A Review of Subthreshold Micropulse Laser for Treatment of ... · A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders Paula Scholz. Lebriz Altay. Sascha Fauser

REVIEW

A Review of Subthreshold Micropulse Laserfor Treatment of Macular Disorders

Paula Scholz . Lebriz Altay . Sascha Fauser

Received: March 30, 2017 / Published online: May 24, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Micropulse laser treatment is an alternative tothe conventional continuous-wave laser for thetreatment of retinal or macular diseases. Incontrast to the conventional laser, the thera-peutic effect of the subthreshold micropulselaser is not accompanied by thermal retinaldamage. This fact is of particular importancewhen a treatment near the fovea is required.Micropulse treatment is applied in indicationssuch as central serous chorioretinopathy (CSC),diabetic macular edema (DME), or macularedema due to retinal vein occlusion (RVO). Thisreview outlines and discusses the published lit-erature of subthreshold micropulse laser treat-ment for CSC, DME, and macular edema afterRVO.

Keywords: Central serous chorioretinopathy;Diabetic macular edema; Micropulse laser;

Ophthalmology; Retinal vein occlusion;Subthreshold laser

INTRODUCTION

Traditional laser photocoagulation has beenused to treat different retinal diseases for manyyears [1–5]. Here, the endpoint is a visiblewhitening of the retina due to thermal damageof the retinal pigment epithelium (RPE) and theinner retina. However, apart from the favoredtherapeutic effect, the treatment can lead toundesirable side effects like visual field defects,epiretinal fibrosis, and choroidal neovascular-ization (CNV) in the area of the laser scar [6–10].The mechanisms which are responsible for thetherapeutic effect are still poorly understood.

Scarring seems not to be necessary to achievea therapeutic effect. It might be the stimulationof the RPE alone and not the destroying of thephotoreceptors that is needed to reach a thera-peutic effect of laser photocoagulation [11]. Thelaser energy stimulates the RPE, which leads torepair of the inner blood retinal barrier [12]. Amodification of the gene expression initiated bythe wound healing response after laser photo-coagulation could be responsible for the bene-ficial effect of laser photocoagulation.Sublethally injured RPE cells induce an up- anddownregulation of various factors [pigmentepithelium-derived factor (PEDF), vascularendothelial growth factor (VEGF) inhibitors,

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P. Scholz (&) � L. Altay � S. FauserDepartment of Ophthalmology, University Hospitalof Cologne, Cologne, Germanye-mail: [email protected]

S. FauserF. Hoffmann-La Roche, Basel, Switzerland

Adv Ther (2017) 34:1528–1555

DOI 10.1007/s12325-017-0559-y

http://orcid.org/0000-0002-1730-0566

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VEGF inducers, permeability factors, etc.] whichrestores the pathologic imbalance. RPE cellsdestroyed by thermal heat are not capable ofinducing this biologic activity [13, 14]. Inagakiet al. [15] showed that sublethal photothermalstimulation with a micropulse laser inducesheat shock protein expression in RPE cellswithout cellular damage in a model of humanRPE.

In subthreshold micropulse laser (SML), dif-fusion of heat to surrounding tissues is mini-mized and thereby scarring is prevented.

The neural retina can be spared by applyingthe minimum laser irradiance (watts per squaremeter) needed to raise the temperature of theRPE, but without exceeding the protein denat-uration threshold. This leads to the requiredactivation of the RPE cells, but the thermal wavewill only reach the neural retina at temperaturesbeneath the protein denaturation threshold.Since the RPE and the neural retina are closetogether, the laser pulse has to be in themicrosecond range and not in the millisecondrange like the traditionally used supra thresholdlaser. For safety reasons it is not possible todeliver the required energy in one short enoughlaser pulse. A single laser pulse would require somuch energy that there would be a high risk ofbubble formation and micro-explosions,accompanied by retinal hemorrhages [16].Those side effects can be avoided by using arepetitive series of very short pulses with lowenergy instead of a continuous-wave laser pulse[17–19].

The micropulse operating mode and termi-nology were described by Dorin [20]. In thetraditional continuous-wave mode, a singlelaser pulse of 0.1–0.5 s delivers the preset laserenergy. In the micropulse mode, a train ofrepetitive short laser pulses delivers the laserenergy within an ‘‘envelope’’ whose width istypically 0.1–0.5s. The normal length of eachpulse is 100–300 ls. The ‘‘envelope’’ includes‘‘ON’’ time, which is the duration of eachmicropulse, and ‘‘OFF’’ time, which is the timebetween the micropulses. The ‘‘OFF’’ time isimportant since here the originated heat cancool down. The sum of the ‘‘ON’’ and ‘‘OFF’’times is the period T and its reciprocal 1/T is thefrequency (pulses per second) f in hertz (Hz).

The duty cycle in percent is the ratio between‘‘ON’’ time and the period T.

DIFFERENT LASERS AVAILABLEWITH MICROPULSE MODE

810-nm Diode Laser

The commercially available diode lasers emit ata wavelength of 810 nm, which is in thenear-infrared range of the spectrum. A feature ofthe 810-nm wavelength is its deep penetrationinto the choroid, but it is not clear if thischaracteristic is relevant in micropulse treat-ment. For all indications requiring a treatmentnear the foveal avascular zone, the 810-nm laserhas the advantage that the laser energy willrelatively spare the inner neurosensory retinaand affect mainly the deeper layers [21–24]. Thedeep penetration is a possible benefit especiallyfor central serous chorioretinopathy (CSC) sincethe choroid may play a role in the pathogenesisof CSC. A potential disadvantage of the 810-nmlaser is a possible sensation of pain duringtreatment with a diode laser [24, 25], althoughthis is a rare problem in the micropulse mode.

577-nm Yellow Laser

Another laser type which is available formicropulse treatment is the 577-nm yellowlaser. The yellow laser has the advantage thatxanthophyll, the pigment which is located inthe inner and outer plexiform layers of themacula, absorbs the yellow light only mini-mally so treatment near the fovea is relativelysafe [26].

APPLICATIONSFOR SUBTHRESHOLD MICROPULSELASERS

In this article we will review the applications formicropulse laser in macular diseases, namelyCSC, diabetic macular edema (DME), and reti-nal vein occlusion (RVO). We will give anoverview of the available literature and outline

Adv Ther (2017) 34:1528–1555 1529

the current evidence for micropulse laser treat-ment in each field.

The literature search was performed in Eng-lish language in the PubMed database. We usedpairings of the terms ‘‘micropulse’’, ‘‘laser’’,‘‘subthreshold’’, and ‘‘central serous chori-oretinopathy’’, ‘‘chorioretinopathy’’, ‘‘centralserous retinopathy’’, or ‘‘diabetic macularedema’’, ‘‘macular edema’’ and ‘‘retinal veinocclusion’’, ‘‘branch retinal vein occlusion’’,‘‘central retinal vein occlusion’’. Additionally,the references of the resultant articles werechecked for publications missing in the primarysearch. Until February 2017 we found 18 articles[27–44] concerning micropulse laser in CSC; noarticles were excluded and all articles are listedin Table 1. As a result of the high number ofpublications related to DME and micropulsetreatment, we only listed the 11 prospectivestudies [45–55] in Table 2. We found four stud-ies [56–59] investigating micropulse laser forRVO, which are all listed in Table 3.

As a result of different study designs, uneveninclusion and exclusion criteria, different lasertypes, treatment parameters, and various out-come measures, a direct comparison of thestudies is limited. We looked for similaritiesreferring to the outcome measures for makingcomprehensive conclusions regarding thetreatment outcome. In Tables 1, 2, and 3, allstudies are listed, but individual studies wereexcluded from the calculations as a result ofmissing information or prior treatment. Thestudies had a high variety regarding the fol-low-up visits. If available, after calculation ofthe decrease in central retinal thickness (CRT)in optical coherence tomography (OCT) in allindividual studies, a weighted average value wascalculated on the basis of the number ofpatients in each study. The best corrected visualacuity (BCVA) was not consistently presented inthe different studies. To compare the BCVA, weconverted all visual acuity data to Early Treat-ment Diabetic Retinopathy Study (ETDRS) let-ters equivalent using the formula ETDRSletters = 85 ? 50 9 log (Snellen fraction) [60]. Ifa large enough number of studies providedinformation about a control group, we addi-tionally analyzed the control group regardingCRT, BCVA, and treatment outcome.

This article was based on previously con-ducted studies and did not involve any newstudies of human or animal subjects performedby any of the authors.

CENTRAL SEROUSCHORIORETINOPATHY (CSC)

In CSC a serous detachment of the neurosensoryretina leads to decreased vision [61]. The acuteform of CSC is often self-limiting so that treat-ment is not always necessary. But some patientsdevelop the chronic form of CSC with impendingpermanent structural damage and vision loss[62–64]. For patients with extrafoveal leakage, acontinuous-wave laser photocoagulation is atreatment option. Studies showed an accelera-tion of subretinal fluid (SRF) resolution but nochange in final visual acuity or recurrence rateafter conventional laser. Furthermore, adverseevents like CNV, scotomas, enlargement of thelaser spot, and reduction of contrast sensitivitycan occur [3, 62, 65–67]. Another treatmentoption is photodynamic therapy (PDT) which isused also in juxtafoveal or subfoveal leakage. Buteven with reduced treatment settings, compli-cations like RPE atrophy, choroidal hypoperfu-sion, transient reduction of macular function,and CNV can occur [68–71].

Bandello et al. [72] presented the first pilotstudy investigating SML treatment for CSC in2003. They reported a high treatment successwith complete resorption of SRF in five out of fiveeyes within 1 month and no recurrence of SRFduring follow-up of 2–6 month after non-visiblesubthreshold micropulse diode laser (810 nm)treatment. No evidence of RPE or retinal changeswas discernible at fluorescein angiography (FA)or fundus biomicroscopy after laser treatment.

Table 1 shows all identified studies investi-gating micropulse laser treatment for CSC. InTable 4, the treatment outcome after SML, PDT,and observation for CSC is presented.

Treatment Response

Most studies defined a treatment response as areduction in CRT measured in spectral domain

1530 Adv Ther (2017) 34:1528–1555

Table1

Overviewof

thestudiesinvestigatingsubthreshold

micropulse

lasertreatm

entforcentralserous

chorioretinopathy

Autho

rsYear

Eyes

Disease

duration

Laser

type

andparameters

Stud

ydesign

Ricci etal.

[27]

2004

1eye

Chronic,C

6months

IrisMedicalOculight

SLx

810nm

,Ønotshow

n,10%DC,0.5s,

power:500mW

Casereport,S

MLafterIC

Ginjection

Ricci etal.

[28]

2008

7eyes

Chronic,C

6months

IrisMedicalOculight

SLx

810nm

,Ø112.5lm

,10%

DC,0

.5s,

power:500mW

Prospective,interventional,n

on-com

parative

case

series,S

MLafterIC

Ginjection

Chen

etal.

[29]

2008

26eyes

Group

1:Source

leakagewithout

RPE

atrophy,

n=

6

Group

2:Source

leakagewithRPE

atrophy,n=

9

Group

3:DiffuseRPE

decompensationwith

indeterm

inatesource

leakage,n=

11

Chronic,[

4months

IrisMedicalOculight

SLx

810nm

,Ø125lm,1

5%DC,0

.2s,

power:titration

Prospective,non-comparative,interventional

case

series

Lanzetta

etal.

[30]

2008

24eyes

Chronic,[

3months

IrisMedicalOculight

SLx

810nm

,Ø200lm,1

5%DC,0

.2s,

power:1000–2

000mW,m

ean

1350

mW


on-com

parative

case

series

Gupta

etal.

[31]

2009

5eyes

Chronic,C

4weeks

IrisMedicalOculight

SLx

810nm

,Ø125lm,1

5%DC,0

.2s,

power:titration

Retrospective,n

on-com

parative,caseseries

Kossetal.

[32]

2011

52eyes

SML:n=

16

BCZ:n=

10

Observation:n=

26

Chronic,[

3months

IrisMedicalOculight

SLx

810nm

,Ø125lm,1

5%DC,0

.2s,

power:titration

Prospective,comparative,n

onrand

omized

interventionalcase

series

Roism

anet

al.

[33]

2013

15eyes

SML:n=

10

SHAM:n=

5

Chronic,[

6months

OptoFastPu

lse

810nm

,Ø125lm,1

5%DC,0

.3s,

power:1.29

threshold

Prospective,rand

omized,d

ouble-blind,

sham

-controlledpilottrial,crossover

after

3months

Malik etal.

[34]

2015

11eyes

Chronic,[

3months

IrisMedicalOculight

SLx

810nm

,Ønotshow

n,5%

DC,

0.2–

0.3s,power:750–

1000

mW

Retrospective,interventional,

non-comparative

case

series

Kretz etal.

[35]

2015

62eyes

SML:n=

20

HdP

DT:n=

24

Observation:n=

18

Chronic,[

3months

IrisMedicalOculight

SLx

810nm

,Ø75–1

25lm,1

5%DC,

0.3s,power:average1500

mW

Prospective,rand

omized,interventional,

comparative

trial

Adv Ther (2017) 34:1528–1555 1531

Table1

continued

Autho

rsYear

Eyes

Disease

duration

Laser

type

andparameters

Stud

ydesign

Elham

id[36]

2015

15eyes

Chronic,[

3months

Iridex

IQ577

577nm

,Ø200lm,1

0%DC,0

.2s,

power:titration


on-com

parative

clinicalstudy

Scholz

etal.

[37]

2015

38eyes

Chronic,[

6weeks

QuantelMedical

SupraScan

577nm

,Ø160lm,5

%DC,0

.2s,

power:50%

ofthreshold

Retrospective,n

on-com

parative

case

series

Kim

etal.

[38]

2015

10eyes

Chronic,[

6months

QuantelMedical

SupraScan

577nm

,Ø100lm,1

5%DC,0

.2s,

power:50%

ofthreshold

Retrospective,n

on-com

parative

case

series

Gaw

ecki

[39]

2015

1eye

Chronic,(diseaseduration

notdefin

ed)

Modelnotmentioned

577nm

,Ø160lm,5

%DC,0

.2s,

power:550mW

Retrospective

case

report

Yadav etal.

[40]

2015

15eyes

Chronic,[

3months

QuantelMedical

SupraScan

577nm

,Ø100lm,1

0%DC,0

.2s,

power:50%

ofthreshold

Retrospective,n

on-com

parative

case

series

Breukink

etal.

[41]

2016

59eyes

(Alleyesreceived

HdP

DT,10eyeswithpersistent

SRFafterup

to2HdP

DT

sessions

received

SML)

Chronic,(diseaseduration

notdefin

ed)

IrisMedicalOculight

SLx

810nm

,Ø125lm,5

%DC,0

.2s,

power:B1800

mW

Prospective,interventionalnon-comparative,

case

series

Ozm

ert

etal.

[42]

2016

33eyes

SML:n=

15

HfPDT:n=

18

Chronic,[

6months

QuantelMedical

SupraScan

577nm

,Ø160lm,5

%DC,0

.2s,

power:titration

Retrospective,com

parative

case

series

Ambiya

etal.

[43]

2016

10eyes

C3monthswithout

signsof

RPE

atrophyor

diffuse

leakage

Navilas

577nm

,Ø100lm,5

%DC,0

.1s,

power:30%

ofthreshold

Prospective,interventionalnoncom

parative,

case

series

Scholz

etal.

[44]

2016

100eyes

SML:n=

42

HdP

DT:n=

58

Chronic,C

6weeks

QuantelMedical

SupraScan

577nm

,Ø160lm,5

%DC,0

.2s,

power:50%

ofthreshold

Retrospective,com

parative,interventional

case

series

1532 Adv Ther (2017) 34:1528–1555

Table1

continued

Autho

rsFU

Treatmentrespon

seCentral

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Laser

sessions

Ricci etal.

[27]

8weeks

1week:

SRFwas

reduced(1/1)

Not

show

nBL:0.3logM

AR

1week:

0.0logM

AR

8weeks:-0.1logM

AR

Nosignsof

lasertreatm

entwere

visibleon

FA1

8weeks:Com

pleteresolution

(1/1)

Ricci etal.

[28]

Minim

um12

months

Response*:2weeks:7/7(100%)

8weeks:7/7(100%)

Com

plete*:5/7(71%

)

*12months:no

recurrence

inpatientswithcomplete

resolution

ofSR

F.No

worsening

ofSR

Fin

patients

withincompleterecovery

Not

show

n2weeks:allpatientsshow

edim

provem

ent

12months:no

worsening

ofthe

BCVA

Change:?0.19

logM

AR

Significant

increase

ofBCVA

after

12months(p\

0.05)

Nolaserlesionswerevisiblevia

fund

uscopicexam

inationand

onFA

1

Chen

etal.

[29]

Minim

um6months

(9.5±

2.6months)

FFU

response:

Group

1:6/6(100%)

Group

2:8/9(89%

)

Group

3:5/11(46%

)

Alleyes:19/26(73%

)

Group

1:

BL:339±

67lm

FFU:136±

26lm

Group

2:

BL:342±

84lm

FFU:139±

34lm

Group

3:

BL:340±

121lm

FFU:192±

103lm

Significant

CRT

decrease

inall

patients(p\

0.001)

Group

1:

BL:0.18

±0.08

logM

AR

FFU:0.00

±0.00

logM

AR

Group

2:

BL:0.38

±0.19

logM

AR

FFU:0.07

±0.06

logM

AR

Group

3:

BL:0.41

±0.28

logM

AR

FFU:0.24

±0.22

logM

AR

Significant

BCVA

increase

inall

patients(p

=0.01)

Nopatientsdeveloped

laser-relatedscotom

a1–

3

FFU

complete:

Group

1:6/6(100%)

Group

2:8/9(89%

)

Group

3:5/11

(46%

)

Alleyes:19/26(73%

)

Lanzetta

etal.

[30]

3–36

months(m

ean

14months)

Response:

1month:16/24(67%

)

FFU:18/24(75%

)

BL:328lm

(range

162–

720lm)

1month:197lm

(range

93–4

03lm

)

FFU:168lm

(range

107–

340lm)

Significant

CRT

decrease

at1month

(p=

0.0003)andFF

U(p\

0.0001)

BL:20/32Snellen

1month:20/25Snellen

FFU:20/25Snellen

Nosignificant

increase

inBCVAat

1month

(p=

0.64)or

FFU

(p=

0.062)

-5/24

eyes

show

edRPE

changesat

thesite

ofSM

Lspots

Nocomplications

1–5

Com

plete:

1month:9/24

(38%

)

FFU:17/24(71%

)

Adv Ther (2017) 34:1528–1555 1533

Table1

continued

Autho

rsFU

Treatmentrespon

seCentral

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Laser

sessions

Gupta

etal.

[31]

Minim

um6months

FUresponse:5/5(100%)

Not

show

nIm

provem

entin

BCVA

inallpatients

Nocomplications

mentioned

1–2

FUcomplete:4/5(80%

)

Koss etal.

[32]

10months

FUresponse:notshow

n

FUcomplete:notshow

n

Leakage

activity

inFA

10months:

SML:2/16

(12.5%

)

BCZ:6/10

(60%

)

Observation:24/26(92%

)

SMLleadsto

significantly

moreleakageactivity

reductionthan

BCT

(p=

0.0239)and

observation(p

=0.0054)

SML:

BL:419±

59lm

6weeks:387±

94lm

6months:329±

69lm

10months:325±

93lm

BCZ:

BL:393±

84lm

6weeks:355±

114lm

6months:334±

59lm

10months:355±

73lm

Observation:

BL:388±

59lm

6weeks:396±

57lm

6months:388±

63lm

10months:415±

53lm

Significant

decrease

inCRT

at(p

=0.0098)butnotafterBCZor

observation

SML:

BL:45.4±

7.2ETDRS

6weeks:47.8±

6.8ETDRS

6months:50.5±

7.3ETDRS

10months:51.6±

7.0ETDRS

BCZ:

BL:44.1±

10.8

ETDRS

6weeks:41.9±

11.3

ETDRS

6months:42.4±

13.6

ETDRS

10months:43.5±

14.5

ETDRS

Observation:

BL:46.4±

6.1ETDRS

6weeks:46.3±

6.9ETDRS

6months:44.9±

5.1ETDRS

10months:44.3±

5.2ETDRS

SMLbetter

than

BCZ(p

=0.000047)

andobservation(p

=0.0054)at

10months

Noocular

adverseevents,i.e.,

intraocularinflammation,

bleeding,o

rIO

Prise,w

ere

observed

1–3

Roism

anet

al.

[33]

Minim

um6months

Not

show

nSM

L:

BL:420±

112lm

1month:307±

55lm

3months:265±

98lm

SHAM:

BL:350±

61lm

1month:351±

94lm

3months:290±

78lm

Nosignificant

decrease

inCRTat

3monthsafterSM

L(p

=0.091)

orSH

AM

treatm

ent(p

=0.225)

SML:

BL:35.4±

11.6

ETDRS

1month:44.4±

8.1ETDRS

3months:47.9±

8.0ETDRS

SHAM

BL:26.6±

6.8ETDRS

1month:26.8±

7.6ETDRS

3months:25.6±

8.9ETDRS

Significant

BCVA

increase

at3months

afterSM

L(p

=0.008)

butnotafter

SHAM

treatm

ent(p

=0.498)

Nolaserscarsobserved

atfund

uscopicexam

inationor

onFA

1–2

1534 Adv Ther (2017) 34:1528–1555

Table1

continued

Autho

rsFU

Treatmentrespon

seCentral

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Laser

sessions

Maliketal.

[34]

Minim

um2months

(2–1

2months)

FUresponse:8/11

(72%

)

FUcomplete:notshow

n

BL:414±

137lm

FFU:316±

97lm

Significant

CRTdecrease

after

SML(p

=0.0046)

BL:39.2±

15.1

ETDRS

FFU:45.5±

12ETDRS

Noevidence

ofRPE

damagein

FAFor

inFA

1–2

Kretz

etal.

[35]

4months

4-month

response

(reduction

ofleakageactivity):

SML:12/20(60%

)

HdP

DT:16/24(67%

)

Observation:7/18

(38%

)

Significant

reductionof

leakageactivity

inboth

treatm

entgroups

compared

tothecontrolgroup

ChangeBL/4

months:

SML:-69.7lm

HdP

DT:-109.8lm

Observation:-89

lm

ChangeBL/4

months:

SML:?6.7ETDRS

HdP

DT:?8.5ETDRS

Observation:?1.5ETDRS

Noevidence

ofsecond

aryRPE

damagein

FAFafterboth

treatm

ents

1–3

Elham

id[36]

6months

Response:

3months:15/15(100%)

BL:390±

46lm

6months:264±

24lm

Significant

CRTdecrease

after

SML(p\

0.05)

BL:0.67

±0.10

Snellen

6months:0.85

±0.10

Snellen

Significant

BCVA

increase

after

SML( p\

0.05)

Nosign

oflaser-inducedlesions

1–2

Com

plete:

3months:11/15(73%

)

6months:13/15(86%

)

Scholz

etal.

[37]

Minim

um6weeks

(mean

5±

3months)

Response:

6weeks:24/38(63%

)

3months:20/23(87%

)

6months:11/14(79%

)

FFU:28/38(74%

)

BL:402±

139lm

6weeks:309±

86lm

FFU:287±

75lm

Significant

CRTdecrease

after

SML(p\

0.001)

BL:0.36

±0.24

logM

AR

6weeks:0.33

±0.24

logM

AR

FFU:0.30

±0.25

logM

AR

Significant

BCVA

increase

after

SML(p

=0.039)

Nolaserburnsweredetected

withany

imagingmodality

1–3

Com

plete:

6weeks:5/38

(13%

)

3months:7/23

(30%

)

6months:2/14

(14%

)

FFU:9/38

(24%

)

Adv Ther (2017) 34:1528–1555 1535

Table1

continued

Autho

rsFU

Treatmentrespon

seCentral

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Laser

sessions

Kim

etal.

[78]

Minim

um3months

There

were2patientswho

hadrecurrentCSC

.One

at6months,oneat

10months.One

patient

hadpersistent

SRFfor

3monthsdespitetotalof4

lasersessions

BL:349±

53lm

3months:251±

29lm

FFU:261±

38lm

Significant

CRT

decrease

at3months(p

=0.009)

andFF

U(p

=0.009)

BL:0.21

±0.21

logM

AR

3months:0.06

±0.09

logM

AR

FFU:0.04

±0.06

logM

AR

Significant

BCVA

increase

at3months(p

=0.020)

and

FFU

(p=

0.012)

Nolaserscar

was

detected

incolor

fund

usphotographs,SD

OCT,o

rnear-in

frared

images

1–5

Gaw

ecki

[39]

Not

specified

Response:0/1

After

1sttreatm

ent:no

change

After

2ndtreatm

ent:‘‘significant

amount

ofSR

Fpresentin

themacular

area’’

BL:0.63

decimal

FU1st*:no

change

FU2nd*:0.32

decimal

treatm

ent*

FAFshow

edhyperfluorescentpunctate

areasreferringto

multispot

SML

pattern

2

Com

plete:0/1

Yadav etal.

[40]

Minim

um4weeks

(4–1

9weeks)

FU:

Response:15/15(100%)

Com

plete:6/15

(40%

)

CRT

notshow

n

SRF(high):

BL:232lm

FU:49

lm

Significant

decrease

inSR

F(p\

0.001)

Change:1lin

e

BL:20/40Snellen

FU:20/30Snellen

Significant

BCVA

increase

(p=

0.015)

Noevidence

ofRPE

orretinaldamage

onSD

OCT,F

A,o

ron

FAF

1

Breukink

etal.

[41]

8–118weeks

Aftermean8.7weeks,(range:

4–18

weeks)

Com

pleteafter:

1stHdP

DT:37/59(63%

)

2ndHdP

DT:7/19

(37%

)

1stSM

L:1/10

(10%

)

Not

show

nBL(all):0.28

logM

AR

FFU

(all):0.16

logM

AR

Nodifference

ineyes

after

HdP

DT

orSM

L

1–2 HdP

DT

1SM

L

Ozm

ert

etal.

[42]

Minim

um12

months

SML:

Response:13/15(87%

)

Com

plete:12/15(80%

)

HfPDT:

Response:14/18(78%

)

Com

plete:13/18(72%

)

SML:

BL:287.3±

126lm

12months:138.0±

40lm

HfPDT:

BL:242.8±

80lm

12months:156.9±

60lm

Significant

CRT

decrease

afterSM

L(p

=0.003),b

utnotafterhfPD

T(p

=0.098)

SML:

BL:67.3±

14.2

ETDRS

12months:71.5±

21.4

ETDRS

HfPDT:

BL:60.7±

16.3

ETDRS

12months:64.4±

24.9

ETDRS

Nosignificant

increase

inboth

groups

SML:p=

0.285,

hfPD

T:p=

0.440

Novisibleretinalscarring

1–2

1536 Adv Ther (2017) 34:1528–1555

Table1

continued

Autho

rsFU

Treatmentrespon

seCentral

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Laser

sessions

Ambiya

etal.

[43]

6months

Response:

1month:10/10

Com

plete:

1month:4/10

(40%

)

3month:6/10

(60%

)

6months:6/10

(60%

)

BL:298±

129lm

1month:200±

72lm

3months:179±

53lm

6months:215±

90lm

Significant

CRTdecrease

at6months(p

=0.03)

BL:73.3±

16.1

ETDRS

1month:73.1±

16.3

ETDRS

3months:75.8±

14.0

ETDRS

6month:76.9±

13.0

ETDRS

Nosignificant

increase

inBCVA

(p=

0.59)

Noevidence

oflaserspotsviafund

uscopic

exam

ination,

onSD

OCT,and

onFA

F

Nocomplications

1–2

Scholz

etal.

[44]

6weeks

SML6weeks:

Response:33/42

(79%

)

Com

plete:15/42

(36%

)

HdP

DT

6weeks:

Response:34/58

(59%

)

Com

plete:12/58

(21%

)

SMLshow

edhigher

treatm

entresponse

than

HdP

DT

(p=

0.036)

SML:

BL:445±

153lm

6weeks:297±

95lm

HdP

DT:

BL:398±

88lm

6weeks:322±

93lm

Significant

decrease

inboth

groups

(SML:p\

0.001,

hdPD

T:p \

0.001)

CRT

decrease

better

afterSM

L(p

=0.041)

SML:

BL:0.39

±0.24

logM

AR

6weeks:0.31

±0.27

logM

AR

HdP

DT:

BL:0.35

±0.24

logM

AR

6weeks:0.31

±0.24

logM

AR

Significant

BCVA

increase

afterSM

L(p

=0.003),but

notafterHdP

DT(p

=0.07)

Nolaserspotsdetectableby

fund

uscopic

exam

inationor

onFA

1

BCVAbestcorrectedvisualacuity,B

CZbevacizumab

(intravitreal),B

Lbaselin

e,CRTcentralretinalthickness,CSC

centralserouschorioretinopathy,DCduty

cycle,ETDRSEarlyTreatment

DiabeticRetinopathy

StudyGroup

letters,FA

fluorescein

angiography,FA

Ffund

usautofluorescence,FU

follow-up,FF

Ufin

alfollow-up,HdP

DThalfdosephotodynam

ictherapy,HfPDThalf

fluence

photodynam

ictherapy,ICG

indocyanin

green,

IOPintraocularpressure,logM

ARlogarithm

oftheminim

umangleof

resolution,OCT

opticalcoherencetomography,RPE

retinal

pigm

entepithelium,S

DOCTspectraldomainOCT,S

MLsubthreshold

micropulse

laser,SR

Fsubretinalfluid,Ø

spot

size

Adv Ther (2017) 34:1528–1555 1537

Table2

Overviewof

thestudiesinvestigatingsubthreshold

micropulse

lasertreatm

entfordiabeticmacular

edem

a

Autho

rsYear

Eyes

Inclusioncriteria

Laser

type

andparameters

Stud

ydesign

Fazelet

al.[45]

2016

68eyes

SML:n=

34

CL:n=

34

DME*

CRT\450lm

Without

PDR

Without

previous

IVTor

anyretinal

laser

QuantelMedical

810nm

,Ø50–1

00lm,0

.1s,power:adjusted

QuantelMedical

810nm

,Ø75–1

25lm,

15%

DC,0

.0003s,

power:29

threshold

Prospective,single-blin

d,rand

omized

clinicaltrial

Inagakiet

al.[46]

2015

53eyes

810nm

:n=

24

577nm

:n=

29

DME*,type

II

withor

without

NPD

R/PDR

NoIVTor

laserwithinthelast

3months

Patientswithisolated

localF

Adyewere

excluded

IrisMedicalIQ

577

577nm

,Ø200lm

15%

DC,0

.2s,power:

29threshold,

(mean204mW)

IrisMedical

OcuLight

SLX,

810nm

,Ø200lm

15%

DC,0

.2s,power:29

threshold,

(mean955mW)

Prospective,

non-rand

omized,interventionalcase

series

Additionalmicro-aneurysm

closurein

both

groups

atBL

Vujosevicet

al.[47]

2015

53eyes

810nm

:n=

27

577nm

:n=

26

DME*\

400lm

,typeI/IIdiabetes

Nomacular

therapy,IVT,

laser,ppVpreviously

IrisMedicalIQ

577

577nm

,Ø100lm

,5%

DC,0

.2s,

power:250mW,H

Dtreatm

ent

IrisMedical

OcuLight

SLX,

810nm

,Ø125lm

,5%

DC,0

.2s,

power:750mW,H

Dtreatm

ent

Prospective,masked,

rand

omized,

comparative

pilotstudy

Othman

etal.[48]

2014

220eyes

Group

1Prim

arytreatm

ent

(n=

187)

Group

2Second

arytreatm

ent

(n=

33)

DME*without

PDRandfoveal

ischem

ia

Group

1without

prior

treatm

ent,BCVA

atleast20/80

Group

2withpriorCL,

BCVA

atleast20/200

IrisMedical

OcuLight

SLX

810nm

,Ø75–1

25lm

,15%

DC,0

.3s,

power:650–

1000

mW

confl

uent

Prospective,single-center,

nonrandomized,

interventionalcase

series

1538 Adv Ther (2017) 34:1528–1555

Table2

continued

Autho

rsYear

Eyes

Inclusioncriteria

Laser

type

andparameters

Stud

ydesign

Venkatesh

etal.[49]

2011

46eyes

SML:n=

23

CL:n=

23

DME*without

PDR

Nopriormedicalor

laser

treatm

entwithin

thelast6months

IrisMedical

OcuLight

SLX,8

10nm

,Ø125

lm,1

0%DC,2

s,power:

80–1

30mW

ZeissVisulas

Nd:YAG

LC

532nm

,Ø50–1

00lm,0

.1s,power:

90–1

80mW

Prospective,rand

omized

interventionalstudy

Lavinskyet

al.[50]

2011

123eyes

ND-SLM

:n=

39

HD-SLM

:n=

42

CL:n=

42

DME*withCRTC250lm

Nopriormacularlaseror

IVTforDME

Nopanretinallaserwithinlast4months

OptoFastPu

lse

810nm

,Ø125lm

,15%

DC,0

.3s

0.3s,power:1.29

threshold

ND-SML:2invisibleburn

widthsapart

HD-SML:Confluentinvisibleburn

Iridex,N

d:YAG

LC

532nm

,Ø75

lm,0

.05–

0.1s,power:titration

mETDRSgrid

Prospective,rand

omized,controlled,

double-m

askedclinicaltrial

Ohkoshi

and

Yam

aguchi

[51]

2010

43eyes

DME*withCRTB600lm

without

PDR

TypeII

Patientswithisolated

localF

Adyewere

excluded

Nopriormedicalor

lasertreatm

ent

withinlast6months

IrisMedical

OcuLight

SLX

810nm

,Ø200lm

,15%

DC,0

.2–0

.3s,

power:520–

100mW

confl

uent

Prospective,nonrandomized

interventionalstudy

Nakam

uraet

al.[52]

2010

28eyes

DME*

Nopriorlaseror

surgical

therapywithinlast6months

IrisMedical

OcuLight

SLX

810nm

,Ø200lm

,15%

DC,0

.2s,

power:titrated,

grid

patternwas

used

Prospective

Adv Ther (2017) 34:1528–1555 1539

Table2

continued

Autho

rsYear

Eyes

Inclusioncriteria

Laser

type

andparameters

Stud

ydesign

Vujosevicet

al.[53]

2010

62eyes

SML:n=

32

CL:n=

30

DME*,type

II

Nopriormedical/laser/surgical

treatm

entwithinlast6months

CoherentNovus

Omni

laser,

514nm

,Ø100lm,0

.1s,

power:80–1

00mW

mETDRSgrid

CL

IrisMedical

OcuLight

SLX

810nm

,Ø125lm

5%DC,0

.2s,power:750m

W

Prospective,rand

omized

clinicaltrial

(retreatmentafter3monthsif:

CMTC250lm

orCMT

reductionB50%

orBCVA

decrease[5ETDRSletters)

Figueira

etal.[54]

2009

84eyes

SML:n=

44

CL:n=

40

Botheyes

DME*,type

II,\

80years

without

PDR

Nopriorlasertreatm

ent

Iridex

OculiteGLxargongreen

514nm

,Ø100–

200lm

0.1s,power:titration

IrisMedical

OcuLight

SLX

810nm

,Ø125lm

15%

DC,0

.3s,power:titration

Prospective,rand

omized,

controlled,

double-

maskedtrial

Laursen

etal.[55]

2004

23eyes

SML:n=

12

(Diffuse,n=

6;focal:n=

6)

CLn=

11

(Diffuse,n=

6;focal,n=

5)

DME*without

PDR

Without

priorLC

Without

retinalsurgery

IrisMedical

OcuLight

SLX

810nm

,Ø125lm

5%DC,0

.1s,power:titration

Novus

200argongreen

514nm

,Ø100lm

,0.1s,power:titration

Prospective,rand

omized

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Fazelet

al.[45]

4810nm

SML:

BL:373±

56lm

4months:344±

60lm

810nm

CL:

BL:355±

53lm

4months:350±

54lm

SMLsuperior

toCL

(p=

0.001;

4months)

810nm

SML:

BL:0.59

±0.3logM

AR

4months:0.52

±0.3logM

AR

810nm

CL:

BL:0.58

±0.3logM

AR

4months:0.60

±0.3logM

AR

SMLsuperior

toCL

(p=

0.015;

4months)

NolaserscarsafterSM

L

Laser

scarsafterCL

Not

mentioned

1540 Adv Ther (2017) 34:1528–1555

Table2

continued

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Inagakiet

al.[46]

12810nm

:

BL:488±

176lm

3month:404.5lm

6months:394.4lm

12months:361.8lm

577nm

:

BL:417±

113lm

3months:345.8lm

6months:340.6lm

12months:335.2lm

Nosignificant

difference

betweengroups

after12

months

810nm

:

BL:0.59

±0.41

logM

AR

3months:0.57

logM

AR

6months:0.53

logM

AR

12months:0.54

logM

AR

577nm

:

BL:0.31

±0.31

logM

AR

3months:0.32

logM

AR

6months:0.32

logM

AR

12months:0.28

logM

AR

BCVAstablein

both

groups,intergroupdifferences

werenotevaluated

Nolaserscarsin

either

group

810nm

:12.5%

Re-SM

L,

4.2%

IVT

(bevacizum

ab)

5–577nm

:3.4%

Re-SM

L

Vujosevicet

al.[47]

6810nm

:

BL:340±

36lm

6months:335±

55lm

577nm

:

BL:358±

46lm

6months:340±

56lm

Significant

decrease

for577nm

groupat

6months(p

=0.009)

andnotfor810nm

(p=

0.45)

Nosignificant

difference

between

thegroups

at6months

810nm

:

BL:78.6±

7.5ETDRS

3months:79.3±

6.8ETDRS

6months:77.3±

8.2ETDRS

577nm

:

BL:79.7±

6.1ETDRS

3months:79.4±

7.6ETDRS

6months:78.7±

7.4ETDRS

Nosignificant

difference

ofBCVAbetweengroups

at3months(p

=0.3)

and

at6months(p

=0.62)

Nolaserscarsor

visible

second

aryeffectsof

laser

spotsin

either

group

810nm

:85.2%

Re-SM

L

5–577nm

:88.5%

Re-SM

L

Adv Ther (2017) 34:1528–1555 1541

Table2

continued

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Othman

etal.[48]

12810nm

:Prim

arytreatm

ent(1)

BL:353±

80lm

4months:257±

51lm

12months:215±

27lm

810nm

:Second

arytreatm

ent(2)

BL:429±

69lm

4months:356±

64lm

12months:263±

59lm

Inboth

groups,C

RT

decrease

was

significant

at4and

12months(p\

0.05)

810nm

:prim

arytreatm

ent(1)

BL:0.21

logM

AR

4months:0.15

logM

AR

12months:0.18

logM

AR

810nm

:second

arytreatm

ent(2)

BL:0.50

logM

AR

4months:0.44

logM

AR

12months:0.46

logM

AR

Ingroup1,

BCVAim

proved

at4months(p

=0.017)

and

was

stableat

12months

for85%

oftheeyes

Ingroup2,

nosignificant

BCVAchange

was

observed

Laser

marks

seen

aspigm

entary

changeswerenoted3.3%

via

fund

uscopicexam

ination

and5.7%

viaFA

Group

1:

23%

Re-SM

L(m

edian29

SML)

11.7%

IVT

(triam

cinolone)

3.2%

ppV

Group

2:

33%

IVT

(triam

cinolone)

Venkatesh

etal.[49]

6810nm

SML:

BL:299±

50lm

3months:287±

53lm

6months:275±

63lm

532nm

YAG

CL:

BL:313±

47lm

3months:296±

34lm

6months:287±

33lm

Nodifference

between

SMLandCL

(p=

0.064)

810nm

SML:

BL:0.41

±0.3logM

AR

3months:0.41

±0.3logM

AR

6months:0.43

±0.3logM

AR

532nm

YAG

CL:

BL:0.33

±0.2logM

AR

3months:0.36

±0.2logM

AR

6months:0.41

±0.3logM

AR

Nodifference

between

SMLandCL(p

=0.77)

forBCVA.B

etterpreservation

ofretinalsensitivityin

SMLgroup

InmfERG:

810nm

SML:4/23

eyes

withfocalvoid

regions

532nm

YAG-CL:18/23

eyes

withfocalvoid

regions

Not

mentioned

1542 Adv Ther (2017) 34:1528–1555

Table2

continued

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Lavinskyet

al.[50]

12810nm

ND-SML:

BL:379(279–6

19)lm

3months:332(223–6

10)lm

6months:316(215–6

27)lm

12months:311(207–5

99)lm

810nm

HD-SML:

BL:371(297–8

79)lm

3months:301(203–6

98)lm

6months:291(201–5

77)lm

12months:226(187–5

13)lm

532nm

YAG

mETDRSCL:

BL:370(269-710)lm

3months:306(209–5

12)lm

6months:290(208–5

01)lm

12months:249(199–4

75)lm

HD-SML,C

Lweresuperior

toND-SLM

group(p\

0.001)

Nodifference

between

HD-SDM

andCL

groups

(p=

0.75)

810nm

ND-SML:

BL:0.70

(0.4–1

.3)logM

AR

3months:0.80

(0.4–1

.3)logM

AR

6months:0.80

(0.4–1

.3)logM

AR

12months:0.80

(0.3–1

.3)logM

AR

810nm

HD-SML:

BL:0.90

(0.3–1

.3)logM

AR

3months:0.70

(0.2–1

.3)logM

AR

6months:0.60

(0.2–1

.3logM

AR

12months:0.52

(0.2–1

.3)logM

AR

532nm

YAG

mETDRSCL:

BL:0.80

(0.3–1

.3)logM

AR

3months:0.75

(0.3–1

.3)logM

AR

6months:0.70

(0.2–1

.3)logM

AR

12months:0.65

(0.3–1

.3)logM

AR

HD-SMLwithsignificant

BCVAincrease

12months(p

=0.009),

ND-SMLandCLgroup:

Noim

provem

ent

SML:Nolaserscarsor

visiblelaser

burnsafterSM

L,alth

ough

some

very

light

laser-inducedlesions

couldbe

identified

CL:laserscarsafterCL

810nm

ND-SML:

21%

re-SML(once)

77%

Re-SM

L(twice)

810nm

HD-SML:

38%

Re-SM

L(once)

13%

Re-SM

L(twice)

532nm

CL:

32%

Re-CL(once)

24%

Re-CL(twice)

Ohkoshi

andYam

aguchi

[51]

12810nm

SML:

BL:342±

119lm

3months:301±

124lm

6months:292±

122lm

12months:290±

123lm

CRTreductionwas

significant

at3months(p

=0.05)and

stableafterwards

810nm

SML:

BL:0.12

±0.2logM

AR

3months:0.12

±0.2logM

AR

6months/12

months:N/A

StableBCVA

until12

months

Nolaserscars,

noevidence

oflasertreatm

ent

After

1year,o

nepatientshow

edpigm

entary

changes

19%

re-SML(once)

7%19

grid

CL

2%19

CLof

microaneurysm

2%IVT

4%ppV

Adv Ther (2017) 34:1528–1555 1543

Table2

continued

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Nakam

ura

etal.[52]

3810nm

SML,C

FTchanges:

BL:481±

110lm

3months:388±

127lm

Significant

CFT

reductionat

3months(p

=0.004)

810nm

SML

BL:0.47

±0.2logM

AR

3months:0.40

±0.2logM

AR

Significant

BCVAim

prove

at3months(p

=0.03)

Nolaserscars,

noevidence

oflasertreatm

ent

Not

mentioned

Vujosevicet

al.[53]

12810nm

SML:

BL:358±

94lm

3months:341±

114lm

6months:346±

113lm

12months:312±

76lm

514nm

argonCL:

BL:378±

95lm

3months:338±

72lm

6months:327±

77lm

12months:310±

87lm

Nosignificant

difference

betweenCLandSM

L

810nm

SML:

BL:0.21

±0.30

logM

AR

3months:0.23

±0.29

logM

AR

6months:0.24

±0.32

logM

AR

12months:0.24

±0.25

logM

AR

514nm

argonCL:

BL:0.29

±0.30

logM

AR

3months:0.32

±0.33

logM

AR

6months:0.29

±0.27

logM

AR

12months:0.30

±0.30

logM

AR

Nosignificant

difference

betweenCL

andSM

L

SML:Nosignsof

lasertreatm

ent

viafund

uscopicexam

ination

andon

FA

CL:laserscarsafterCL

Num

berof

treatm

ents:

SML:2.03

±0.75

CL:

2.10

±1.0

Figueira

etal.[54]

12810nm

SML:

BL:249±

59lm

12months:291±

104lm

514nm

Argon

CL:

BL:255±

62lm

12months:284±

105lm

Nosignificant

differences

betweenCLandSM

L(p

=0.81)

810nm

SML:

BL:78.4±

8.1ETDRS

12months:71.8

ETDRS

514nm

argonCL:

BL:78.0±

7.8ETDRS

12months:70.70ETDRS

Nosignificant

differences

betweenCLandSM

L(p

=0.88)

SML:13.9%

ofthetreatedeyes

show

edlaserscars

CL:59%

ofthetreated

eyes

show

edlaserscars

Not

mentioned

1544 Adv Ther (2017) 34:1528–1555

Table2

continued

Autho

rsFU

(mon

ths)

Central

retinalthickn

ess

Bestcorrectedvisual

acuity

Safety

Add

itionaltreatm

ents

Laursenet

al.[55]

5–8

FocalLC/diffuseLC

Centralretinalthickness

810nm

SMLfocalLC

(n=

6):

BL:275lm

3months:250lm

6months:256lm

810nm

SMLdiffuseLC:(n

=6)

BL:293lm

3months:318lm

6months:341lm

514nm

argonfocalLC

(n=

5)

BL:325lm

3months:338lm

6months:330lm

514nm

argon

diffuseLC

(n=

6):

BL:272lm

3months:308lm

6months:90

lm

Inallpatientswithfocal

edem

aCRTdecrease

significant

(p=

0.02)

BLBCVAcann

otbe

extracted!

810nm

SMLfocalLC

(n=

6)

3months:?2.8ETDRS

6months:?3.5ETDRS

810nm

SMLdiffuseLC

(n=

6)

3months:-0.8ETDRS

6months:-1.6ETDRS

514nm

Argon

focalLC:(n

=5)

3months:?4.6ETDRS

6m:?3.5ETDRS

514nm

argondiffuseLC

(n=

6):

3months:-1.7ETDRS

6months:?0.6ETDRS

Nosignificant

differencesbetweengroups

Nolasercomplications

wereobserved

inboth

groups

Not

mentioned

BL

baselin

e,CLconventional

laser,CRT

centralretinalthickness,DC

duty

cycle,DMEdiabetic

macular

edem

a,ETDRSEarly

TreatmentDiabeticRetinopathy

StudyGroup

letters,FA

fluorescein

angiography,

FUfollow-up,

HD-SLM

high

densitysubthreshold

micropulse

laser,

logM

AR

logarithm

oftheminim

umangleof

resolution,IVT

intravitreal

drug

therapy,

mfERG

multifocalelec-

troretinography,mETDRSmodified

ETDRS(EarlyTreatmentDiabeticRetinopathy

StudyGroup)Grid,ND-SLM

norm

aldensitysubthresholdmicropulse

laser,NdY

AGneodym

ium–yttrium

–aluminum

garnet

laser,PD

Rproliferative

diabeticretinopathy,ppVparsplanavitrectomy,OCTopticalcoherencetomography,SM

Lsubthreshold

micropulse

laser,Ø

spot

size

*Clin

icallysignificant

DME

Adv Ther (2017) 34:1528–1555 1545

Table 3 Overview of the studies investigating subthreshold micropulse laser treatment for macular edema after branchretinal vein occlusion

Authors Year Eyes Inclusion criteria Laser type andparameters

Study design

Parodi

et al.

[56]

2015 35 eyes

Group 1:

SML: n = 18

Group 2:

IVT

Bevacizumab

(PRN after 3

initial injections)

n = 17

ME to due BRVO

CFT[250 lm

Without

non-perfusion C 5

disc areas

All eyes were previously

treated with

conventional grid laser

Iris Medical

OcuLight SLX

810 nm, Ø 125 lm, 15%

DC, 0.3 s, power:

titration

Prospective, randomized,

interventional

Inagaki

et al.

[57]

2014 32 eyes

Group 1:

BCVA B20/40

n = 15

Group 2:

BCVA[20/40

n = 17

ME due to BRVO

(ischemic/

non-ischemic)

CRT\600 lm

No prior macular

therapy (LC, IVT etc.)

within last 6 months

Iris Medical

OcuLight SLX,

810 nm, Ø 200 lm, 15%

DC, 0.2 or 0.3 s,

Power:

750–1500 mW (90%)

for 0.2 s or

360–2000 mW (60%)

for 0.3 s

Retrospective, single-center,

nonrandomized,

interventional case series

Parodi

et al.

[58]

2008 24 eyes

Group 1:

SML only

n = 13

Group 2:

SML ? IVT

Triamcinolone

n = 11

ME due to BRVO

CRT[212 lm

No prior laser

treatment

Without

non-perfusion C5 disc

areas

Iris Medical

OcuLight SLX,

810 nm

Ø 125 lm

15% DC, 0.3 s

Power: titration

Prospective randomized pilot

clinical trial

Parodi

et al.

[59]

2006 36 eyes

Group 1:

SML grid

n = 17

Group 2:

Krypton grid

n = 19

ME due to BRVO

CRT[210 lm

No prior laser

treatment

Without non-perfusion

C5 disc areas

Iris Medical

OcuLight SLX 810 nm

Ø 125 lm, 10% DC,

0.2 s, power: titration

Novus Omni Krypton

Ø 100 lm, 0.1 s

Prospective, randomized

clinical trial

1546 Adv Ther (2017) 34:1528–1555

Table 3 continued

Authors FU(months)

Central retinal thickness Best corrected visual acuity Safety Additionaltreatments

Parodi et al.[56]

12 SML group (CFT):

BL: 485.5 lm

3 months: 472.0 lm

6 months: 475.0 lm

9 months: 475.0 lm

12 months: 445.0 lm

IVT group (CFT):

BL: 484.2 lm

3 months: 305.0 lm

6 months: 266.0 lm

9 months: 265.0 lm

12 months: 271.0 lm

IVT group significantly better(p = 0.001)

SML group:

BL: 0.92 logMAR

3 months: 0.89 logMAR




IVT group:

BL: 0.94 logMAR





IVT group significantly better(p = 0.0085)

No laserscars

Not mentioned

Inagaki et al.[57]

12 Group 1: (BCVA B20/40Snellen)

BL: 409.3 lm

1 month: 394.3 lm

3 months: 371.3 lm

6 months: 313.5 lm

12 months: 303.5 lm

Group 2: (BCVA[20/40Snellen)

BL : 373.3 lm

1 month: 353.5 lm

3 months: 313.1 lm

6 months: 294.1 lm

12 months: 320.1 lm

Significant CRT decrease at 3,6,

and 12 months for bothgroups. No

significant difference betweenthe

groups at any time point

Group 1: (BCVA B 20/40Snellen)

BL: 0.59 logMAR

1 month: 0.54 logMAR




Group 2: (BCVA[20/40Snellen)

BL: 0.13 logMAR





No laserscars

Group 1:

n = 8 (53.3%)

Group 2:

n = 3 (17.6%)

Adv Ther (2017) 34:1528–1555 1547

Table 3 continued

Authors FU(months)

Central retinal thickness Best corrected visual acuity Safety Additionaltreatments

Parodiet al.[58]

12 SML only:

BL: 429 lm

3 months: 364 lm

6 months: 320 lm

9 months: 290 lm

12 months: 278 lm

SML ? IVT (triamcinolone):

BL: 476 lm

3 months: 269 lm

6 months: 276 lm

9 months: 260 lm

12 months: 283 lm

Combined SML ? IVT showedbetter response at 3 months(p\0.001). No differencebetween groups from 9th monthon

SML only:

BL: 0.76 logMAR





SML ? IVT (triamcinolone):

BL: 0.67 logMAR





Combined SML ? IVT showedsignificant better response at 9thand 12th months (p\0.009,p = 0.011, respectively)

NoLaserscars

Notmentioned

Parodiet al.[59]

24 SML grid:

BL: 480 lm

6 months: 457 lm

12 months: 217 lm

18 months: 215 lm

24 months: 208 lm

Krypton grid:

BL: 454 lm

6 months: 252 lm

12 months: 226 lm

18 months: 229 lm

24 months: 217 lm

Krypton showed better response at3 months and 6 months(p\0.001). SML showed betterresponse from 12th month on(p\0.001)

SML grid:

BL: 0.70 logMAR





Krypton grid:

BL: 0.69 logMAR



12 months 0.57 logMAR

24 m: 0.56 logMAR

No statistical difference betweengroups

NolaserscarsafterSML

Notmentioned

BRVO branch retinal vein occlusion, BL baseline, CFT central foveal thickness, CRT central retinal thickness, DC dutycycle, FA fluorescein angiography, IVT intravitreal drug therapy, logMAR logarithm of the minimum angle of resolution,ME macular edema, PRN pro re nata, SML subthreshold micropulse laser

1548 Adv Ther (2017) 34:1528–1555

OCT (SDOCT). A complete resolution of SRF inSDOCT was defined as a complete treatmentresponse. Two studies measured the leakageactivity in FA as a parameter for treatmentresponse [32, 35]. For simplicity reasons we donot distinguish between the different defini-tions for treatment response in our calculations.Few studies did not mention the amount ofpatients with treatment response. If we wereable to work out the treatment response fromthe data shown in the paper, we quote theresponse; otherwise the studies were excludedfrom the calculations [33, 38]. One case reportwas excluded from the calculation because ofprior bevacizumab treatment [39], and twostudies were excluded since they includedpatients with prior PDT [37, 41]. Few studiesmentioned only the response or the completeresponse, and those studies were included in thecalculations.

We included 191 patients from 12 studies forthe calculations of the treatment response and176 patients from 11 studies for the completeresponse. A total of 156 (79.6%) of the 191patients showed a treatment response at the last

mentioned follow-up: 112 (63.6%) of the 176patients had a complete resolution of SRF. Onlytwo studies showed data concerning theimprovement rate in an untreated controlgroup: a complete resolution of SRF was seen in2 (8%) out of 26 eyes at the last follow-up and areduction in SRF in 7 (39%) out of 18 eyes.

Four studies had a control group consistingof patients receiving PDT treatment (half dosePDT in three studies and half fluence PDT inone). The treatment response could be calcu-lated from 100 patients in three studies and thecomplete treatment response from 135 patientsin three studies. A total of 64 (64%) of the 100patients responded to PDT and 62 (46%) of 135patients showed complete response.

Safety

The majority of studies described no visibleretinal changes after the micropulse laser treat-ment. In six patients from two studies [30, 39]pigmentary changes at the level of the RPE wereseen after SML but without any visual implica-tions for the patients. Complications like scar

Table 4 Treatment outcome after SML, PDT, observation and conventional laser for CSC, DME, and BRVO

Treatment Change in CRT (lm) Change in BCVA (ETDRS letters)

CSC SML -131 (range -69.7 to -204)a 6.34 (range -15 to 20)d

PDT -85 (range -76 to -109.8)b 3.87 (range 2 to 8.5)b

Observation -25 (range 26 to -89)c 0.67 (range -2.1 to 2.5)c

DME SML -74.9 (range -138 to 48)e 1.26 (range -6.6 to 19)e

Conventional laser -43.6 (range -145 to 28.7)f -0.29 (range -7.3 to 7.5)f

BRVO SML -122.59 (range -272 to -40.5)g 2.98 (range -3.5 to 9.5)g

CSC central serous chorioretinopathy, DME diabetic macular edema, BRVO branch retinal vein occlusion, BCVA bestcorrected visual acuity, CRT central retinal thickness, ETDRS Early Treatment Diabetic Retinopathy Study Group letters,PDT photodynamic therapy, SML subthreshold micropulse lasera 199 patients from 11 studies, 7 studies excluded from the calculations, one due to prior PDT treatment [37], six due toabsence of information about the CRTb 100 patients from 3 studiesc 49 patients from 3 studiesd 216 patients from 14 studies, two studies excluded due to prior PDT [37, 41], two due to absence of information aboutthe concrete BCVA [28, 31]e 613 patients from 11 studiese 195 patients from 7 studiesf 80 patients from 3 studies, one study excluded from the calculation due to prior conventional laser treatment [56]

Adv Ther (2017) 34:1528–1555 1549

formation, visible laser burns, or CNV did notoccur.

DIABETIC MACULAR EDEMA (DME)

DME is a frequent complication of diabeticretinopathy (DR) and the most common causeof visual impairment in patients with DR [5].Since the ETDRS trial [1, 73] showed that laserphotocoagulation reduced the risk of moderatevisual loss by 50% in eyes with clinically sig-nificant macular edema, laser photocoagulationbecame the standard therapy for DME for manyyears. Depending on the kind of edema, thetreatment pattern can be selected: a focal pho-tocoagulation for localized areas of leakage anda grid pattern for a diffuse macular edema.Continuous-wave photocoagulation comeswith potential side effects like epiretinal fibro-sis, CNV, and enlargement of laser scars[7, 8, 74]. Table 3 shows only the prospectivestudies investigating micropulse laser treatmentfor diabetic macular edema. A total of 613patients from 11 studies were included in thecalculations. The inclusion and exclusion crite-ria varied between studies; some did not allowprior treatment at all, most of them onlyexcluded patients with treatment in the prior3–6 months. All listed studies were included inthe calculations for change in CRT and BCVA.Seven studies had a control group consisting of195 patients treated with conventional laser.The same calculations were performed for thosestudies.

Table 4 displays the treatment outcome afterSML and conventional laser for DME.

Safety

In the majority of studies no laser scars occurredafter SML. Four studies reported scar formationor pigmentary changes in a small amount ofeyes after SML treatment [48, 50, 51, 54]. Reti-nal changes were only observed in eyes treatedwith duty cycles of 15%; lower duty cycles didnot lead to scar formation in the listed studies.

Venkatesh [49] et al. reported focal voidregions in multifocal electroretinogram in 4 outof 23 eyes after SML treatment with 10% duty

cycle compared to 18 out of 23 eyes after con-ventional laser.

MACULAR EDEMA DUE TO RETINALVEIN OCCLUSION (RVO)

Macular edema is a common complication ofbranch RVO (BRVO) [75]. Grid laser photoco-agulation reduces the visual acuity loss afterBRVO with macular edema [75]. Parodi et al.[59] reported a similar outcome in visual acuityimprovement and resolution of macular edemaafter SML treatment compared to conventionallaser, but without retinal changes after SML.Table 3 summarizes studies investigating SMLtreatment for macular edema after BRVO. Intotal 80 patients from three studies could beincluded in the calculations, and one study wasexcluded because of prior conventional lasertreatment [56]. As a result of the small numberof studies and the variety in control groups(bevacizumab, SML ? triamcinolone, conven-tional laser), the control groups were not sepa-rately analyzed. Only one study [48] had acontrol group where patients were treated withanti-VEGF agents, the current standard therapyfor macular edema due to BRVO.

Table 4 presents the treatment outcome afterSML for macular edema after BRVO.

Safety

No study described complications like scar for-mation, visible laser burns, or CNV.

PROBLEMS AND CHALLENGESOF SML TREATMENT

Although the majority of the studies showedsome efficacy of the SML treatment for CSC,DME, or BRVO, the treatment parameter dif-fered significantly between the individualstudies. No study compared the outcome ofSML with different treatment parameters likehigher or lower duty cycle. Concerning thetreatment power, most authors titrated thepower individually for each patient, but the

1550 Adv Ther (2017) 34:1528–1555

path was not consistent. The titration is proba-bly the most challenging part of the SMLtreatment. Since the laser surgeon did not seean effect of the treatment, there is a high risk ofundertreatment and treatment failure accord-ingly. A solution to this problem could be to usefixed laser parameters with the same power forall patients. But so far there is not enoughpublished data to choose the best treatmentpower and to evaluate the safety and the treat-ment success of subthreshold micropulse treat-ment with fixed parameters. For the future,controlled trials comparing treatment outcomeand safety of individual titrated SML treatmentand SML treatment with fixed parameterswould be desirable. Those studies shouldinclude safety follow-up with multimodalimaging including autofluorescence, OCT, andfundus photographies as well functional fol-low-up with microperimetry or multifocalelectroretinogram.

CONCLUSION

For CSC, the presented studies showed a higherefficacy of the micropulse laser treatment forboth morphology and visual function in com-parison to no treatment or PDT. The decrease inCRT was highest after SML (-131 lm), followedby PDT (-85 lm) and the no-treatment group(-25 lm). Moreover, 64% of patients showedno SRF after SML compared to 46% after PDTand 8% after observation.

No study reported any complications afterup to five SML treatment sessions, so even anearly treatment could be considered for poten-tially better results. Chen et al. [29] showed thatthe SML treatment outcome was best in patientswith source leakage without RPE atrophy. Theinvestigated literature did not allow an evalua-tion of the best treatment parameter or the bestlaser wavelength.

Regarding the treatment of DME, the inves-tigated studies showed efficacy also in mor-phology and function. The decrease in CRT andincrease in BCVA after SML (-74.9 lm and?1.26 ETDRS letters) was better than after con-ventional laser (-43.6 lm and -0.29 ETDRSletters), but no study had a control group in

which patients were treated with anti-VEGFagents. After the RISE and RIDE studies [76] andthe approval of ranibizumab for the treatmentof DME, anti-VEGF agents became the standardtreatment for DME. Without any trial, com-paring SML treatment with anti-VEGF agents,we do not know when SML treatment could bean alternative first-line treatment for DME.Nevertheless, SML might be an option inpatients not responding sufficiently to, or whoare not able to follow an anti-VEGF therapy(e.g., high costs, compliance problems due tofrequent visits for the injections and ophthal-mological controls). Chen et al. [77] had cometo a similar result in their meta-analysis of ran-domized controlled trials comparing sub-threshold micropulse diode laserphotocoagulation and conventional laser. Theyreported a significantly better visual acuity anda similar decrease in CRT after SML compared toconventional laser. They underline the advan-tage of the SML treatment in terms of theaffordability compared to the cost-intensiveanti-VEGF therapy.

On the subject of macular edema after BRVO,SML treatment shows some efficacy as well. Butin comparison to the current standard treatment,intravitreal anti-VEGF, SML was inferior tointravitreal bevacizumab [56]. However, similarto DME, SML treatment could be an option foradjunct treatment for selected patients.

In summary, in all three indications micro-pulse laser is an efficacious and safe treatmentoption. Owing to its higher efficacy and theexcellent safety profile compared to PDT, itcould become the first-line therapy in CSC,potentially even in acute cases.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Adv Ther (2017) 34:1528–1555 1551

Disclosures. Paula Scholz received a speakerhonorarium from Quantel Medical. Sascha Fau-ser received a speaker honorarium from QuantelMedical. Lebriz Altay has nothing to disclose.

Compliance With Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. The datasets generatedand analyzed during the current study areavailable from the corresponding author onreasonable request.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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