Pulse in Pulse Intense Pulsed Light for Melasma Treatment: A Pilot Study JONG YOON CHUNG, MD,* MIRA CHOI, MD,† JAE HYUNG LEE, MD,* SOYUN CHO, MD, PHD,† JONG HEE LEE, MD, PHD*
AND
BACKGROUND A new type of intense pulsed light IPL with pulse-in-pulse (PIP) mode (multiple fractionated subpulses in one pulse width) has recently been developed. OBJECTIVE
To evaluate the clinical efficacy and safety of PIP IPL in patients with melasma.
MATERIALS AND METHODS Half of each patient’s face was treated with IPL and six treatment sessions with a low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser (IPL/T) every 2 weeks. The other half was treated with PIP IPL. Outcome assessments included photography, modified Melasma Area and Severity Index (MASI) score, and patient satisfaction. The melanin and erythema indices were used for objective evaluation. Patients were followed up for 6 months after the last treatment. RESULTS All patients completed the study successfully. On both treated sides, the melanin index decreased significantly after treatment. The modified MASI score also fell 54.4% on the PIP IPL side and 50.0% on the IPL/T side. No patients reported serious aggravation of melasma for 6 months after the last treatment. Patients favored PIP IPL due to less discomfort during and after treatments. CONCLUSION
PIP IPL may be a safe and promising treatment for melasma.
The authors have indicated no significant interest with commercial supporters.
S
ince the early 2000s, intense pulsed light (IPL), emitting milliseconds of pulse width, has been proven to be effective in most clinical conditions such as pigmentation, telangiectasia, and even wrinkles.1 Previous studies2–5 also reported its efficacy and safety for the treatment of melasma. Melasma is a complex multifactorial disorder with increased pigmentation and increased vascularity associated with pigmentation.6 Therefore, IPL emitting a broad spectrum of light absorbed simultaneously to melanin and hemoglobin was expected to be a better treatment modality for melasma than other conventional pigment lasers, although aggravation and recurrence is not uncommon even after successful treatments using IPL.3,4
The pulse duration of IPL is usually milliseconds, which is much longer than thermal relaxation time of melanosomes. Therefore, IPL cannot selectively target activated melanocytes but can influence all of the structure-containing melanosomes and melanin pigments in the epidermis through photothermal reaction, clearing out pigmentation through transepidermal elimination.7 Unwanted thermal stimulation through IPL with millisecond pulse duration and high fluence might aggravate melasma. Unlike conventional IPL system, pulse-in-pulse IPL (PIP IPL) emits multiple fractionated subpulses within one pulse duration of 10 ms. PIP IPL does not elevate the temperature of target tissue high enough
*Department of Dermatology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea; † Department of Dermatology, Seoul National University Boramae Hospital, Seoul, Korea © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2014;40:162–168 DOI: 10.1111/dsu.12414 162
CHUNG ET AL
to destroy it. It gradually increases skin temperature and might be safer than conventional IPL especially for the treatment of melasma. We conducted this clinical study to evaluate the clinical efficacy and safety of PIP IPL in individuals with melasma. When we applied a lower fluence of IPL, similar to low-fluence quality-switched (QS) neodymium-doped yttrium aluminum garnet (Nd: YAG) laser (laser toning) on individuals with melasma, this treatment modality does not appear to be effective.8 PIP IPL does not induce any microcrusts and can be applied every other week, yet conventional IPL for the treatment of pigmentary disorder induces microcrusts after treatments, and the usual treatment interval with IPL is supposed to be at least 3 to 4 weeks. Therefore, it is hard to compare PIP IPL with conventional IPL treatment. Our previous study on melasma demonstrated that IPL and laser toning combination treatment (IPL/T) every or every other week provided better long-term clinical benefits with fewer adverse effects than laser toning.9,10 Therefore, we designed a split-face study with PIP IPL and IPL/T combination treatment not with low-fluence IPL or conventional IPL treatment.
Materials and Methods Individual with melasma were eligible to enroll this study after voluntary agreement under institutional review board approval. Exclusion criteria were pregnancy, current oral medications that might influence treatment of melasma (e.g., oral contraceptives, thyroid hormones), prior use of topical bleaching or whitening medication on face, and previous laser or light treatment for melasma 6 months before enrollment. One half of the face received one treatment session of conventional IPL (Ellipse, Danish Dermatologic Development, Hørsholm, Denmark) and six successive treatments using a low-fluence QS Nd:YAG laser (Spectra, Lutronic Co., Seoul, Korea) (IPL/T combination treatment). The treatment parameter of IPL was a 2.5-ms double pulse with a 10-ms pulse delay, 9.0 to 9.4 J/cm2 of fluence, and one pass of IPL
exposure delivered on the patient’s face. A lowfluence QS Nd:YAG laser (8-mm collimated spot size, 10-ns pulse width, 1.0 to 1.2 J/cm2 of fluence, multiple passes to achieve mild transient erythema around melasma lesion) was used. The other half of the face was treated using PIP IPL (E-toning, Union Medical Co., Seoul, Korea), emitting a 550- to 800nm wavelength, an applied fluence of 12 to 15 J/cm2, in two tho three passes to obtain mild perilesional erythema response, which disappeared in a few minutes. Treatments were administered to each side of the face at 2-week intervals for a total of seven sessions Patients were followed up for 6 months after the last treatment. From 2 weeks after the last treatment, they were instructed to apply topical hydroquinone 4% at night and topical antioxidant cream with a broad-spectrum sunscreen in the morning during the 6-month-follow up period (Figure 1). At each visit, the melanin (MI) and erythema indices (EI) were measured on the same spot on both sides of the face. Photographs were taken under the same conditions. Two blinded investigators who were not involved in the enrollment and treatment procedure evaluated a modified MASI score at baseline, 2 weeks after the last treatment, and at 6 months of follow-up (Figure 1). The modified MASI score9,11 counted only a confined portion of the malar area (cheek) and was calculated based on the percentage of involved area (A, 0–6: 0 = 0%, 1 = 1–10%, 2 = 10–29%, 3 = 30–49%, 4 = 50–69%, 5 = 70–89%, 6 = 90–100%); darkness of pigment (D, 0–4: 0 = normal skin color without evidence of hyperpigmentation, 1 = slight visible hyperpigmentation, 2 = mild visible hyperpigmentation, 3 = marked hyperpigmentation, 4 = severe hyperpigmentation), and homogenicity or density of hyperpigmentation(number of pigmented lesions per unit facial area (H, 0–4: 0 = minimal, 1 = slight, 2 = mild, 3 = marked, 4 = severe). Modified MASI ¼ ðDarkness of pigment þ HomogenicityÞ Area Patients marked their clinical improvement on a visual analog scale (0–4: 0 = no change or worse to
40:2:FEBRUARY 2014
163
MELASMA TREATMENT WITH PIP IPL
statistically significant. Values were documented as means standard deviations. Result Twelve women (aged 37.4 7.7) with melasma were enrolled in and completed the study.
Figure 1. Treatment protocol. Every 2 weeks, one half of the face received PIP IPL and the other half was treated with IPL and low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser. The treated side was randomly determined on each patient. Photographs were taken and the modified Melasma Area and Severity Index (MASI) score was evaluated. Erythema index (EI) and melanin index (MI) were measured at each visit. During 6 months of follow-up, patients were instructed to use topical 4% hydroquinone at night and antioxidant cream with a broad-spectrum sunscreen during the day. V, Visit, T, treatment (T1 = 2 weeks after the first treatment).
4 = excellent >75% improvement). Any serious adverse effects were documented. Statistical Analysis Using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA), paired t-tests and Wilcoxon rank-sum tests were used to compare the clinical responses between each treatment modality and between before and after treatment. p < .05 was considered
Mean erythema index (EI) before treatment was 225.1 35.1 on the PIP IPL side and 218.0 12.8 on the IPL/T side. It decreased slightly 2 weeks after the last treatment (210.9 22.4 and 211.2 23.9, respectively), although the differences between the PIP IPL and IPL/T sides were not statistically significant. At 6-month follow up, there was a statistically significant increase in the EI on both treated sides from 2 weeks after the last treatment (p < .05) (Figure 2). After all treatments, there was a significant decrease in the melanin index (MI) on both sides compared with baseline (PIP IPL: 201.3 28.7–140.2 21.3, p < .001; IPL/T: 192.9 24.3–131.0 19.3, p < .001). On the PIP IPL side, the MI tended to decrease as treatment sessions continued, and after the fourth treatment, a significant reduction in the MI from baseline was observed (p < .001). On the IPL/T side, there was considerable reduction of MI after the first treatment (p < .05, vs baseline), and a
Figure 2. Erythema index (EI) after treatments. There was no much difference after treatment from baseline, although there was a statistically significant difference in EI 2 weeks after the first treatment on the intense pulsed light low-fluence qualityswitched neodymium-doped yttrium aluminum garnet (IPL/T) side. *p < .05, pulse-in-pulse (PIP) IPL vs IPL/T. +p < .05, T7 vs 6-month follow-up. T, treatment.
164
DERMATOLOGIC SURGERY
CHUNG ET AL
Figure 3. Melanin index (MI) after treatments. On the pulse-in-pulse intense pulsed light (PIP IPL) treated side, MI decreased with treatment sessions, whereas a significant reduction in the MI after IPL treatment and a slight improvement with lowfluence quality-switched neodymium-doped yttrium aluminum garnet laser was observed on the IPL/T side. *p < .05 versus baseline, **p < .001 versus baseline, +p < .05 PIP IPL versus IPL/T. T, treatment.
gradual decrease in the MI was noticed afterward. No statistically significant differences were found after the last treatment and at 6-month follow-up between the treated sides (Figures 3 and 4).
Destruction of unwanted target tissue (e.g. hemoglobin, melanin, water) without causing damage to surroundings was the main focus and interest in the development of laser- and light-based devices.
The modified MASI score showed that PIP IPL and IPL/T treatment worked on melasma (54.4% vs 50.0% reduction of modified MASI score: from baseline to 2 weeks after the seventh treatment, p < .01) (Table 1).
With melasma, high-fluence laser- and light-based treatment for targeting pigment is not useful, because these treatments can aggravate melasma. From this point of view, low-fluence QS Nd:YAG laser treatment (laser toning) has been extensively used, especially in Asian countries, with success.14,15 It applies very low fluence and does not destroy active melanocytes with melanosomes. Repetitive sessions of laser toning exhaust melanocytes and inactivate them so that they no longer produce or transfer melanin pigments.16,17 When Kim and colleagues17 biopsied skin treated with multiple sessions of laser toning, the remaining melanocytes were found to be inactive but the treatment does not stimulate activity of these dormant melanocytes, hence, it can achieve clinical improvement in melasma. Moreover, this treatment does not involve downtime or pain, which makes some patients believe that this treatment is very safe and free of adverse effect, but nanosecond-domain QS laser exposure can provoke explosive mechanical waves even though it is set at a low fluence.18 These characteristics, together with repeated treatments
All patients rated the clinical outcomes as good to excellent on both sides (>50% clinical improvement), although six patients favored PIP IPL because there was no discomfort during and after treatment. The rest reported that they had no preference for one treatment modality over the other. No serious adverse effects on were noticed either side during or after treatment.
Discussion Pulse width and wavelength are important factors for selectivity of photothermolysis in target tissue, and a fluence high enough to increase the temperature of target tissue within a certain time is one decisive factor in destroying it through a photothermal or photomechanical reaction.12,13
40:2:FEBRUARY 2014
165
MELASMA TREATMENT WITH PIP IPL
(A)
(B)
Figure 4. Clinical photograph of the most-responsive patient. She was 40 years old. Pulse-in-pulse intense pulsed light (PIP IPL) (A) and IPL with quality-switched neodymium-doped yttrium aluminum garnet laser (IPL/T). (B) Treated side showed considerable improvement in melasma, and, no serious aggravation of pigmentation was observed at 6-month follow-up.
TABLE 1. Modified Melasma Area and Severity Index Score Before and After Treatment Pulse in Pulse IPL
IPL/T
Mean Standard Deviation Baseline (before treatment) 2 weeks after 7th treatment 6-month follow-up
14.9 3.6
13.8 4.1
6.8 2.3†
6.9 1.8†
8.2 1.9*
8.8 2.1*
IPL/T, intense pulsed light (IPL) with low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser combination treatment. *p < .05, †.01 versus baseline.
over a short period, may be responsible for punctate leukoderma, which is cosmetically unacceptable and may persist if left untreated.18–20 Punctate leukoderma or confetti-like hypopigmentation was first reported in patients who developed multiple
166
DERMATOLOGIC SURGERY
hypo- or depigmented spots after oral psoralen with phototherapy.21 It has also been reported that repetitive treatment sessions of low-fluence QS Nd: YAG laser can induce these hypopigmented lesions.18–21 Chan and colleagues18 emphasized the risk of punctuate leukoderma when laser toning was considered for the treatment of melasma. It too from 6 to 50 treatment sessions for punctate leukoderma to develop (mean 22.1 sessions).18,19 Treatment intervals also varied in previous reports (weekly, every 2 weeks, every 3 weeks, or monthly).18–20 Cumulative frequent sublethal insult to melanocytes might be associated with this adverse effect.21,22 Therefore, efforts to reduce the number of treatment session and to determine optimal treatment intervals and parameters while still achieving satisfactory results should be made in the clinical field. A previous pilot study8 using low-fluence IPL (one-third or a half the fluence of conventional
CHUNG ET AL
uses) was ineffective in the treatment of melasma and sometimes touched off aggravation of melasma. PIP IPL was designed to overcome this limitation of clinical efficacy of low-fluence IPL. PIP IPL emits the same wavelength as other conventional IPL devices. Instead of lowering applied fluence, it fractionates a pulse duration of 10 ms into 100 subpulses in which the pulse width of one subpulse is 40 ls. Through these fractionated pulses, PIP IPL can achieve gentle removal of unwanted pigmentation without following aggravation or flare ups of melasma. Two to three passes of PIP IPL were usually required to achieve subtle, transient erythema around the melasma lesion, the optimal response to treat melasma, whereas one pass of IPL was enough to induce it. From this finding, we can also confirm that PIP IPL cannot raise target tissue temperature high enough to break down. PIP IPL might suppress activities in melanosomes and exhaust melanocytes the way laser toning does, so it might be assumed that it is a kind of IPL toning and work on the dermal environment in a softer, gentle way than conventional high fluence IPL treatment. This feature indicates lower risk of aggravation or recurrence of melasma. This study demonstrates that PIP IPL treatment at every 2 weeks can be as effective as IPL/T combination treatment. PIP IPL led to gradual improvement in pigmentation along with treatment sessions; after the fourth treatment, was MI significantly reduced from baseline. IPL/T treatment brought about initial substantial improvement of pigmentation and laser toning appeared to play a role in suppression of flare up of pigmentation at this treatment setting. After IPL exposure, melanosomes in the epidermis are thermally denatured, and these destroyed epidermal melanosomes aggregate and move rapidly up to the skin surface and are shed off with microcrusts. This process takes about 1 to 2 weeks depending on the patient’s age and skin condition. Afterward, it appears that melanosomes are replenished and melanocytes are reactivated to produce melanin pigment in patients who showed
hyperpigmentation after treatment.3,7 IPL works well on epidermal pigmentation, and successive exposure to low-fluence QS Nd:YAG laser can suppress the activity of the survived melanosomes and inactivate melanocytes. Like laser toning, PIP IPL requires multiple treatment sessions to achieve clinical improvement. It does not provoke mechanical shockwaves like other conventional QS lasers,8 and no cases of punctate leukoderma related to IPL or other longer-pulsed laser devices have been reported until now, to the best of our knowledge. Nevertheless, it cannot be said that PIP IPL is free of adverse effects such as punctate leukoderma. In this study, no punctuate leukoderma was noticed during or after treatments on the PIP IPL or IPL/T treated sides, but this potential adverse effect should be kept in mind because we only followed patients for 6 months, and it can be a late phenomenon after treatments. Moreover, punctate leukoderma is often clinically associated with melasma in everyday practice. Thorough examination of patients if they have preexisting punctate leukoderma may be helpful before treatment is initiated. We performed seven treatment sessions every other week in this study based on previous experience,8 but the MI demonstrated that four or five treatment sessions of PIP IPL and IPL/T induced definite clinical improvement. Fewer treatment sessions (4–5) may be enough to achieve clinical improvement under the treatment settings used in this study, and it may have the added benefit of avoiding possible adverse effects. Half of the patients favored PIP IPL over IPL/T because of pain and discomfort. PIP IPL did not cause any pain or discomfort during or after treatments, whereas some patients complained of mild pain or heating sensation during IPL treatment, although it was only transient. Patients were instructed to apply topical 4% hydroquinone cream at night and antioxidant cream
40:2:FEBRUARY 2014
167
MELASMA TREATMENT WITH PIP IPL
with a broad spectrum sunscreen during the day for 6 months after treatments. After 6-month follow-up, MI tended to increase, but no patients experienced significant aggravation or recurrence of melasma on either side. A significant increase in the EI was noticed at follow-up, which continuous use of topical 4% hydroquinone at night may have caused, although the efficacy of both treatments can be well maintained using a simple topical agent for 6 months. This study has the limitation that it was performed on a small number of patients, although all patients completed the study and were followed for 6 months after the last treatment, which indicates that these treatments are not temporary but could provide longterm benefit for up to 6 months. PIP IPL treatment may be a promising therapeutic option for the treatment of melasma without serious adverse effects. The working mechanisms of PIP IPL should be studied further, and clinical study with more patients would be required.
References 1. Moreno Arias GA, Ferrando J. Intense pulsed light for melanocytic lesions. Dermatol Surg 2001;27:397–400. 2. Wang CC, Hui CY, Sue YM, Wong WR, et al. Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg 2004;30:1196–200. 3. Li YH, Chen JZ, Wei HC, Wu Y, et al. Efficacy and safety of intense pulsed light in treatment of melasma in Chinese patients. Dermatol Surg 2008;34:693–700. 4. Zoccali G, Piccolo D, Allegra P, Giuliani M. Melasma treated with intense pulsed light. Aesthetic Plast Surg 2010;34(4):486–93. 5. Zaleski L, Fabi S, Goldman MP. Treatment of melasma and the use of intense pulsed light: a review. J Drugs Dermatol 2012;11:1316–20. 6. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am Acad Dermatol 2011;65:699–714. 7. Yamashita T, Negishi K, Hariya T, Kunizawa N, et al. Intense pulsed light therapy for superficial pigmented lesions evaluated by reflectance-mode confocal microscopy and optical coherence tomography. J Invest Dermatol 2006;126:2281–6. 8. Lee SM, Haw S, Won CH, Chang SE. Split-face comparison of conventional IPL versus novel IPL with pulse in pulse mode on melasma in Asian 2012. Presented at the annual meeting of Korean Dermatologic Association, 2012.
168
DERMATOLOGIC SURGERY
9. Na SY, Cho S, Lee JH. Better clinical results with long term benefits in melasma patients. J Dermatolog Treat 2013;24:112–8. 10. Na SY, Cho S, Lee JH. Intense Pulsed Light and Low-Fluence Q-Switched Nd:YAG Laser Treatment in Melasma Patients. Ann Dermatol 2012;24:267–73. 11. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histolotical studies. J Dermatol 1998;25:587–96. 12. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220:524–7. 13. Anderson RR, Margolis RJ, Watenabe S, Flotte T, et al. Selective photothermolysis of cutaneous pigmentation by Q-switched Nd: YAG laser pulses at 1064, 532, and 355 nm. J Invest Dermatol 1989;93:28–32. 14. Polnikorn N. Treatment of refractory dermal melasma with the MedLite C6 Qswitched Nd:YAG laser: two case reports. J Cosmet Laser Ther 2008;10:167–73. 15. Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Qswitched neodymium-doped yttrium aluminum garnet (1,064 nm) laser for the treatment of facial melasma in Asians. Dermatol Surg 2010;36:76–87. 16. Mun JY, Jeong SY, Kim JH, Han SS, et al. A low fluence Q-switched Nd:YAG laser modifies the 3D structure of melanocyte and ultrastructure of melanosome by subcellularselective photothermolysis. J Electron Microsc 2011;60:11–8. 17. Kim JE, Chang SE, Yeo UC, Haw S, et al. Histopathological study of the treatment of melasma lesions using a low-fluence Q-switched 1064-nm neodymium:yttrium-aluminium-garnet laser. Clin Exp Dermatol 2013;38:167–71. 18. Chan NP, Ho SG, Shek SY, Yeung CK, et al. A case series of facial depigmentation associated with low fluence Q-switched 1,064 nm Nd:YAG laser for skin rejuvenation and melasma. Lasers Surg Med 2010;42:712–9. 19. Kim T, Cho SB, Oh SH. Punctate leucoderma after 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet laser with low-fluence therapy: is it melanocytopenic or melanopenic? Dermatol Surg 2010;36:1790–1. 20. Kim MJ, Kim JS, Cho SB. Punctate leucoderma after melasma treatment using 1064-nm Q-switched Nd:YAG laser with low pulse energy. J Eur Acad Dermatol Venereol 2009;23:960–2. 21. Kim HS, Jung HD, Kim HO, Lee JY, et al. Punctate leukoderma after low fluence 1,064 nm quality-switched neodymium-doped yttrium aluminum garnet laser therapy successfully managed using a 308 nm excimer laser. Dermatol Surg 2010;38:821–3. 22. Falabella R, Escobar CE, Carrascal E, Arroyave JA. Leukoderma punctate. J Am Acad Dermatol 1998;18:485–94.
Address correspondence and reprint requests to: Jong Hee Lee, MD, PhD, Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, or e-mail: [email protected]
AND
BACKGROUND A new type of intense pulsed light IPL with pulse-in-pulse (PIP) mode (multiple fractionated subpulses in one pulse width) has recently been developed. OBJECTIVE
To evaluate the clinical efficacy and safety of PIP IPL in patients with melasma.
MATERIALS AND METHODS Half of each patient’s face was treated with IPL and six treatment sessions with a low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser (IPL/T) every 2 weeks. The other half was treated with PIP IPL. Outcome assessments included photography, modified Melasma Area and Severity Index (MASI) score, and patient satisfaction. The melanin and erythema indices were used for objective evaluation. Patients were followed up for 6 months after the last treatment. RESULTS All patients completed the study successfully. On both treated sides, the melanin index decreased significantly after treatment. The modified MASI score also fell 54.4% on the PIP IPL side and 50.0% on the IPL/T side. No patients reported serious aggravation of melasma for 6 months after the last treatment. Patients favored PIP IPL due to less discomfort during and after treatments. CONCLUSION
PIP IPL may be a safe and promising treatment for melasma.
The authors have indicated no significant interest with commercial supporters.
S
ince the early 2000s, intense pulsed light (IPL), emitting milliseconds of pulse width, has been proven to be effective in most clinical conditions such as pigmentation, telangiectasia, and even wrinkles.1 Previous studies2–5 also reported its efficacy and safety for the treatment of melasma. Melasma is a complex multifactorial disorder with increased pigmentation and increased vascularity associated with pigmentation.6 Therefore, IPL emitting a broad spectrum of light absorbed simultaneously to melanin and hemoglobin was expected to be a better treatment modality for melasma than other conventional pigment lasers, although aggravation and recurrence is not uncommon even after successful treatments using IPL.3,4
The pulse duration of IPL is usually milliseconds, which is much longer than thermal relaxation time of melanosomes. Therefore, IPL cannot selectively target activated melanocytes but can influence all of the structure-containing melanosomes and melanin pigments in the epidermis through photothermal reaction, clearing out pigmentation through transepidermal elimination.7 Unwanted thermal stimulation through IPL with millisecond pulse duration and high fluence might aggravate melasma. Unlike conventional IPL system, pulse-in-pulse IPL (PIP IPL) emits multiple fractionated subpulses within one pulse duration of 10 ms. PIP IPL does not elevate the temperature of target tissue high enough
*Department of Dermatology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea; † Department of Dermatology, Seoul National University Boramae Hospital, Seoul, Korea © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2014;40:162–168 DOI: 10.1111/dsu.12414 162
CHUNG ET AL
to destroy it. It gradually increases skin temperature and might be safer than conventional IPL especially for the treatment of melasma. We conducted this clinical study to evaluate the clinical efficacy and safety of PIP IPL in individuals with melasma. When we applied a lower fluence of IPL, similar to low-fluence quality-switched (QS) neodymium-doped yttrium aluminum garnet (Nd: YAG) laser (laser toning) on individuals with melasma, this treatment modality does not appear to be effective.8 PIP IPL does not induce any microcrusts and can be applied every other week, yet conventional IPL for the treatment of pigmentary disorder induces microcrusts after treatments, and the usual treatment interval with IPL is supposed to be at least 3 to 4 weeks. Therefore, it is hard to compare PIP IPL with conventional IPL treatment. Our previous study on melasma demonstrated that IPL and laser toning combination treatment (IPL/T) every or every other week provided better long-term clinical benefits with fewer adverse effects than laser toning.9,10 Therefore, we designed a split-face study with PIP IPL and IPL/T combination treatment not with low-fluence IPL or conventional IPL treatment.
Materials and Methods Individual with melasma were eligible to enroll this study after voluntary agreement under institutional review board approval. Exclusion criteria were pregnancy, current oral medications that might influence treatment of melasma (e.g., oral contraceptives, thyroid hormones), prior use of topical bleaching or whitening medication on face, and previous laser or light treatment for melasma 6 months before enrollment. One half of the face received one treatment session of conventional IPL (Ellipse, Danish Dermatologic Development, Hørsholm, Denmark) and six successive treatments using a low-fluence QS Nd:YAG laser (Spectra, Lutronic Co., Seoul, Korea) (IPL/T combination treatment). The treatment parameter of IPL was a 2.5-ms double pulse with a 10-ms pulse delay, 9.0 to 9.4 J/cm2 of fluence, and one pass of IPL
exposure delivered on the patient’s face. A lowfluence QS Nd:YAG laser (8-mm collimated spot size, 10-ns pulse width, 1.0 to 1.2 J/cm2 of fluence, multiple passes to achieve mild transient erythema around melasma lesion) was used. The other half of the face was treated using PIP IPL (E-toning, Union Medical Co., Seoul, Korea), emitting a 550- to 800nm wavelength, an applied fluence of 12 to 15 J/cm2, in two tho three passes to obtain mild perilesional erythema response, which disappeared in a few minutes. Treatments were administered to each side of the face at 2-week intervals for a total of seven sessions Patients were followed up for 6 months after the last treatment. From 2 weeks after the last treatment, they were instructed to apply topical hydroquinone 4% at night and topical antioxidant cream with a broad-spectrum sunscreen in the morning during the 6-month-follow up period (Figure 1). At each visit, the melanin (MI) and erythema indices (EI) were measured on the same spot on both sides of the face. Photographs were taken under the same conditions. Two blinded investigators who were not involved in the enrollment and treatment procedure evaluated a modified MASI score at baseline, 2 weeks after the last treatment, and at 6 months of follow-up (Figure 1). The modified MASI score9,11 counted only a confined portion of the malar area (cheek) and was calculated based on the percentage of involved area (A, 0–6: 0 = 0%, 1 = 1–10%, 2 = 10–29%, 3 = 30–49%, 4 = 50–69%, 5 = 70–89%, 6 = 90–100%); darkness of pigment (D, 0–4: 0 = normal skin color without evidence of hyperpigmentation, 1 = slight visible hyperpigmentation, 2 = mild visible hyperpigmentation, 3 = marked hyperpigmentation, 4 = severe hyperpigmentation), and homogenicity or density of hyperpigmentation(number of pigmented lesions per unit facial area (H, 0–4: 0 = minimal, 1 = slight, 2 = mild, 3 = marked, 4 = severe). Modified MASI ¼ ðDarkness of pigment þ HomogenicityÞ Area Patients marked their clinical improvement on a visual analog scale (0–4: 0 = no change or worse to
40:2:FEBRUARY 2014
163
MELASMA TREATMENT WITH PIP IPL
statistically significant. Values were documented as means standard deviations. Result Twelve women (aged 37.4 7.7) with melasma were enrolled in and completed the study.
Figure 1. Treatment protocol. Every 2 weeks, one half of the face received PIP IPL and the other half was treated with IPL and low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser. The treated side was randomly determined on each patient. Photographs were taken and the modified Melasma Area and Severity Index (MASI) score was evaluated. Erythema index (EI) and melanin index (MI) were measured at each visit. During 6 months of follow-up, patients were instructed to use topical 4% hydroquinone at night and antioxidant cream with a broad-spectrum sunscreen during the day. V, Visit, T, treatment (T1 = 2 weeks after the first treatment).
4 = excellent >75% improvement). Any serious adverse effects were documented. Statistical Analysis Using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA), paired t-tests and Wilcoxon rank-sum tests were used to compare the clinical responses between each treatment modality and between before and after treatment. p < .05 was considered
Mean erythema index (EI) before treatment was 225.1 35.1 on the PIP IPL side and 218.0 12.8 on the IPL/T side. It decreased slightly 2 weeks after the last treatment (210.9 22.4 and 211.2 23.9, respectively), although the differences between the PIP IPL and IPL/T sides were not statistically significant. At 6-month follow up, there was a statistically significant increase in the EI on both treated sides from 2 weeks after the last treatment (p < .05) (Figure 2). After all treatments, there was a significant decrease in the melanin index (MI) on both sides compared with baseline (PIP IPL: 201.3 28.7–140.2 21.3, p < .001; IPL/T: 192.9 24.3–131.0 19.3, p < .001). On the PIP IPL side, the MI tended to decrease as treatment sessions continued, and after the fourth treatment, a significant reduction in the MI from baseline was observed (p < .001). On the IPL/T side, there was considerable reduction of MI after the first treatment (p < .05, vs baseline), and a
Figure 2. Erythema index (EI) after treatments. There was no much difference after treatment from baseline, although there was a statistically significant difference in EI 2 weeks after the first treatment on the intense pulsed light low-fluence qualityswitched neodymium-doped yttrium aluminum garnet (IPL/T) side. *p < .05, pulse-in-pulse (PIP) IPL vs IPL/T. +p < .05, T7 vs 6-month follow-up. T, treatment.
164
DERMATOLOGIC SURGERY
CHUNG ET AL
Figure 3. Melanin index (MI) after treatments. On the pulse-in-pulse intense pulsed light (PIP IPL) treated side, MI decreased with treatment sessions, whereas a significant reduction in the MI after IPL treatment and a slight improvement with lowfluence quality-switched neodymium-doped yttrium aluminum garnet laser was observed on the IPL/T side. *p < .05 versus baseline, **p < .001 versus baseline, +p < .05 PIP IPL versus IPL/T. T, treatment.
gradual decrease in the MI was noticed afterward. No statistically significant differences were found after the last treatment and at 6-month follow-up between the treated sides (Figures 3 and 4).
Destruction of unwanted target tissue (e.g. hemoglobin, melanin, water) without causing damage to surroundings was the main focus and interest in the development of laser- and light-based devices.
The modified MASI score showed that PIP IPL and IPL/T treatment worked on melasma (54.4% vs 50.0% reduction of modified MASI score: from baseline to 2 weeks after the seventh treatment, p < .01) (Table 1).
With melasma, high-fluence laser- and light-based treatment for targeting pigment is not useful, because these treatments can aggravate melasma. From this point of view, low-fluence QS Nd:YAG laser treatment (laser toning) has been extensively used, especially in Asian countries, with success.14,15 It applies very low fluence and does not destroy active melanocytes with melanosomes. Repetitive sessions of laser toning exhaust melanocytes and inactivate them so that they no longer produce or transfer melanin pigments.16,17 When Kim and colleagues17 biopsied skin treated with multiple sessions of laser toning, the remaining melanocytes were found to be inactive but the treatment does not stimulate activity of these dormant melanocytes, hence, it can achieve clinical improvement in melasma. Moreover, this treatment does not involve downtime or pain, which makes some patients believe that this treatment is very safe and free of adverse effect, but nanosecond-domain QS laser exposure can provoke explosive mechanical waves even though it is set at a low fluence.18 These characteristics, together with repeated treatments
All patients rated the clinical outcomes as good to excellent on both sides (>50% clinical improvement), although six patients favored PIP IPL because there was no discomfort during and after treatment. The rest reported that they had no preference for one treatment modality over the other. No serious adverse effects on were noticed either side during or after treatment.
Discussion Pulse width and wavelength are important factors for selectivity of photothermolysis in target tissue, and a fluence high enough to increase the temperature of target tissue within a certain time is one decisive factor in destroying it through a photothermal or photomechanical reaction.12,13
40:2:FEBRUARY 2014
165
MELASMA TREATMENT WITH PIP IPL
(A)
(B)
Figure 4. Clinical photograph of the most-responsive patient. She was 40 years old. Pulse-in-pulse intense pulsed light (PIP IPL) (A) and IPL with quality-switched neodymium-doped yttrium aluminum garnet laser (IPL/T). (B) Treated side showed considerable improvement in melasma, and, no serious aggravation of pigmentation was observed at 6-month follow-up.
TABLE 1. Modified Melasma Area and Severity Index Score Before and After Treatment Pulse in Pulse IPL
IPL/T
Mean Standard Deviation Baseline (before treatment) 2 weeks after 7th treatment 6-month follow-up
14.9 3.6
13.8 4.1
6.8 2.3†
6.9 1.8†
8.2 1.9*
8.8 2.1*
IPL/T, intense pulsed light (IPL) with low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser combination treatment. *p < .05, †.01 versus baseline.
over a short period, may be responsible for punctate leukoderma, which is cosmetically unacceptable and may persist if left untreated.18–20 Punctate leukoderma or confetti-like hypopigmentation was first reported in patients who developed multiple
166
DERMATOLOGIC SURGERY
hypo- or depigmented spots after oral psoralen with phototherapy.21 It has also been reported that repetitive treatment sessions of low-fluence QS Nd: YAG laser can induce these hypopigmented lesions.18–21 Chan and colleagues18 emphasized the risk of punctuate leukoderma when laser toning was considered for the treatment of melasma. It too from 6 to 50 treatment sessions for punctate leukoderma to develop (mean 22.1 sessions).18,19 Treatment intervals also varied in previous reports (weekly, every 2 weeks, every 3 weeks, or monthly).18–20 Cumulative frequent sublethal insult to melanocytes might be associated with this adverse effect.21,22 Therefore, efforts to reduce the number of treatment session and to determine optimal treatment intervals and parameters while still achieving satisfactory results should be made in the clinical field. A previous pilot study8 using low-fluence IPL (one-third or a half the fluence of conventional
CHUNG ET AL
uses) was ineffective in the treatment of melasma and sometimes touched off aggravation of melasma. PIP IPL was designed to overcome this limitation of clinical efficacy of low-fluence IPL. PIP IPL emits the same wavelength as other conventional IPL devices. Instead of lowering applied fluence, it fractionates a pulse duration of 10 ms into 100 subpulses in which the pulse width of one subpulse is 40 ls. Through these fractionated pulses, PIP IPL can achieve gentle removal of unwanted pigmentation without following aggravation or flare ups of melasma. Two to three passes of PIP IPL were usually required to achieve subtle, transient erythema around the melasma lesion, the optimal response to treat melasma, whereas one pass of IPL was enough to induce it. From this finding, we can also confirm that PIP IPL cannot raise target tissue temperature high enough to break down. PIP IPL might suppress activities in melanosomes and exhaust melanocytes the way laser toning does, so it might be assumed that it is a kind of IPL toning and work on the dermal environment in a softer, gentle way than conventional high fluence IPL treatment. This feature indicates lower risk of aggravation or recurrence of melasma. This study demonstrates that PIP IPL treatment at every 2 weeks can be as effective as IPL/T combination treatment. PIP IPL led to gradual improvement in pigmentation along with treatment sessions; after the fourth treatment, was MI significantly reduced from baseline. IPL/T treatment brought about initial substantial improvement of pigmentation and laser toning appeared to play a role in suppression of flare up of pigmentation at this treatment setting. After IPL exposure, melanosomes in the epidermis are thermally denatured, and these destroyed epidermal melanosomes aggregate and move rapidly up to the skin surface and are shed off with microcrusts. This process takes about 1 to 2 weeks depending on the patient’s age and skin condition. Afterward, it appears that melanosomes are replenished and melanocytes are reactivated to produce melanin pigment in patients who showed
hyperpigmentation after treatment.3,7 IPL works well on epidermal pigmentation, and successive exposure to low-fluence QS Nd:YAG laser can suppress the activity of the survived melanosomes and inactivate melanocytes. Like laser toning, PIP IPL requires multiple treatment sessions to achieve clinical improvement. It does not provoke mechanical shockwaves like other conventional QS lasers,8 and no cases of punctate leukoderma related to IPL or other longer-pulsed laser devices have been reported until now, to the best of our knowledge. Nevertheless, it cannot be said that PIP IPL is free of adverse effects such as punctate leukoderma. In this study, no punctuate leukoderma was noticed during or after treatments on the PIP IPL or IPL/T treated sides, but this potential adverse effect should be kept in mind because we only followed patients for 6 months, and it can be a late phenomenon after treatments. Moreover, punctate leukoderma is often clinically associated with melasma in everyday practice. Thorough examination of patients if they have preexisting punctate leukoderma may be helpful before treatment is initiated. We performed seven treatment sessions every other week in this study based on previous experience,8 but the MI demonstrated that four or five treatment sessions of PIP IPL and IPL/T induced definite clinical improvement. Fewer treatment sessions (4–5) may be enough to achieve clinical improvement under the treatment settings used in this study, and it may have the added benefit of avoiding possible adverse effects. Half of the patients favored PIP IPL over IPL/T because of pain and discomfort. PIP IPL did not cause any pain or discomfort during or after treatments, whereas some patients complained of mild pain or heating sensation during IPL treatment, although it was only transient. Patients were instructed to apply topical 4% hydroquinone cream at night and antioxidant cream
40:2:FEBRUARY 2014
167
MELASMA TREATMENT WITH PIP IPL
with a broad spectrum sunscreen during the day for 6 months after treatments. After 6-month follow-up, MI tended to increase, but no patients experienced significant aggravation or recurrence of melasma on either side. A significant increase in the EI was noticed at follow-up, which continuous use of topical 4% hydroquinone at night may have caused, although the efficacy of both treatments can be well maintained using a simple topical agent for 6 months. This study has the limitation that it was performed on a small number of patients, although all patients completed the study and were followed for 6 months after the last treatment, which indicates that these treatments are not temporary but could provide longterm benefit for up to 6 months. PIP IPL treatment may be a promising therapeutic option for the treatment of melasma without serious adverse effects. The working mechanisms of PIP IPL should be studied further, and clinical study with more patients would be required.
References 1. Moreno Arias GA, Ferrando J. Intense pulsed light for melanocytic lesions. Dermatol Surg 2001;27:397–400. 2. Wang CC, Hui CY, Sue YM, Wong WR, et al. Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg 2004;30:1196–200. 3. Li YH, Chen JZ, Wei HC, Wu Y, et al. Efficacy and safety of intense pulsed light in treatment of melasma in Chinese patients. Dermatol Surg 2008;34:693–700. 4. Zoccali G, Piccolo D, Allegra P, Giuliani M. Melasma treated with intense pulsed light. Aesthetic Plast Surg 2010;34(4):486–93. 5. Zaleski L, Fabi S, Goldman MP. Treatment of melasma and the use of intense pulsed light: a review. J Drugs Dermatol 2012;11:1316–20. 6. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am Acad Dermatol 2011;65:699–714. 7. Yamashita T, Negishi K, Hariya T, Kunizawa N, et al. Intense pulsed light therapy for superficial pigmented lesions evaluated by reflectance-mode confocal microscopy and optical coherence tomography. J Invest Dermatol 2006;126:2281–6. 8. Lee SM, Haw S, Won CH, Chang SE. Split-face comparison of conventional IPL versus novel IPL with pulse in pulse mode on melasma in Asian 2012. Presented at the annual meeting of Korean Dermatologic Association, 2012.
168
DERMATOLOGIC SURGERY
9. Na SY, Cho S, Lee JH. Better clinical results with long term benefits in melasma patients. J Dermatolog Treat 2013;24:112–8. 10. Na SY, Cho S, Lee JH. Intense Pulsed Light and Low-Fluence Q-Switched Nd:YAG Laser Treatment in Melasma Patients. Ann Dermatol 2012;24:267–73. 11. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histolotical studies. J Dermatol 1998;25:587–96. 12. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220:524–7. 13. Anderson RR, Margolis RJ, Watenabe S, Flotte T, et al. Selective photothermolysis of cutaneous pigmentation by Q-switched Nd: YAG laser pulses at 1064, 532, and 355 nm. J Invest Dermatol 1989;93:28–32. 14. Polnikorn N. Treatment of refractory dermal melasma with the MedLite C6 Qswitched Nd:YAG laser: two case reports. J Cosmet Laser Ther 2008;10:167–73. 15. Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Qswitched neodymium-doped yttrium aluminum garnet (1,064 nm) laser for the treatment of facial melasma in Asians. Dermatol Surg 2010;36:76–87. 16. Mun JY, Jeong SY, Kim JH, Han SS, et al. A low fluence Q-switched Nd:YAG laser modifies the 3D structure of melanocyte and ultrastructure of melanosome by subcellularselective photothermolysis. J Electron Microsc 2011;60:11–8. 17. Kim JE, Chang SE, Yeo UC, Haw S, et al. Histopathological study of the treatment of melasma lesions using a low-fluence Q-switched 1064-nm neodymium:yttrium-aluminium-garnet laser. Clin Exp Dermatol 2013;38:167–71. 18. Chan NP, Ho SG, Shek SY, Yeung CK, et al. A case series of facial depigmentation associated with low fluence Q-switched 1,064 nm Nd:YAG laser for skin rejuvenation and melasma. Lasers Surg Med 2010;42:712–9. 19. Kim T, Cho SB, Oh SH. Punctate leucoderma after 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet laser with low-fluence therapy: is it melanocytopenic or melanopenic? Dermatol Surg 2010;36:1790–1. 20. Kim MJ, Kim JS, Cho SB. Punctate leucoderma after melasma treatment using 1064-nm Q-switched Nd:YAG laser with low pulse energy. J Eur Acad Dermatol Venereol 2009;23:960–2. 21. Kim HS, Jung HD, Kim HO, Lee JY, et al. Punctate leukoderma after low fluence 1,064 nm quality-switched neodymium-doped yttrium aluminum garnet laser therapy successfully managed using a 308 nm excimer laser. Dermatol Surg 2010;38:821–3. 22. Falabella R, Escobar CE, Carrascal E, Arroyave JA. Leukoderma punctate. J Am Acad Dermatol 1998;18:485–94.
Address correspondence and reprint requests to: Jong Hee Lee, MD, PhD, Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, or e-mail: [email protected]
