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.

Articles

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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	2. Ulbig MR, Arden GB, Hamilton AP. Color contrast sensitivity and pattern electroretinographic findings after diode and argon laser photocoagulation in diabetic retinopathy. Am J Ophthalmol. 1994;117(5):583-588.
	3. Dorin G. Evolution of retinal laser therapy: minimum intensity photocoagulation (MIP). Can the laser heal the retina without harming it? Semin Ophthalmol. 2004;19:62-68.
	4. Scholz P, Altay L, Fauser S. A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders. Adv. 2017;34:1528-1555.
	5. Vujosevic S, Martini F, Longhin E, Convento E, Cavarzeran F. Subthresold micropulse yellow laser versus subthresold micropulse infrared laser in center-involving diabetic macular: Morphologic and Functional Safety. Retina. 2015;35:1594-1603.
	6. Chhablani J , Alshareef R , Kim DT, Narayanan R,  Goud A et al. Comparison of different settings for yellow subthreshold laser treatment in diabetic macular edema. BMC Ophthalmol. 2018;18:168.
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	8. Terashima H, Hasebe H, Okamoto F, Matsuoka N, Sato Y et al. Combination therapy of intravitreal ranibizumab and subthreshold micropulse photocoagulation for macular edema secondary to branch retinal vein occulsion: 6 month result. Retina. 2019;39:1377-1384.
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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.

Ophthalmologists Neil E. Kelly and Robert T. Wendel described the first modern surgical approach to MHs in 1991. This technique is still used today and is standard procedure for holes under 400 µm in diameter.

The procedure consists of the following stages:

An extensive 23- to 27-gauge pars plana vitrectomy;

Detachment of the posterior vitreous cortex with internal limiting membrane (ILM)-peeling.

Epi-retinal membrane (ERM) peeling around the hole and thorough fluid-gas exchange (gas tamponade);

Followed by postoperative face-down positioning.

The preoperative diameter of the MH plays an important role in choosing the best surgical technique and in predicting postoperative closure of the hole and visual outcome.

 It is therefore advisable to consider the need to accurately measure the width of each hole with an OCT caliper before choosing the surgical approach. Indeed, for all types of vitreoretinal surgery, a good preoperative strategy helps to achieve the best outcome.

A study published in Ophthalmology in 2010 described the classic ILM-flap technique,

 and it was subsequently revised in 2015, when the temporal inverted-ILM-flap technique was introduced. With this method, following core vitrectomy and dye staining, the ILM is not completely removed from the retina but is left in place, attached to the edges of the MH. This ILM remnant is then inverted to cover and fill the MH. Finally, fluid-air exchange is performed.

According to another study, which compared the use of inverted ILM-flap, free-flap and conventional ILM peeling, although all techniques showed a tendency towards visual improvement, the inverted-flap technique seemed to induce a faster and more significant recovery in the short term.

From our point of view, despite the optimal anatomical results, it remains unclear as to how good a substrate the ILM flap is for the remodelling of the neuro-sensitive retina, given the fibrogenic potential of the ILM plug and the uncertainty as to the role fibrotic proliferation may play in restoring visual function.

Until recently, our surgical approach for large and recurrent MHs was to inject autologous whole blood of the patient into the macular defect: a three-port 23-gauge pars plana vitrectomy was undertaken and the central portion of the retina coloured with indocyanine green. ILM peeling then took place with the help of scraper and thumb forceps.

A partial fluid–air exchange followed, as well as the injection of one to two drops of blood.

After aspiration of excessive fluid and blood, the surgery was completed with a low-density silicon oil tamponade.

Anatomical results using this technique were relatively satisfying but functional ones controversial.

Interestingly, Purtskhvanidze et al. compared both anatomical and functional success when using platelet concentrate or whole blood to induce closure of persistent MHs. Their results indicated that the former approach seemed to give better results.

In particularly large or recurrent MHs in which the ILM has already been removed during previous surgery, transplantation may offer a solution to close the holes. A study published in 2016 reported using the lens capsule in an attempt to close MHs, with promising results.

Another autologous transplant was then introduced. It consisted of a neurosensory peripheral retinal transplant, followed by tamponade: either silicone oil tamponade, or shortterm perfluoro-n-octane heavyliquid tamponade. Anatomical results were good but success in postoperative visual acuity was limited.

A novel, less invasive alternative to autologous tissue transplantation in the surgical treatment of large and recurrent MHs is the use of human amniotic membrane (hAM) transplantation (or implantation). With this method, the lens capsule and the peripheral retina of the affected eye are left intact. A plug of lyophilised or cryopreserved hAM is used instead of the patients’ tissues to repair the MH.

Use of hAM in medicine is not new. Applications of hAM in medicine in general, and in surgical ophthalmology in particular, have been reviewed.

 Until 2018, the use of hAM in clinical ophthalmology had been confined to the ocular surface.

In one study published in 2018, hAM patches were placed via an intraocular approach to repair large and recurrent MHs.

 Interestingly, from a historical point of view, repair of MHs with hAM had already been attempted in the mid 20th century, with a surgically complicated retro-bulbar approach in 1957 and in 1964.

Animal and in vitro experiments preceded present day clinical use of hAM. Experiments carried out in pigs’ eyes showed the effect of transplanted amniotic membrane on subretinal wound healing.

Amniotic membrane modified choroidal neovascularisation after mechanical damage to Bruch’s membrane and seemed to behave as a basement membrane substitute for the proliferation of retinal pigment epithelium (RPE).

 In vitro, it was demonstrated that RPE cells cultured on hAM had an epithelial phenotype and secreted growth factors essential for retinal homeostasis.

A 2018, prospective, consecutive case-series described positive results when hAM was implanted in eight patients who had large recurrent MHs. All patients had already undergone pars plana vitrectomy with ILM peeling and gas tamponade. The hAM was delivered cryopreserved from a human tissue bank and was defrosted intraoperatively before insertion.

In all patients, OCT at 1 week postoperatively showed MH closure with neurosensory retina overfilling the hAM. Best corrected visual acuity improved from 1.48±0.49 logarithm of the minimal angle of resolution (logMAR), (20/800) preoperatively to 0.71±0.37 logMAR (20/100) 3 months postoperatively, and to 0.48±0.14 logMAR (20/50) 6 months after the procedure. No ophthalmological adverse events were seen during follow-up.

In a further study, hAM was used in ten patients with high myopia and MHs associated with retinal detachment who had undergone at least one pars plana vitrectomy. Half of the patients received silicon oil and half 10% octafluoropropane as tamponade at the end of surgery.

Silicon oil was removed 2 months after surgery. Results were very satisfying since retinal re-attachment
	was achieved in all patients and visual acuity improved from 1.73 logMAR to 0.94 logMAR after 6 months.

It appears that hAM is well tolerated. The possibility of hAM rejection has also been considered. In 1999, subretinal implantation of hAM in a rabbit model caused no evidence of inflammation or rejection.

In the wake of these results, we started implanting amniotic membranes in patients who had large or recurrent MHs. However, a few of the steps in our surgical approach differs from that described by the aforementioned study: like them, we use a 23-gauge access but unlike their approach, we do not use a chandelier, so the method is not bimanual. The amniotic membrane is managed with a crocodile forceps.

A partial fluid–air exchange takes place, leaving a minimal amount of fluid at the foveal level in order to facilitate the manoeuvre of insertion of the amniotic plug. Implantation of the membrane may be facilitated by the use of a Tano scraper. No perfluorocarbon (PFCL) is used. Surgery is completed with fluid–air exchange and, finally, washout with perfluoropropane takes place.

The best possible outcome, in terms of anatomical results as well as visual acuity, is achieved when patients are able to remain in a facedown position for several days. In those who have physical disabilities or high comorbidities and who are, therefore, unable to hold the facedown position for a long time, silicon oil is used to keep the amniotic membrane in place after insertion.

Clinical studies are currently underway to confirm the promising results obtained so far with subretinal implantation of hAM plugs in the treatment of large and recurrent MHs. It seems that, in addition to anatomical success, the amniotic membrane stimulates retinal ingrowth and leads to improvements in visual acuity.

For this reason, we think attempts should be made to further the understanding of this novel technique in order to analyse its capability to restore visual function. We would suggest an accurate comparison of preoperative and postoperative measured parameters such as visual field assessment and electroretinogram exams, which can validate this technique.

In conclusion, we would affirm that the implantation of amniotic membrane may offer new hope in restoring vision in patients with an otherwise grim outlook.

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Role of human amniotic membrane in surgery of recurrent macular holes

, shares an update on how the company's operations have shifted during the coronavirus pandemic, as well as the record-breaking impact on one of its telehealth platforms.
	 

COVID-19: How Orbis International is managing operations 

Patients with diabetic macular edema (DME) being treated in a real-world clinical practice receive fewer injections of anti-vascular endothelial growth factor (VEGF) injections and their visual gains may be worse compared with patients who are in randomized clinical trials (RCTs).

Many studies performed in a real-world setting have reported that patients with DME receive as little as three to seven treatments during their first year of treatment for DME, and this has resulted in consistently suboptimal visual outcomes, according to Thomas Ciulla, MD, and colleagues John Pollack, MD, and David Williams, MD.

In a previous study that included a 1-year cohort of 5,860 eyes with DME, Dr. Ciulla et al. reported that after the patients were treated with a mean of 7.8 anti-VEGF injections, 0.2 focal laser treatments, and 0.1 corticosteroid injections, the mean change in visual acuity (VA) was +5.2 letters.

In the current retrospective study, the investigators wanted to assess the treatment intensity and its association with the visual outcomes. The study included 28,658 treatment-naÃ¯ve eyes with DME treated from 2013 to 2018. The mean patient age was 62.1 years, and the mean baseline VA was 59.2 letters (20/60 Snellen). The patients had been treated for 1 year as follows: aflibercept (Eylea, Regeneron Pharmaceuticals), 23%; ranibizumab (Lucentis, Genentech), 24%; and bevacizumab (Avastin, Genentech), 53%.

The authors found, “At 1 year, 28, 658 patient eyes underwent a mean of 6.4 anti-VEGF injections, gaining a mean of +4.2 letters (95% confidence interval for mean gain: +4.0 to +4.5 letters, p < 0.001).” The study results were reported in the British Journal of Ophthalmology (http://dx.doi.org/10.1136/bjophthalmol-2020-315933).

Stratification by the anti-VEGF medication and the study years showed no clinically meaningful differences in injection frequency or 1-year VA changes.

After 1  year of treatment, half of the eyes had received six or fewer injections, and fewer than 20% of patients received 10 to 13 injections, which is equivalent to monthly treatment.

The authors commented that generally a linear relationship was seen between the mean number of letters gained at 1  year and the mean number of anti-VEGF injections, beyond two injections.

“The mean 1-year VA change tended to increase in patient eye with both increased anti-VEGF frequency and decreased baseline VA, although there were some ceiling effects related to the baseline VA, with the exception of those who had received from 10 to 13 anti-VEGF injections,” they said.

The study also found that patients treated in a real-world scenario and not a RCT who had relatively good baseline VA of 20/40 or better generally were at risk of VA loss at 1 year. In contrast, the patients with DME with moderately severe baseline visual impairment (20/70 to 20/200) who received 10 or more injections improved by a mean of +10.3 letters.

“As the healthcare system shifts to value-based approaches, real-world outcomes assume greater importance; these results highlight the necessity for patient counseling on treatment frequency with current anti-VEGF therapy also highlight the unmet need for longer duration therapies that can address treatment burden,” the study concluded.

Dr. Ciulla is from Indiana University School of Medicine and the Midwest Eye Institute, Indianapolis.
	Dr. Pollack is from Rush University, and Illinois Retina Associates, both in Chicago.
	Dr. Williams is from the University of Minnesota and VitreoRetinal Surgery, PA, both in Minneapolis.

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

Adding AI technology using deep-learning systems in a semi-automated model to the process has been shown to be equally effective as the assessment performed by trained human graders for detecting DR.

Diabetic retinopathy (DR) is a vision-stealing complication of diabetes that has been effectively assessed by human graders of fundus photographs using tele-ophthalmology screening.

Adding artificial intelligence (AI) technology using deep learning systems in a semi-automated model to the process has been shown to be equally effective as the assessment performed by trained human graders for detecting DR. The added bonus is that the technology is substantially more cost-effective.

The study investigators explained that “before the deep learning era, a few UK studies suggested that automated DR grading using feature-based learning might be cost-effective as a DR screening tool. Since the advent of deep learning, a few studies have shown that [it] could have comparable diagnostic performance to human graders in detecting DR.”

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