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.

Articles

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.

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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. 

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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.

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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.

In addition, goblet cell loss results in further tear film instability or imbalance and thus, dryness. The drier the eyes become, the more inflammatory they become and the greater the inflammation, the more the eyes continue to dry out, i.e., a vicious cycle occurs (see Figure 1).

To give more context on the vicious cycle theory, the dryness of the eye stimulates the nerves, the inflammatory reaction and inflammatory cells, and those act as stimulation for further damage, and so tears and their quality are reduced further, resulting in the disease becoming chronic.

Overall, the disease is very complex, with many risk factors, causes and aetiologies having been defined. As a result, it is difficult to resolve.

How are primary and secondary inflammatory processes involved in the disease?

There is a constant state of inflammation with the most severe dry eye cases, and this can be primary; for example, as seen with Sjogren syndrome, where inflammatory cells infiltrate and block the lacrimal glands, as well as the conjunctiva and cornea, and thus invade the whole ocular surface. Secondary processes are also involved: the various types of stress including mechanical and osmotic factors also stimulates inflammatory cells and results in a chronic inflammatory state.

What do you think future treatment strategies need to focus on?

The increasing interest in the idea of the vicious cycle allows us to discriminate between different levels of events: the mechanical stress, the osmotic stress and the inflammatory stress, for example. This new way of understanding the disease may allow the physician firstly to try to prevent the patient from entering the cycle, which is important and can be made possible by controlling the environment, improving the eyelid and decreasing inflammation. Secondly, each part of the loop can be targeted with a specific approach such as lubrication, eyelid hygiene, anti-inflammatory strategies and maybe even Omega-3.

And so there are different complementary approaches that can improve the patient’s symptoms. That said, sometimes it is very difficult to help the patient and they can suffer a lot.

To discuss a further complication of dry eye, we are increasingly starting to understand the concept of neuropathic pain in dry eye disease. Sometimes, the overstimulation of the nerve causes chronic pain and so even when the cornea and tears have been improved, patients can continue to suffer.

And once neuropathic pain has been stimulated, it can be very difficult to control it. Therefore, a good future treatment approach would be to find the best ways of relieving pain symptoms either locally or systemically.

Another consideration is in how we treat and control inflammation. In Europe, there is only one ciclosporin formulation indicated for severe dry eye disease with corneal damage, Ikervis (Santen), whilst the United States market has the prescription eyedrop Restasis (Allergan).

Another medication for the treatment of signs and symptoms of dry eye, which is available in some countries, is lifitegast (Xiidra, Takeda Pharmaceutical), which blocks the activation of lymphocytes. Unfortunately, this drug is not available in Europe and so other anti-inflammatory strategies are needed here.

In addition, the eyelids are likely to be the location of a lot of inflammation and so represent potential targets. In fact, various strategies to treat the eyelids have been developed, based on pulse light or warming and massaging devices, and are certainly a good way of relieving the patient’s symptoms.

Has the incidence of dry eye disease increased during the COVID-19 pandemic as screen time has increased?

We do not yet have epidemiological data to assess, however, it is clear that long hours working at, or reading on, a computer do affect dry eye and there is a clear association between the two. So, most likely, patients who have dry eye are suffering more during this time.

Furthermore, it has also been found that wearing a mask seems to interfere with eyelids and lead to meibomian gland dysfunction, perhaps by blocking the lymphatics at the level of the eyelids or by focusing an air flow on the eyes, so some people are finding that their dry eyes have been worsening due to their mask use.


Prof. Baudouin is professor and chair of ophthalmology at Quinze-Vingts National Eye Hospital & Vision Institute, University Paris Saclay, Paris, France. He has no financial interest in the subject matter.

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

How dry eye disease can become a complex vicious cycle

Roche announced positive results from 2 global Phase 3 studies evaluating its investigational bispecific antibody, faricimab, in people living with diabetic macular oedema (DME).

The YOSEMITE and RHINE studies met their primary endpoint and showed that faricimab given every 8 weeks and at personalised dosing intervals of up to 16 weeks demonstrated non-inferior visual acuity gains compared with aflibercept given every 8 weeks.

According to a prepared statement, faricimab was generally well tolerated, with no new safety signals identified. The studies each have 3 treatment arms, with participants randomly assigned to receive either faricimab or aflibercept at fixed 8-week intervals, or faricimab at personalised intervals of up to 16 weeks, following a loading phase.

“These positive results show that faricimab has the potential to offer lasting vision improvements for people with diabetic macular oedema, while also reducing the treatment burden associated with frequent eye injections,” said Dr Levi Garraway, Roche’s chief medical officer and head of global product development, in the statement. “We look forward to discussions with global regulatory authorities, with the aim of bringing this potential new treatment option to people with this condition as soon as possible.”

In a secondary endpoint, across both studies, more than half of participants in the faricimab personalised dosing arms achieved an extended time between treatments of 16 weeks at year 1.

According to the release, this was the first time any investigational medicine has achieved this level of durability in a phase III study of people with DME.

YOSEMITE (NCT03622580) and RHINE (NCT03622593) are two identical, randomly assigned multicenter, double-masked, global phase III studies, evaluating the efficacy and safety of faricimab compared with aflibercept in 1,891 people living with diabetic macular oedema (940 in YOSEMITE and 951 in RHINE).

According to the release, the studies each have 3 treatment arms: faricimab 6.0 mg administered at personalised dosing intervals of up to 16 weeks; faricimab 6.0 mg administered at fixed 8-week intervals; aflibercept 2.0 mg administered at fixed 8-week intervals.

In all 3 arms, sham injections were administered at study visits when treatment injections were not scheduled, to maintain the masking of investigators and participants.

According to the release, the primary endpoint of the studies is the average change in best-corrected visual acuity (BCVA) score from baseline at 1 year.

Secondary endpoints include safety; the percentage of participants in the personalised dosing arm receiving treatment every 4, 8, 12 and 16 weeks, at week 52; the percentage of participants achieving a 2-step or greater improvement from baseline in diabetic retinopathy severity at week 52; the percentage of participants achieving a gain of at least 15 letters in BCVA from baseline over time; the percentage of participants avoiding a loss of at least 15 letters in BCVA from baseline over time; and change in central subfield thickness from baseline over time.

In addition to the YOSEMITE and RHINE studies, the phase III Rhone-X study is investigating the long-term safety and tolerability of faricimab for the treatment of DME.

Faricimab is also being studied in the phase III TENAYA and LUCERNE studies as a potential treatment for neovascular or “wet” age-related macular degeneration (nAMD).

Faricimab is the focus of the YOSEMITE and RHINE studies, which investigators say show that the investigational bispecific antibody has the potential to offer lasting vision improvements for patients with diabetic macular oedema.

Roche’s DME candidate hits mark in 2 global Phase 3 studies

In news from the American Academy of Ophthalmology (AAO), in just 2 months, 3 patients at New York’s Northwell Health hospital were diagnosed with keratitis that quickly led to endophthalmitis and vision loss.

In 1 patient, the disease was so severe that an eye had to be removed. All 3 of the patients tested positive for COVID-19.

Results of the retrospective study were released at the AAO’s 2020 virtual annual meeting. Investigators said they hoped their findings would encourage the medical community to consider the eye when evaluating the role of anti-infectious treatment and immunomodulation.

Investigators noted that while the evidence does not show that the virus caused the devastating eye infections, the occurrence of keratitis leading to rapid perforation and endophthalmitis is exceedingly rare.

Moreover, with 3 cases present in the span of 2 months in New York, which has been a COVID-19 epicenter, more study was warranted, according to investigators.

According to Dr Amilia Schrier, a professor of ophthalmology at the Zucker School of Medicine at Hofstra University in Hempstead, New York, the 3 patients, all in their 60s, and from Manhattan, Brooklyn, and Long Island, presented to the Northwell Health Ophthalmology Department within a 2-month period. Two were outpatients and 1 was in the hospital at the time of keratitis diagnosis. Each of the patients tested positive for COVID-19.

According to Schrier, each patient had a different organism on culture, including 

While investigators could not say for sure that COVID-19 caused the endophthalmitis, it also could not be ruled out. She also noted that it is unusual for keratitis to progress to endophthalmitis.

“A 2012 study reported only 27 out of 9,934 eyes in a 15-year period experienced endophthalmitis caused by keratitis,” she said.

Schrier also pointed out in a statement that 3 of these cases in a 2-month period with COVID-19 positivity suggests that there may be an association between COVID-19 infection and severe eye disease.

Dr Sonal S. Tuli, a clinical spokesperson for the AAO who was not involved in the study, urged caution in interpreting the results while that while these findings do require further research.

“The findings do not suggest that COVID-19 causes endophthalmitis but that there is some relationship between the two,” she said in a statement.

Tuli explained that there could have been some other underlying health issue in each of the patients that made them more liable to contract COVID-19 as well as a severe infection in their eye. Those health issues could include a compromised immune system or nutritional deficiencies.

“It is also possible that these findings are incidental because of the large numbers of COVID-positive patients presenting to New York hospitals during the peak of the pandemic in New York,” she concluded.

In a separate study, investigators from Tel Aviv, Israel, cautioned recently that patients who wear face masks during the administration of intravitreal injections could be at a higher risk for the development of endophthalmitis.

To date, the only other eye condition linked to COVID-19 has been conjunctivitis.

In June, a team of investigators at the University of Alberta reported that a case of pink eye was being considered as a reason to be tested for COVID-19.

While coughing, fever and difficulty breathing are common symptoms of the illness, a recent case study involving an Edmonton woman and published in the 

 determined that conjunctivitis and keratoconjunctivitis can also be primary symptoms.

A cluster of COVID-19 positive patients developed endophthalmitis, and investigators are searching for a link.

Study: Identifying link between endophthalmitis, coronavirus

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

This article was reviewed by Dr Frank G. Holz.

A proposed biosimilar to ranibizumab (FYB201, bioeq) demonstrated similar clinical efficacy, safety, and immunogenicity as a treatment for newly diagnosed subfoveal neovascular age-related macular degeneration (AMD) compared with reference ranibizumab (Lucentis, Roche/Genentech), said Dr Frank G. Holz.

Outcomes of patients treated with the reference ranibizumab and biosimilar were investigated in the prospective COLUMBUS-AMD trial. Holz presented the research at the 2020 virtual meeting of the American Academy of Ophthalmology.

“Biosimilars are less-expensive alternatives to reference biologic medicines. To receive marketing approval, biosimilars need to undergo comprehensive studies demonstrating high similarity with the reference biologic in all critical quality attributes, including physical, chemical, and biological properties,” said Holz, professor and chair, Department of Ophthalmology, University of Bonn, Bonn, Germany.

“The COLUMBUS-AMD study investigated the clinical equivalence of the biosimilar candidate FYB201 and reference ranibizumab," Holz added. "The findings of this study demonstrated the biosimilarity of FYB201 and reference ranibizumab with regard to efficacy as well as safety in patients with newly diagnosed neovascular AMD. They suggest that FYB201 may offer a new, high-value treatment option for patients with neovascular AMD.”

COLUMBUS-AMD enrolled patients age 50 years and older with subfoveal or juxtafoveal choroidal neovascularization (CNV) with foveal-involving leakage related to the CNV activity. Eligible patients needed to have foveal center point (FCP) retinal thickness ≥350 µm on spectral-domain OCT, a total lesion area ≤12 MPS disc areas, total CNV area ≥50% of total lesion area, and BCVA between 20/32 and 20/100 in the study eye.

The patients were randomly assigned 1:1 to receive monthly intravitreal injections of FYB201 0.5 mg or reference ranibizumab 0.5 mg for up to 48 weeks. The primary endpoint was change from baseline BCVA after 8 weeks. Key secondary endpoints included change from baseline BCVA at 48 weeks and change from baseline FCP retinal thickness at 48 weeks, as well as safety and immunogenicity.

A total of 477 patients were randomized to the two treatment arms. The two groups were well balanced at baseline with respect to median age (76 years), gender distribution (~44% male), and distribution of BCVA.

The study met its primary endpoint, showing that the 90% confidence interval for the change from baseline in ETDRS BCVA after 8 weeks was within the predefined equivalence margin. The analysis of least squares mean change in BCVA showed improvements of 5.1 ETDRS letters in eyes treated with FYB201 and 5.4 ETDRS letters in eyes treated with reference ranibizumab. The least-squares mean difference between groups of study eyes was -0.4 ETDRS letters with a 90% confidence interval of -1.6 to 0.9 ETDRS letters; the predefined equivalence margin was -3.5 to 3.5 ETDRS letters. At all follow-up visits, mean study eye BCVA and mean change from baseline in study eye FCP retinal thickness were highly similar between the groups of eyes treated with FYB201 and reference ranibizumab.

The overall safety profiles were also highly similar for the two study groups. Rates of any adverse event, drug-related adverse events, and serious drug-related adverse events in the FYB201 group were 64.7%, 8.4%, and 1.3%, respectively; corresponding rates in the reference ranibizumab group were 69.9%, 10.5%, and 1.3%, respectively. All-cause treatment-emergent intraocular inflammation occurred in 8.4% of eyes in both groups; the rate of treatment-emergent intraocular inflammation considered related to the investigational medicinal product was 0.8% in both groups. The types of ocular adverse events occurring in the two treatment groups were also similar, and most adverse events in both groups were mild or moderate in severity.

“No clinically relevant differences in safety profiles were identified between the treatment groups,” Holz said.

The immunogenicity analyses characterized the development of anti-drug antibodies and neutralizing antibodies and showed FYB201 and reference ranibizumab had comparable immunogenicity profiles. The rate of anti-drug antibody development was 5.9% in both treatment groups, and the ADA titers were also similar in the two groups. A single patient in the FYB201 group developed neutralizing antibodies between week 24 and week 48.

Holz receives research grants from bioeq/Formycon, and research grants, and honoraria for consultancy from Novartis (not related to the COLUMBUS-AMD study reported here).

Prospective randomised trial demonstrates clinical equivalence of biosimilar and reference ranibizumab

What a proposed biosimilar may bring to subfoveal wet AMD 

Michael R. Robinson, MD, vice president, Global Therapeutic Area Head, Ophthalmology at Allergan, an AbbVie company, discusses the results from a presentation titled, "Two Phase b Study Results for the Development of a Proprietary Formulation for the Treatment of Presbyopia," presented during the virtual AAO 2020 meeting.

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Michael R. Robinson, MD, Allergan, discusses the results from a study analyzing an investigational ophthalmic solution for treatment of symptoms associated with presbyopia presented during the virtual AAO 2020 meeting.

Analysis of an investigational ophthalmic solution for treating presbyopia-related symptoms

Minimally invasive surgeries (MIGS) have become popular in recent years. Nevertheless, current technologies have some drawbacks: Schlemm’s-canal-based operations are limited by a modest intraocular pressure (IOP) reduction and the impossibility of predicting the level of IOP reduction in a particular patient, while subconjunctival MIGS share with trabeculectomy the need for bleb management and all its drawbacks.

The suprachoroidal space has significant potential, but all previous efforts to exploit this area for reducing IOP have been unsuccessful. Is there any hope for the future or should this pathway be abandoned?

The uveoscleral outflow pathway, first described by Anders Bill in 1965,

is driven by the negative pressure gradient present in the suprachoroidal space. Traumatic disinsertion of the ciliary body results in IOP reduction.

The suprachoroidal space has been explored as a target for glaucoma surgery for over a century, from the initial simple creation of a cyclodialysis with a spatula to the use of different materials to keep the path from the anterior chamber to the suprachoroidal space open.

Suprachoroidal filtration has several potential advantages: unlike the trabecular outflow it does not depend on episcleral venous pressure; it can be easily accessed via an ab interno approach; it produces a significant IOP drop; and the surgical technique needed to access this space has a very short learning curve. Nevertheless, all efforts to use this route have proven unsuccessful.

Recent experience with the CyPass (Alcon) device led to its removal from the market because of endothelial cell damage.

 A second problem is the potential sudden closure of the fluid channel due to fibrosis, which results in a marked increase in IOP.

iSTAR Medical is pioneering a new product called Miniject that addresses some of the drawbacks of previous devices. The surgical procedure is ab interno, which allows for sparing of the conjunctiva and the sclera for further surgery if needed.

The material used is soft and flexible and protrudes only minimally into the anterior chamber; these characteristics are intended to minimise endothelial cell damage.

The material is made of hollow silicone spheres, providing a high degree of biocompatibility and bio-integration.

 demonstrated that the material is colonised by host cells, a process that minimises fibrotic encapsulation around the device. These healthy cells do not prevent aqueous humour drainage but rather minimise the occurrence of long-term IOP spikes due to fibrosis.

All these observations are essential because a possible reason why previous attempts to utilise the suprachoroidal space as a viable surgical alternative in the treatment of glaucoma may have failed is that the devices were made of unsuitable materials.

To date, approximately 130 patients have been implanted with the device in different stand-alone trials.

 trials, mean postoperative pressure at 6 months was 14.5 mmHg on an average of 0.7 IOP-lowering medications with an IOP reduction of 40%, which is quite impressive compared with other technologies, especially considering that we are talking about stand-alone procedures.

Results at 24 months in the STAR-I trial showed a sustained IOP reduction of 41% to a mean of 13.8 mmHg on an average of one medication.

Furthermore, pooled data across all trials of the device show that secondary glaucoma surgery occurred at a low rate of 5%.

Hypotony (<6 mmHg) was present in a low number of patients (1% in STAR-I, II, III trials), and transient. Transient hyphemia occurred in 11% of patients across all the trials, which may be linked to the first-generation dual-operator delivery injector that has since been replaced by a single-operator delivery tool. Rates of hyphema are particularly relevant in procedures undertaken in combination with cataract surgery, due to the high visual expectations of patients.

Long-term reduction in mean visual acuity reduction (≥2 lines) was experienced by up to 11% of pooled patients and was mainly due to cataract progression. Little can be said at present regarding endothelial cell density (ECD) loss because longer follow-up is necessary. However, only a 5% mean corneal ECD loss has been reported with the device over 24 months, and no patient manifested a decrease ≥30%.

The delivery system has been improved over the years: it started as a two-operator procedure but now has a much more user-friendly inserter using a wheel for implantation and requiring only one operator. The width of the delivery device, nevertheless, requires some improvements in order to avoid unnecessarily wide clefts. A significant clinical study and further recent product development have evaluated the best sheath curvature and tip sharpness to enable effective penetration into the supra-choroidal space.

Dr Fea is an aggregate professor at the University of Torino, Italy, and an attached scientist at SERI. In recent years he has been involved in the development and clinical evaluation of several minimally invasive techniques for the treatment of glaucoma. Dr Fea is a consultant for iSTAR, Glaukos, Ivantis, Lasersight and EyeD and has received contributions for research or presentations from Allergan.

Bill A. The aqueous humor drainage mechanism in the cynomolgus monkey (

) with evidence for unconventional routes. 

https://www.alcon.com/media-release/alcon-announces-voluntary-global-market-withdrawal-cypass-micro-stent-surgical

Lass JH, Benetz BA, He J, et al. Corneal endothelial cell loss and morphometric changes 5 years after phacoemulsification with or without CyPass micro-stent. 

Grierson I, Minckler D, Rippy MK, et al. A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration. 

iSTAR Medical press release, 29 September 2020. https://www.istarmed.com/2020/09/29/positive-outcomes-for-istar-medicals-migs-miniject-shown-in-trials-of-over-130-glaucoma-patients/

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