This article was reviewed by William S. Gange, MD.

A retrospective study including a large patient sample shows that a small but significant proportion of individuals who are newly diagnosed with type 2 diabetes develop severe diabetic eye disease within 5 years. 

According to the research, the risk for early development of this microvascular complication of diabetes is particularly high among patients with a history of renal disease, insulin use, A1c >9%, peripheral circulatory disease, neurologic disease, Black race, and advanced age at diagnosis.

“Currently, there are 30 million people with diabetes in the United States, and the number is expected to reach 40 million by 2030. As the population of diabetics continues to grow, screening all patients for diabetic eye disease at guideline-recommended intervals becomes a public health challenge,” said William S. Gange, MD, presenting the data at ARVO 2020.

“The findings of our study investigating risk factors for early development of severe diabetic eye disease can help to identify patients who are likely to benefit most from improved rates of screening,” Gange added.

Gange, resident USC Roski Eye Institute, Los Angeles, conducted the study with Brian Toy, MD, retina specialist and Assistant Professor of Clinical Ophthalmology, USC Roski Eye Institute, and faculty at the USC Schaeffer Center for Health Policy.

Employing a commercial claims database, they identified patients aged ≥18 years who were newly diagnosed with type 2 diabetes between 2007 and 2015 and who had at least 1 year of continuous enrollment preceding the diagnosis and a minimum of 2 years of continuing enrollment post-diagnosis.

Development of severe diabetic eye disease was identified by the presence of an ICD-9 or CPT code indicating a diagnosis of proliferative diabetic retinopathy, tractional retinal detachment, neovascular glaucoma, or blindness following the diagnosis of diabetes. Patients with any of these diagnoses prior to the initial diagnosis of diabetes were excluded.

The rate of development of the composite endpoint was analyzed at both 2 and 5 years post-diagnosis of diabetes. Patients included in the 5-year analysis had to have had at least 5 years of continuous enrollment after being diagnosed with diabetes.

For the 2-year risk analysis, 277,400 patients met the inclusion/exclusion criteria, of which approximately 4,000 (1.44%) developed severe diabetic eye disease by 2 years after their diabetes diagnosis. The 5-year analysis included approximately 71,000 patients, of which about 2,100 (2.91%) had developed severe diabetic eye disease.

“Proliferative diabetic retinopathy accounted for the majority of cases of severe diabetic eye disease, but a significant number of patients had developed blindness – 0.55% by 2 years and 1.18% by 5 years," Gange noted. "Tractional retinal detachment and neovascular glaucoma, however, were rare."

Comparisons between patients with and without severe diabetic eye disease showed a number of statistically significant differences between the two groups in demographic and clinical characteristics at 2 and 5 years. 

However, several of the differences dropped out in the regression model.

The finding that individuals who were younger at diagnosis were less likely than their advanced age counterparts to have developed severe diabetic eye disease may seem counterintuitive knowing that the risk for diabetic eye disease increases with time since diagnosis and that patients diagnosed with diabetes at a younger age will go on to develop significant amounts of diabetic eye disease. 

Gange explained, however, that the results of the study are understood by its design.

“Our study was based on longitudinal follow-up of patients that began at time of diagnosis," Gange said. "It is likely that patients who were older when diagnosed with diabetes had a longer duration of undiagnosed diabetes that would lead to higher rates of severe eye disease."

This article was adapted from Gange’s presentation at the 2020 virtual meeting of the Association for Research in Vision and Ophthalmology. Gange did not indicate any proprietary interests relevant to the subject matter.

Articles

An analysis using a large commercial claims database found that almost 3% of patients developed severe diabetic eye disease within 5 years of being diagnosed with type 2 diabetes. Clinical and demographic risk factors were also identified.

Identifying risk factors for severe diabetic eye disease

This article was reviewed by Sandeep N. Shah, MD

A post-hoc analysis of data from the DRCR Network Protocol V provides new insight on outcomes of eyes with center-involved diabetic macular edema (CI-DME) and good best-corrected visual acuity (BCVA) if treated with anti-VEGF therapy only if vision worsened. The research also identified features associated with a need for intervention.

 on Feb. 20, 2020 [Glassman AR, et al; DRCR Retina Network. 

. 2020;138(4):341-9] and presented at ARVO 2020 by Sandeep N. Shah, MD.

“Protocol V randomized adults with type 1 or 2 diabetes who had CI-DME and Snellen equivalent BCVA of 20/25 or better to initial management with aflibercept, focal/grid laser, or observation with aflibercept given in the laser and observation groups if VA decreased from baseline. At 2 years, there was no difference in VA loss between the three study arms, and mean VA was 20/20 in all groups. Based on these results, many clinicians and patients might choose initial observation for eyes with CI-DME and good VA, withholding anti-VEGF treatment unless VA worsens,” said Shah, Principal Investigator for Protocol V at the Retina Vitreous Center, Oklahoma City, OK.

“Overall, the data from Protocol V show that some patients will do quite well if managed with observation, and that using the DRCR Retina Network protocol-defined approach combining BCVA and OCT-measured central subfield thickness (CST) is an effective strategy for determining when to initiate anti-VEGF treatment," Shah added. "Knowing risk factors that predispose to the need for anti-VEGF therapy helps in deciding follow-up intervals and patient education.”

In Protocol V, a total of 236 eyes were randomized to initial management with observation. Per the protocol, patients were to be followed initially after 2 months. Anti-VEGF treatment was initiated if VA worsened by ≥10 letters or more from baseline at any visit or if there was a loss of 5 to 9 letters at two consecutive visits.

The schedule for ongoing follow-up of eyes that did not have worsening of VA was determined based on findings of the OCT. If the CST worsened, defined by an increase of at least 10% from the last visit or an increase to >400 microns, the follow-up interval was reduced to a minimum of 1 month.

However, the maximum follow-up interval was extended to every 4 months for eyes that did not have a worsening of CST.

During the 2 years of follow-up in the observation group, 19% of eyes experienced a BCVA loss of 10 or more letters at least once and 39% experienced a 5- to 9-letter loss at least once. At the next follow-up visit, however, only 32% of eyes had a sustained VA loss and began aflibercept, whereas 46% of these eyes never went on to need aflibercept during the 2 years of the trial.

“These data show how important the role of repeatability of VA change is in an overall treatment regimen,” Shah said.

At the end of the 2-year follow-up, 66% of eyes did not require anti-VEGF treatment with aflibercept and 31% of those eyes had spontaneous resolution of DME with a median VA of 20/20. Within the subgroup of eyes that received anti-VEGF treatment per study criteria, VA was still good at 2 years (median 20/25) and 70% did not lose ≥1 line of VA.

The analysis of factors associated with receipt of aflibercept showed greater baseline CST, having advanced diabetic retinopathy, and need for treatment of DME in the fellow eye increased the likelihood for intervention. Eyes with baseline CST ≥300 µm were approximately twofold more likely to go on to anti-VEGF treatment than eyes with less macular thickening. 

The impact of diabetic retinopathy severity was analyzed with eyes classified using the ETDRS grading system. It found that eyes with a DRSS level ≥47 (moderately severe nonproliferative diabetic retinopathy and above) were 2.22 times more likely than eyes with a DRSS level ≤43 (moderate NPDR and below) to need aflibercept treatment. 

A need for DME treatment in the fellow eye within 4 months of randomization increased the likelihood that a patient would receive aflibercept in the study eye by 2.55-fold.

“However, even in these three higher risk groups, only about 50% of the eyes received anti-VEGF treatment. Therefore, although clinicians and patients should understand treatment expectations when they are in the higher risk groups, many of these eyes still will not need treatment,” said Adam R. Glassman, MS, lead author of the 

 paper and Director, DRCR.net Coordinating Center, Jaeb Center for Health Research, Tampa, FL.

Discussing the limitations of the report, Shah identified the post-hoc nature of the analysis and that it did not evaluate the laser group, which required fewer injections than the aflibercept group. 

In addition, some of the associations identified may have been due to chance considering that multiple characteristics were evaluated. 

Finally, the treatment decisions were guided by VA measurements obtained with the E-ETDRS testing protocol refraction, which may differ from the approach used in clinical settings.

Shah and Glassman have no relevant financial interests to disclose.

A new analysis from the DRCR Network Protocol V showed that many patients with center-involved diabetic macular edema and good vision do not require treatment for visual acuity loss. 

New Protocol V findings offer guidance for managing DME 

Face-down positioning is associated with a reduction in certain complications following macula-involving retinal displacement (RD) repair, according to researchers.

“To our knowledge, this is the first study to systematically examine retinal displacement or postoperative distortion at different points after RD repair,” wrote Edward J. Casswell of Moorfields Eye Hospital, London, UK, and colleagues. They published the finding in 

While macula-involving rhegmatogenous RD repair usually succeeds from an anatomical point of view, as many as 89% of patients experience postoperative distortion. Vitreoretinal surgeons advise various positions after this procedure, but with little evidence to show that one is better than another.

To fill this gap, Mr Casswell and colleagues randomly assigned patients to either face-down or support-the-break positioning, and they were immediately placed in the positions. Support-the-break positioning depended on the location of retinal breaks. They positioned patients with superior breaks upright and those with nasal, temporal or inferior breaks on the contralateral cheek.

The researchers provided the face-down group with an inflatable travel pillow during the first 24 hours. After that, they positioned all the participants in the support-the-break regimen for a further 6 days.

They asked the patients to hold their positions for at least 50 minutes of every hour and throughout the night, and also asked them to complete a positioning and adverse events diary. The researchers recruited 262 patients but excluded those with retinal redetachment. Of the 239 who completed the study, 171 were male and the mean age was 60.8 years.

At 8 weeks, analysis of the 103 gradable images in the support-the-break group revealed a 94% greater risk of retinal displacement. At 6 months, 77% more of the patients in the support-the-break group had retinal displacement compared with the face-down group.

Examining the variables, the researchers found that neither extent of retinal detachment; route of drainage; involvement of superior quadrants; duration of visual loss; preoperative lens status; nor gas tamponade were associated with retinal displacement at 6 months.

At both 8 weeks and 6 months postoperatively, the degree of displacement was also greater in the support-the-break group. After 6 months, the support-the-break group had 0.7 more quadrants and 0.42 more fundal degrees of retinal displacement than the face-down group.

Noting a reduction in both D chart and weighted D chart scores in both groups between 2 months and 6 months, the researchers speculated that distortion may resolve over time. “It has previously been suggested that the ghost vessels may move closer together over time,” they wrote.

The researchers found no statistically significant differences in best-corrected visual acuity in distortion scores or in quality of life scores between the two groups. However, they noted an increased rate of binocular diplopia in the support-the-break group, which they attributed to the increased amplitude of displacement observed in this group, impairing patients’ ability to vertically fuse images.

Although they did not detect a statistically significant difference in best-corrected visual acuity, the researchers speculated that there were not enough patients in their study to detect that or a difference in distortion between the two groups.

They did find that the amplitude of retinal displacement was associated with higher distortion scores and worse visual acuity. “We think this highlights the importance of avoiding retinal displacement given its potential consequences on visual function,” they said.

They recorded a higher rate of transient neck pain or stiffness in the face-down group. Also, the face-down group had a higher intraocular pressure (IOP) and the researchers speculated that this could result from residual intraocular fluid containing inflammatory mediators being displaced toward the iridocorneal angle, leading to inflammation and a delayed elevation in IOP.

Previous studies exploring the benefits of the face-down position have either been retrospective or have not formally evaluated displacement or distortion, the researchers reported. They have either found no difference between positions, or shown an advantage for the face-down position.

The study did not examine “no-position” or a macula-dependent position, which is advocated by some surgeons, the researchers acknowledged.

Face-down positioning better after detached retina repair

A novel gene therapy treatment may hold prom­ise for treating an inherited ocular dis­ease, achromatopsia, after a study found it provided some visual improvements in treated patients.

The disease, for which there is no cur­rent treatment, affects the retinal cone receptors, and is characterized by day blindness, glare, poor vision, nystagmus, and partial or total absence of color vision. Affected patients have no cone response from birth, which is in contrast to the more common types of color blindness that result from changes in the opsin genes that only impact patients’ efficiency with which they detect light frequency or wavelength, according to M. Dominik Fischer, MD, PhD.

Fischer is professor of ophthalmology at the Oxford University Hospitals NHS Foundation Trust, Oxford, UK and at the Centre for Ophthalmology, Eberhard Karls Universität Tübingen, Tübingen, Germany, and lead author of the study.

“Members of the RD-CURE consor­tium have started to look into achro­matopsia already 25 years ago, identi­fying its genetic basis and developing treatment options,” he said.

Achromatopsia had previously been considered to be nonprogressive; how­ever, recent research has identified struc­tural changes with increasing age that investigators found to be consistent with slowly progressive deterioration and loss of the cone photoreceptor cells.

Ninety percent of cases are asso­ciated with variants in 6 genes, and the most prevalent of these variants are in 2 genes, he explained, that encode the α _and β _subunits of the cone cyclic nucleotide-gated channel, 

. The former occurs in from 25% to 28% of cases in Europe and the United States and the latter in half of cases.

“The CNG channels are essential components of the phototransduction process in cone photorecep­tors, which enable daylight vision, high spatial and temporal resolution, color discrimination, and stable fixation,” Fischer said.

Fischer and his colleagues conducted an open-label exploratory, nonrandomized, controlled trial to deter­mine the safety and efficacy achieved with one sub­retinal injection of gene vector therapy adeno-associ­ated virus CNGA3. Three doses of the therapy were tested, 1.0 x 1010 vector genomes (vg), 5.0 x 1010 vg, and 1.0 x 1011 vg. Three patients each received one of the doses. The study patients, all of whom had con­firmed achromatopsia and variants in 

The primary outcome was safety and the secondary outcomes were changes in visual function, including spatial and temporal res­olution and chromatic, luminance, and contrast sen­sitivity over the 12 months of the study.

The study included 9 patients (8 men, 1 woman; mean age, 39.6 years). The surgeries were performed with no complications; no substantial safety issues arose during the follow-up period.

The investigators reported, “despite the congenital deprivation of cone photoreceptor-mediated vision in achromatopsia, all 9 treated eyes dem­onstrated some level of improvement in secondary end points regarding cone function, including mean change in vi­sual acuity of 2.9 letters. Contrast sensi­tivity improved by a mean of 0.33 log.”

This study provided clinical proof of concept for viral vector-mediated gene supplementation therapy of inherited day blindness caused by pathogenic variants in the cone photoreceptor-specific gene 

“While all applied dose levels showed some benefit, we will continue with the highest tolerated dose in a phase IIb trial,” Fischer said.

This next investigator-led trial looks at the feasi­bility of earlier treatment in patients who are about 7 to 8 years of age to determine whether earlier in­tervention will provide greater benefit.

This study provided clinical proof of concept for viral vector-mediated gene supplementation therapy of inherited day blindness caused by pathogenic variants in the cone photoreceptor-specific gene CNGA3. 
 


Subretinal gene therapy safe with visual benefit


Diabetic macular edema (DME) is a significant cause of vision loss in patients with diabetes.

In the 1980s, the Early Treatment Diabetic Retinopathy Study (ETDRS) established focal laser photocoag­ulation as the standard of care for eyes with clinically significant macular edema (CSME).

Although laser treatment decreased the risk of moderate vision loss by 50%, the rate of visual gain following focal laser treat­ment is low.

Over the past decade, ETDRS focal laser treatment for CSME has largely been replaced by anti- VEGF injections.

Patients who receive anti-VEGF injections are more likely to achieve visual gain than those who undergo conventional focal laser treatment. However, regular ongoing injections are required and can carry risks, including endophthalmitis and uveitis. Systemic risks are low, but are also a consideration in patients with diabetes.

From a practical standpoint, monthly visits are a significant burden, and not all patients respond completely to anti-VEGF injections.

Intravitreal steroid injections are also available for patients with DME and may extend the treatment interval from several months (Ozurdex, Allergan) 4 to 3 years (Iluvien, Alimera Sciences).

In addition to the possibility of endophthalmi­tis, intraocular steroid injections pose significant risks of glaucoma and cataract progression. Re­searchers have continued their effort to develop effective treatment for DME with a more advan­tageous risk profile.

Conventional ETDRS focal laser treatment uses a continuous wave (CW) laser, where the clinical endpoint is a visible retinal burn.

The mechanism of action involves the laser ra­diation absorption primarily by melanin in the retinal pigment epithelium and choroid, where it is converted into heat. This heat may spread to adjacent tissues, increasing the risk of causing collateral thermal damage.

 The size of the laser scars increases over time.

If such laser burns are placed too close to the fovea, risk of central vision loss may increase. Even with properly per­formed CW focal laser treatment, there can be loss of contrast sensi­tivity and/or visual field.

With the development of sub­threshold (ST) laser treatment— which breaks the laser exposure into a train of brief subpulses—ther­mal injury is reduced while still inducing the outer retinal metabo­lism.

 There is also evidence that this approach decreases the collateral damage.

In 2009, a study comparing ST micropulse laser treatments with CW focal laser for CSME showed the ST treatment proved to be equally effective with less reti­nal scarring.

In 2011, a randomized controlled study of 123 patients showed greater improvement in func­tional and anatomical outcome measures with high-density ST micropulse laser treatment com­pared with the modified ETDRS focal/grid laser.

Based on these results, ST laser therapy could provide an adjunctive treatment option for pa­tients with CSME, with a safer risk profile com­pared with the standard ETDRS CW focal laser treatment or anti-VEGF or steroid injections alone.

For CSME treatment, my colleagues and I have been offering the addition of ST laser therapy com­bined with CW focal laser treatment where indi­cated, in hopes of reducing the number of intra­vitreal injections patients may need while main­taining excellent visual and anatomic outcomes.

Study: Adjunctive treatment with ST laser therapy

With institutional review board approval, we per­formed a retrospective chart review of patients with at least 6 months follow-up after adjunctive treatment with the ST laser.

Endpoints included best-corrected visual acuity (BCVA) (in logMAR), central foveal thickness (CFT), and macular vol­ume. Values were reported at base­line and at a 6-month follow-up.

In addition, the number of in­travitreal injections during the 6 months before baseline was com­pared with the number of treat­ments (intravitreal injections and/ or additional lasers) during the 6 months after baseline. All statistics were performed with a spreadsheet program (Microsoft Excel).

Means before and after baseline were compared with paired t tests.

All treatments were performed using a laser (Smart532, Lumenis) featuring a multi-wavelength photocoagulator with green wavelengths.

In eyes with focal extrafoveal leakage on fluo­rescein angiography, extrafoveal microaneurysms were treated in the CW mode; the laser signal consisted of a single pulse with a duration of 50 to 100 msec.

The spot size was 50 to 100 μm. Power was titrated to obtain a light-gray endpoint, usually between 90 to 140 mW.

Areas of leakage identified on fluorescein an­giography and thickening on optical coherence tomography (OCT) were treated with ST laser ther­apy, using the SmartPulse mode.

In this mode, each pulse consisted of a train of brief (100 ms) subpulses, delivered at a duty cycle of 5%, with a 200-μm spot size.

A titration procedure was also performed to determine the power.

Starting in the CW mode, a single spot was applied in an extrafoveal area, using an initial power of 80 mW and gradually increasing it until a gray response was obtained.

Next, the laser was switched to SmartPulse mode, and the power was multiplied by 3 (up to a maximum of 400 mW). With these settings, the tissue reaction was subthreshold. A scanner was used to deliver 3 x 3 patterns with a spacing of 0.25 spot size. Patterns were overlapped to en­sure contiguous treatment.

During the 6 months after baseline testing, eyes were evaluated to determine whether they were stable or improving or if further treatment was needed.

Additional treatment could be an intravitreal anti-VEGF, a steroid injection, or an additional ST laser treatment.

Outcomes suggest possible benefits of ST laser therapy

Twenty eyes of 15 patients with DME had 6-month follow-up after ST laser treatment (Table 1). Six eyes (30%) had proliferative diabetic retinopa­thy, and 14 (70%) had nonproliferative diabetic retinopathy.

In 18 eyes (90%), there was a history of prior intravitreal injections, and 12 eyes (60%) had re­ceived focal laser treatment.

In the 6 months prior to baseline, 15 eyes (75%) were treated with 3.07 ± 0.96 (mean ± SD; range, 1-4) anti-VEGF injections. Two eyes (10%) were treated with 1 steroid injection each. For the en­tire cohort of 20 eyes, the average number of in­travitreal injections (anti-VEGF or steroids) was 2.4 ± 1.64.

Outcome measures at baseline and final 6-month follow-up are shown in Table 2. BCVA and CFT remained stable (

= .478, respec­tively), while macular volume decreased by 3% (

The number of anti-VEGF injections decreased by 72%, from 2.3 to 0.65 (

<.001), and the total number of intravitreal injections decreased by a similar proportion, from 2.4 to 0.7 (

<.001). In 2 cases, additional ST laser treatments were given after the baseline.

For a fair comparison, we tallied any treatments given during these 2 periods, including both types of injections and ST laser therapy. The number of treatments significantly decreased by 67%, from 2.4 to 0.8 (

<.001). No adverse events or com­plications were observed.

CFT indicates central foveal thickness; SD, standard deviation; VEGF, vascular endothelial growth factor.

Figure 1, on Page 20, shows OCT scans of a 56-year-old male with a history of stroke and non­proliferative diabetic retinopathy/DME in his left eye, with a BCVA of 20/50 at presentation. The CFT was 270 μm with intraretinal fluid.

In the 6 months before baseline, his eye was treated with 2 ranibizumab injections (Lucentis, Genentech). At baseline, extrafoveal microaneu­rysms were treated focally with a CW laser, and then the central DME was treated with ST laser therapy.

With no additional injections, at the 6-month follow-up, the patient’s BCVA improved to 20/40 and the CFT decreased 15% to 229 μm. On OCT, the intraretinal fluid was essentially resolved.

In this retrospective study of patients with DME treated with the Lumenis Smart532 laser, there was a good safety profile.

Following treatment, the number of injections decreased by more than half, while visual acuity and central retinal thickness were maintained. This decrease in treatment burden is encourag­ing for patients.

Most studies of anti-VEGF treatment for CSME (eg, RISE/RIDE,

 and PROTOCOL T of the Diabetic Retinopathy Clinical Research network

) excluded patients with very good vision and/or with mild macular edema.

ST laser therapy is of particular interest for in­vestigators in light of Diabetic Retinopathy Clini­cal Research Protocol V. Patients with 20/25 or better vision and CSME treated with observation only, CW focal laser, or aflibercept (Eylea, Regen­eron) showed no significant differences in visual acuity at 2 years, but there was a trend toward better vision with laser or aflibercept, compared with observation.

Given the excellent safety profile of the ST laser, this may be a reasonable treatment approach in such patients, either alone or in combination with a CW focal laser.

It is encouraging to find that ST laser therapy may help reduce the treatment burden for pa­tients with DME by decreasing the number of intravitreal injections needed, while maintain­ing visual acuity.

Randomized prospective studies are needed to further elucidate the merits of this approach. 

1. Early treatment diabetic retinopathy study research group. Early treatment diabetic retinopathy study report number 1. 

2. Elman M, Ayala A, Bressler N, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. 

3. Wells J, Glassman A, Ayala A, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. 

4. Singer M, Dugel P, Fine H, Capone AJ, Maltman J. Real-world assessment of dexamethasone intravitreal implant in DME: findings of the prospective, multicenter REINFORCE study. 

5. Augustin A, Bopp S, Fechner M, et al. Three-year results from the Retro-IDEAL study: real-world data from diabetic macular edema (DME) patients treated with ILUVIEN (0.19 mg fluocinolone acetonide implant). 

6. Mainster M. Decreasing retinal photocoagulation damage: principles and techniques. 

7. Desmettre T, Mordon S, Buzawa D, Mainster M. Micropulse and continuous wave diode retinal photocoagulation: visible and subvisible lesion parameters. Br J Opthalmol. 2006;90:709-712.

8. Schatz H, Madeira D, McDonald H, Johnson R. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. 

9. Yu A, Merrill K, Truong SFK, Morse LTD. The comparative histologic effects of subthreshold 532- and 810-nm diode micropulse laser on the retina. 

10. Jain A, Blumenkranz M, Paulus Y, et al. Effect of pulse duration on size and character of the lesion in retinal photocoagulation. 

11. Figueira J, Khan J, Nunes S, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. 

12. Lavinsky D, Cardillo J, Melo LJ, Dare A, Farah M, Belfort RJ. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. 

13. RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. 

14. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 

15. Heier J, Korobelnik J, Brown D, et al. Intravitreal aflibercept for diabetic macular edema: 148- week results from the VISTA and VIVID studies. 

16. Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness Randomized Clinical Trial. 

17. Diabetic Retinopathy Clinical Research Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. 

Dr Merrill is a partner at Illinois Retina Associates, as well as associate professor and section director for uveitis, Rush University, Chicago. She has received numerous honors, including the American Academy of Ophthalmology Achievement Award and the American Society of Retina Specialists Senior Honor Award.

Dr Merrill reports research grants/funding from Gilead, Lumenis, the National Eye Institute, and Santen, and has served as a consultant with Alimera Sciences, Genentech, Graybug, Lumenis, and Santen. The author thanks Yair Manor, PhD, clinical director, BU Vision, for his assistance with the study and statistical analysis.

Used as an adjunct, ST laser therapy may reduce the treatment burden for patients while maintaining visual acuity. 

ST laser therapy may reduce DME intravitreal injections

Studies show that the micropulse laser represents a safe treatment for macular disorders involving the foveal area. Further and larger studies are needed to prove the real effectiveness related to all the macular pathologies, but it can be used as an add-on to treat complex cases.

The micropulse laser represents a relatively new frontier among retinal specialists. The subthreshold energy it can deliver without damaging retinal tissue is being exploited in various macular diseases, including central serous chorioretinopathy (CSC), diabetic macular oedema (DME), and macular oedema due to branch retinal vein occlusions (BRVO).

There is increasing evidence that subthreshold micropulse laser (SML) treatment (Iridex) can serve as an additional valuable therapeutic option to intravitreal injections (anti-VEGF and/or steroids), mostly for retinal vascular diseases. And, since standardised therapies or established ‘best practice’ guidelines do not yet exist for CSC, the opportunity exists for the micropulse laser to join the armamentarium, particularly in those patients which do not tolerate eplerenone tablets.

In my clinical practice, I am currently using the laser sub-threshold therapy to treat CSC both as monotherapy and in combination with systemic treatments, such as eplerenone or spironolactone.

Conventional laser photocoagulation is widely used to obtain thermal and beneficial effects on the retina; however, it can induce side effects such as chorioretinal atrophy, formation of epiretinal scars, choroidal neovascularisation and visual field defects

The SML acts only to stimulate retinal pigment epithelium (RPE) cells to regulate different factors, such as anti-VEGF inhibitors, pigment epithelium-derived factor (PEDF) and permeability factors, sparing the neural retinal and preserving the functional integrity of the photoreceptors

 delineated well the difference between conventional laser photocoagulation and the micropulse mode. A conventional laser is characterised by the so-called continuous wave (CW) mode, in which the laser energy is delivered with a single pulse, whereas the micropulse mode delivers a train of repetitive short pulses (typically of 100–300 ms), with alternating ‘on’ and ‘off’ times.

The length of time the power is ‘on’ divided by the total time the laser is used gives rise to a ratio known as the ‘duty cycle’. The presence of the so-called ‘off’ time allows the heat to dissipate, thus minimising the thermal effect and reducing retinal injury.

As rigorously covered in recent review by Scholz et al.

, there are currently two different types of micropulse laser. The first is a diode laser with a wavelength of 810 nm, which is able to penetrate up to the choroid.

The other available SML system is the 577-nm yellow laser, which has the advantage that the xanthophyll, a pigment present in the macular layers, absorbs only a minimal amount of yellow light, thereby increasing the safety of a laser procedure close to the fovea. The development of navigated laser systems has considerably improved the accuracy and safety of the micropulse laser treatment. The eye-tracking technology minimises the eye movements of patients, and the presence of special software allows one to plan treatment based on the images obtained with fluorescein angiography (FA) and/or indocyanine angiography (ICG), optical coherence tomography (OCT) and OCT angiography.

In my hospital-based setting, I use the micropulse laser mode with a navigated system and, based on the different macular diseases, I optimise the treatment with the multimodal imaging modality. For example, in the case of CSC, I acquire the FA and ICG images where possible to evidence a typical leakage hot spot, as well as the OCT scan, to demonstrate the presence of subretinal fluid (SRF).

After taking a fundus photo of the patient’s macula, the navigated system is able to superimpose the fundus photo and the OCT/FA/ICG images, and, finally, I can perform the micropulse laser with different energies and duty-cycle at the level of the hot spot evidenced by the FA/ICG and directed to the SRF as illustrated by the OCT scan.

Before the era of anti-VEGF and intravitreal injections, laser photocoagulation was the standard treatment for DME, but severe complications such as accidental foveal damage and expansion of macular scars were observed, and so the method took a back seat.

However, the recent advent of SML has provided a new age for the laser treatment of DME and researchers have sought to assess the safety and efficacy of this therapeutic approach.

 evaluated functional and morphological parameters after SML treatment with both infrared and yellow systems, showing that the lowest duty cycle (5%) setting seemed to be the safest in order to preserve the visual function and maintain the macular integrity. Moreover, Chhablani et al.

 demonstrated the safety of the two most-used subthreshold parameters (duty cycle 5% and 15%) of the yellow laser compared with conventional laser and found that the 15% duty cycle achieved better anatomical, visual and functional outcomes.

In my routine laser practice, with DME patients, I usually set the duty cycle to 10% with a power energy between 120 and 160 mW, associated with the laser-navigated treatment mode. So far, I have not had any cases of choroidal neovascularisation, photoreceptor integrity damage or laser-related visual function deterioration, which I believe demonstrates how safe the micropulse procedure is.

Another interesting field is the application of the micropulse laser for the treatment of patients with macular oedema (MO) following an episode of BRVO. As recently summarised in a review by Eng et al.

, SML appears to be safer than conventional laser photocoagulation and is as efficacious, improving visual function and reducing the intraretinal fluid accumulation in such patients.

In a small retrospective series presented by our team at the European Society of Retina Specialists (EURETINA) congress, we analysed the safety and efficacy of the yellow navigated micropulse laser treatment in 17 patients (18 eyes) affected by MO due to BRVO with a follow-up of 3 months. We observed a statistically significant improvement of the visual acuity without a corresponding decrease in macular thickness.

Interestingly, we found that the photoreceptor structures were restored, particularly in terms of renewal of the ellipsoid zone integrity. Moreover, confirming the previous data regarding the safety of the procedure, we saw no cases of chorioretinal atrophy, scarring or choroidal neovascularisation. We had set the duty cycle to 10% and used 130 mW as medium energy with circa 600 spots at the level of the increased macular thickness (see Figure 1A–C).

Combining the micropulse laser with intravitreal injections can help to reduce the burden of numerous injections. In a recent study, Terashima et al.

 determined the efficacy and safety of the combination therapy between the yellow SML and intravitreal ranibizumab, showing that visual acuity was maintained with a decreased number of intravitreal procedures needed.

I agree with this treatment modality and in my practice I tend to combine the intravitreal approach (anti-VEGF and steroid implants) with the micropulse laser to tackle the disease in different ways, and so reduce patients’ stress and achieve the best functional result.

The standardised treatment for CSC has been the subject of debate due to the lack of data from randomised controlled trials. The first pilot study to investigate the role of micropulse laser treatment for CSC was presented in 20039. The SML (with 810-nm diode laser) led to the complete resorption of SRF 1 month after the treatment with no recurrence at 6-month follow-up.

Since 2003, many different studies have analysed the efficacy of the micropulse laser for chronic CSC, with encouraging results. Nevertheless, the PLACE trial10, an open-label, multicentre, randomised, controlled clinical study, recently demonstrated that a significantly higher proportion of patients receiving half-dose photodynamic therapy (PDT) achieved complete resolution of SRF and functional improvement than those subjected to high-density SML (HSML).

However, in the literature there are other interesting studies which prove the efficacy of the micropulse laser for cases of CSC.

 conducted a retrospective study with a 3-year follow-up demonstrating a complete SRF reabsorption in 81.5% of patients affected by chronic CSC who were treated with yellow 577-nm SML.

Unlike the other published studies, which used a conventional treatment duration of 100–300 ms, the research group opted for just 20 ms, with a 15% duty cycle and a power ranging from 200 to 400 mW, applying the energy both over the area of RPE leakage and all areas of serous retinal detachment, including the fovea.

In my clinic, I follow the indications of the previous study, but slightly modifying the parameters: for the leakage point assessed by multimodal imaging modality (FA/ICG), when it is located far away from the foveal zone, I use a 15% duty cycle, 20-ms treatment duration and 300 mW of energy; whereas, for the SRF, mostly if it is localised at the foveal level, I usually use a 10% duty cycle, 20-ms duration and 150-mW energy, in order to stimulate only the RPE cells, avoiding damage to the foveal area.

Studies show that the micropulse laser represents a safe treatment for macular disorders involving the foveal area. Regarding the efficacy, the results are not still uniform and for this reason we need further and larger studies to prove the real effectiveness related to all the macular pathologies.

In my opinion, we can currently consider the micropulse laser as an additional therapy, which may help physicians to treat disorders with complex pathophysiology, such as DME, MO due to BRVO, and CSC. The feasibility of using the micropulse laser in combination with intravitreal injections in the case of MO related to vascular disorders offers the potential to relieve the burden of injections, help with patient compliance and optimise functional outcomes.

In the case of CSC, the laser acts as another therapeutic option besides PDT with minimal risks and good efficacy, both as monotherapy and when associated with other treatment strategies, such as eplerenone and spirinolactone.


	Dr Di Carlo is a vitreoretinal consultant at the ophthalmology department of the StÃ¤dtisches Klinikum Karlsruhe, Germany. His main interests are micropulse laser and new frontiers of vitreoretinal surgery. He has no financial interests in the subject matter.


	Dr Simini is an ophthalmology resident at StÃ¤dtisches Klinikum Karlsruhe, Germany, which is directed by Prof. A.J. Augustin. Her main interests are: medical and surgical retina. She has no financial disclosures.

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Turning to new frontier in micropulse laser treatment for retinal disorders

Clinical studies are under way to confirm the promising results obtained so far with subretinal implantation of human amniotic membrane plugs in the treatment of large and recurrent macular holes.

Macular holes (MHs) are tears in the retina’s fovea centralis, and can be acquired, acute or subacute, spontaneous or traumatic. They can cause the severe deterioration of eyesight if left untreated. Since our clinical practice in the ophthalmology unit of the StÃ¤dtisches Klinikum in Karlsruhe is one of the largest medical centres in the southwest region of Germany, we encounter and treat a significant number of patients affected by this disorder.

Recent, novel surgical methods in the management of MHs offer the chance to improve visual acuity in patients with large or recurrent holes who would otherwise be doomed to lose vision in the affected eye.

Following a short overview of MHs, this article provides an update on surgical treatment approaches. The first description of MHs dates back to Hermann Knapp in 1869,

 who reported them as resulting from direct blunt ocular trauma. Patients with MHs without a history of eye trauma were increasingly observed, and by 1970, only 5–10% of them were ascribed to trauma, with the rest considered idiopathic.

 Presently, the vast majority of MHs are attributed to vitreomacular traction.

Clinical suspicion is confirmed by slit-lamp fundoscopic examination, which shows a well-defined round or oval lesion in the macula with yellow-white deposits at the base.

 Optical coherence tomography (OCT) confirms the diagnosis and allows the lesion to be classified into one of Gass’ four stages.

Noninfectious uveitis: Meeting the challenge

Improving patient comfort with intravitreal injections

Antihyperglycemic drug associated with reduced risk of new onset AMD

Identifying risk factors for severe diabetic eye disease

New Protocol V findings offer guidance for managing DME

Face-down positioning better after detached retina repair

Subretinal gene therapy safe with visual benefit

ST laser therapy may reduce DME intravitreal injections

Turning to new frontier in micropulse laser treatment for retinal disorders

Role of human amniotic membrane in surgery of recurrent macular holes

COVID-19: How Orbis International is managing operations

How DME patients may fare differently in ‘real world’ versus trials

Screening DR + tele-ophthalmology AI: Less expensive than human assessment