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. 

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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. 

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Articles

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.

Videos

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

Tanner Ferguson, MD, an ophthalmology resident at the Cleveland Clinic's Cole Eye Institute, discusses findings from the study "Trabecular Micro-bypass Stent Implantation (iStent)" + Phacoemulsification in PXG: Six-Year Outcomes," during the virtual AAO 2020 meeting. 


Tanner Ferguson, MD, Cole Eye Institute, discusses findings from the study "Trabecular Micro-bypass Stent Implantation (iStent)" + Phacoemulsification in PXG: Six-Year Outcomes," during the virtual AAO 2020 meeting. 

Evaluating long-term safety for micro-bypass implant + phaco in PXG

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. 

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.

Treating vitreous opacities with YAG vitreolysis

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

It takes a village to beat visual system diseases in children