Prof. Dr. Emin ÖZMERT

Ankara University Faculty of Medicine, Ankara / TURKEY

Tehran - 2017, IRAN

Subthreshold 577 nm SubLiminal (= micropulse) Laser Therapy:Benefits in Various Macular Edema

Central Serous Chorioretinopathy (CSSR)

Financial Disclosure

Consulting and training agreement with “Quantel Medical, Inc.”

Protokol T: 2-year results

Wells J, Glassman A, Ayala A: Ophthalmology 2016; 27

Mild vision loss

Moderate or worse vision loss

Required at least one rescue macular laser:Aflibercept: 41 %Bevacizumab: 64 %Ranibizumap: 52 %

Suggested treatment algorithm for DME

Mitchell P: Am J Ophthalmol 157: 505-513, 2014

DME

VA ≤ 20/30

Foveal involved DME

Anti VEGF

VA > 20/30

Focal /Grid laser treatment

According to ETDRS protocol

Non-center involved DME

Non-responder

Conventional grid / focal thermal laser photocoagulation:

• The clinical endpoint is an ophthalmoscopically visible retinal burn

• About 10 to 40 % of the energy delivered damage adjacent tissues

Collateral thermal damageMainster M. Semin Ophthal 1999 Desmettre TJ, et al Br J Ophthalmol 2006

Conventional thermal laser photocoagulation

Iatrogenic collateral chorioretinal thermal damage

• Enlargement of laser scars into the fovea

• Change in contrast / macular sensitivity (microperimetry)

• Macular / peripheral scotomas

• Choroidal neovascularization, submacular fibrosis

• Loss of color vision

• Reduced night vision

• Inadvertent foveal burn

• Transient increase of edema, and decrease in VA

Suggested treatment algorithm for DME

Mitchell P: Am J Ophthalmol 157: 505-513, 2014

DME

VA ≤ 20/30

Foveal involved DME

Anti VEGF

VA > 20/30

Focal /Grid laser treatment

According to ETDRS protocol

Non-center involved DME

Non-responderSubtreshold laser modalities:

CW single spot: lightCW pattern: PASCAL, NAVILASMicropulse = Subliminal

What can be done to reduce the devastating effect of conventional thermal laser ?

• To prefer 577 nm yellow wavelenghth over532 nm green

• Light, subthreshold burns with conventional CW laser

• Modified – ETDRS protocol

• Pattern scanning (multispot) subthresholdburns with CW

( Pascal, Navilas )

• Tissue-sparing Micropulse laser stimulation:

SubLiminal laser:

pattern (multispot) + 577 nm yellow

wavelenght

SubLiminal (Easyret)

A new term “photostimulation” as opposed to “photocoagulation”

Advantages of yellow wavelenght multispot SubLiminal laser:

• Excellent combined absorption by melanin & oxyhemoglobin

* Max. absorption in RPE, choriocapillaris

* Needs less power with more uniform treatment

* Better penetration through the cataract and hazy media

• Negligible xanthophyll absorption compare to green 532nm

(Allows to treat closer to the macula)

• Reduce collateral damage, well-protected macular sensitivity

Mainster MA: Wavelength selection in macular photocoagulation.Tissue optics,thermal effects,and laser systems. Ophthalmology.1986;93:952-958

Subtreshold Micropulse(=SubLiminal) mode

From photocoagulation to photostimulation…

• CW laser emission is choped into spaced repetitive micropulses within an envelope

• Major advantages:

• No thermal damage to adjacent tissues

• Minimal energy use

• Time for tissue cooling between pulses

Continuous (CW) laser: 100 % Duty CycleLaser energy is delivered in one single laser pulse

Micropulse laserA train of ultra-short repetitive microsecond pulses

1- Yoon Hyung Kwon, Dong Kyu Lee, Oh Woong Kwon. The short-term efficacy of subthreshold micropulseyellow (577-nm) laser photocoagulation for diabetic macular edema. Korean J Ophthalmol 2014;28(5):379-385 2- Scholz P, Ersoy L, Boon CJF, FauserS. Subthreshold Micropulse Laser (577 nm). Treatment in Chronic Central Serous Chorioretinopathy. Ophthalmologica 2015 DOI: 10.1159/000439600

200 ms

MicroPulse PrincipleSubLiminal Technology

Pre-laser 4 months post laser

Traditional thermal laser treatment

8 months post laser 12 months post laser

Victor Chong MD, Oxford Eye Hospital

ExudatesLaser spots

Pre-treatment (BCVA 37 letters) 12 months post-treatment (BCVA 57 letters)

Micropulse Yellow Laser

Fong KCS, University of Malaya ( YELL-1 Study )

SubThreshold treatment modes based on a train of microsecond pulses ------------ micropulse laser

Same technology, but different trademarked names

IridexQuantel Medical

SubLiminal ? MicroPulse ?

Tissue-Sparing Subthreshold Micropulse Laser (= SubLiminal Laser)

EASYRET: 577 nm Yellow, multispotsSUPRA SCAN 577: Yellow, multispots

How does micropulse laser therapy work ?

Heated sublethal tissue that remains viable after MPL, stimulates the RPE, and triggers a stress response

Over-express more than 25 genes. These genes represent diverse biological functions:

* Modulates beneficial intracellular biological factors ( PEDF, TSP1, SDF1, ß-Actin, VEGF )

* Alteration and normalization of cytokine expression

* Heat Shock Proteins:

- Inhibit protein aggregation

- Guide proteins to the correct organe

These factors are primarily anti-angiogenic and restorative

1. Shafiee A, IOVS 2000; Figueroa J, BJO 2009; Vojosevic S, Retina 2010

2. Lavinsk D, Retina 2014Wilson AS,et al: Invest Ophthalmol Vis Sci. 2003; 44:1426-1434.

3. Wilson AS,et al: Invest Ophthalmol Vis Sci. 2003; 44:1426-1434.

4. Sramek C, et al: Invest Ophthalmol Vis Sci. 2011; 52:1780-7.

Terminology on Micropulse(=SubLiminal) Technology

• Pulse ON time: Duration of each micropulse

• Pulse OFF time: Interval between micropulses

• Period ( T ): ON time + OFF time

• Exposure duration ( Envelope ): no of micropulses X T

• Duty Cycle ( % ): ON time / T X 100

Expression of the energy delivered on tissues ( 5, 10, 15 % )

LOW DUTY CYCLE

Low thermal diffusion due to the long “OFF” time

between each Pulse

HIGH DUTY CYCLE

More energy is delivered with more thermal diffusion

during the “ON” time

Micropulse(=SubLiminal) / Multispot ( pattern ) laser stimulation: Parameters

- Duration: 200 ms =0,2 s- Spot size:160 microns- Duty Cycle: % 5- Power: MPL, barely visible spot / 2- Various pattern choice: Multispot delivery

Since the laser spots are not visible, this pattern ensuresa homogenous application and a dense placement of the subthreshold laser spots

Low intensity: % 5 Duty CycleHigh dansity : contiguous ( confluent ) applications (no overlapping burns )

More RPE cells are exposed to thermal stress which improve its efficacy

Customizable macular grid

Fovea landmark

Non-treatment area (blue circle)

Treatment area (spots)

Treatment area (spots)

Laser aiming beam OCT

Laser aiming beam OCT

Square

SubLiminal Treatment Guidelines

DME: OCT- guided SubLiminal (=micropulse) treatment

Pre op OCT - BCVA 20/40

Post op OCT - BCVA 20/20

160 μm spot size / DC 5% / 200 msTitrate Power: Single spot outside arcades until bare visible burn Treatment Power: 50% of the power level obtained during the titrate step

- No visible reaction must be observed - There is no need to change power with

different degrees of edema

Wait for min 3 months

0,5 0,8 0,4 0,7

Pattern scan Subliminal laser applied on thickened area of OCT

- No visible reaction must be observed - There is no need to change power with different degrees of edema

Mİ: MPL applied on both eyes

24.02.2016 24.02.2016 /15.03.20171xMPL: 2xMPL:

26.07.201726.07.2017

Cataract developed Hard exudates increased

RE LE

SS: 71 years old, BRVO

CMT:483 µm

3 months later CMT: 272 µm

Parafoveal macular edema

Retinal arterial macroaneurism – CMEYellow MPL applied into the macroaneurism

FAF: CME,premacular hem.VA: 20/200

After MPL

Test spots2 years later after MPLVA: 20/20

Radiation retinopathy / 2xMPL

4 months later after the last application

Idiopathic Macular Telengiectasia- Type 2Intraretinal melanin clumping

Hypofl. dots due to melanin

clumping in retina

Melanin is black on both

FFA and FAF

SO: Idiopathic Parafoveal Telengiectasia / MPLThere is no proven therapyRestorative effect of MPL ??

Postop 2 months BCVA:0,3 CMT:102 µm

Preop BCVA: 0,3 CMT: 120 µm

HT: Idiopathic Parafoveal Telengiectasia / MPL

5 months later after MPL

Diminishing in size of neurodegenerative area

Cavitation within the retina due toneural dejeneration

Central Serous ChorioretinopathyTreatment options: No proven standard thraphy established

• Observation without treatment for 6-8 weeks for spontaneous resolution

• Conventional argon laser treatment extrafoveal RPE leakage, associated with inevitable collateral damage

• Intravitreal Anti-VEGF injection: Poor evidence, needs frequent injections, local / systemic side effects

• Half-dose PDT: effective, invasive, risk of RPE atrophy, CNV and choroidal ischemia

• Subthreshold Micropulse (=SubLiminal) : effective, non-invasive, no side effects

Acute CSCR: FA / ICGA Guided SubLiminal Treatment

- Hyperfluorescent areas on mid-phase ICGA

- Hot spots on mid-phase FA

- 500µm distance from foveal center

FA ICGA SubLiminal Laser Treatment

160 μm spot size / DC 5% / 200 msTitrate Power: Single spot outside arcades until bare visible burn Treatment Power: 50% of the power level obtained during the titrate step

Wait for min 6 weeks

AK: A 42 year-old female, micropulse laser therapy

VA: 0.2

VA: 1.012th month

TŞ: Parafoveal focal leaking point lasting 6 months

5 month later after MPL: VA 1.0

MPL was applied to the area of focal angiographic leakage: VA 0.8

CHRONIC CENTRAL SEROUS CHORIORETINOPATHY

• Usually seen in patients aged > 50

• Persistent subretinal fluid

accumulation for at least 6 months

• Irreversible visual loss due to

widespread areas of pigment

mottling, atrophic changes,

staining and leaks of RPE

• Rarely, CNV developes as a

complication

Chronic CSCR-FAF

Multiple mottled FAF:

* Leakage points, RPE atrophy, photoreceptor damage -------- black dots

* Increased RPE activity, pholorophore in subretinal fluid ----- white dots

• FAF is useful to differantiate acute and choronic SSCR

• If there is no fluid on OCT, diagnosis of chr. SSCR is difficult

There is mottled FAF ( aggregates ) on the area of attached serous retinal detachment , which was previously detached

SY : 56 years old, female, Chr. CSCR

4 months later

VA: 0.4 ----- 1.0

Sometimes it resembles AMD

and adult-onset vitelliform lesions

IB: 46 years old, male, Chr. CSCR

Preoperative, BCVA:0.7

Preoperative SRF: 394 µm

1 month later, BCVA: 0.8 SRF: 259 µm 3 months later, BCVA:1.0 SRF: 32 µm

28.2.2014

20.3.2014

11.03.2015

1 year after one session MPL VA: 10/10, no distortion

MPL

Z.Ş. Right Eye

Differential Diagnosis:Pachychoroid Spectrum Disease

• Pachychoroid pigment epitheliopathy

• Pachychoroid neovasculopathy

• Polypoidal choroidal neovasculopathy

• Chronic Central Serous Chorioretinopathy + CNV

PCV + CNV

Chronic CSC+ CNV

- Chronic subfoveal fluid accumulation- Flat (Shallow) -irregular Pigment Epithelial Detachment- Thick choroid or large choroirdal vessels on EDI-OCT

OCT-Angiography: CNV, feding vessel

Pachychoroid neovasculopathy

ICG: RPE atrophyCNV ? Large choroidal vessels?

Submacular fluidFlat-irregular PEDDilated choroidal vessels

Central Serous Chorioretinopathywith serous PED

Polypoidal Choroidal Vasculopathy (PCV)

MPL is not useful,

Low-fulence PDT Treatment is preferred

PCV

Chronic Central Serous Chorioretinopathy + CNVAnti-VEGF injections and MPL are not useful

Unresponsive to Anti-VEGF After PDT

In 30 % of Chr. CSCR cases, type 1 CNV developes during the follow-up period

Marco Antonio Bonini Filho et al. JAMA Ophthalmol 2015

Hage R , Mrejen S, Krivosic V, et al. A. Am J Ophthamol 2015

Clinical Studies

Purpose:

To compare the efficacy and safety of:

• 577 nm yellow wavelength multispots MPL

and

• Low-fluence photodynamic therapy (PDT)

in the treatment of chronic central serous chorioretinopathy

Journal of Ophthalmology, Vol: 2016Article ID: 3513794

Treatment parameters:

• Micropulse yellow wavelength (577 nm) laser ------ (15 eyes)

Tissue-Sparing /Subthreshold Micropulse(=SubLiminal) Laser Stimulation

• Low-fluence PDT group ------------(18 eyes)• Verteporfin: 6 mg/m2 over ten minutes

• 689 nm laser for 83 seconds,

reduced light dose of 25 J/cm2,

intensity of 300 mW / cm2

Results-1

The changes in ETDRS letters throughout the follow-up

0

10

20

30

40

50

60

70

80

baseline 1st month 3rd month 6th month 9th month 12th month

ETD

RS

lett

ers

Micropulse laser

Photodynamictherapy

Results-2

Final best corrected visual acuity changes: improvement rate is higher with MPL

BCVA change Low-fluence PDT

n (%)

MPL

n (%)

Increase ≥ 5 ETDRS letters 6 (33.3%) 10 (66.7%)

Stable (within ± 4 ETDRS letters) 6 (33.3%) 1 (6.7 %)

Decrease ≥ 5 ETDRS letters 6 (33.3%) 4 (26.7%)

Total 18 15

p=0,101

Results-3The changes in subretinal fluid height throughout the follow-up:

The resorption rate of subretinal fluid is slower with MPL

0

20

40

60

80

100

120

140

baseline 1stmonth

3rdmonth

6thmonth

9thmonth

12thmonth

Su

bre

tin

alF

luid

He

igh

t(µ

m)

Micropulse laser

Photodynamic therapy

Results-4

Treatment response of subretinal fluid: There is no unresponsive case with MPL

Treatment response Low-fluence PDT

n (%)

MPL

n (%)

Complete resolution of SRF 13 (72.2%) 12 (80.0%)

Incomplete resolution of SRF 1 (5.6%) 1 (6.7%)

Unresponsive 3 (16.7%) None

Recurrence 1 (5.6%) 2 (13.3%)

Total 18 15

p=0,486

Recurrence rate is higher with MPL, because we could not differentiate the Pachychoroid Spectrum Diseasebefore the invention of OCT-Angiography

Conclusion: 577 nm SubLiminal micropulse multispots laser

• As effective as low-fluence PDT in providing resorption of SRF

with some additional benefits

• A non-invasive procedure

• Tissue-sparing effect without termal damage

• Ensure safe re-treatment after 3 months

Further investigation of macular function by

microperimetry, ERG and FAF may provide additional

useful information on MPL

THANK YOU