Emiliano Di Carlo, MD

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.

1. Seiberth V, Alexandridis E, Feng W. Function of the diabetic retina after panretinal argon laser coagulation. Graefes Arch Clin Exp Ophthalmol. 1987;225(6):385-390.
	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.
	7. Eng VA, Leng T. subthreshold laser therapy for macular oedema from branch retinal vein occlusion: focused review. Br J Ophthalmol. 2020 Feb 7 [Online ahead of print].
	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.
	9. Bandello F, Lanzetta P, Furlan F, Polito A. Non-visible subthreshold micropulse diode laser treatment of idiopathic central serous chorioretinopathy. A pilot study. Investig Ophtalmol Vis Sci. 2003;44:4858.
	10. van Dijk EHC, Fauser S, Breukink MB, Blanco-Garavito R, Groenewoud JMM et al. Half-dose photodynamic therapy versus high-density subthreshold micropulse laser treatment in patients with chronic central serous chorioretinopathy: the PLACE trial. Ophthalmology. 2018;125:1547-1555.
	11. Kim YJ, Kim SY, Ha S, Moon D, Seong S et al. Short-duration multiple-session subthreshold micropulse yellow laser (577 nm) for chronic central serous chorioretinopathy: results at 3 years. Eye (Lond). 2019;33:819-825.

Articles

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.

1. Knapp, H. Ãber isolierte Zerreissungen der Aderhaut infolge von Traumen auf dem Augenapfel. Arch Augenheilkunde. 1869;1:6-29.
	2. Aaberg, TM. The macular holes. A Review. Surv Ophthalmol. 1970;15:139-162.
	3. Stalmans P, Benz M, Gandorfer A et al. Enzymatic vitreolysis with ocriplasmin for vitreo-macular traction and macular holes. New Engl J Med. 2012;367:606-615.
	4. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holes. Results of a pilot study. Arch Ophthalmol. 1991;109:654-659.
	5. Tadayoni R, et al. Relationship between macular hole size and the potential benefit of internal limiting membrane peeling. Br J Ophthalmol. 2006;90:1239-1241.
	6. Ullrich,et al. Macular hole size as a prognostic factor in macular hole surgery. Br J Ophthalmol. 2002;86:390-393.
	7. Michalewska, et al. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010;117:2018-2025.
	8. Michalewska, et al. Temporal inverted internal limiting membrane flap technique versus classic inverted internal limiting membrane flap technique: a comparative study. Retina. 2015;35:1844-1850.
	9. Velez-Montoya R, et al. Inverted ILM flap, free ILM flap and conventional ILM peeling for large macular holes. Int J Retina Vitreous. 2018;19:8.
	10. Purtskhvanidze K, et al. Persistent full-thickness idiopathic macular hole: anatomical and functional outcome of revitrectomy with autologous platelet concentrate or autologous whole blood. Ophthalmologica. 2017;239;1:19-26
	11. Chen SN, et al. Lens capsular flap transplantation in the management of refractory macular hole from multiple etiologies. Retina. 2016;36:163-170.
	12. Grewal, et al. Autologous neurosensory retinal free flap for closure of refractory myopic macular holes. JAMA Ophthalmol. 2016;134:229-230.
	13. Murube J. Early clinical use of amniotic membrane in medicine and ophthalmology. The Ocular Surface. 2006;4:114-119.
	14. Rizzo, et al. A human amniotic membrane plug to promote retinal breaks repair and recurrent macular hole closure. Retina. 2018. doi.org/10.1097/
	IAE.0000000000002320.
	15. Csapody I. Amnion Implantation gegen Maculaloch (Amniotic membrane implantation against macular holes). Ophthalmologica, 1957;134:273-275.
	16. Bechrakis E, Soellner F. Zur Amnion Implantation bei Makulaforamen [On amnion implantation in macular foramina.] Ber Zusammenkunft Dtsch Ophthalmol Ges. 1964;65:81-83.
	17. Kiilgaard JF, et al. Transplantation of amniotic membrane to the subretinal space in pigs. Stem Cells Int, 2012. Doi. org/10.1155/2012/716968.
	18. Ohno-Matsui K, et al. The effects of amniotic membrane on retinal pigment epithelial cell differentiation. Mol Vis. 2005;6:1-10.
	19. Caporossi T, et al. A human Amniotic Membrane plug to manage high myopic macular hole associated with retinal detachment. Acta Ophthalmol. 2019.doi. org/10.1111/aos.14174
	20. Rosenfeld PJ, et al. Subretinal implantation of human amniotic membrane: a rabbit model for the replacement of Bruch’s membrane during submacular surgery. Invest Ophthalmol Vis Sci. 1999;40:206.

Author | Emiliano Di Carlo, MD

Articles

Turning to new frontier in micropulse laser treatment for retinal disorders

Role of human amniotic membrane in surgery of recurrent macular holes