Evidence Mounts in Support of Supplements for Ocular Health

by Brooke Herron

For elderly patients, losing vision due to chronic disease like age-related macular degeneration (AMD) and diabetic retinopathy (DR) is a serious cause for concern. As there is no cure, these progressive diseases require consistent monitoring and are often treated using repeated anti-vascular endothelial growth factor (VEGF) injections to reduce vascularization in the eye.

However, as we further our understanding of these conditions’ underlying mechanisms, the role of micronutrients has been evaluated for their potential benefits in reducing the risk or progression of these debilitating conditions. For example, groundbreaking studies AREDS/ AREDS 2 demonstrated that oral supplementation with antioxidant vitamins and minerals showed beneficial effects on the development of advanced AMD. Further, the investigators shared that nutritional supplements could further reduce risk of AMD progression. 1 Switzerland-based Aprofol AG is one company that’s taken notice of these potentially sight saving results with the creation of Ocufolin® forte. A FMSP (or food for special medical purposes), Ocufolin® provides the needed nutrients that are insufficiently absorbed in diseases like AMD and DR. And recently, numerous studies have been published exploring the benefits of Ocufolin® in these patients.

How does it work?

To understand how these supplements work, we must first understand the disease mechanism causing the nutritional deficit. The main player here is homocysteine (Hcy) — and when it is not metabolized correctly, it can lead to a host of health problems, including vascular, neurodegenerative and ocular diseases. To metabolize Hcy, enzymes with vitamins including Vitamin B9 (folate) and vitamins B6 and B12 are required, and therefore, studies have recommended treatment with folate and B12 to reduce Hcy levels. 2

In search of further evidence, investigators from the Medical University of Vienna recently completed a pilot study to look into the effects of supplements on Hcy plasma concentrations and ocular blood flow in 24 diabetic patients who received Ocufolin. They found that after three months, plasma Hcy concentration significantly decreased from 14.2 ± 9.3 to 9.6 ± 6.6 µmol/L (p < 0.001). The authors also saw a tendency toward an increased total retinal blood flow from 36.8 ± 12.9 to 39.2 ± 10.8 µl/ min, but noted that this didn’t reach the level of significance (p = 0.11, n = 13). In addition, a small but significant decrease in intraocular pressure (IOP) was observed. 3

This data led the authors to conclude that consuming dietary supplements like Ocufolin®, which contains L-methylfolate, can

significantly reduce blood Hcy levels in patients with diabetes.

These results were further confirmed by Wang, et al, in a retrospective case review on retinopathy reversal in patients on Ocufolin®, and a similar nonprescription multivitamin, Eyefolate. 4 Results showed that all microaneurysms (MAs) were resolved, and exudates were decreased in 8/8 cases after taking the FMSP. Retinal edema was found in 2/8 cases and improved or resolved in both cases. Dr. Wang concluded that “it appears that the use of nutritional supplements and medical foods containing L-methylfolate and vitamin D may be effective in facilitating the improvement of diabetic and hypertensive retinopathy.”

Further delving into the function of nutritional supplements and eye health was Shi, et al. 5 “Patients with DR have high incidences of deficiencies of crucial vitamins, minerals and related compounds, which also lead to elevation of Hcy and oxidative stress,” the authors explained. In addition, they explain that “common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity.”

Therefore, addressing the effects of the MTHFR polymorphism and comorbid deficiencies as well as insufficiencies could reduce the impact and severity of the disease. After a comprehensive review, they reported that combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid and N-acetylcysteine are identified for protecting the retina and choroid. 5

Additionally, further studies are underway to assess the impact of Ocufolin® on intraocular pressure (IOP), particularly the effect of L-methylfolate on patients with elevated retinal venous pressure.

Further applications of nutritional supplements

Benefits of supplements like Ocufolin® could extend beyond the eye, and indeed, help boost the immune system to fight off other infectious pathogens.

To help substantiate the claims of nutrients on the immune system, the European Food Safety Authority (EFSA) has asked the Panel on Dietetic Products, Nutrition and Allergies (NDA) to support the scientific substantiation of claims on the maintenance of (unspecified) functions of the immune system based on the essentiality of nutrients (e.g. vitamins C, D, A, B12, B6, zinc, copper, folate, iron, selenium), were evaluated with a favorable opinion. 6

And off course, boosting immune systems is of high importance — especially now, in the midst of the COVID-19 pandemic. In fact, one Italian study suggests routine determination of plasma Hcy as a potential marker for severe disease in SARS-CoV-2 patients. 7

A study by Bayer et al., notes that folate is critical to proper cell function and metabolism. 8 They hypothesized “that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection and, ultimately, the development of unchecked autoimmune responses to infected tissue.”

Much research, in the context of diabetes, has neglected the role of natural killer (NK) cells, the authors shared. “Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity . . . this would suggest a critical role for NK cells in (type 1) diabetes development linked to viral infection and the importance of the folate pathway in maintaining proper NK response,” the authors concluded.

Another study from Angstwurm et al. 9 , found that “d-dimer plasma levels strongly correlated with the severity of the disease and organ dysfunction in patients with circulatory impairment or infections.” Importantly, this suggests that elevated d-dimer levels may reflect the extent of microcirculatory failure.

Thus, the mounting evidence shows that lowering Hcy, through supplements like Ocufolin®, might not only reduce the risk of progression of chronic eye disease — they might also support the immune system in the fight against viral infections, like COVD-19.

References:

1

2 AREDS2 Research Group; Chew EY, Clemons T, SanGiovanni JP, et al. The AgeRelated Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012;119(11):2282-2289. Ajith TA, Ranimenon. Homocysteine in ocular diseases. Clin Chim Acta. 2015;23 (450):316-321.

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4

5

6

7

8

9 Schmidl D, Howorka K,Szegedi S, et al. A pilot study to assess the effect of a threemonth vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes. Mol Vis. 2020;26:326-333. eCollection 2020. Wang J, Brown C, Shi C, et al. Improving diabetic and hypertensive retinopathy with a medical food containing L-methylfolate: a preliminary report. Eye Vis. 2019; 6:21 Shi C, Wang P, Airen S, et al. Nutritional and medical food therapies for diabetic retinopathy. Eye Vis. 2020; 7:33. Guidance on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms. EFSA Journal. 2016;14 (1): 4369 Ponti G, Ruini C, Tomasia A. Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19. Med Hypotheses. 2020;143:109859. Bayer AL, Fraker CA. The Folate Cycle As a Cause of Natural Killer Cell Dysfunction and Viral Etiology in Type 1 Diabetes. Front Endocrinol (Lausanne). 2017;8:315. Angstwurm MWA, Reininger AJ, Spannagl M.D-dimer as marker for microcirculatory failure: correlation with LOD and APACHE II scores. Thromb Res. 2004;113(6):353-359.

Safe and Effective Laser

Therapies Targeting Retinal Diseases Amidst COVID-19

by Brooke Herron

In this time of uncertainty, one thing is certain (at least in ophthalmology): Retinal pathologies are not going anywhere.

In fact, chronic conditions like agerelated macular degeneration (AMD) and diabetic retinopathy (DR) are thought to be causing more concerns during this period of worldwide lockdown and social distancing. Either out of safety concerns, or because their doctor’s practice is closed, some patients are not visiting clinics for screening, diagnosis, monitoring or treatment — all of which can lead to sight-threatening vision loss.

As a result, laser is stepping up as a popular (yet, perhaps underutilized) treatment modality for retinal pathologies. Indeed, doctors and patients alike are turning toward laser to reduce repeated in-person office visits — which are required for effective anti-vascular endothelial growth factor (VEGF) treatment.

To learn more, Quantel Medical, an ophthalmic laser manufacturer based in Cournon-d’Auvergne, France, sponsored a recent webinar called Modern Laser Therapy for the Treatment of Retinal Diseases, which addressed the benefits of laser from two retinal specialists, Drs. Kenneth Fong and Victor Chong.

Peripheral treatments: Best cases for laser

Now that patients are making fewer visits to eye clinics, Dr. Fong, from OasisEye Specialists in Kuala Lumpur, Malaysia, suggests that retinal laser should be considered to reduce further risk in patients with diabetic retinopathy (DR) and associated conditions. While Dr. Fong notes that the older versions of PRP (panretinal photocoagulation) could cause severe anatomical damage to the peripheral retina, he says the newer PRP has several benefits. “It’s really considered a cure,” said Dr. Fong. “Thanks to multi-spot laser technology, we can complete the entire PRP treatment in one session, without the need for further anti-VEGF injections.”

“Given the chronic nature of proliferative diabetic retinopathy (PDR) and the intravitreal half-life of antiVEGF drugs currently in use, the main disadvantage of anti-VEGF monotherapy for PDR is that these drugs need to be administered periodically,” said Dr. Fong. “Interruption of treatment can be catastrophic and may lead to irreversible blindness.”

Macular laser: Comparing apples and oranges

Not all lasers are created equal — and as the technology has advanced so has the understanding in regard to safety and efficacy. And indeed, finding the balance between delivering more energy, but with less anatomical damage, is crucial to positive outcomes. From conventional laser, the evolution to Endpoint Management (PASCAL; Topcon, California, USA) decreased the power and duration, said Dr. Chong, from London Medical and the Royal Free Hospital in London.

“However, this modality offers a very small therapeutic window, so you have to be very precise: Too much energy and there is damage, too little and you cannot see the benefits.”

Additionally, this modality shows scarring on optical coherence tomography (OCT), fundus fluorescein angiography (FFA) and autofluorescence (AF).

“This is why, for many years, we have been working on a system that can deliver more energy with less damage thanks to a pulsed laser delivery mode,” he said. “The good thing about SubLiminal is that you don’t kill any cells — or at least you aim not to.”

Meanwhile, the SubLiminal laser from Quantel Medical has the energy to target the RPE and is effective without scarring on OCT, FFA and AF. Thus, according to Dr. Chong, SubLiminal threshold laser may hold the key. “We have previously published that using

SubLiminal Laser Technology

Images courtesy of Victor Chong

this type of methodology improves retinal sensitivity and reading speed,” he shared, adding that there are multiple papers on the safety and efficacy of SubLiminal laser.

“SubLiminal laser has a long track record, and over the years we have improved the protocol and we can show the clinical benefit,” shared Dr. Chong.

He also briefly discussed the selective retinal therapy laser (2RT; Nova Eye, California, USA), which he noted has a very short duration of 3 nanoseconds. However, it can also produce some scarring, which can be seen on OCT, FFA and AF.

Digging deeper into SubLiminal laser therapy

Dr. Fong helpfully summed up the SubLiminal laser treatment guidelines as follows: 577 nm wavelength; 160 µm spot size; 5% duty cycle; 0.2 second exposure time. Since there is no intended thermal injury using SubLiminal laser, “the key is doing a dense treatment, using a large spot size of 160 µm,” explained Dr. Fong, adding that the most important step is power titration, as every patient is different. “Once the thermal threshold is achieved, the power should be reduced by 50%, and then the laser should be performed,” he said.

As far as efficacy, SubLiminal laser is ideal for patients with non-center involving macular edema because those areas can be treated easily. “For those with fovea-involving, I would usually give anti-VEGF first to reduce the thickness, and then I would supplement it with laser. At one month after anti-VEGF, we are ready to treat the remaining thickened areas, avoiding the fovea at all times.”

SubLiminal laser treatment can also be used in chronic CSC (central serous chorioretinopathy) and is an alternative to mid-fluence PDT (photo dynamic therapy) in first-line treatment.

“For DME patients, I just use an OCT thickness map,” he continued. “For patients with CSC, you need indocyanine green angiography (ICGA) for complex cases or FA-guided (for simple cases) because it’s important to be precise of where you are treating.”

So, how long does it take to see improvement following treatment? For DME patients, it takes a minimum of about 3 months; for CSC, the result is much faster, at about 6 weeks.

Expanding clinical applications

According to Dr. Chong, SubLiminal laser therapy may be trending toward increased uptake. The therapy is already established as effective and safe for treating DME and CSC. It can also be used in branch retinal vein occlusion (BRVO) — although in some cases of BRVO it doesn’t always work, so it can be a supplement to anti-VEGF, noted Dr. Chong.

It has also been effective with macroaneurysms, but it is not applicable in cases of PDR for which multispot laser is the treatment of choice, he explained. It could also possibly be an option for nAMD patients who are nonresponsive to antiVEGF. “SubLiminal technology might be able to revitalize RPE cells and make them more responsive to antiVEGF treatment,” shared Dr. Chong.

There is some evidence that SubLiminal laser could work in PCV (polypoidal choroidal vasculopathy), but it would likely need anti-VEGF in combination. “But if you catch some of the earlier polyps with laser, then that certainly seems to work,” he continued.

Regarding applicability to drusen, Dr. Chong said that they are working on a study — but it’s currently on hold due to COVID-19, with plans to resume in the fall. However, he did point to some other smaller studies, one of which found that out of 30 cases, drusen load was reduced in 20 using SubLiminal laser.

“In summary, I think it’s very clear that in DME and CSC patients, it works. In BRVO and macroaneurysm, it seems to work — and it could possibly work in PCV and drusen. But, I don’t think it works in PDR,” concluded Dr. Chong.

Editor’s Note:

The webinar, Modern Laser Therapy for the Treatment of Retinal Diseases, sponsored by Quantel Medical, was held on 22 nd June 2020. Reporting for this story also took place during the said event.

Worlds Apart?

Outcomes of Anti-VEGF for Diabetic Macular Edema in Routine Clinical Practice by Rod McNeil

Treatment outcomes observed in routine clinical practice are often inferior to those of clinical trials using the same intervention. Variable treatment patterns, more diverse patient presentations and missed or cancelled appointments may all contribute to poorer results in real life.

Randomized, controlled trials demonstrate that treatment with intravitreal anti-vascular endothelial growth factor (VEGF) therapy can reduce edema, improve vision and prevent further visual loss in eyes with diabetic macular edema (DME). Through one year, continued treatment with anti-VEGF agents generally yielded substantial improvement in mean visual acuity (VA) with one third or more of patients gaining at least 15 letters in vision (3 lines) from baseline.

Let’s take a closer look at recentlypublished evidence from well-designed observational studies of real-world outcomes in patients treated with antiVEGF for DME.

The United States

Real-world DME patients in the United States receive fewer injections and achieve worse vision outcomes compared with patients in clinical trial settings. 1 Among 28,658 treatmentnaïve eyes treated with anti-VEGF for DME from 2013 to 2018, mean VA improved by 4.2 letters with a mean of 6.4 injections over one year. Outcomes improved with increasing injection frequency, reaching a plateau at 9 or more injections.

Global

The global LUMINOUS observational study of treatment-naïve patients with DME revealed a one-year mean vision gain of 3.5 letters (n=502) from a mean baseline VA of 57.7 letters, with a mean of 4.5 ranibizumab 0.5mg injections. 2 Significantly larger VA gains were recorded in patients who received 5 or more injections compared with those receiving ≤4 injections, particularly in those receiving a monthly loading schedule (Figure 1). The mean change in VA was highest in patients from the UK (+6.9) who received a mean of 6.0 injections. Variable access to funded care, with many paying for their own treatment, and delays in follow-up presentations, all impacted injection frequency, noted investigators.

The United Kingdom

A recent retrospective cohort study from Moorfields Eye Hospital in London evaluated aflibercept therapy for DME (99 eyes of 89 patients). 3 A majority (86%) received the recommended

Figure 1. LUMINOUS study of effectiveness of ranibizumab in DME over 12 months: greater vision gains achieved in patients who received ≥5 injections, particularly with a loading phase.

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DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; M12, month 12; VA, visual acuity. Adapted from Mitchell P, et al. PLoS ONE. 2020.

treatment initiation of 5 consecutive monthly injections, reflecting good compliance with the product label regimen. The total cohort received a mean of 6.9 injections through 12 months, with a mean of 7.4 and 6.6 injections, respectively, in subgroups with baseline best-corrected visual acuity (BCVA) <69 letters and ≥69 letters.

Mean (standard deviation [SD]) BCVA at presentation was 59.7 (16.1) ETDRS letters and the mean improvement in vision at month 12 were 9.9 letters. Even better outcomes were seen in the subgroup with baseline BCVA <69 letters (66% of the total study population), where mean BCVA improvement at month 12 was 13.8 letters. A gain of 2.6 letters was observed in the subgroup having baseline BCVA ≥69 letters (34%), reflecting a ceiling effect related to starting vision, but this group overall secured better final VA. Overall, 34% of eyes gained ≥15 letters through month 12 and 97% maintained vision (i.e., losing <15 letters from baseline).

A previous study at Moorfields Eye Hospital assessed 12-month outcomes with ranibizumab for DME involving 200 eyes of 164 consecutive patients, demonstrating outcomes comparable to those from clinical trials. 4 Treatment was initiated with three monthly injections, followed by as needed retreatment based on OCT and visionrelated criteria. From a mean (SD) VA at baseline was 54.4 (±15.26) letters, there was a mean letter improvement of 6.6 (±13.35), and 25.1% gained at least 15 letters, with an average of 7.2 (±2.3) injections, over 12 months.

France

Improvements in functional and anatomic outcomes over 12 months were also observed in both treatmentnaïve and previously treated patients with DME treated with aflibercept in French clinical practice, according to an interim analysis of the APOLLON study. 5 At month 12, the mean (SD) change in BCVA was +7.8 (12.3) letters from baseline BCVA (SD) of 62.7 (14.3) for treatment-naïve patients, and +5.0 (11.3) letters from baseline BCVA of 60.0 (13.7) letters in previously treated patients. Mean CRT decreased in both patient cohorts, with a total mean reduction of 133.2µm for the overall population.

While patients in APOLLON received a mean of 7.6 injections over the year, which is close to the label regimen for aflibercept, less than half of the cohort completed the full 5 initial doses within the first 5 months. Among the treatment-naïve cohort, greater VA gains were achieved in those who received initial treatment with 5 monthly loading doses (51.9%, n=40) compared with those who did not (48.1%, n=37); change in mean (SD) BCVA was +8.4 (13.98) vs. +7.2 (10.4), respectively. The proportion of three-line gainers was also markedly higher in those receiving treatment initiation with 5 monthly doses (35% vs. 24.3%, respectively, for those with and without the full loading phase).

Figure 2 charts reported outcomes from Moorfields Eye Hospital and French clinical practice alongside results from the aflibercept DME registration studies and the DRCR.net Protocol T study.

Australia

Among study eyes with a baseline VA < 69 letters in the DRCR.net Protocol T study, the mean (±SD) letter score improvement at 1 year was 18.9 ± 11.5 for aflibercept and 14.2 ± 10.6 for ranibizumab, with a median of 9 and 10 injections, respectively. 6

Both ranibizumab and aflibercept improved vision and decreased macular thickness in a cohort of treatment-naive eyes with DME (n=383) from the Fight Retinal Blindness! Registry [Bhandari 2020]. 7 In eyes with baseline VA of 20/50 or worse, mean change in VA from baseline to month 12 was +10.6 letters in the aflibercept group and +7.6 letters in the ranibizumab group (mean difference +3 letters, P <0.01). Aflibercept-treated eyes received a median of 8 injections compared with 6 injections in the ranibizumab group.

Conclusions

“Clinical trials give us the ideal results in terms of treatment efficacy and

Figure 2. Real-world one-year outcomes of aflibercept for DME in France and the UK compare favorably to landmark clinical trials.

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VIVID RCT

DRCR.net Protocol RCT

VISTA RCT

DME, diabetic macular edema; DRCR.net, Diabetic Retinopathy Clinical Research Network; ETDRS, Early Treatment Diabetic Retinopathy Study; M12, month 12; MEH, Moorfields Eye Hospital; RCT, randomized clinical trial; RW, real world; VA, visual acuity. Adapted from: Korobelnik JF, et al. Graefes Arch Clin Exp Ophthalmol. 2020; Lukic M, et al. Eur J Ophthalmol. 2020; Korobelnik JF, et al. Ophthalmology. 2014; The Diabetic Retinopathy Clinical Research Network. N Engl J Med. 2015.

safety that we might strive to achieve with practical protocols in the real world,” observed Dr. Marko Lukic, consultant ophthalmologist, Moorfields Eye Hospital, London, speaking in a telephone interview with the author.

He added: “The approach to antiVEGF dosing regimen in the first year of treatment is important in order to achieve maximum visual improvement early on. Using aflibercept for DME, we start with 5 initial monthly injections, which is our loading phase, followed by 3 bimonthly injections after loading for most patients and then retreatment as needed beyond year one.”

A further real-life study of aflibercept for treatment-naïve DME at Moorfields showed significant improvements in VA and anatomical outcomes sustained over 36 months of follow-up (n=64 eyes). 8 From a mean (SD) baseline VA of 61.45 (16.30) letters, the mean VA gain was 6.89 letters and one quarter of eyes gained ≥15 ETDRS letters through 36 months. Patients received a mean of 12.59 injections over the 3 years, with fewer than 3 injections in years 2 and 3.

Figure 3. In VIVID and VISTA, the proportion of aflibercept-treated eyes that gained or lost ≥5 letters in BCVA compared with the previous visit during the initial monthly loading phase (n=576), showing rapid, continuous vision improvement.

Proportion (%) of eyes that gained or lost ≥5 ETDRS letters

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BCVA, best-corrected visual acuity; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study. Adapted from Ziemssen F, et al. Int J Retina Vitreous. 2016.

Resolution of edema and VA response continue to improve in most DME cases through 6 months of consecutive monthly anti-VEGF injections. 6 A review of VIVID and VISTA DME outcomes among aflibercept-treated patients (n=576) demonstrated a continuous improvement in BCVA throughout the monthly loading schedule (Figure 3). 9 Moreover, patients are unlikely to lose vision if treated intensively at the start and given subsequent injections or laser treatments as needed to achieve stability. 10

TAKE-HOME MESSAGES

• Real life patients with DME differ from participants in clinical trials and are often undertreated in everyday practice • Vision gains are greater in patients treated with the recommended initiation protocol of monthly loading • Patients with higher baseline VA often achieve the best final vision at one year, illustrating the benefit of early intervention • Same-day injections for patients with bilateral DME may alleviate overall attendance burden and improve adherence • Rapid improvements in vision may be maintained longer term, with a reduced retreatment burden over time

Editor’s Note:

Rod McNeil is an independent medical journalist.

References:

Ciulla TA, Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular edema: a real-world analysis of 28 658 patient eyes. Br J Ophthalmol. 2020. pii: bjophthalmol-2020-315933. [Epub ahead of print] Mitchell P, Sheidow TG, Farah ME, et al, LUMINOUS study investigators. Effectiveness and safety of ranibizumab 0.5 mg in treatmentnaïve patients with diabetic macular edema: results from the real-world global LUMINOUS study. PLoS One. 2020;15(6):e0233595. Lukic M, Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema: Moorfields’ real-world 12-month visual acuity and anatomical outcomes. Eur J Ophthalmol. 2020;30(3):557-562.

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5

6

7 Patrao, NV, Antao, S, Egan, C, et al. Real-world outcomes of ranibizumab treatment for diabetic macular edema in a United Kingdom National Health Service setting. Am J Ophthalmol. 2016;172:51–57. Korobelnik JF, Daien V, Faure C , et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol. 2020;258(3):521-528. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-203. Bhandari S, Nguyen V, Fraser-Bell S , et al. Ranibizumab or aflibercept for diabetic macular edema: comparison of 1-year outcomes from the Fight Retinal Blindness! Registry.

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9

10 Ophthalmology. 2020;127(5):608-615. Lukic M, Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema in real-world: 36-month visual acuity and anatomical outcomes. Eur J Ophthalmol. 2020;30(3):557-562. Ziemssen F, Schlottman PG, Lim JI, et al. Initiation of intravitreal aflibercept injection treatment in patients with diabetic macular edema: a review of VIVID-DME and VISTA-DME data. Int J Retina Vitreous. 2016;2:16. Bressler NM, Beaulieu WT, Glassman AR, et al, Diabetic Retinopathy Clinical Research Network. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2018;136:257-269.

Retinopathy of Prematurity

Fine-tuning Current Treatments to Optimize Patient Outcomes by Olawale Salami

Each year, up to 20,000 newborn infants worldwide face the grim risk of blindness due to retinopathy of prematurity (ROP). ROP poses an even greater challenge in low income countries in South Asia Sub-Saharan

Africa, due to higher numbers of preterm births coupled with inadequate neonatal care. Therefore, research into understanding the limits of existing treatments in different stages of ROP and patient populations is urgently needed.

VEGFs in retinal hyperoxia: More harm than good?

Research and development into new drugs to prevent ROP-associated blindness has gained attention globally in the last decade with the increasing understanding of the vital role of growth factors, like vascular endothelial growth factor (VEGF) in normal physiologic and pathologic retinal angiogenesis. Thus, inhibition of VEGF using anti-vascular endothelial growth factors (anti-VEGF) such as bevacizumab, ranibizumab and aflibercept administered via the intravitreal route, has been shown to reduce retinal non-perfusion and consequent neovascularization, demonstrated by numerous clinical studies. In many countries, anti-VEGFs have become the primary mode of treatment for ROP over traditional laser photocoagulation to the avascular retina.

The variations in retinal oxygen levels in preterm infants and the role of retinal hyperoxia in ROP underscores the importance of studying available VEGFs in different scenarios of retinal perfusion. Dr. Swati Agarwal-Sinha, Dr. W. Clay Smith and their team of

researchers at the Department of Ophthalmology, University of Florida College of Medicine, have been studying the effects of aflibercept on retinal blood vessels exposed to a hyperoxic state. Their findings were published recently in the peer-reviewed journal Ophthalmic Research titled Efficacy of Aflibercept Treatment and its Effect on the Retinal Perfusion in the OxygenInduced Retinopathy Mouse Model of Retinopathy of Prematurity.*

Their research was driven by existing knowledge gaps in previous work in the field which showed that although aflibercept promoted neovascular tuft regression, higher doses inhibited normal retinal revascularization, and potentially led to permanent changes in neuroretinal structures. The causes of

this seemingly paradoxical effect, according to the publication, could be related to differences in capacities of VEGF to vitreous and retinal tissues.

Furthermore, differential effects of how aflibercept blocks VEGF in physiological, compared to pathological, angiogenesis could may be important. But what if it’s related to how much aflibercept is administered? Could there be a dose relationship that is critical in determining the trajectory of aflibercept-induced retinal nonperfusion? According to Dr. AgarwalSinha: “One of the questions that needs to be addressed is the effective dosage of the anti-VEGF used and its effects on physiological angiogenesis.”

Finding the right dose

To understand the differences in retinal nonperfusion at varying doses of aflibercept, Dr. Agarwal-Sinha and her team designed experiments using a well-characterized oxygeninduced retinopathy (OIR) model in mice. The purpose of their study was to determine if a lower dose of aflibercept could lead to significant reduction in areas of nonperfused retina, while simultaneously preserving normal retinal vascular angiogenesis in the OIR mouse model. The team focused on areas of nonperfusion, as these represent the driving factor for

VEGF production and consequent neovascularization.

In this study, Dr. Agarwal-Sinha and team assigned newborn mice to two groups: a control group in which mice were exposed to room air; and a hyperoxia group, where mice were exposed to 75% oxygen. Subsequently, 14 days after birth, (PN14) the mice in the hyperoxia group were then assigned to 3 different groups, with each group given one of three intravitreal doses of aflibercept: 0 ng, 100 ng or 1000 ng.

The study enforces the need for precise titration of anti-VEGF dose to balance inhibition of neovascularization with retinal nonperfusion, and longer observation after anti-VEGF treatment to evaluate its effect on vascular recovery and physiological angiogenesis.

- Dr. Swati Agarwal-Sinha

Eyes were evaluated at PN17 and PN25 post-injection using a variety of imaging techniques. The results, according to Dr. Agarwal-Sinha and colleagues show a significant reduction of retinal nonperfusion at PN25 in mice given both the 100 ng and 1000 ng aflibercept doses. However, it was the 100 ng aflibercept treatment group at day 11 postinjection which displayed vascular recovery and preserved physiologic angiogenesis, when compared to the 100 ng and 1000 ng treated groups at day 3 post-injection. The higher dose 1000 ng aflibercept treatment group did not show a significant difference in nonperfusion. The data showed that treatment with aflibercept can reduce nonperfusion of retinas exposed to hyperoxia in the mouse model of OIR, although treatment effects may not be observed until 11 days post-treatment (PN25 group).

Dr. Agarwal-Sinha emphasized: “Screening and providing treatment for retinopathy of prematurity has gained awareness around the world in preventing blindness. Anti-VEGF injections are now used primarily for the treatment of type 1 ROP, taking precedence over the traditional laser photocoagulation.”

“Though anti-VEGFs regress the neovascularization, they also inhibit the physiological angiogenesis of the normal retinal vasculature, which is seen as persistent avascular retina post-treatment,” said Dr. AgarwalSinha.

Furthermore, she said: “The study enforces the need for precise titration of anti-VEGF dose to balance inhibition of neovascularization with retinal nonperfusion, and longer observation after anti-VEGF treatment to evaluate its effect on vascular recovery and physiological angiogenesis.”

Randomized clinical trials in patients across many countries have recently commenced to study the efficacy of aflibercept in the treatment of ROP.

Amin S, Gonzalez A, Guevara J, et al. Efficacy of Aflibercept Treatment and its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity. Ophthalmic Res. 2020. [Online ahead of print.]

Contributing Doctor

Swati Agarwal-Sinha, MD, is an associate professor in the Department of Ophthalmology and the chief of Retinopathy of Prematurity (ROP) Services in the J. Hillis Miller Health Science Center, UF College of Medicine (Gainesville, Florida, USA). Her research interests include anti-angiogenesis treatments and retinal imaging (ocular coherence tomography, fluorescein angiography) in retinopathy of prematurity and pediatric retinal diseases.

sxapublish@gmail.com

AN INNOVATIVE RECENTLY DEVELOPED NEW BLUE DYE

DOUBLE Lutein Blue ™

Non toxic intraocular dye for ILM and ERM staining

PBB ® (Pure benzyl-Brilliant Blue) PATENTED

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by Andrew Sweeney

“It’s your retina Marty, something’s got to be done about your retina!”

Now while we wouldn’t recommend using Doc Brown’s manner when communicating with patients, what is certainly true, however, is that there’s plenty being done in the retina field today. Retina is all the rage — innovative technologies are emerging and new treatments offer a tantalizing taste of future advancements. It’s an exciting time to work in the retina segment.

More exciting than a time traveling DeLorean? You better believe it, the developments taking place will leave you spinning around like the aforementioned DeLorean’s licence plate. Indeed, if you had an actual time machine, this would be a good period to return to in the future, if someday you felt the need for buzz and excitement.

Good things often come in threes (like the Back to the Future film trilogy) and the same applies to the retina field today. The most exciting developments are mainly found in medical retina (such as gene therapy), imaging devices and new technologies. That’s not to say there aren’t innovations in other areas of course, but this tech triumvirate is what excites us the most.

Why are we so excited about these three areas of the retina field? It comes down to two factors: the huge impact these technologies and techniques will have on patient outcomes (both medically and socially), and their promise as a launching pad for further progress. Gene therapy serves as a good example.

Gene therapy is allowing ophthalmologists to treat eye conditions in ways that wouldn’t have been thought possible 10 years ago; it can prevent hereditary blindness, improve visual acuity (VA), and is propelling the development of advanced drugs. Developments in imaging are providing patients with advanced screening methods across further distances than previously thought possible. Artificial intelligence (AI), along with its close relatives augmented reality (AR) and virtual reality (VR), are revolutionizing prosthesis production, surgery, and a variety of other areas.

All in all, it’s a veritable smorgasbord of science — a plerotha of advances that Doc Brown himself would be proud of.

Are you telling me you built a time machine?

Recent developments are all the more remarkable when you view them through the lens of history. If we are to head back to the future (see what we did there?), we must also remember how far we’ve already traveled. Ophthalmology is one of the oldest medical disciplines, with records of treatment going back more than 4,000 years.

Indeed, the earliest recorded mention of a medical issue comes from Hammurabi, a king of the ancient Babylonian civilization. In 2550 B.C. King Hammurabi propagated laws on ophthalmology, more specifically, on malpractice.1 For example, according to the king’s law, if a physician opens an abscess in their patient’s eye with a bronze lancet and saves the eye, they are to be rewarded with ten shekels.

However, if the physician destroyed the eye instead — by accident or negligence — then they would lose their fingers. Ouch.

As a speciality, retina is young and owes much of its existence to increased life expectancies. According to the Retina Research Foundation, at the turn of the 20th century, retinal diseases were not frequently encountered, as lifespans in the West averaged around 49 years.2 As people began to live longer, retinal diseases began to be encountered more frequently.

Ever since Jules Gonin introduced his Iginipuncture in 1919, retina treatment has improved exponentially. Robert Machemer would go on to develop vitreous surgery in 1972; retinal tacks implantation would follow a decade later — and now treatments like antivascular endothelial growth factor therapy (anti-VEGF) have become highly popular and effective.3

The development of retina has been spurred by aging populations across the globe and by diseases caused by lifestyle choices, like diabetic retinopathy. This means that a once rarely encountered mystery, retina is now one of the greatest focuses of ophthalmology.

The future of medical retina

Indeed, the explosion in the number of retinal issues is not just a medical phenomenon, it is also sociological in nature. We don’t need finger-chopping Hammurabi to make us realize that the medical impact on retina conditions is important. For Dr. Ashish Sharma, an ophthalmologist at the Lotus eye Hospital and Institute in Tamil Nadu, India, brolucizumab (Beovu; Novartis, Basel, Switzerland) is symbolic of the issue.

“We have many promising original molecules in the pipeline and gene therapy has shown signs of advancement. However, I still feel that gene therapy has a long way to go,” Dr. Sharma said.

“If brolucizumab can find a way out to control retinal vasculitis it could be a transformational change. The biggest impact the molecule can have is the reduced frequency of injections. Frequent hospital visits are not only a financial burden for the patient and healthcare system, it also takes a major portion of the chair time for retinal physicians,” he said.

With innovation comes risk, and brolucizumab has come into its own share of controversy after 14 patients using the drug in a trial were diagnosed with vasculitis. Novartis was quick to emphasize its overall safety, and Dr. Sharma’s own brolucizumab study argues in favor of its safety, with reports showing safety and efficacy in stabilizing best corrected visual acuity (BCVA) in patients.4

Dr. Hudson Nakamura, from the Brazilian Center for Eye Study, believes other medicines deserve greater attention. One such is Luxturna (voretigene neparvovec-rzyl; Spark Therapeutics, Pennsylvania, USA), a gene therapy medication used to treat inherited retinal disease. According to one study, Luxturna offers a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity, however, observation will be required for four years.5

“The second is abicipar pegol — DARPin — a naturally occurring protein that can be used to treat agerelated macular degeneration (AMD) complications. Studies compared the drug with ranibizumab showed that the endpoint results were satisfactory, despite inflammation issues,” Dr. Nakamura said.

“Still, it was not enough for the drug to be approved by the U.S. FDA, citing a benefit-risk ratio for its approval. However, we cannot give it up as more studies and products are being tested,” he added.

A revolution in imaging

Optical coherence tomography (OCT) imaging is hardly new (it was first presented at a conference in 1990), but it is undergoing revolution. A number of studies are examining the use of deep learning AI in OCT to provide more accurate and detailed diagnoses than previously possible. For Dr. Sharma, this combination of OCT and AI is highly promising.

“Shortcomings such as speed, artifacts and area of imaging have now improved, thanks to better wavelengths with swept-source (SS-OCT). It will help us to better understand the pathology of diseases, such as AMD and diabetic retinopathy,” Dr. Sharma said.

“It is a revolution and retina specialists cannot afford to miss out on using it, as it might help us to make better decisions about the futility aspect, an emerging concept in AMD,” he added.

SS-OCT is a variation of OCT and includes hardware that differs in several ways, including the light source, bulk optics components and photodetection device. SS-OCT utilizes a point photodetector, whereas SD-OCT uses a spectrometer consisting of a diffraction grating, Fourier transform lens, and a detector array.6

iOCT systems are basically adaptations of OCT systems to be used specifically during surgery. iOCT images are usually displayed live and some dynamic information is also revealed including movement of tissues when force is applied.7

Dr. Sharma’s views are echoed by Dr. Cynthia X. Qian, head of the

electrophysiology laboratory and pediatric retina service at the University of Montreal, Canada. She views OCT as a catalyst in more than just patient treatment and diagnosis. She believes that OCT-based technology will have farreaching consequences for ophthalmic education.

“Intraoperative OCT (iOCT) and 3D heads-up display [which uses a microscopic image on a panel display sent from a 3D camera during surgery] are two of the imaging modalities that I currently use in my vitreoretinal surgeries, they are very useful and I find them to be enjoyable,” said Dr. Qian.

“They provide new unparalleled imaging information which was previously unavailable, and wonderful image documentation for future review of surgical cases, allowing for in-depth analysis and learning opportunities after the actual surgery itself,” she said.

This represents a cyclical approach where data gathered via OCT is used to educate new ophthalmologists, who then go on to use the equipment and continue the cycle. Simply put, it’s a little bit like going “back to the future” . . . and it’s not the only fascinating concept to emerge from the academic sphere.

Are we going to get bionic eyes?

In June this year, a group of scientists at the Hong Kong University of Science and Technology (HKUST) announced that they had developed the world’s first 3D artificial eye. A remarkable achievement in and of itself — but the scientists also claim that the eye’s capabilities are better than existing bionic eyes — and could even exceed those of regular human eyes. 8 So, can we expect to see widely available 3D eyes in the next decade? “Let’s stick with reality, we already have very good 3D visualization with wide angle vitrectomy viewing systems, as well as 3D heads-up vitrectomy. This is already a great advance in and of itself,” said Dr. Nakamura.

A 3D eye, with an accompanying 3D retina, represents extraordinary progress, but compared with AI, it’s very much stuck back in 1985, regardless of the HKUST study. Where 3D holds tremendous future potential, AI is already having an impact in the retina field. While it’s not surprising to learn that AI is being used in operating theatres and research labs, the data aspect of the technology is also proving beneficial to ophthalmologists.

“I was very impressed by the data shown by Google AI, which showed that while studying diabetic retinopathy and large data sets of retinal fundus images, the deep learning algorithm was able to detect information such as an individual patient’s gender, age, smoking-status and 10-year risk of cardiovascular diseases,” said Dr. Qian.

“I think this is an immensely powerful tool that shows great promise in more areas than we can anticipate as of yet,” she added.

This demonstrates the broad applicability and appeal of AI as it can be utilized by ophthalmologists in a variety of circumstances. We should drop the mindset of viewing AI simply as robotics, even when it pertains to surgery. AI has far more applicability than medical haemonculi, and robotic surgery itself may be too far off, according to Dr. Nakamura.

“If we compare today’s technology to 30 or 35 years ago, we are in the best times of retina and vitreoretinal surgery. Robotic surgery is too far ahead for us to think about right now,” Dr. Nakamura said.

2020’s Favorite words

If Marty McFly was to pilot his DeLorean to this point in time and ask an ophthalmologist what the biggest developments have been in the last 12 months (beyond the aforementioned triumvirate) the answer would likely be two-fold. The first would be telemedicine, and the second would be anti-VEGF. Indeed, these two terms have become buzzwords.

Telemedicine is the word of 2020 thanks to coronavirus, while antiVEGF treatment represents one of the most exciting developments in retina specifically, and in ophthalmology in general. Every single conference this year had seminars and symposia on the subject. Similar to some of the other issues we’ve covered, anti-VEGF holds more than just potential for physicians — according to many clinicians, it could have a beneficial impact on wider society too.

“The use of anti-VEGF to treat vascular conditions of the retina over the past decade-and-a-half has had the largest impact on our field and made a positive difference and quality-of-life in the lives of millions of patients worldwide,” Dr. Qian said.

“The advent of anti-VEGF intravitreal injections has brought a big change during the last decade. With newer molecules on the horizon and biosimilar drugs on the edge of approval, treatment cost might come down. This may lead to better compliance towards the treatment especially in the developing world,” added Dr. Sharma.

While the advantages of anti-VEGF treatment are numerous, some clinicians are sounding a note of caution. For Dr. Caroline Baumal from Tufts University Medical Center in Boston, Massachusetts, USA, anti-VEGF should be recognized as a great development, but they are still something of a work in progress.

“The efficacy and safety of the traditional anti-VEGF agents will be a high bar for new therapeutics to reach. Thus far, it appears that increasing the dose of some of the current anti-VEGF agents does not increase effectiveness,” Dr. Baumal said.

“As a result, the search for combination therapies, new molecules and sustained drug delivery to increase efficacy and durability continues. The concept of gene therapy to deliver a vector, which can lead to prolonged production of VEGF binding antibody, is also appearing,” she concluded.

Contributing Doctors

Dr. Hudson Nakamura

is a medical specialist in ophthalmology and specializes in retina and vitreous. He completed a fellowship in vitreoretinal diseases in Canada at the University of Toronto, and another retinal fellowship in his hometown, Goiânia, Brazil, at the Brazilian Center for Eye Surgery. He completed his medical studies at the School of Medicine at the Federal University of Goiás – UFG, and was a resident at the Base Hospital of the Federal District in Brasília. He is currently a professor at the Department of Retina and Vitreous Course of Medical Residency in Ophthalmology at the Bank of Goias Eye Foundation. He is the founder of the Retinawesome meeting, which brings together retinal specialists and vitreoretinal surgeons around the world for discussions on many subjects in retina and retinal surgery. In addition, he is also a member of the Brazilian Council of Ophthalmology.

hudson.nakamura@gmail.com

Dr. Cynthia X. Qian is an assistant professor in the Department of Ophthalmology and the head of the electrophysiology laboratory and the pediatric retina service at the University of Montreal, Canada. Dr. Qian completed medical school at McGill University. She completed her residency at the University of Montreal, where she was voted chief resident and graduated as the school valedictorian. She completed dual fellowships in surgical retina at the Massachusetts Eye and Ear Infirmary at Harvard Medical School in Boston, and in inherited retinal diseases at the Kellogg Eye Center, University of Michigan. She is the current vice president of the Canadian Retina Society and the provincial representative for Quebec in ophthalmology at the Royal College of Physicians and Surgeons of Canada. She is a fellow of the Royal College of Physicians and Surgeons of Canada and of the American Academy of Ophthalmology, and a member of the Canadian Ophthalmological Society, the Association for Research in Vision and Ophthalmology, the American Society of Retina Specialists, and the Pan-American Association of Ophthalmology.

qian.cynthia@gmail.com

Dr. Caroline R. Baumal

is a professor of ophthalmology and director of retinopathy of Prematurity Service at the New England Eye Center at Tufts Medical Center in Boston, Massachusetts. She specializes in diseases and surgery of the retina and vitreous. Her research interests include novel retinal imaging and drug development. Her clinical interests include age-related maculopathy, diabetic retinopathy, complex vitreoretinal surgery and retinopathy of prematurity. Dr. Baumal completed her medical school and ophthalmology residency at the University of Toronto after undergraduate studies at McGill University. She completed two fellowships: one at the New England Eye Center in medical retina and lasers and another in vitreoretinal diseases and surgery at Wills Eye Hospital in Philadelphia. Dr. Baumal is board certified by the American Board of Ophthalmology. She has received multiple awards from various societies including the American Academy of Ophthalmology, The American Society of Retinal Surgeons, The Retinal Hall of Fame, the Donald J. Gass Beacon of Sight Award from the Florida Ophthalmologic Society and recently was awarded the Crystal apple award from the ASRS. She is on the editorial board for Retina Cases and Brief Reports and Ophthalmic Surgery, Lasers and Imaging (OSLI) Retina. Dr. Baumal has authored over 100 publications, 28 book chapters on retinal diseases and recently edited the book Treatment of Diabetic Retinopathy. She is actively involved in teaching vitreoretinal fellows and residents and was previously director of education and the residency program at the New England Eye Center.

cbaumal@gmail.com

Dr. Ashish Sharma is an ophthalmologist at the Lotus Eye Hospital and Institute in Coimbatore, Tamil Nadu, India. He previously held a position at the Prasad Eye Institute, Hyderabad, Andhra Pradesh, India and was a part-time faculty member at the University of California in Irvine, California. He received his MBBS degree from MGM Medical College, Indore, Madhya Pradesh, India, went on to become an intern and then a resident at Maharaja Yeshwantrao Hospital in Indore, before becoming a medical research and retinal fellow at the University of California and a research fellow at the Bascom Palmer Eye Institute, Miami, Florida. Dr. Sharma holds board certification from the Medical Council of India (MP5527) and is a member of the American Academy of Ophthalmology, the All Indian Ophthalmic Society and the Vitreo-Retina Society of India. He holds two patents, the Portable Fundus Imaging Device (MII Ret Cam) and the Smartphone-Based Imaging Device for the Diagnosis of Glaucoma.

drashish79@hotmail.com

References:

Wheeler JR. History of Ophthalmology Through the Ages. Br J Ophthalmol. 1946; 30(5): 264–275. Retina Research Foundation. History. Available from: https://retinaresearchfnd.org/about-rrf/history/. Accessed August 26, 2020. Machemer R, Buettner H, Norton EW, Parel JM. Vitrectomy: A Pars Plana Approach. Trans Am Acad Ophthalmol Otolaryngol. 1971;75(4):813-820. Sharma A, Kumar N, Parachuri N, et al. Brolucizumab — Early Real World Experience: BREW study. Eye (Lond). 2020 Jul 24. [Online ahead of print.] Maguire AM, Russell S, Wellman JA, et al. Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation–Associated Inherited Retinal Dystrophy. Ophthalmology. 2019;126(9):1273-1285. Cole ED, Duker JS. (2017, April 7). OCT Technology: Will We Be “Swept” Away? Review of Ophthalmology. Available from: www.reviewofophthalmology.com/ article/oct-technology-will-we-be-swept-away. Accessed August 27, 2020. Tadayoni R. Intraoperative OCT: Would You Like Some Extra Information? Ophthalmol Retina. 2018;2(4):261-262. Gu L, Poddar S, Lin Y, et al. A biomimetic eye with a hemispherical perovskite nanowire array retina. Nature, 2020; 581 (7808): 278

Seeing the Unseeable Innovations in Retinal Imaging

By the end of the 19 th century, the first photograph of the human retina had been obtained . . . and since then, we’ve come a long way. Optical imaging has played a major role in our understanding of retinal and choroidal disease. “We currently stand on the cusp of a revolution in retinal optical imaging with numerous recent advances, including

OCT, OCTA, adaptive optics, SLO, fundus autofluorescence (FAF), photoacoustic microscopy (PAM), and molecular imaging,” noted Li et al., in a report titled Advances in Optical Imaging.*

Below, we look at some of our old favorites, as well as some new standouts, in retinal imaging.

Optical coherence tomography (OCT)

has been widely adopted in ophthalmology. It allows for an unparalleled combination of high axial resolution (1–10µm) with appropriate tissue penetration depth (1–2mm in tissue)

Swept-source OCT (SS-OCT)

is the latest development in OCT technology and enables deeper penetration, excellent axial resolution and fewer motion artifacts, to generate ultrahighdefinition B-scan images of the retinal microstructure.

Fluorescein angiography (FA) is a vitally important diagnostic tool and has been the gold standard disease — however, it is an invasive test and requires typically 10–15 min to obtain images. The author notes: “OCTA, in comparison, is a non-invasive technique and has the capability to image all layers of the vasculature.”

I m a g e o f m o v i n g t i s s u e s , l i k e f a s t c a r T h e S S - O C T d o e s t h a t ( w h a t t h e O C T s , i s h a r d t o c a p t u r e . c a n n o t ) , s o t o s p e a k .

for the evaluation of patients with retinal

o n l y t h e f l u o r e s c e n c e i n F A i s a s e o f t h i s H u m p h e a d . . . n o m o r x e t i r a v i s i b l e a s t h e s k i n n v a s i v e i s s u e s ! f I

Scanning laser ophthalmoscopy (SLO) uses a single, monochromatic laser with low power and a confocal raster scanning technique to collect an image of the retina and optic nerve head. SLO images demonstrate higher contrast than standard fundus camera photos as they can reduce the effect of light scatter.

OCT angiography (OCTA)

is a new, noninvasive imaging technique based on OCT imaging which allows for the visualization of the retinal and choroidal microvasculature without the injection of exogenous dyes. “OCTA can clearly visualize and quantify nonperfusion, neovascularization, and the foveal avascular zone (FAZ) area change, which can be helpful to identify non-proliferative DR and macular ischemia in patients with DR.” development process. No clinically approved system exists for eyes, and all the photoacoustic imaging work

Imaging. Photonics. 2018;5(2):9 [Epub 2018 Apr 27]

d e n t s i n t h e ‘ 9 0 s t h o u g h t t h e e l e c t r o n m i c r o s c o p e w a s t h e ‘ b o m b ’ i n l o o k i n g a t c e l l s i n v i v o . H e r e c o m e s t h e F A F . . . a n d t h e y e a r i s 2 0 2 0 . “ T h e r e s o m e t h i n g i n y o u r e y e ” s u d d e n l y h a s a d e e p e r m e a n i n g . . . l i k e , f o r r e a l . u t S

“ N o m o r e d y e s , ” s a y s t h e O C T A .

Fundus autofluorescence

(FAF) imaging is a noninvasive imaging modality for in vivo mapping of naturally or pathologically occurring fluorophores of the ocular fundus.

Adaptive optics (AO) is an emerging discipline that seeks to improve the performance of an optical system by reducing the effects of wavefront

Photoacoustic microscopy (PAM) remains at an early stage in the L i g h t a n d s h a d e . . . a n d s o u n d M i g h t b e s o m e l i g h t - y . e C a p t u r e t h a t ! a r s a w a y .

distortions. in eyes has been performed in Molecular animals or in vitro,” noted the imaging authors. (MI) is an area that combines retinal molecular biomarkers and advanced ocular imaging technologies and has the potential to visualize the earliest cellular and biochemical proces *Li Y, Xia X, Paulus YM. Advances in Retinal Optical retinal disease. s before advanced