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`
`100
`
`Current Diabetes Reviews, 2014, 10, 100-112
`
`Laser Treatment for Diabetic Macular Edema in the 21st Century
`
`1
`Pedro Romero-Aroca
`
`2
`*, Javier Reyes-Torres
`
`3
`, Marc Baget-Bernaldiz
`
`4
` and Cristina Blasco-Suñe
`
`1Professor, Director of Department of Ophthalmology, University Hospital Sant Joan, University Rovira i Virgili, Insti-
`tut de Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; 2Fellow of Department of Ophthalmology, University
`Hospital Sant Joan, University Rovira i Virgili, Institut de Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain;
`3Senior Ophthalmologist Department of Ophthalmology, University Hospital Sant Joan, University Rovira i Virgili, In-
`stitut de Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; 4Fellow of Department of Ophthalmology, University
`Hospital Sant Joan, University Rovira i Virgili, Institut de Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
`
`Abstract: Diabetic macular edema (DME) is the leading cause of blindness in the diabetic population. The diabetes Con-
`
`trol and Complications Trial reported that 27% of patients affected by type 1 diabetes develop DME within 9 years of on-
`
`set. Other studies have shown that in patients with type 2 diabetes, the prevalence increased from 3% to 28% within 5
`
`years of diagnosis to twenty years after the onset. At the present time, despite the enthusiasm for evaluating several new
`treatments for DME, including the intravitreal therapies for DME (e.g., corticosteroids, and anti-VEGF drugs), laser pho-
`
`tocoagulation remains the current gold standard and the only treatment with proven efficacy in a wide range of clinical tri-
`
`als for this condition. Despite being the standard technique for comparison and evaluation of the emerging treatments, we
`
`have generally poor understanding of the ETDRS recommendations, and we often forget about the results of laser in
`
`DME. The purpose of this review is to update our knowledge on laser photocoagulation for DME with an extensive re-
`
`view of the ETDRS results and discuss the laser techniques. Furthermore, we will describe the new developments in laser
`
`systems and review the current indications and results. Finally, we will discuss the results of laser treatments versus the
`
`current pharmacological therapies. We conclude by trying to provide a general overview that which laser treatment must
`
`be indicated and what types of lasers are currently recommended.
`
`Keywords: Laser, grid laser, focal laser, pan-retina-photocoagulation, anti-VEGF injections, diabetic retinopathy, diabetic
`macular edema, clinically significant macular edema, diffuse macular edema, focal macular edema.
`
`INTRODUCTION
`
`Diabetes is a chronic disease that typically causes
`
`changes in the small vessels of the whole body, changes that
`
`are referred to as diabetic microangiopathy. The ocular form
`
`is called diabetic retinopathy (DR). Approximately 25% of
`
`the people with diabetes have at least some form of diabetic
`
`retinopathy, and the incidence increases with the duration of
`
`the disease [1]. Eye diseases in diabetic population are the
`
`leading cause of blindness in adults under 75 years of age in
`
`developed countries [2]. There are two main complications
`
`of DR that cause visual loss: the proliferative diabetic reti-
`
`nopathy (PDR) and the presence of diabetic maculopathy
`
`[3].
`
`Diabetic maculopathy may appear in two forms:
`
`1) Diabetic macular edema (DME)
`
`2) Diabetic macular ischemia (DMI)
`
`DME is defined as an accumulation of fluid between the
`
`outer plexiform and the inner nuclear layers, as well as a
`
`of the retinal extracellular space, in some cases involving the
`
`intracellular, both in the macular area. The prevalence of
`
`DME is higher in type 2 (DM2) than that in type 1 (DM1)
`
`diabetic patients. Our study group in 2007 found a preva-
`
`lence of DME of 12.9% in DM2 patients and 7.86% in DM1
`
`patients [4].
`
`The Diabetes Control and Complications Trial (DCCT)
`
`[5] reported that 27% of DM1 patients develop DME within
`
`9 years of diabetes onset. Other studies have shown that in
`
`patients with type 2 diabetes, the prevalence increased from
`
`3% to 28% within 5 years of diagnosis to twenty years after
`
`the onset [6]. DME tends to be a chronic disease, although it
`
`is important to recognize that about 33% to 35% of patients
`
`with DME resolve the condition spontaneously after 6
`
`months [7, 8]. The edema in the macular area occurs secon-
`
`dary to an abnormal permeability of the capillaries surround-
`
`ing the macula (failure of inner retinal blood barrier), and in
`
`turn to a failure in the outer retinal barrier (formed by the
`
`retinal pigmented epithelium). These two mechanisms are
`
`responsible for the accumulation of interstitial fluid at the
`
`swelling of the Müller cells of the retina, causing expansion
`
`macula [9, 10].
`
`*Address correspondence to this author at the Department of Ophthalmol-
`
`ogy, University Hospital Sant Joan, University Rovira i Virgili, Institut de
`
`Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain, Avda. Josep
`
`Laporte 1, 43204 Reus, Spain; Tel: 0034977310300; Fax 003497732375;
`
`E-mails: romeropere@gmail.com, promero@grupsagessa.com
`
`While there is currently no treatment for DMI, there are
`
`different treatments for patients with macular edema, includ-
`
`ing the photocoagulation treatment with focal or grid laser,
`
`which remains the gold standard of treatment for DME. In
`
`recent years new treatment regimens with intravitreal corti-
`costeroid or anti-VEGF injections and anti-VEGF drugs, and
`
`1875-6417/14 $58.00+.00
`
`© 2014 Bentham Science Publishers
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2126 Page 1
`
`

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`Laser for Diabetic Macular Edema
`
`Current Diabetes Reviews, 2014, Vol. 10, No. 2 101
`
`combined treatments of laser and intravitreal injections have
`
`3) A zone, or zones, of retinal thickening 1 disk area or
`
`been studied. Finally, in cases where vitreous traction is
`
`demonstrated, the treatment of choice is to perform a poste-
`
`rior vitrectomy surgery (VPP). The use of the laser source as
`
`a method of treatment for DME was first evaluated in a pro-
`
`tocol within the Diabetic Retinopathy Study (DRS) in 1981
`
`[11]. The effectiveness of the xenon arc source and argon
`
`laser light in the treatment of proliferative diabetic retinopa-
`
`larger, any part of which is within 1 disk diameter (1
`disc = 1500 μm) of the centre of the macula.
`
`The most useful classification used for clinical diagnosis,
`
`and subsequent DME treatment, is based on macular distri-
`
`bution [18, 19], which classifies them as focal or diffuse
`
`macular edema:
`
`thy was verified, with a reduction in visual acuity of less
`
`1) Focal macular edema is associated with circinate rings
`
`than 5/200 in 50% of cases, and with a stability of visual
`
`of hard exudates resulting in leakage from microaneu-
`
`acuity for at least 4 months. The next clinical trial of diabetic
`
`rysms that would lead to macular edema. Focal macular
`
`retinopathy, the Early Treatment Diabetic Retinopathy Study
`
`edema can be unique, with only one focus of macular
`
`(ETDRS) evaluated the efficacy of laser treatment in 3.711
`
`edema, or multi-focal (with more than one focus).
`
`patients, assigning patients randomly into two groups, the
`
`first receiving laser treatment immediately and the second,
`
`subjected to treatment with aspirin and laser, being delayed
`
`until five years [11-14].
`
`2) Diffuse macular edema represents a more extensive
`
`breakdown of the blood retinal barrier with leakage from
`both microaneurysms and retinal capillaries (Fig. 1).
`This type is observed during late hyperfluorescence an-
`
`The ETDRS results suggested that scatter laser photoco-
`
`giography of a significant size (typically more than two
`
`agulation should be considered for all eyes with severe non-
`
`papillary diameters) with scarce microaneurysms and
`
`proliferative diabetic retinopathy or worse, because the rate
`
`hard exudates.
`
`of severe loss was reduced by more than 50% of those
`
`treated with early laser photocoagulation compared with eyes
`
`DIFFERENT LASERS USED IN OPHTHALMOLOGY
`
`assigned to deferred laser photocoagulation. Regarding
`
`macular edema treatment, the ETDRS, further concluded that
`
`focal or grid laser photocoagulation was effective [13, 15].
`
`Classification of the ocular tissue lesion produced by la-
`
`ser [20]
`
`Despite the fact that ETDRS study has been the gold stan-
`
`1) Photocoagulation: thermal effect. Lesions are caused by
`
`dard in the classification and treatment of diabetic retinopa-
`
`an increase in tissue temperature, causing vaporization
`
`thy and macular edema, it seems that DME photocoagulation
`
`of liquids within and outside tissues and denaturalizing
`
`laser treatment has been replaced by the new intravitreal
`
`proteins, resulting in cellular death (apoptosis). Lasers
`
`of this kind are called photocoagulators, some of which
`
`drugs. This work aims to review the knowledge we currently
`
`have on the importance of laser photocoagulation, the differ-
`
`are of argon (514.4 green and 488 blue-green nanome-
`
`ent techniques and laser sources, and the current indication
`
`in patients with DME.
`
`DEFINITION OF MACULAR EDEMA AND CLINI-
`CALLY SIGNIFICANT MACULAR EDEMA
`
`In clinical care we use two different terms to define
`
`macular edema secondary to diabetes mellitus [16, 17]:
`
`1) Diabetic macular edema (DME)
`
`2) Clinically significant macular edema (CSME)
`
`Both terms are different and are a source of confusion. In
`
`many studies, the terms are used indifferently and have led
`
`to confusing results.
`
`ters) and krypton (647.1 red nanometers), which require
`
`a water refrigeration system. Currently, the most com-
`
`monly used are double-diode (532 nanometers) and
`
`double-YAG (532 nanometers), which do not require
`
`cooling systems.
`
`2) Disruption: electromechanical effect. These lasers use a
`burst of optical pulses of high power and short duration,
`
`achieving ionization of the tissue, forming plasma that
`
`expands at high temperature, which causes an acoustic
`
`shock wave that breaks the target tissue. Lasers of this
`
`type are called photodisruptors and Neodimio YAG (Yt-
`
`trium-Aluminum-Garnet) operated with a longitudinal
`
`wave of 1064 nanometers is the one most commonly
`
`used. Its usefulness is in carrying out a capsulotomy af-
`
`Diabetic macular edema (DME) is defined as retinal
`
`ter opacification following cataract surgery, and periph-
`
`thickening (associated with the typical lesions such as mi-
`
`croaneurysms, retinal edema and hard exudates) within 1
`
`disc diameter from the foveal centre and with two disc di-
`ameters wide (1 disc diameter = 1500 μm); it can either be
`focal or diffuse in distribution.
`
`eral iridotomy to prevent risks of acute angle-closure
`glaucoma.
`
`3) Photochemical, in which the lasers are used to alter the
`
`chemical composition of the target tissue, producing a
`
`molecular alteration of the cells subjected to a prior pho-
`
`Clinically significant macular edema (CSME) is a form
`
`tosensitization. This type of treatment is called photody-
`
`of DME that was precisely defined by the ETDRS [32] as
`
`namic therapy. In this type of laser, the treatment is car-
`
`ried out by photosensitization of the tissues, using pho-
`
`tosensitizing agents like verteporfin (with a laser light
`
`absorption peak of 689 nm), which binds to the lipopro-
`
`teins LDL-cholesterol. The activation is done by a non-
`
`any of the following criteria being met:
`
`1) Any retinal thickening within 500 μm of the centre of
`the macula.
`
`2) The presence of hard exudates at or within 500 μm of
`the centre of the macula, if associated with thickening of
`
`the adjacent retina (not residual hard exudates remaining
`
`thermal diode laser of 689 nm for 83 seconds, giving a
`2
`dose of 50 jules/cm
`3
`
` luminous
`
`light intensity of
`
`600mW/cm
`
`. Once activated, verteporfin radicals re-
`
`after the disappearance of retinal thickening)
`
`lease oxygen, a process that alters the membranes of en-
`
`
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2126 Page 2
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`102 Current Diabetes Reviews, 2014, Vol. 10, No. 2
`
`Romero-Aroca et al.
`
`Fig. (1). Red-free fundus photography showing diffuse diabetic macular edema.
`
`
`
`dothelial cells of the ocular blood vessels. This produces
`
`beam. At the same time, the ruby laser was being evaluated
`
`a platelet aggregation and forms a thrombus, resulting in
`
`[23]; the long wavelength and very brief exposure time of
`
`an occlusion of the vessels. This technique is currently
`
`the ruby laser limited burns mainly to the outer layers of the
`
`used in the treatment of exudative AMD (age related
`
`retina, without immediate visible effects in new vessels,
`
`degeneration).
`
`leading to the abandonment of the technique.
`
`4) Photodecomposition. This is the result of the interaction
`
`Diabetic retinopathy and diabetic macular edema are
`
`of the laser with the tissues, which emits ultraviolet light
`
`treated by lasers that produce thermal photocoagulation. As
`
`at the target tissue. In this case, the laser photons are ab-
`
`commented, the first laser used in retina treatment was the
`
`sorbed at the molecular level, resulting in fragmentation
`
`argon laser, which was then followed by the red krypton
`
`of the molecules. They emit ultraviolet radiation of 193
`
`laser and finally the dye laser (which allowed the light to
`
`nanometers in pulses of 10 nanoseconds and the emitted
`
`change from yellow to green, according to the needs of the
`
`radiation destroys molecular unions forming a volatile
`
`retina. These types of lasers have been changed for solid
`
`phenomenon called photodecomposition. The Excimer
`
`lasers (doubled-diode or doubled-YAG). Unlike the argon
`
`lasers (Argon - Fluoride) used in refractive surgery
`
`and krypton lasers, the doubled diode or YAG lasers are
`
`sculpt the corneal stroma using the photoablation.
`
`much more power efficient, allowing them to be connected
`
`Of the lasers described above, the treatment of DR and
`
`the DME appearing there is carried out with photocoagulator
`
`lasers. The first of their type used were argon and krypton,
`
`which were very cumbersome owing to the need for water
`
`cooling facilities. These have been replaced by the so-called
`
`solid lasers, which use diode or YAG, doubled to a produced
`
`radiation of 532 nanometers.
`
`to standard power outlets available in any hospital or clinic.
`
`The laser emission is located in the green 532 nm, being
`
`much more effective than conventional argon lasers. The
`
`tissue response at wavelength 532 nm is more similar to that
`
`with the dry yellow-green argon (514 nm) and almost the
`
`same as the Krypton yellow (568 nm). Compared with the
`
`argon (514 nm) laser, doubled diode or YAG lasers have
`
`higher absorption of oxyhaemoglobin (HbO) and haemoglo-
`
`One type of laser also used in DME is the diode of 810
`
`bin (Hb), less dispersion (the long wavelength) and low ab-
`
`nanometers and acts in micropulses of 0.1 ms duration.
`
`sorption of xanthophyll pigment.
`
`PHOTOCOAGULATION
`
`The first clinical trial was initiated by a British multicen-
`
`tre research that used xenon arc photocoagulation [24], and
`
`The initial laser used in retina treatment with a thermal
`
`later by the National Eye Institute’s Diabetic Retinopathy
`
`effect was the xenon arc photocoagulator. It is, in fact, not a
`
`Study [25], known as the DRS, which compared xenon arc
`
`true laser; it was introduced by Meyer-Schwickerath [21, 22]
`
`and argon laser photocoagulation. The DRS studied patients
`
`who, in a large series of publications, demonstrated in prolif-
`
`with proliferative diabetic retinopathy in at least one eye or
`
`erative diabetic retinopathy the effectiveness of light burns
`
`severe non-proliferative DR in both eyes, with a visual acu-
`
`over new vessels. This technique changed to a long, slow,
`
`ity of at least 20/100 in each eye. Patients were assigned to
`
`moderately intense burning, turning the retina white adjacent
`
`xenon arc or argon laser photocoagulation treatment, and
`
`to the new vessels, and sometimes causing them to narrow,
`
`followed at four months intervals. At two-years follow up,
`
`slowing the flow within them. A true laser was made later;
`
`the DRS concluded that prompt laser treatment for eyes with
`
`the first to be introduced was the argon laser. This produced
`
`severe non-proliferative DR or proliferative DR was effec-
`
`a blue-green beam with sufficient intensity to reproduce the
`
`tive. Furthermore, the DRS concluded that because the harm-
`
`effects of a xenon arc with more intensity and a narrower
`
`ful effects were higher with xenon arc than argon laser, the
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2126 Page 3
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`

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`Laser for Diabetic Macular Edema
`
`Current Diabetes Reviews, 2014, Vol. 10, No. 2 103
`
`latter laser was a preferable treatment for diabetic retinopa-
`
`0.05 to 0.1 second duration, the end point of treatment is
`
`thy [26].
`
`Laser Effect Mechanism
`
`The effect of laser photocoagulation on the retina for dia-
`
`betic retinopathy is still unknown, although different expla-
`
`nations have been put forward. The first is the occlusion of
`
`microaneurysms. In focal laser treatment in cases of focal
`
`macular edema, it is thought that direct microaneurysm pho-
`
`tocoagulation around macular area reduces the leakage from
`
`the MA with a consequent decrease in macular edema. How-
`
`ever, in the grid laser treatment technique, this mechanism
`
`might only function partially, so other possible mechanisms
`
`have been suggested:
`
`1) Oxygen increases through the laser scar. One explana-
`
`tion involves laser-induced destruction of oxygen-
`
`consuming photoreceptors; the laser scars produce an
`
`apoptosis of photoreceptors, retinal pigment epithelium
`
`and choriocapillaries, and the scars allow oxygen (that
`
`normally diffuses from the choriocapillaries into the
`
`outer retina) to diffuse through the laser scar into the in-
`
`ner retina, thus relieving the inner retinal hypoxia [27].
`
`2) A decrease in autorregulatory vasoconstriction. In dia-
`
`betic retinopathy (also in DME), retinal vascular perfu-
`
`whitening or darkening of focal lesions. Microaneurysms
`below 40 (cid:1)m in diameter had successful results with low
`laser intensity, but microaneurysms with more than 40 (cid:1)m
`diameter needed more intense laser burns (a more whitening
`
`result) and sometimes needed a re-treatment. The clusters of
`
`microaneurysms, in particular those with hard exudate rings,
`may be treated with larger spots (200 to 500 (cid:1)m), with sub-
`sequent re-treatment of any large microaneurysms within the
`cluster with 50 (cid:1)m spots to obtain darkening or whitening.
`The treatment of lesions of more than 3000 (cid:1)m from the
`centre is recommended if prominent leaks are present and
`
`associated with retinal thickening or hard exudates that ex-
`tend closer to the center (Table 1).
`
`Grid laser, in which mild power laser impacts were made
`with a spot size of 50 to 200 (cid:1)m, for a duration of 0.05 to 0.5
`sec obtained a mild retinal pigment epithelium whitening,
`
`with power adjustment to prevent the burns from spreading
`to more than 200 (cid:1)m in diameter. Grid treatment is not
`placed within 500 (cid:1)m of the center of the macula or within
`500 (cid:1)m of the disc margin, but may be placed in the papil-
`lomacular bundle. Grid can extend up to 2 disk diameters
`(3000 (cid:1)m) from the centre of the macula or to border pan-
`retinal photocoagulation treatment, if present (Fig. 2). Any
`focal leaks within the areas of the grid treatment are treated
`
`sion is increased with an arteriolar and venular dilata-
`
`focally. The laser burns are placed approximately two visible
`
`tion. Following laser photocoagulation, Gottfredsdottir
`
`burn widths apart in the areas of the macular edema (retinal
`
`et al found that arteriolar branches constricted by 20.2%
`
`and the venular branches by 13.8%. The authors hy-
`
`pothesized that the improved retinal oxygenation leads
`
`thickening) that are thought to be related to diffuse leakage
`or capillary loss (Table 1).
`
`to autoregulatory vasoconstriction with subsequent im-
`
`Mild Macular Laser Photocoagulation (MMG)
`
`provement in the DME [28].
`
`This new approach to macular laser photocoagulation has
`
`3) A decrease in the whole area of abnormal leakage. Wil-
`
`recently become the focus of interest for ophthalmologists.
`
`son et al demonstrated a reduction in the retinal capillary
`
`In this new method, the burns are applied to the entire area
`
`area in the laser photocoagulation zone, and suggested
`
`(as described below) for treatment (including unthickened
`
`that when the area of abnormal leaking vessels is re-
`
`retina). Burns are focused/located over 500 to 3000 microns
`
`duced, the amount of leakage would be reduced, which
`
`above, nasally and under the center of macula, and 500 to
`
`would result in the macular edema being resolved [29].
`
`3500 microns towards the temples [35]. There are no burns
`
`4) Restoration of retinal pigment epithelium (RPE) barrier.
`
`The RPE cells might respond to the laser injury in sev-
`eral ways: if the lesion is small (<125 (cid:1)m) the RPE de-
`fect can be filled by spreading, but if the defect is rela-
`
`tively large the RPE cells proliferate to resurface the
`area, and the new RPE cells produce cytokines (e.g.
`TGF-(cid:2)) that antagonize the effects of VEGF (the most
`important vasculogenic molecule, implicated in DME
`
`production) [30, 31].
`
`DIABETIC MACULAR EDEMA, TREATMENT
`TECHNIQUES
`
`Laser treatment was defined by the ETDRS study in its
`
`Reports number 3 and number 4, [32-34]. According to the
`ETDRS, there are two different techniques:
`
`Focal Laser, Focal treatment is required for focal lesions
`located between 500 and 3000 (cid:1)m from the centre of the
`macula. The term ‘focal lesions’ according to the ETDRS
`
`within 500 microns of the disc. The burn intensity of the grid
`
`laser is barely visible (light grey); 200 to 300 burns in total
`
`are distributed evenly over the treatment area (approx. 2 to 3
`
`burn widths apart). The MMG burns are lighter and more
`
`diffused in nature and are distributed over the whole macula
`
`in both areas of thickened and unthickened retina. Microan-
`eurysms are not directly photocoagulated (Table 1). In con-
`trast, the ETDRS focal/grid photocoagulation comprised of
`
`treating only areas of thickened retina (and areas of retinal
`
`nonperfusion) and leaking microaneurysms. The Diabetic
`
`Retinopathy Clinical Research Network (DRCR.net) com-
`
`pared this technique [35] with the previously described
`
`modified-ETDRS gold standard technique. Between July
`
`2003 to October 2004, 263 patients (with a total of 323 eyes)
`
`were enrolled and assigned randomly to each technique (n =
`
`162 eyes to the mETDRS technique and n = 161 eyes to the
`
`MMG technique). Despite the hopes for this new method,
`
`there was no indication that the eyes treated with MMG had
`
`a better outcome after 12 months of follow up than those
`
`classification includes: microaneurysms, intraretinal mi-
`
`receiving mETDRS treatment. In fact, eyes in the mETDRS
`
`crovascular abnormalities (IRMA) and short capillary seg-
`
`group experienced a slightly greater reduction in retinal thic-
`
`ments that show focal fluorescein leakage. The treatment
`consists of burns of 50 to 100 (cid:1)m of moderate intensity and
`
`kening and a trend towards a slightly better visual acuity out-
`come. In conclusion, despite potential advantages in theory,
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2126 Page 4
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`

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`104 Current Diabetes Reviews, 2014, Vol. 10, No. 2
`
`Romero-Aroca et al.
`
`Table 1. Laser photocoagulation techniques for DME, attending the original ETDRS, modified ETDRS and the MMP technique.
`
`
`
`Direct/ Grid Photocoagulation
`
`Direct/ Grid Photocoagulation
`
`Mild Macular Grid Photocoagulation
`
`Original ETDRS
`
`Modified ETDRS
`
`Technique
`
`Directly treat all leaking MA in areas of
`
`Directly treat all leaking MA in areas of
`
`Lighter and more diffuse in nature and
`
`Characteristic of direct
`
`retinal thickening between 500 and 3000
`
`retinal thickening between 500 and 3000
`
`are distributed throughout the macula in
`
`treatment
`
`microns from the centre of the macula
`
`microns from the centre of the macula
`
`both areas of thickened and unthickened
`
`(but not within 500 microns of disc)
`
`(but not within 500 microns of disc)
`
`retina
`
`Change in microaneu-
`
`rysms colour with direct
`
`treatment
`
`Burn size for direct
`
`treatment
`
`Required at least a mild white burn
`
`should be evident beneath all MA
`
`Not required, but at least a mild gray-
`
`white burn should be evident beneath all
`
`MA
`
`Microaneurysms are not directly
`
`photocoagulated
`
`50 to 100 microns
`
`50 microns
`
`Not applicable
`
`Burn duration
`
`0.05 to 0.1 sec
`
`0.05 to 0.1 sec
`
`Not applicable
`
`Grid treatment
`
`or nonperfusion within area described
`
`or nonperfusion within area described
`
`for treatment (including unthickened
`
`Applied to all areas with diffuse leakage
`
`Applied to all areas with diffuse leakage
`
`Applied to entire area described below
`
`below for treatment
`
`below for treatment
`
`retina)
`
`500 to 300 microns superiorly, nasally
`
`500 to 300 microns superiorly, nasally
`
`500 to 300 microns superiorly, nasally
`
`and inferiorly from the centre of macula.
`
`and inferiorlyfrom the centre of macula.
`
`and inferiorly from the centre of macula.
`
`Area considered for grid
`
`500 to 3500 microns temporally from
`
`500 to 3500 microns temporally from
`
`500 to 3500 microns temporally from
`
`treatment
`
`macula centre.
`
`macula centre.
`
`macula centre.
`
`No burns are placed within 500 microns
`
`No burns are placed within 500 microns
`
`No burns are placed within 500 microns
`
`of disc
`
`of disc
`
`of disc
`
`Burns size for grid
`
`treatment
`
`
`
`50 to 100 microns
`
`50 microns
`
`50 microns
`
`with either approach are not significantly different. This
`
`study does not therefore provide data to suggest that a larger
`
`long-term trial of the MMG technique is likely to show sub-
`
`stantial clinical benefit over the current mETDRS approach.
`
`Subthreshold Diode Micropulse Laser Photocoagulation
`(MPD)
`
`This recent technique uses a subthreshold laser micro-
`
`pulse, using an 810 nanometre diode laser; the desired effect
`
`is to reduce the laser damage to ocular tissue; its application
`
`in the macular area is very promising in order to treat DME
`
`with the less retinal damage. Although conventional photo-
`
`coagulation is a destructive procedure, chorioretinal damage
`
`can be minimized by modifying laser parameters and clinical
`
`endpoints in the following ways: by decreasing wavelength,
`
`spot size, retinal irradiance or pulse duration. In continuous
`
`wave mode, the laser energy is delivered as a single pulse,
`
`with a typical width in the range of 0.1-0.5 seconds expo-
`
`sure. In micropulse mode, the laser energy is delivered with
`
`a train of repetitive short pulses (typically 100x300 msec.
`
`
`
`each) in packets. The greatest limitation of MPD laser pro-
`
`cedures is the difficulty of the treatment without the feed-
`
`Fig. (2). Macular fibrosis secondary to a grid laser treatment. Spec-
`
`back of an ophthalmoscopically visible endpoint. Con-
`
`tral Domain-OCT image shows the subretinal fibrosis. The red-free
`
`versely, minimizing chorioretinal laser damage allows con-
`
`fundus photography shows a scar located at fovea, surrounded by
`
`the laser impact sites.
`
`after 12 months of follow up the MMG laser technique is
`
`less effective in reducing OCT measure retinal thickening
`
`than the mETDRS technique frequently used in current clini-
`
`cal practice. Having said that, the visual acuity outcomes
`
`fluent therapy and re-treatment of the same areas, which may
`
`be needed in macular edema. Re-treatment is feasible after
`
`MPD, because it does not produce chorioretinal scars that
`
`might expand or increase the risk of choroidal neovasculari-
`
`zation. The treatment protocol is not yet well established in
`
`terms of the exact laser irradiance (power per unit of area)
`
`that should be delivered to the retina.
`
`
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2126 Page 5
`
`

`

`Laser for Diabetic Macular Edema
`
`Current Diabetes Reviews, 2014, Vol. 10, No. 2 105
`
`The introduction of the infra-red diode laser and its
`
`proven efficacy in treating DME has provided a valuable
`
`insight into the mechanism of action of retinal laser therapy.
`
`Direct closure of microvascular abnormalities with a rela-
`
`tively heavy burn is not necessary to achieve the desired
`
`clinical therapeutic endpoint. Micropulsed diode laser ther-
`
`apy has laid further weight to this concept, with an increas-
`
`ing body of clinical evidence suggesting that resolution of
`
`retinal vascular pathology is possible with low energy, sub-
`
`threshold lesions.
`
`The literature reports some studies of its uses; the first
`
`published data was by McHugh [36], who showed a clini-
`
`cally significant burn in the pigment epithelium by photoco-
`
`agulation with a diode laser (810 nm). However, it caused
`
`less damage to the retina than argon laser photocoagulation,
`
`and the pain associated with treatment was reported as com-
`
`parable. In another study Ulbig [37] showed that CSME was
`
`completely or partially resolved in 82% of eyes treated with
`
`a diode laser, and visual acuity deteriorated in 3% of treated
`
`eyes after 6 months of follow-up. Finally, Akduman [38]
`
`compared the diode and argon green laser treatment for dif-
`
`fuse DME. Results at the 24-month follow-up showed that
`
`
`
`92% of eyes treated with the diode laser and 95% of eyes
`
`Fig. (3). Retinal fundus photography after ten years of a laser
`
`treated with the argon green laser had complete or partial
`
`treatment. There is an observable increase in the size of the initial
`
`resolution of the macular edema, and the visual acuity re-
`
`laser spots, and a lot of hyperpigmented areas can be seen in the
`
`mained unchanged in 75% of eyes treated with the diode
`
`laser scars.
`
`laser and in 74% of eyes treated with the argon green laser.
`
`Further studies have been published reviewing the protocol
`
`of applying subthreshold micropulse diode laser photocoagu-
`
`lation and describe the parameters needed for DME treat-
`
`ment [39, 40]. There are currently not enough evidence-
`
`based clinical practice guidelines for its use, therefore further
`
`large studies are required using this technique before a rec-
`
`ommended new treatment for DME can be established.
`
`Follow up After Laser Treatment
`
`The ETDRS indicates when treatment is needed for new
`
`lesions or recurrent leakage in macular area. A new treat-
`
`ment is recommended when clinically significant macular
`
`edema and lesions suitable for focal or grid treatment are
`
`present. New treatment can be carried out at a six-week fol-
`
`low up visit if it is apparent that treatable lesions have obvi-
`
`ously been missed during the initial treatment. Further treat-
`
`ment can be delayed until the next four-monthly visit, and
`
`each subsequent 4-monthly follow up visit. At all these vis-
`
`its, treatment can be repeated if macular edema persists and
`
`involves the centre of the macula, that means, there is a pres-
`
`ence of clinically significant macular edema.
`
`LASER PHOTOCOAGULATION COMPLICATIONS
`
`Laser photocoagulation is not a harmless technique. The
`
`laser burn induced in the retinal layers, in particular the de-
`
`struction of the retinal pigment epithelium, might lead to
`
`apoptosis of the surrounding retinal cells. In the macular
`
`area, this secondary effect might affect the visual acuity.
`
`One of the most important effects that can reduce visual
`
`acuity is the enlargement of a laser scar, referred to as ‘atro-
`phic creep’, as we can observe in (Fig. 3), where the initial
`laser scars increase in size and coalesce each other, with a
`
`the laser scars might threaten the visual prognosis if the laser
`
`is applied too close to the fovea. Schatz [41] reported that
`
`enlarged laser scars reached the central fovea in 11 of 203
`
`eyes with diabetic macular edema after grid laser photoco-
`
`agulation. Brancato [42] reported that the scars enlarged by
`
`an average of 103% after treatment of choroidal neovascu-
`
`larization in degenerative myopia. Shah [43] observed ex-
`
`pansion of laser scars after treatment of extrafoveal choroidal
`
`neovascularization