMT) was also significantly greater in the cases compared with controls. Among patients with DMO, cystic changes and spongiform changes were the most common phenotypes identified on OCT.

The cytokine analyses showed that the aqueous humour concentration of TGF-β1 was significantly greater in the DMO eyes compared with the controls, whereas the reverse relationship was observed in serum. TGF-β2 also was present in a significantly higher concentration in the aqueous humour of the cases compared with controls, but its concentration in serum did not differ significantly between the two groups.

Further analyses showed that the ratio of TGF-β1 in aqueous humour serum was disproportionately elevated in the DMO cases compared with controls. In addition, a significant positive correlation was found in the DMO group between aqueous humour concentration and maximal CMT. The correlation between serum concentration and maximal central macular thickness was negative for TGF-β1 and positive for TGF-β2.

The concentration of BIGH3 was significantly higher in both serum and aqueous humour in the DMO group compared with controls. The ratio of BIGH3 concentration in aqueous humour to serum was not significantly different comparing cases and controls, and it did not correlate with CMT or OCT subtypes in the eyes with DMO.


Dr Perez-Ortiz has no relevant financial interests to disclose.

Articles

Results of a study analysing cytokine levels in the aqueous humour and serum of patients with nonproliferative diabetic retinopathy with and without diabetic macular oedema support further research investigating transforming growth factor-β-induced Gene Human Clone 30 (BIGH3) as a potential biomarker for DMO.

Investigators explore pathogenic cytokines as biomarkers for DMO

In the past, attempts at bleb repair after trabeculectomy and introduction of the use of mitomycin C (MMC) to improve surgical success rates resulted in blebs that were avascular and prone to leaks. According to Prof. Neeru Gupta, chief of glaucoma at the University of Toronto, Canada, and president-elect of the World Glaucoma Association, this situation is a “time bomb”. She said: “Left unchecked, it can lead to blebitis and possibly endophthalmitis, and myriad other problems, such as hypotony with associated anatomic disruptions such as vision-blurring corneal striae, shallow anterior chambers, buildup of excess fluid leading to dome-shaped choroidals and hypotony maculopathy.”

Techniques that have attempted to address the problem of leaky blebs include conservative treatment with antibiotics; aqueous suppressants; steroids; collagen shields; bandage contact lens; pressure patches; cyanoacrylate tissue glue; autologous blood; and argon laser or Nd:YAG laser. The microsurgical approaches include bleb resuturing, and bleb excision and conjunctival advancement with or without various grafting techniques.

Despite all this, no procedure stands out as effective. “Despite the number of attempted procedures, we continue to struggle with managing bleb leaks,” Prof. Gupta said.

Prof. Gupta developed the minimally invasive conjunctival surgery incision-free procedure to address late-onset bleb leaks close to the limbus. A patient had a history of high myopia, advanced pigmentary glaucoma, retinal detachment treated with pars plana vitrectomy and later with pneumatic retinopexy and cryotherapy. They had used multiple glaucoma medications for advanced glaucoma, thin corneas, bilateral cataracts and had remaining central islands of vision of 20/60 to 20/70.

Prof. Gupta performed bilateral trabeculectomies with MMC. Vision was stable with intraocular pressures (IOPs) of 8–10 mm Hg bilaterally. In 2012, however, the vision in the left eye decreased to 20/100 with an IOP of 2 mm Hg and an avascular leaking bleb. Three days later, the vision was 20/200 with an IOP of 0 mm Hg.

In surgery, Prof. Gupta acted to address this situation without undoing the previous treatments. Instead of excising the bleb and covering the area with conjunctiva, she injected subconjunctival lidocaine above the bleb.

She described the conjunctival epithelium as highly voluminous and able to move freely. With gentle tugging and without disturbing Tenon capsule, she pulled a sizable area of the conjunctival tissue to the limbus over the leaking area and put in a series of stitches (typically three to four) without using a great deal of pressure that resulted in a sealed wound.

“This was a short, incision-free procedure,” she said of this first such case. The patient has done well during the ensuing 8 years. Prof. Gupta reported that she has performed this procedure in 14 cases and reported the results in the 

In all cases, the patients have remained stable and medication-free from 2 weeks to 5 years later. She said that with time the transposed conjunctival tissue becomes translucent and seems to take on the characteristics of the early bleb that was leaking.

Prof. Gupta enumerated the surgical benefits of this procedure. “It is short and incision free with good success; the bleb is preserved; the procedure is relatively simple, inexpensive, efficient and accessible; and the patients are comfortable postoperatively and can return to normal activities,” she said. “They leave after the surgery with an antibiotic and a steroid. She advised that studies are needed to determine the long-term outcomes.

Prof. Gupta has no financial interest in this subject matter

Gupta N. Incision-free minimally invasive conjunctival surgery (MICS) for late-onset bleb leaks after trabeculectomy (an American Ophthalmological Society thesis). Am. J. Ophthalmol. 2019;207:333-342.

Surgeons can consider a relatively simple, inexpensive, efficient and accessible incision-free procedure to preserve blebs. 

Straightforward procedures for leaking blebs: No incision required

YAG laser vitreolysis is a less-invasive option than pars plana vitrectomy for patients who are affected by vitreous opacities (floaters), according to Dr Netan Choudhry of Vitreous Retina Macula Specialists, Toronto, Canada. Although floaters are typically clinically inconsequential, a small subset of patients have debilitating symptoms that interfere with their vision and require treatment.

During the American Society of Retina Specialists virtual annual meeting, co-author Dr Collier Jiang, University of Calgary Department of Ophthalmology, presented outcomes from the VOYAGE study evaluating the impact the surgical procedure has on visual outcomes and on optical coherence tomography (OCT) imaging in patients with symptomatic vitreous floaters. As background, Dr Jiang said few publications exist on the treatment since it is so new, and those that have been published have shown varying degrees of visual function improvement after the procedure. “Up to this point, we really have not had an objective way of evaluating the opacity, what it looks like, where is it, what it is doing … what the end point for treatment is,” Dr Choudhry said.

In the VOYAGE study, 35 patients (mean age 59; 43% female) with symptomatic floaters (n=40 eyes) were treated with YAG laser vitreolysis. All patients had a dilated eye examination to confirm the floaters as well as pre- and post-treatment ultra-widefield imaging.

Best corrected visual acuity (BCVA) was measured and swept-source OCT conducted prior to and after treatment. Dr Jiang noted that five patients received bilateral YAG laser vitreolysis due to symptomatic vitreous floaters in both eyes.

All treatments were performed by a single surgeon using the Ultra Q Reflex Laser (Ellex) after dilation and anaesthesia, using a single mid-vitreous contact lens that was applied to the cornea using GenTeal ointment (Alcon).“The energy level was initially set for 5 mJ and titrated up to a maximum of 20 mJ to achieve plasma formation with the creation of bubbles and opacity destruction,” Dr Jiang said. Patients were re-treated if they reported ongoing symptoms during follow-up; 37% of eyes required a second treatment and 35% required a third treatment to resolve symptoms.

Overall, patients experienced an improvement in mean BCVA after the first YAG treatment compared with baseline (0.14 ±0.20 logMAR units vs 0.11 ±0.20 logMAR units, respectively), however BCVA was not significantly different after the second and third treatments compared with baseline. Furthermore, just over half of the patients (55%) reported an improvement in their symptoms after their final YAG treatment, Dr Jiang said.

“Overall, this study showed a significant improvement in mean BCVA after the first YAG laser vitreolysis treatment compared with baseline,” he said. “Ninety percent of patients reported resolution of their symptomatic visual disturbance after the final treatment session. There were no retinal detachments or retinal tears.”

The VOYAGE study “used a variety of novel imaging techniques to quantify and follow changes in the vitreous opacities,” Dr Jiang said, adding that scanning laser ophthalmoscopy and dynamic OCT visualisation were particularly useful tools. For example, he said by increasing the gain by 55% to 75% from an unaltered swept-source OCT scan, clinicians are able to view the opacities that were previously unable to be imaged.

Furthermore, “dynamic OCT imaging can capture the movement of the patient’s vitreous in real time and help localise vitreous opacities during treatment,” he said. “OCT can provide useful information. When the depth is increased to 6 mm, we can identify some vitreous opacities that may have been missed with the standard 3 mm depth.”

Dr Carl Regillo, Wills Eye Hospital, led the paper discussion, and noted that about two-thirds of patients needed re-treatments. “Why aren’t we doing this across the board? Most vitreoretinal surgeons are not doing YAG vitreolysis. Is it time consuming? Is it challenging?” he asked.

“These procedures can take some time, probably 10 to 15 minutes,” Dr Choudhry said. “The reason that it was broken up into, on average, two sessions, was because after a certain amount of power was administered to the eye, there was a risk of an increase in IOP. We wanted to limit all complications or [adverse] effects.”

Dr Choudhry elaborated on the unique imaging used, noting that swept-source OCT was vital to “identify the opacities that the patients were complaining about and then titrate the treatment to the end point of the disappearance of those opacities, to know that we have hit an end point for the therapy.” In terms of clinical practice implementation and patient selection, he noted that clinicians should not forget that not every patient who has floaters needs treatment.

“I have been doing [YAG vitreolysis] for the past year-and-a-half successfully in the patients [who] really need it,” he said. “Of course, in the world of optics, the definitive result will always be with the complete clearing of the vitreous, but if we can avoid vitrectomy and the small risk of complication from vitrectomy in those patients [who] are good for this procedure, then why not?” Dr Choudhry did note, however, that vitrectomy is the first and only option for certain opacities of the amorphous variety or multiple diffuse floaters.


Dr Choudhry has no financial disclosures related to this content.

Ivanova T, Jalil A, Antoniou Y, et al. Vitrectomy for primary symptomatic vitreous opacities: an evidence-based review. 

Study found that YAG laser vitreolysis was less invasive than pars plana vitrectomy for patients with vitreous opacities.

Treating vitreous opacities with YAG vitreolysis

Presbyopia combined with any refractive error has been a significant treatment challenge for refractive surgeons. Traditionally, the principles used for monovision contact lenses have been applied to corneal refractive surgery.

 However, this retains many of the limitations found with such contact lenses, including loss of fusion and stereoacuity.

Multifocal corneal ablation profiles have also been suggested; however, although an overall improvement in visual acuity has been recorded for both near and distance vision, the efficacy has remained relatively low

, and safety and quality of vision can be compromised.

 A better solution that offers improved visual results and greater tolerance is still required.

It is helpful to consider presbyopia as the inability to accommodate rather than a decrease in depth of field of the eye. This decrease can be overcome, at least in part, by using an optimised ablation profile that controls postoperative spherical aberration, thus increasing the depth of field of each eye without significantly compromising visual quality, contrast sensitivity or night vision. The optimisation is based on the patient’s age, refraction, preoperative spherical aberration, tolerance for anisometropia and treatment centred on the corneal vertex.

We learned in the 1990s that spherical aberration increased in myopic ablations, leading to a decrease in visual quality and contrast sensitivity.

 My early work in wavefront-guided repair of night vision disturbances using what was at the time the highest resolution aberrometer (210 µm) coupled with Gaussian small-spot (0.7 mm) high repetition rate excimer laser ablation taught me that even a modest (27%) decrease in harmful levels of spherical aberration restored contrast sensitivity and night vision quality to normal.

This led me to consider up to approximately 0.6 µm of spherical aberration (Optical Society of America, 6 mm) as tolerable – this level can be filtered by the brain. This led to the concept of using spherical aberration to increase the depth of field of the eye.

Within a few years, several researchers were able to experimentally duplicate this concept using adaptive optics systems and to demonstrate that extended depth of field increased linearly with the increase in spherical aberration, but only up to a certain point.

 Most important to note here is that adaptive optics studies proved that the depth of field increased with both positive and negative spherical aberration, showing that the effect was due to the spherical aberration itself rather than a zonal change in refractive sphere power (e.g., in positive spherical aberration, the larger the pupil, the more myopic the sphere of the refraction).

These laboratory experiments confirmed our surgical clinical research findings that a ‘therapeutic’ range for spherical aberration producing extended depth of field existed, beyond which there were ‘toxic’ effects of halos and reduced contrast sensitivity. During my early work developing an algorithm for presbyopic correction, the initial aim was to be able to adjust depth of field enough to provide clear vision from distance through intermediate to near, creating an eye that could see 20/20 at distance and also see a computer screen and read J1.

We discovered that with photopic pupil diameters, the depth of field could be safely increased to 1.50 D for any starting refractive error. Given a 1.50 D depth of field, it would not be possible to get full distance and full near vision monocularly; therefore, based on the time-tested concept of introducing a degree of anisometropia between the eyes, the non-dominant eye was set up to be slightly myopic, so that the predominantly distance (dominant) eye was able to see at distance to intermediate while the predominantly near (non-dominant) eye was able to see in the near range and up to intermediate.

Both eyes had similar acuity in the intermediate region, an optimal situation for stereopsis. Micro-anisometropia in this case draws on the inherent cortical processes of neuronal gating and blur suppression by ‘interocular rivalry’ (the ability for conscious attention to be directed to the specific area with the best image quality within the entire visual field of both eyes). This contrasts with other attempts to treat presbyopia by inducing a cornea with two distinct focal points within the same eye: ‘intraocular rivalry’.

A further component contributing to the increase in depth of field, which persists even in eyes that have lost the ability to change crystalline lens power during the accommodative effort, is the increase in depth of field afforded by pupil constriction during accommodation. The combination of controlled induced corneal aberrations and pupil constriction significantly increases the depth of field on the retinal image.

Intraretinal and cortical processing and edge detection are the final components of laser blended vision: the pure retinal image, which is modified by spherical aberration, is further enhanced by central processing to yield the perception of clear, well-defined edges. In principle, as described above, the depth of field can be enhanced through the introduction of either positive corneal spherical aberration, in which case corneal power increases with zonal diameter, or negative aberration, where power decreases with distance from the corneal vertex.

Most patients have some nascent positive spherical aberration before treatment, which is added to by the positive spherical aberration induced by standard myopic ablation. The important thing is to control the induction of spherical aberration to avoid increasing it above the tolerance threshold, which can cause loss of contrast sensitivity and night vision disturbances and can result in a topographic central island. To account for this, the ablation profile includes a pre-compensation factor.

A standard large zone (7 mm) hyperopic ablation induces negative spherical aberration that, in the case of hyperopic correction, is unlikely to increase above the tolerance threshold even with up to +7.00 D correction because most patients start with some positive spherical aberration and the range of hyperopic treatments is smaller than the range of myopic treatments.

 In emmetropic patients, you cannot rely on the ablation inducing spherical aberration, so the spherical aberration component of the calculation is increased.

This has an impact on the refractive accuracy. As emmetropic patients have high expectations and low tolerance to refractive inaccuracy, the best option is to increase the depth of field somewhat and make sure that the micro-anisometropia component is as accurate as possible.

The ablation profiles, taking age and preoperative spherical aberration into account, are referred to as non-linear aspheric ablation profiles because the spherical aberration component is governed by a non-linear function.

The outcomes using Presbyond laser blended vision with the MEL 80 excimer laser (Carl Zeiss Meditec) have been published for myopia up to –8.50 D,

 All treatments were performed as bilateral simultaneous LASIK.

For inclusion, patients had to be medically suitable for LASIK, presbyopic with corrected distance visual acuity (CDVA) no worse than 20/25 in either eye and have a tolerance of at least -0.75 D anisometropia.The standard micro-monovision protocol corrected the dominant eye to plano and the non-dominant eye to –1.50 D irrespective of age.

At 1-year follow-up, binocular uncorrected distance visual acuity was 20/20 or better and binocular uncorrected near visual acuity was J2 or better in 95% of myopes, 77% of hyperopes and 95% of emmetropes. Retreatment rate was 19%, 22% and 12%, respectively, although this would have been 5%, 6% and 4% had the criterion for retreatment been 20/32. The safety in terms of CDVA and contrast sensitivity was the same as for standard LASIK, with no eyes losing more than one line.

Mean mesopic contrast sensitivity either remained the same or improved slightly at 3, 6, 12 and 18 cycles per degree for all three populations. Stereoacuity, although slightly reduced, has been shown to be maintained at a functional level of 100–400 seconds. Similar results have been reported by other groups.

The principle of correcting refractive error while modulating spherical aberration to benefit the depth of field can be equally applied to cataract surgery with IOL placement. A previously pseudophakic patient can be treated by laser blended vision protocols to set a total final spherical aberration of the eye that gives an extraordinary range of vision.

Performing cataract surgery on a patient with prior laser blended vision in the cornea enables the choice of a monofocal IOL of appropriate asphericity to leave the eyes with optimised spherical aberration, without resorting to diffractive optics and all of the quality of vision and adaptation issues that are introduced by intraocular rivalry, reduced contrast and the selective quantisation of the reading distance.

The combination of micro-anisometropia with increased depth of field through appropriate non-linear aspheric ablation profiles substantially improves visual outcomes in comparison with the conventional monovision approach. This can be achieved in the cornea and in conjunction with cataract surgery.

Trials show that laser blended vision is effective in presbyopic patients with refractive errors between +5.75 and –9.00 D, including emmetropic presbyopes. With the safety advantages of modern femtosecond LASIK, the rapid bilateral surgical procedure and a recovery time of a few hours, patient satisfaction is extremely high.

Reinstein, MA(Cantab), FRCSC, DABO, FRCOphth, FEBO

Dr Reinstein founded the London Vision Clinic in 2002, and holds professorships at Columbia, Ulster and Sorbonne Universities. He is a consultant for Carl Zeiss Meditec and has a financial interest in ArcScan Inc.

Goldberg DB. Laser in situ keratomileusis monovision. 

Fawcett SL, Herman WK, Alfieri CD, et al. Stereoacuity and foveal fusion in adults with long-standing surgical monovision. 

El Danasoury AM, Gamaly TO, and Hantera M. Multizone LASIK with peripheral near zone for correction of presbyopia in myopic and hyperopic eyes: 1-year results. 

Pinelli R, Ortiz D, Simonetto A, et al. Correction of presbyopia in hyperopia with a center-distance, paracentral-near technique using the Technolas 217z platform. 

Rocha KM, Vabre L, Chateau N, Krueger RR. Expanding depth of focus by modifying higher-order aberrations induced by an adaptive optics visual simulator. 

Reinstein DZ, Archer TJ, Couch D, et al. A new night vision disturbances parameter and contrast sensitivity as indicators of success in wavefront-guided enhancement. 

Marcos S, Barbero S, Jimenez-Alfaro I. Optical quality and depth-of-field of eyes implanted with spherical and aspheric intraocular lenses. 

Reinstein DZ, Carp GI, Archer TJ, et al. LASIK for the correction of high hyperopic astigmatism with epithelial thickness monitoring. 

Reinstein DZ, Archer TJ, Gobbe M. LASIK for myopic astigmatism and presbyopia using non-linear aspheric micro-monovision with the Carl Zeiss Meditec MEL 80 platform.

Reinstein DZ, Couch DG, Archer TJ. LASIK for hyperopic astigmatism and presbyopia using micro-monovision with the Carl Zeiss Meditec MEL80. 

Reinstein DZ, Carp GI, Archer TJ, Gobbe M. LASIK for the correction of presbyopia in emmetropic patients using aspheric ablation profiles and a micro-monovision protocol with the Carl Zeiss Meditec MEL80 and VisuMax. 

Ganesh S, Brar S, Gautam M, Sriprakash K. Visual and refractive outcomes following laser blended vision using non-linear aspheric micro-monovision. 

Falcon C, Norero Martinez M, Sancho Miralles Y. [Laser Blended Vision for presbyopia: Results after 3 years]. 

Prasad KK, Smitha TS, Shetty SS, Poojary P. Laser Blended Vision-LASIK for presbyopia and initial clinical experience in 100 Indian patients.

Zhang T, Sun Y, Weng S, et al. Aspheric micro-monovision LASIK in correction of presbyopia and myopic astigmatism: early clinical outcomes in a Chinese population. 

Presbyopia can be treated in emmetropic, myopic and hyperopic patients with refractive errors between +5.75 and -9.00 D using corneal non-linear aspheric ablation profiles to increase the depth of field in both eyes, in combination with micro-monovision. Patient satisfaction with this approach is high.

Non-linear aspheric corneal ablation can be used to treat presbyopia

New standards have emerged for treating visual diseases in paediatric populations during the previous two decades, thanks to community involvement and external funding of research, according to Dr Richard W. Hertle, who described the progress achieved in various diseases as a result of these factors. Such progress is likely to continue in the future and spark continuing improvements in the treatment of a range of disorders.

Dr Hertle is chief of paediatric ophthalmology and director of the Vision Center at Akron Children’s Hospital in Akron, Ohio, United States. He is also director of the hospital’s paediatric ophthalmology fellowship programme, the Dr Robert “Boomer” and Jill Burstine Chair in paediatric Ophthalmology, and a professor of surgery at Northeast Ohio Medical University in Rootstown, Ohio.

Numerous studies of retinopathy of prematurity (ROP) have evaluated interventions such as cryotherapy, supplemental oxygen, light reduction and early laser treatment, which reduced blindness caused by abnormal development of blood vessels in thousands of infants annually to about 500.

Cryotherapy decreased blindness by 50% in infancy and 17% by age 10 according to the study ‘Cryotherapy for Retinopathy of Prematurity’;

Supplemental oxygen therapy did not stop progression of ROP (as seen in ‘Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity Study’) and nor did reduction of ambient light (‘Light Reduction in Retinopathy of Prematurity Study’);

Early laser application reduced blindness by another 5% (‘Early Treatment for Retinopathy of Prematurity [ETROP] Study’); and

Artificial intelligence and use of telemedicine approaches for evaluating acute ROP decrease blindness worldwide.

A more recent treatment is injection of intraocular bevacizumab (Avastin, Genentech), which, when compared with laser therapy, has been found by physicians to be equally efficacious, with the same long-term benefits and fewer adverse effects, Dr Hertle said.

The Pediatric Eye Disease Investigator Group in the US, a collaborative that conducts multicentre clinical research in strabismus, amblyopia and other diseases treated by paediatric ophthalmologists, functions internationally with hundreds of physicians. These trials, funded by more than $65 million raised since inception of the group in 1997, have developed new treatment protocols for strabismus, amblyopia, nasolacrimal duct obstruction, myopia, hyperopia and uveitis.

Dr Hertle further recounted major findings of this group that were not the standard of care before the clinical trials, including the following:

Patching for 2 hours is as effective as patching for 6 or 8 hours in patients with moderate amblyopia;

Patching over 6 hours works as well as full-time patching in patients with dense amblyopia;

Atropine use can be as effective as patching; and

Spectacle use alone can treat amblyopia without patching or drops in strabismic amblyopia.

“The changes in the current standards of practice in common eye diseases are the result of these large clinical trials,” Dr Hertle explained. “We are moving from anecdotes to the ability to practice rigorous ways to treat amblyopia and strabismus.”

 evaluated the use of an intraocular lens (IOL) compared with a contact lens during the first 6 months of life to treat unilateral congenital cataract. The results showed equal vision with both.

Children aged between 9 and younger than 18 years diagnosed with this disorder, which is present in 5–7% of children, were treated in a multicentre, randomised clinical trial

 to determine the effectiveness offour therapies: office-based vergence/accommodative therapy plus home reinforcement; home-based pencil push-ups; home-based computer vergence/accommodative therapy and pencil push-ups; and office-based placebo therapy.

“The results showed that doing therapy in the office with home reinforcement was better than any other type of therapy, including pencil push-ups,” Dr Hertle said. A separate convergence trial that included 221 patients showed that convergence therapy to treat attention and reading was ineffective for attention and reading and only helped convergence.

When considering all the studies performed in thousands of patients with a variety of visual diseases, the community support was the most consequential factor.

“By allowing the family and their children to participate in these trials and the grants, gifts, endowments and time, we were able to progress in paediatric eye care,” Dr Hertle said.


Dr Hertle has no financial interest in this subject matter.

Suelves AM, Shulman JP. Current screening and treatments in retinopathy of prematurity in the US. Eye Brain. 2016;8:37-43.

Barry GP, Tauber KA, Greenberg S, et al. A comparison of respiratory outcomes after treating retinopathy of prematurity with laser photocoagulation or intravitreal bevacizumab. Ophthalmol Retina. Published online 5 June 2020. DOI:10.1016/j.oret.2020.06.002

Beck RW. Clinical research in pediatric ophthalmology: the Pediatric Eye Disease Investigator Group. Curr Opin Ophthalmol. 2002;13:337-340.

Gunton KB. Advances in amblyopia: what have we learned from PEDIG trials? Pediatrics. 2013;131:540-547

Lambert SR, Aakalu VK, Hutchinson AK, et al. Intraocular lens implantation during early childhood: a report by the American Academy of Ophthalmology. Ophthalmology. 2019;126:1454-1461.

CITT-ART Investigator Group. Treatment of symptomatic convergence insufficiency in children enrolled in the Convergence Insufficiency Treatment Trial–Attention & Reading Trial: a randomized clinical trial. Optom Vis Sci. 2019;96:825-835.

Community support is the most important factor in ascertaining effective treatments for paediatric eye diseases.

It takes a village to beat visual system diseases in children

Diabetes mellitus (DM) is a metabolic disease of high glucose levels or poor glucose utilisation that leads to significant morbidity, particularly kidney, eye, heart and cerebrovascular disease, and premature mortality.

 Type 1 diabetes is one of the most common chronic diseases in children and represents a global public health challenge;

 the prevalence of type 2 diabetes ranges from 1 to 51 per 1,000.

Although children and adolescents with type 1 diabetes are threatened daily with acute complications of hypoglycaemia and ketoacidosis, it is the long-term microvascular and macrovascular complications of the disease that place them at the greatest risk of serious morbidity and early mortality.

DM can affect any ocular tissue, although the retinal microvascular changes of diabetic retinopathy (DR) are thought to be the most important long-term complication.1,2 DR, which can occur in all types of DM, can have a debilitating effect on visual acuity and ultimately lead to blindness in some cases.

The risk for and time to develop DR is variable, but it may already be present at the time of DM diagnosis. A Danish prospective cohort study that followed children and adolescents with type 1 DM for 8 years reported the prevalence of any level of DR as 17.7% in children aged 12–15 years and 45.4% in the 16–20 years age group, increasing to 67.6% after 20 years.

 confirmed that DR was variable but uncommon before 12 years of age.

Specifically, mild DR occurred in 10% of UK children at 12–13 years; only 0.17% had sight-threatening DR.

 A multicentre study based in north-west England reported a DR prevalence of 11% in children with T1 DM.

Of these, 44% had background DR whilst 56% had pre-proliferative DR, with early age at diagnosis and poor metabolic control as independent risk factors.

 reported a DR prevalence in children in Ethiopia of 4.7% including two individuals who had maculopathy associated with vision loss.

A recent study from the United States in young people reported an incidence of DR in 20.1% and 7.2% over a median period of 3.2 years in type 1 diabetes and 3.1 years in type 2 DM.

DR risk depends on age at DM onset or diagnosis, duration of disease

 A population-based study from Australia reported that 24% of children and adolescents with type 1 diabetes developed DR after 6 years of DM;

 a similar study in Sweden reported a DR incidence of 27%

 after 13 years of DM. Prepubertal DM duration is strongly associated with the development of DR.

The general management of DM in young patients has improved recently, supported by advancing technology. The development of insulin pumps, digital technology and outcome analyses have led to significant improvements in glycaemic control.

Control of blood pressure and serum lipids is also necessary. Close working with diabetologists as well as renal paediatricians is important in achieving the best outcomes.

The current UK guidance is for annual screening from 12 years and above, based on the low prevalence of DR in younger children.

 A close check should be kept on patients younger than 12 by the diabetologist and appropriate referrals to the Eye Clinic effected as necessary.

The American Academy of Ophthalmology recommends that annual eye examinations in children should start 3–5 years after the diagnosis of type 1 DM.

 The International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes guideline from 2017 recommends that eye examinations for children with type 1 DM commence at 11 years of age and after 2 years of DM duration; in children with type 2 DM, screening should commence from diagnosis.

In populations where DR onset is earlier or more common in children, screening programmes should be appropriately directed at the vulnerable population. Evaluation for other eye changes may be initiated by paediatric diabetes teams as appropriate.

Colour fundus photographs have traditionally been used to document DR. Optical coherence tomography (OCT) and OCT angiography (OCTA) are non-invasive state-of-the-art imaging techniques that are very useful in evaluating the status of the macula and specifically in quantifying diabetic macular oedema (DMO).

 Recently, the advent of spectral domain OCT has allowed diabetic neurodegeneration to be identified, which is thought to precede clinical DR detection.

Unfortunately, the literature on treatment of DR in the young is limited because clinical trials for DR treatments recruit participants aged 18 years or older. The standard treatment for focal DMO located more than 500 microns from the foveal avascular zone edge is focal laser photocoagulation, as per the ETDRS protocol. However, laser photocoagulation should be avoided in diffuse oedema.

Where the DMO is diffuse, or patient cooperation unlikely, pharmacotherapy is more appropriate. Vascular endothelial growth factor (VEGF) blockage through intravitreal injections of anti-VEGF agents is now well established as a treatment for DMO in adults,

 although its safety and efficacy has not been established in children and adolescents. Some limited data on the use of ranibizumab (Lucentis, Genentech/Roche) for the treatment of choroidal neovascularisation in patients between the ages of 12 and 17 years showed that it was well tolerated.

Similarly, no data exist for use of intravitreal steroids in DMO in the young, although non-randomised study data exist for dexamethasone in non-infectious uveitis in a similar age group.

 As intravitreal steroids are cataractogenic, their use in young diabetic patients is best avoided. However, it may be reasonable in older children if the DMO is unresponsive to other therapies, or if a young diabetic patient has to undergo cataract surgery.

It has been suggested that blockage of the renin–angiotensin system withangiotensin-converting enzyme (ACE) inhibitors even in the absence of hypertension may slow progression of DR,

 although this was not supported in a study of adolescent diabetics.

 In summary, as there are limited trial data to guide treatment decisions in young patients, treatments for DR in this patient group should be individually tailored.

Prof. Winfried Amoaku, FRCS, FRCOphth, PhD, AFHEA

Prof. Amoaku is an associate professor/reader in Ophthalmology and honorary consultant ophthalmologist, based in Academic Ophthalmology and Visual Sciences, Division of Clinical Neurosciences, in the Faculty of Medicine and Health Sciences at the University of Nottingham, UK. He has no financial disclosures related to the content of this article to report.

Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel strategies. 

Gardner TW, Gabbay RA. Diabetes and obesity – a challenge for every ophthalmologist.

Mayer-Davis EJ, Kahkoska AR, Jefferies C, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. 

Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. 

Mayer-Davis EJ, Lawrence JM, Dabelea D, et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. 

Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. 

Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epidemiology and treatment. 

Sochett E, Daneman D. Early diabetes-related complications in children and adolescents with type 1 diabetes. Implications for screening and intervention. 

Sayin N, Kara N, Pekel G. Ocular complications of diabetes mellitus. 

Olsen BS, Sjølie AK, Hougaard P, et al. The significance of the pre-pubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes. 

Scanlon PH, Stratton IM, Bachmann MO, et al. Risk of diabetic retinopathy at first screen in children at 12 and 13 years of age.

Abdella K, McReelis KD, Strungaru MH. Diabetic retinopathy screening in a Canadian community pediatric diabetes clinic. 

Ng SM, Ayoola OO, McGuigan MP, Chandrasekaran S. A multicentre study evaluating the risk and prevalence of diabetic retinopathy in children and young people with type 1 diabetes mellitus. 

Shibeshi MS, Fantahun B, Kebede T, Tilahun B. Pediatric diabetic retinopathy: experience of a tertiary hospital in Ethiopia.

Wang SY, Andrews CA, Herman WH, et al. Incidence and risk factors for developing diabetic retinopathy among youths with type 1 or type 2 diabetes throughout the United States. 

Donaghue KC, Craig ME, Chan AK, et al. Prevalence of diabetes complications 6 years after diagnosis in an incident cohort of childhood diabetes. 

Pinhas-Hamiel O, Zeitler P. Clinical presentation and treatment of type 2 diabetes in children. 

Holl RW, Lang GE, Grabert M, et al. Diabetic retinopathy in pediatric patients with type-1 diabetes: effect of diabetes duration, prepubertal and pubertal onset of diabetes, and metabolic control. 

Massin P, Erginay A, Mercat-Caudal I, et al. Prevalence of diabetic retinopathy in children and adolescents with type-1 diabetes attending summer camps in France.

Nordwall M, Hyllienmark L, Ludvigsson J. Early diabetic complications in a population of young patients with type 1 diabetes mellitus despite intensive treatment. 

Prahalad P, Tanenbaum M, Hood K, Maahs DM. Diabetes technology: improving care, improving patient-reported outcomes and preventing complications in young people with Type 1 diabetes. Diabet Med. 2018;35:419-429.

National Institute for Health and Care Excellence (NICE). Diabetes in children and young people: diagnosis and management of type 1 and type 2 diabetes in children and young people. 2015. Available at https://www.nice.org.uk/Guidance/InDevelopment/gid-cgwaver118. Last accessed 1 October 2020.

American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern Guidelines. Diabetic Retinopathy. San Francisco: American Academy of Ophthalmology, 2012.

International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes (IDF/ISPAD). Global IDF/ ISPAD guideline for diabetes in childhood and adolescence. Available at http://www.idf.org/sites/default/files/Diabetes-in-Childhood-and-Adolescence-Guidelines.pdf Last accessed 30 October 2020.

Tekin K, Inanc M, Kurnaz E, et al. Quantitative evaluation of early retinal changes in children with type 1 diabetes mellitus without retinopathy. 

Mameli C, Invernizzi A, Bolchini A, et al. Analysis of retinal perfusion in children, adolescents, and young adults with type 1 diabetes using optical coherence tomography angiography.

El-Fayoumi D, Badr Eldine NM, Esmael AF, Ghalwash D, Soliman HM. Retinal nerve fiber layer and ganglion cell complex thicknesses are reduced in children with type 1 diabetes with no evidence of vascular retinopathy. 

Amoaku WM, Ghanchi F, Bailey C, et al. Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group. Eye (Lond). 2020;34(suppl 1):1-51.

Lucentis® 10 mg/ml solution for injection SmPC. https://www.medicines.org.uk/emc/product/307/smpc.

Lei S, Lam WC. Efficacy and safety of dexamethasone intravitreal implant for refractory macular edema in children. 

Sella R, Oray M, Friling R, et al. Dexamethasone intravitreal implant (Ozurdex®) for pediatric uveitis. 

Ratra D, Barh A, Banerjee M, et al. Safety and efficacy of intravitreal dexamethasone implant for refractory uveitic macular edema in adults and children. 

Chiang JL, Maahs DM, Garvey KC, et al. Type 1 diabetes in children and adolescents: a position statement by the American Diabetes Association. 

Marcovecchio ML, Chiesa ST, Bond S, et al. ACE inhibitors and statins in adolescents with type 1 diabetes.

Diabetes mellitus, which is a common chronic disease in children, can lead to significant eye morbidities with long-lasting effects, including diabetic retinopathy. Treatment should be tailored to the individual patient.

Risks and management of diabetic retinopathy in paediatric patients 

I spoke with Prof. Christophe Baudouin, president of the European Dry Eye Society to find out more about the complex nature of dry eye disease.

Could you tell me more about the pathogenesis of dry eye disease?

Dry eye is a very complex disease. It is not just a question of lack of water and so it is impossible to treat patients just by lubricating the eye with water. It is a disease that involves a series of self-stimulating biological events, and the lack of tears, insufficient tear quality or their instability results in direct mechanical and/or osmotic stress, which causes further damage.

The vicious cycle theory is a new way of understanding dry eye disease and may help improve prevention and treatment strategies. 