toning

							Low fluence and Multiple Pass QS-Nd:YAG Laser Treatment Functionally Inhibits the
pigmentation of Melasma; Functional Photothermolysis


INTRODUCTION


기미는 병인
기미의 치료 - topical, laser, dermabrasion, chemical peel, iontophoresis 등이 있다.
   •     IPL and laser(continuous or quasicontinous at 532nm, 570nm, QS at 695nm,
         QS at 755nm) treatment
            –   High fluence of QS laser and IPL : Temporary effect ( high recurrence
                rate
            –   High fluence of QS laser and both low and high fluence IPL ( PIH
   •     Low fluence multiple pass Q-switched laser treatment : laser toning
            –   To evaluate a long term safety and efficacy


IPL & laser 치료는
1) temporary effect - recur
2) PIH
로 인해 치료가 힘들어 보임




최근 laser toning 이라는 named
local clinic in Asia and Korea,
widely used
1.0~2.0 J / half of cheek 에 1000~2000 shots / endpoint : erythema / QS1064
successfully treated, combined with topical bleaching agents
periodically treated
though some private clinic chain in Korea announces that they have successfully treated
over thousand of patients by a laser toning technique.
, but objective data, literature 가 only a few. (2008 Jan. 논문, case report)


이번연구는
1) low fluence , multiple pass QS Nd:YAG 의 효과에 대해 verify
2) long term efficacy and safty 를 evaluation 위해서 계획됨
This study was aimed to verify the effect of low fluence and multiple pass QS Nd:YAG
treatment on melasma and to evaluate a long term safety and efficacy.
in the past, attempts to treat melasma with lasers, such as Q-switched ruby laser
and Q-switched Nd:YAG laser, was ineffective or worsen the hyperpigmentation. [4]
[6] Though Er:YAG laser resurfacing and dermabrasion have been reported to treat
refractory melasma successfully they may develop serious complication such as
hypertrophic scar. [1,2] [12]
fractional resurfacing may prove to be an effective and modality for melasma, but
only limited data are available for the long term efficacy. [11]




“tophat” profile which delivers constant fluence over a full irradiated site in contrast
to “witch’s hat” profile or Gaussian beam.




METHOD


The partial MASI score counted a confined portion of the cheek and was calculated
based onj the onvlolved area (0-6: 0=0%, 1=10%, 2=10% to 29%, 3=30% to 49%,
4=50% to 69%, 5=70% to 89%, 6=90% to 100%), darkness of the pigment(0-4: 0=absent,
1=slight, 2=mild, 3=marked, 4=severe), and homogenicity (0-4: 0-minimal, 1=slight,
2=mild, 3=marked, 4=severe). pMASI=(darkeness of pigment + homogenicity) * area.
[23]
Any possible complications (edema, erythema, hypopigmentation , hyperpigmentation ,
infection and scar) were recorded. Photographic documentation using a digital camera
(Canon, Canon Inc., Japan) was obtained at baseline and at each subsequent follow-up
visit.




Fontana-Masson staining
Histology of melasma before treatments. Both sections demonstrated epidermal
hyperpigmentation aaround the basal layer, melanocytosis in the upper dermis,
disappearance of rete ridges, and slight thining of the epidermis




epidermal : light brown, melanin increase in the basal , suprabasal and stratum
corneum layers
dermal : ashen or bluish-gray. Preponderance of melanophages in the superficial
and deep dermis


색채계


CIE L*a*b* (CIELAB) is the most complete color space specified by the
international commission on illumination. The three coordinates of CIELAB
represent the lightness of the color (L*=0 : black, 100 : white), its position
between red/magenta and green (a*, negative values indicate green while positive
values indicate magenta) and its position between yellow and blue (b*, negative
values indicate blue and positive values indicate yellow)




CIE 1976 color space(CIELAB, L*,a*,b*) : zygoma
CIELAB(L*,a*,b*) : glabella
Area(cm2)
   •
   •    Prospective study (2008. 1 ~ 2008. 9)
   •   10 patients (Male:1, Female: 9, mean age : 39.3, Skin type III ~ V, Onset
       of melasma : 13.1 year ago)
   •   Total F/U duration : ≥25 wks, 14.4 sessions / 25 wks
             –   Resolution : F/U weekly
                    •   pMASI < 20% of initial pMASI
        or
                    •   pMASI < 5
             –   Maintenance
                    •   Come back to the clinic if the patients recognize a recurrence
      •   Lutronic Spectra VRM III
      •   Pulse width : 5~7 nm
      •   7 mm collimate(top-hat beam) tip
      •   No topical anesthesia


      •   Fluence : 2.2 J/cm2
      •   Number of shots : Total area(cm2) * 50 shots, 10 Hz




11 patients recruited
skin type 3~5


age
duration of melasma
melasma pattern
MASI
area
Lab


total treatment session
resolution time
maintenance duration


exclusion criteria


preg / nursing
no prev. treatment
과거 3 달동안 기미 치료를 받은 환자


Topical bleaching agents, such as tretinoin, hydroxychroloquine and bleaching
cosmetics was prohibited during the treatment period, while sunscreen, moisturizer
and cosmetics which does not have a bleaching component were allowed.


treatment protocols
Q-switched Nd:YAG laser (Spectra VRMIII, Lutronic Corporation, South Korea)
1064 wavelength
pulse width 5-7 nsec


mild steroid(Desowen, Stiefel) was applied after laser treatment
only sunscreen & moisturizer 만 허용되었다.
cosmetics 는 안돼


치료후 erythema 를 모든 환자가 보였고 a few or no petechiae 가 발생하기도 하였다.
all patients treated showed mild erythema immediately after a treatment and two
patients occasionally experiences a few petechiae.


emla 안썼다. pain 이 적어서 emla 필요 없음




resolution 정의 : MASI score 가 10% 미만으로 감소한 경우
resolution 까지 weekly tx.


resolution 이후에는
MASI score 가 10% 이상 재발할 때까지 1wk 씩 interval 증량
재발 하면 1wk interval 감소시키면 적절한 F/U duration 을 정했음


CIE Lab deltaE
http://www.colorwiki.com/wiki/Delta_E:_The_Color_Difference
http://www.aim-dtp.net/aim/evaluation/cie_lab/index.htm


2.2J
multipass
10Hz, 7mm spot, collimated mode,
area / total shots
치료와 측정은 객관성과 consistency 를 유지하기 위해서 한 사람이 하였다.




The total area of melasma was marked to a grid paper and a pixel analysis to
calculate the exact area was done by a GIMP(http://www.gimp.org)


no or a few petechiae
mild erythema
erythema 감소한 시간 :
3 시간 이내 / 6 시간 / 9 시간 / 12 시간 / 12~24 시간 / 24~48 시간 / 48 시간 이상
petechiae 등 기타 감소한 시간 :




modified MASI score


            Area      Homogenity Darkness
0           0         Minimal   Absent
1           <10       Slight    Slight
2           10-29     Mild      Mild
3           30-49     Marked    Marked
4           50-69     Maxium    Severe
5           70-89
6           90-100


Spectrophotometer
객관성 유지하기 위해서 한사람이
chromometer measure - minimal pressure 를 유지한 상태에서 사진에 표시된 같은
부위
glabella , eyelid lateral line 에서 vertinally downward 한 melasma 부위 에서 측정




RESULT


resolution time :
tx. interval :


dermal pigment 는 호전 없음  epidermis 에만 작용 가능성


2~3 주 간격 치료로 효과가 resolution 이 유지되었음
1) 초반에 효과 없다가 5 주째에 효과 많음
2) 5 주쯤에 약간 악화
3) 치료 초기에는 margin 에 PIH (+) <-> 치료 재발시에는 군데군데 재발
4) diffuse hypopig - 다른 사람은 한번도 경험 없었음
5) hypopig lesion or non-melasma site 도 tx 받으면 효과 유지됨
6) guttate hypopigmentation 이 효과가 좋은 사람에게도 보였다.


hypopig & hyperpig 가 2 사람에서 동시에 발생
다른 환자는 hypo & hyper 모두 없었다.




complication


guttate or mottled hypopigmentation 이 정상처럼 보이는 사람도 대부분 관찰됨
vitiligo-like hypopigmentation with hyperpigmentation




PIH 생긴 이유
Histopathologic examination showed that not all pigment-producing structures are
affected in a single QSRL treatment, therefore residing melanocytes may cause
additional pigmentation in patients tending to postlesional hyperpigmentation or
melasma [4]
It seems likely that any intervention resulting in a moderate inflammatory
immediate reaction will cause postinflammatory hyperpigmentation. [10]


Hruza and Dover showed that at high radiant exposures, there is melanosomal
rupture, while at low energies of exposure, paradoxical stimulation of
melanogenesis may occur. [7]


Q-switched laser pulses interact selectively with the cutaneous pigmente system,
by rupturing melanosomes, leading to local cellular distruction or stimulation,
depending on exposure doeses. [8,9]


Immediate postexposure biopsies showed that vacuolization of epidermal
melanocytes and keratinocytes was seen, with rupture of melanosomes. [8,9]
Hypopigmentation
Hypopigmentation was the most common complication encountered in the
treatment of Nevus of Ota with the Q-switched Alexandrite and Q-switched Nd:YAG
lasers. [5] At least in some cases permanent hypopigmentation has occurred. [5]


The mixed group involved the use of both machinses, allowing melanocytic
destruction at different levels and increasing the risk of follicular melanocytic injury
leading to a greater risk of hypopigmentation.[5]


The risk of hypopigmentation is not associated with a corresponding increase in the
clinical efficacy of the systems. [5]




DISCUSSION


melasma 는 치료가 어렵다.
다양한 방법이 시도되었으나 실패. 오직 소수의 의견 (+) --> invasive treatment 임
As there is no curable treatment, melasma is a chronic disease.




laser
PIH 문제 - stimulating melanocyte
low dose IPL treatment only aggrevates the melasma. (weekly, 2J, 3pass, ellipe
I2PL, unpublished data) 이런점에서는 비슷하다.
하지만 경험적으로 최근 low fluence ND YAG 가 효과가 있다. local 에서 laser toning 이
있기 때문임.. 이번 연구에서 성공적으로 치료 했다.


Hypopigmentation
Lam and colleagues achived 50% clearance in 80% of 32 patients with repeated
treatments (2-11) at 2- to 4 week intervals with the Q-switched alexandrite laser.
However 87% developed postinflammatory hyperpigmentation, whereas half
developed hypopigmentation.[15] Several studies used the Q-switched 1,064 nm
Nd:YAG laser; the degree of clearance ranged from 50 to 100%, and the incidence
of postinflammatory hyperpigmenattion ranged from 50 to 100%. [16]
A previous study of a freeze injury in normal human skin showed that a brief(5-
second) freezing of liquid nitrogen caused hypopigmentation, with a peripheral rim
of hyperpigmentation in all frozen lesions. Similarly, a recent study of Datrice et al
also found that transient hyperpigmenatation occurred after cryogen spray cooling
exposure. [18]


The underlying mechanisms and the variablility individuals show for develioping
hyperpigmenattion or hypopigmentation was not well understood. An inherited
individual chromatic tendencvy based on “strong” or weak” melanocytes and their
tendency to respond to trauma or inflammation with either hyperpigmentation or
hypopigmentation has been postulated. [19] Keratinocytes probably play an active
role in the regulation of melanogenesis and can stimulate melanocytes to become
dendritic and transfer melanosomes [20] laser-irradiated melanocyte or
keratinocyte may be more hyperactive to stimuli such as cold temperature. [21]
Epidermal cooling with cold air is associated with an increased risk of PIH after Q-
switched Nd:YAG laser treatment. [21]


Peripheral hyperpigmenattion seen clinically may represent lower energy at the
edges resulting in postinflammatory hyperpigmentation in the areas that have
intact melanocytes.[22]
It may be that the melanocytes in areas of melasma are overactive and that the
inflammation following laser treatment leads to rapid reoccurrence or even
darkening of the treated areas. [22]




Low Fluence Multiple Pass Q-switched Treatment on Melasma
   •   Treatment of refractory dermal melasma with the MedLite C6 Q-switched
       Nd:YAG laser: two case reports.
           –   J Cosmet Laser Ther. 2008 Sep;10(3):167-73
   •   Low-fluence Q-switched Nd:YAG (1064nm) Laser for the Treatment of Facial
       Melasma in Asians
           –   IMCAS Paris 2008 and 8th Asian Dermatological Congress
   •   Copper bromide 578mm Dual/Yellow laser for the new treatment of Melasma
           –   5th Bu-Ul-Gyeong Skin Aesthetic Therapy Symposium & Video
               Lecture
기전은 ?
selective photothermolysis 에 대한 설명 -> 온도 높여서 target 만 denature 시킨다는
개념


--> selective photothermolysis 에 의한 thermodestruction 생각하기에는 에너지가
낮아서 충분한 온도에 도달하기 힘들어 보이므로 완전히 설명하기 힘들어 보인다.


we hypothized functional photothermolysis
that low F / multipass tx 는 melanocyte 의 dysfunction 을 유도




열/infl. 에 에 민감한 melanocyte 의 biology (cryotherapy 등, PIH , infl. 이후에 hypo
가 생기기도 하고 hyper 가 생기기도)




Dmitri O. et al defined laser-activated bubbles as local vapor bubbles emerged
when when cell-averaged thermal effect is relatively small and the local laser-
induced temperature may reach a rather high value and exceed the evaporation
threshold. [3] They suggest laser-activated bubbles may be used as universal and
sensitive non-toxic probes for measuring functional properties of individual cells.


Local light-absorbing target with high absorbance
Laser parameters for generation of the bubbles should provide rapid local heating
to avoid loss of thermal energy through dissipation of heat. That’s why low fluence
IPL does not works on melasma while low fluence Q-switched laser treatment works.


The Photoacoustic effect is a conversion between light and acoustic waves due to
absorption and localized thermal excitation.




근거
1) chromophore 가 적은 hypopigmented lesion or cured lesion 도 laser 를 쏘면
resolution 이 유지되었다.
2) 치료를 하지 않으면 2~3 주 내에 바로 재발 -> 완전한 파괴보다는 기능상실 가능성이
높다.


3) 다른 laser 에 비해서 resolution 오는 기간이 오래걸린다. -> 있는 것 파괴보다는
생산을 막기 때문에 늦게 나타날 가능성


4) hypopig & hyperpig 가 동시에 발생. 다른 환자는 발생 없음. 우연일 수도 있지만 일부
환자에서 dysfunction 에 의해 색소이상 가능


functional photothermolysis 제안


열에너지가 target 에 confine 되어 나타난다는 점에서 selective photothermolysis 와
동일하지만
destruction 을 시키기 보다는 일시적인 melanogenesis 를 dysfunction 을 유발해서
효과를 나타내는 점에서 차이가 있다.


Fig 1.


Zone 1 : classic selective photothermolysis
60 도 이상으로 denaturation 시켜서 target 을 irreversible 하게 파괴 시키는 area
Zone 2 : functional photothermolysis
target 의 dysfunction 유도 , reversible 하게 recover
Zone 3 : photostimulation
UV light 처럼 low energy 를 가진 photon 이 photostimulation


Fig 2.


low fluence multipass laser 에 의해서
휴지기 or non-functional state 로 진입. 2~3 week 후에 회복
periodically laser treatment 의 thermal effect 에 의해 melanocyte 의 function 에
장애가 생김
계속 치료해주면 병변 free 하게 유지할 수 있음


Mechanism of Low Fluence Multiple Pass QS1064 Treatment
Unknown
   1) Selective photothermolysis of epidermal melanin
   2) Decrease in dermal vascularity




Selective Photothermolysis of Epidermal Melanin
   •   Photothermal effect : subthreshold irradiation
   •   Laser activated bubbles : Local laser-induced temperature may reach a
       rather high value and exceed the evaporation threshold
          –   Lasers Surg Med. 2006 Mar;38(3):240-8.
   •   Photoacoustic effect : Local heat  pressure variation in surrounding
       medium
          –   Lasers Surg Med. 1991;11(1):62-8.


vascular component
Decrease in Dermal Vascularity
   •   Melanocytes and keratinocytes express functional VEGF receptors
          –   Exp Dermatol. 2005 Aug;14(8):625-33
   •   Increased vascularity is one of the major findings in melasma
          –     J Dermatol Sci. 2007 May;46(2):111-6.


   •   A* value of color index was significantly decreased after multiple
       treatment in this study.
   •   High fluence(7~15 J/cm2), QS1064 for skin rejuvenation showed
       improvement of 10% to 20% in redness [13]
          –   Arch Dermatol. 2003 Oct;139(10):1265-76
   •   Erythema was improved in clinical assessment after low
       fluence(3.2J/cm2) QS1064 treatment though an increase in vascularity was
       observed on biopsies [14]




Colorimetry
A colorimeter (Minolta CR-200, Minolta, Japan) was used as a measure of erythema
color. The instrument records color reflectance three-dimensionally (L*, a*, b*), as
recommended by CIE. The a* represents the balance between red(+100) and
green(-100) and the b* represents the balance between yellow(+100) and blue(-
100). When recording the color values, the measuring head was held perpendicular
to the skin surface and the aperture was fitted with an applicator, to avoid
compression of subcutaneous capillaries. All measuring processes were performed
by one investigator to avoid the variation between the investigators. The reference
value was obtained form the glabella.


Each value represents the mean +/- S.D (n=xx)
The intensity of the erythema response varies directly with the a* coordicnate.


To indicate skin color change by the multiple indexes, delta E =[(delta a*)2+(delta
b*)2+(delta L*)2]1/2 were calculated.




resolution 온 시간




maintenance 주기




S/E


hyperpigmentation and hypopigmentation -> 치료를 지속해서 크게 만들어주면
미용적으로 좀 더 낫다. / 3 주 정도 후에 모두 회복되었다. -> 일반적인
hypopigmentation 은 시간이 필요하지만 금방 회복됨
vitiligo like looking ?


1 명은 계속 크게 만들어서 호전 시킴
1 명은 hyper & hypo pigmentation 으로 drop 되었음


erythema ->
mild pain


marginal hyperpigmentation -> margin 의 경우 Zone 3 에 해당하기 때문임. PIH -->
치료 범위를 좀 더 넢혀서 해결
mild degree mottled hypopigmentation --> 정상처럼 보이는 사람도 장기 치료시
관찰되었음


치료 초기에 margin 에 PIH lesion 이 많았다. 적당히 약한 에너지를 주면 PIH 를
유발시키는 것으로 추측




Conclusion


Conclusion
   •   Resolution time : 4.78±0.67 weeks
   •   Maintenance interval : 2.03±0.34 weeks
   •   Complication : Diffuse hypopigmentation with marginal hyperpigmentation,
       late guttate hypopigmentation, persistent erythema


   •   Selective photothermolysis of epidermal melanin and a decrease in dermal
       vascularity can be the mechanism of this treatment
   •   Low fluence and multiple pass QS1064 laser treatment is effective on
       melasma, but careful observation during treatment is necessary to prevent
       the complications




resolution 이 5 주만에 왔고
2~3 wk treatment 로 1 년간 resolution 을 유지 시켰다.
S/E 는 hypopigmentation / marginal hyperpigmentation
1 년간 melasma free state 로 유지되었다.


기전은
low fluence, multipass tx 가 melanocyte 의 dysfunction 을 유도하는 functional
photothermolysis 로 생각된다.
이를 뒷받침하기 위해 histologic study 가 필요하다.
downtime 없는 효과적인 치료이다.
hypopigmentation 으로 주의가 필요하다.


pain 이 적고 downtime 이 less than one day 인 기미에 좋은 치료법이다.