ORIGINAL ARTICLE

Intense Pulsed Light for the Treatment of Refractory Melasma in Asian Persons
C HIA -C HEN WANG , MD, n C HUNG -Y EE H UI , MD, w Y UH -M OU S UE , MD, z W EN -R OU W ONG , MD, w AND H ONG -S HANG H ONG , MD, P H D w
n

Department of Dermatology, Cardinal Tien Hospital, Hsintien, Taipei, Taiwan; Graduate Institute of Clinical Sciences and wDepartment of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan; and zDepartment of Internal Medicine, Taipei Medical University, Taipei, Taiwan

BACKGROUND. Patients with dermal or mixed-type melasmas are often refractory to various treatments. Intense pulsed light has been used to treat melanocytic lesions with promising results. OBJECTIVE. The purpose of this study was to clarify the effectiveness of intense pulsed light for refractory melasma in Asian persons. METHODS. Seventeen patients were treated with intense pulsed light, during four sessions at 4-week intervals. The patients were also given 4% hydroquinone cream and broad-spectrum sunscreens to prevent and treat postinammatory hyperpigmentation. Sixteen patients in the control group were treated with hydroquinone cream and sunscreens. The treatment efcacy was evaluated using reectance spectrophotometer and patient satisfaction questionnaire.

RESULTS. Patients in the intense pulsed light group achieved an average of 39.8% improvement in relative melanin index, compared to 11.6% improvement in the control group (po0.05) at Week 16. Six (35%) patients in the intense pulsed light group had more than 50% improvement, compared to two (14%) patients in the control group. Two patients in the intense pulsed light group, however, experienced transient postinammatory hyperpigmentation, and partial repigmentation was noted 24 weeks after the last treatment session. CONCLUSION. Intense pulsed light is a safe and effective treatment for refractory melasma in Asian persons, with minimal side effects. Further treatment sessions are required for maintenance therapy.

CHIA-CHEN WANG, MD, CHUNG-YEE HUI, MD, YUH-MOU SUE, MD, WEN-ROU WONG, MD, AND HONG-SHANG HONG, MD, PHD HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.

MELASMA IS an acquired masklike facial hyperpigmentation and is commonly observed in Asian middleaged women. Genetics, ultraviolet radiation, pregnancy, hormone therapies, and phototoxic drugs have been implicated in the pathogenesis of melasma.1,2 In addition to routine usage of broad-spectrum sunscreens, bleaching agents, such as hydroquinone, tretinoin,24 and chemical peels,5,6 have shown satisfactory results for the patients with epidermal melasma. Nevertheless, patients with dermal or mixed-type melasma are therapeutically challenging. In the past, attempts to treat melasma with lasers that targeted melanin, such as Q-switched ruby laser and Q-switched Nd:YAG laser, yielded disappointing results.7,8 Meanwhile, Er:YAG laser resurfacing, dermabrasion, and a combined ultrapulse CO2 laser with Q-switched alexandrite laser have been reported to treat refractory melasma successfully. Side effects, such as postinammatory hyperpigmentation and hypertroAddress correspondence and reprint requests to: Wen-Rou Wong, MD, Department of Dermatology, Chang Gung Memorial Hospital, 199 Tung-Hwa North Road, Taipei, Taiwan, or e-mail: wongw@adm.cgmh. org.tw.

phic scars, may develop, especially in patients with darker skin.911 Intense pulsed light is a noncoherent, broad-spectrum light, ranging from 500 to 1200 nm.The pulse length, mode, delay between pulses, and uence can all be varied. This exibility in choice of parameters allows performance of different treatments, such as photocoagulation of vascular lesions,12 photoepilation,13 photorejuvenation,14 improvement of striae distensae,15 and removal of melanocytic lesions.1618 For pigment disorders, intense pulsed light is associated with fewer photothermal injuries and fewer side effects, such as postinammatory hyperpigmentation compared with Q-switched lasers.17,18 We conducted a prospective, case-control study among Asian women to clarify whether intense pulsed light is a safe and effective treatment for melasma that is refractory to topical bleaching agents.

Materials and Methods

Thirty-three Taiwanese women with melasma unresponsive to hydroquinone cream for at least 3 months were enrolled in the study. Some patients had also used

r 2004 by the American Society for Dermatologic Surgery, Inc.  Published by Blackwell Publishing, Inc. ISSN: 1076-0512/04/$15.00/0  Dermatol Surg 2004;30:11961200

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topical tretinoin, azelaic acid, l-ascorbic acid, and/or glycolic acid without apparent clinical improvement. Patients with pregnancy, lactation, oral pills, hormone replacement therapy, and major outdoor activities were excluded. One month before enrolling in the study, the patients stopped using bleaching agents, but continued to use sunscreen. An ultraviolet camera was used to determine the type of melasma. Histories regarding age of onset and duration of melasma, Fitzpatrick skin types, and risk factors of pregnancy or oral contraceptives were taken. The study was approved by the Medical Ethics and Human Research Committee of Chang Gung Memorial Hospital. Written informed consent was obtained from each patient before enrollment. Patients were randomly divided into two groups. Seventeen patients were treated with a light emission apparatus of the intense pulsed light family (Vasculight, ESC/Sharplan, Yokneam, Israel), during four sessions at 4-week intervals. A 570-nm cutoff lter was used in the rst session, and 590 to 615 lters were used during subsequent sessions in an attempt to treat residual deeper pigment. During all sessions, patients were treated with uences of 26 to 33 J/cm2; double mode; and pulse lengths of 3 to 4 and 4 to 5 ms, respectively, with a delay of 30 to 35 ms between pulses. During the procedure, chilled, colorless gel was used to protect the epidermis and to aid in delivering the light uniformly onto the skin surface. Mild perilesional erythema and graying of skin lesions indicated the endpoint of each treatment. No local anesthesia was required. Four percent hydroquinone cream and broad-spectrum sunscreens were used throughout the study to prevent possible postinammatory hyperpigmentation. Any other bleaching agents were prohibited. Sixteen patients were in the control group, receiving only hydroquinone cream and broad-spectrum sunscreens. Clinical and instrumental evaluations for the improvement in pigmentation were conducted every 4 weeks for 16 weeks in both groups. In the intense pulsed light group, patients were also followed up at Week 36 to assess the persistence of improvement. Digital photography documentation under the same condition (light source, room, and camera) was taken at baseline and every visit. A reectance spectrophotometer (Mexameter 18, Courage1Khazaka Electronic GmbH, Koln, Germany) was used to quantify changes in melanin level.19 Absolute melanin index of melasma was obtained by taking the mean of ve measurements from a xed spot within the area of pigmentation at each visit. The spot was recorded as the distance in centimeters either from the upper ear pole on line A1, A2, A3, or A4 or from the earlobe on line B1, B2, B3, or B4 on the left or right side of the

Figure 1. The definitions of the lines used to locate the xed spot for the measurement of melanin index. Line A1, from upper ear pole to eyebrow; line A2, from upper ear pole to lateral canthus; line A3, from upper ear pole to nose angle; line A4, from upper ear pole to mouth angle. Line B1, from earlobe to eyebrow; line B2, from earlobe to lateral canthus; line B3, from earlobe to nose angle; line B4, from earlobe to mouth angle.

face, depending on the location of melasma (Figure 1). Relative melanin index was calculated from the difference of the absolute melanin index between melasma and normal skin. Relative melanin index (RMI) 5 Absolute melanin index of melasma Absolute melanin index of normal skin Improvement rate RMIpretreatment RMIposttreatment = RMIpretreatment 100%: An objective assessment of the improvement rate was documented as follows: excellent, 76% to 100%; good, 51% to 75%; fair, 26% to 50%; poor, 0 to 25% or darker. In addition, all patients completed a questionnaire using a grading system to assess their subjective satisfaction with the treatment as follows: very satised, satised, slightly satised, and unsatised. In the intense pulsed light group, the degree of pain, erythema, and blistering was assessed immediately after each treatment as mild, moderate, or severe. Statistical analysis was performed by using t test, paired t test, and simple linear regression. A p value of less than 0.05 dened statistical significance. All values were expressed as means standard deviation.

Results
Thirty-one patients completed the study at Week 16. Two patients in the control group dropped out at Week 8 because of poor compliance. One patient in the intense pulsed light group failed to complete the Week 36 follow-up because she moved away. All patients were women with skin phototypes III or IV and were determined as mixed melasma by ultraviolet camera. There were no significant differences in any variables such as age, duration of melasma, skin

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Table 1. Characteristics of Both Groups of the Melasma Patients

Group General Data Intense Pulsed Light Control 47.3 6.7 10.7 7.0 III, 3; IV, 13 67.2 46.5 (n 5 16) 59.4 44.8 (n 5 14)w Not done

Table 2. Improvement Rate at Week 16 Assessed by Reectance Spectrophotometer

Group Improvement Rate Assessment 76%100% (excellent) 51%75% (good) 26%50% (fair) 0%25% or darker (poor) Intense Pulsed Light (n 5 17) 2 4 6 5 (12%) (23%) (35%) (30%) Control (n 5 14) 0 2 1 11 (0%) (14%) (7%) (79%)

Age (years) 45.0 4.9 Duration (years) 10.1 5.8 Skin phototypes III, 3; IV, 14 Relative melanin index score Baseline 66.1 24.7 (n 5 17) 16 weeks 39.8 22.6 (n 5 17)nw 36 weeks 50.1 18.7 (n 5 16)z
n

Statistically significant improvement within the group (paired t test), po0.005. Statistically significant difference between the intense pulsed light and control group (t test), po0.05. z Statistically significant improvement within the group (paired t test), po0.05.
w

phototypes, and baseline relative melanin index scores between the two groups (p40.05) (Table 1). In the intense pulsed light group, the mean relative melanin index score decreased from 66.1 24.7 at baseline to 49.7 18.3 after only one session of intense pulsed light treatment at Week 4, representing a 24.8% change in pigmentation, which is statistically significant (po0.05). Patients had further improvement in pigmentation with subsequent treatment sessions. After four sessions of intense pulsed light treatment, the mean relative melanin index score decreased to 39.8 22.6 at Week 16, representing a 39.8% improvement compared to that of the baseline (po0.005). The excellent/good (51%100%) level in improvement was achieved for 35% of the patients. The treatment efcacy did not correlate with any variables, such as age, duration of melasma, or skin phototypes. In the control group, the mean relative melanin index score decreased from 67.2 46.5 at baseline to 59.4 44.8 at Week 16, representing a 11.6% change in pigment intensity (p40.05). Only 14% of the patients achieved the good (51%75%) level at the end of treatment. The difference in improvement rate between the two groups was also found to be significant (po0.05), with a better response in the intense pulsed light group. At Week 36 (24 weeks after the last treatment session), the mean relative melanin index score for the intense pulsed light group returned to 50.1 18.7, representing a percentage change of 24.2% compared to baseline (po0.05). These results suggested that additional treatments were necessary to maintain the results (Tables 1 and 2; Figures 24). In the intense pulsed light group, 23.5% of the patients assessed their improvement as satised, 53% as slightly satised, and 23.5% as unsatised. In the control group, 64% of the patients assessed their improvement as slightly satised and 36% as unsatised.

Figure 2. Mean relative melanin index (RMI) score for the intense pulsed light and control groups at different posttreatment intervals.

Figure 3. Standard digital photography at baseline (A) and Week 16 (B) of a 41-year-old woman in the intense pulsed light group.

Few side effects were associated with intense pulsed light treatment. Erythema and pain during and after treatment were mild and disappeared within 1 day. In most patients, microcrust formation was noted, but these disappeared after 1 to 2 weeks. Patients could use makeup immediately after treatment and did not need any wound care. No wound infection or scarring formation was noted. Two patients, however, experienced transient postinammatory hyperpigmentation possibly because of higher uence energy. The hyperpigmentation gradually resolved using hydroquinone

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Figure 4. Standard digital photography at baseline (A) and Week 16 (B) of a 42-year-old woman in the intense pulsed light group.

cream and further intense pulsed light treatment. In addition, most patients skin appeared to be brighter after intense pulsed light treatment. Two patients in the intense pulsed light group who had freckles and lentigines intermingled with melasma also experienced excellent improvement.

Discussion
Intense pulsed light is a noncoherent, broad-spectrum light, ranging from 500 to 1200 nm.Variation of pulse length, mode, delay between pulses, and uence can be chosen. Intense pulsed light has been used to treat melanocytic lesions with promising results. Regarding wavelengths, intense pulsed light sources can be used with lower cutoff lters to treat supercial pigmentation, such as freckles, and higher cutoff lters for deeper lesions, such as nevus spilus.1618 In this study, we demonstrated that intense pulsed light is a safe and effective treatment for refractory melasma in Asian persons. Successful treatment of melasma by intense pulsed light has been reported in studies with small sample in Hispanic and Asian persons. Moreno Arias and Ferrando16 treated two patients with epidermal melasma using a 590-nm lter, a uence energy of 34 J/cm2, a pulse width of 3.8 ms, double mode, and a delay of 20 ms. A clearance rate of 76% to 100% was achieved after two sessions of treatment. Three patients with mixed melasma were treated using a 615-nm lter, a uence energy of 38 J/cm2, a pulse width of 4.5 ms, double mode, and a delay of 20 ms. Nevertheless, the skin lesions showed less than 25% clearance with postinammatory hyperpigmentation after four sessions of treatment. Negishi et al.20 treated 97 patients with photoaging, including 4 cases with melasma, using 550- to 570-nm lters, a uence energy of 28 to 32 J/cm2, a pulse width of 2.5 to 4 and 4 to 5 ms,

double mode, and a delay of 20 to 40 ms, three to six sessions at 2- to 3-week intervals. Topical bleaching agents were used after the third treatment session. Skin texture as well as pigmentation improved. The authors did not mention, however, the type of melasma, and there was no control group in the study. In our experience, patients with epidermal melasma usually had better results than those with mixed-type melasma. Most epidermal melasmas respond well to topical bleaching agents,24 a simpler and less expensive treatment. Chemical peels also show more benets for epidermal melasma than mixed type.5,6 Patients with mixed melasma are more refractory to traditional therapies and need alternative methods. In this study, all enrolled patients had mixed melasma and were refractory to many kinds of bleaching agents, including hydroquinone cream. We used intense pulsed light with low uence and long delay between pulses as treatment modality. Sun protection was advised and 4% hydroquinone cream was applied throughout the study to prevent postinammatory hyperpigmentation rather than treat melasma per se. An improvement rate of 39.8% was achieved after four sessions of treatment and was significantly better than the 11.6% improvement rate of the control group (po0.05). Twenty-four weeks after the last session, partial repigmentation was noted despite the use of hydroquinone cream and broad-spectrum sunscreens, indicating further treatment sessions are required for maintenance therapy. Reectance spectrophotometer is quite useful for estimating accurately the intensity of pigmentation. Both absolute melanin index and relative melanin index had been used in some studies.11,19 Absolute melanin index of normal skin in people with darker skin type may be higher than which of melasma in people with lighter skin type and hence cannot reect the genuine severity of melasma. We used relative melanin index because it indicates the difference in pigmentation between melasma and normal skin and truly reveals the severity of melasma. We did not conduct a side-by-side comparison, a method to avoid individual bias of treatment response, for reasons of ethics and esthetics. Most of our patients refused to receive splitface treatment. The unevenness of pigmentation between two sides of the face lasted up to 36 weeks would be extremely embarrassing and annoying. Er:YAG laser resurfacing, dermabrasion, and combined ultrapulse CO2 laser with Q-switched alexandrite laser were also reported to show benets for refractory melasma.911 Nevertheless, these methods are more invasive and wound care is necessary. In addition, prolonged erythema, hyperpigmentation, hypopigmentation, infection, and hypertrophic scarring are potential side effects. Asian skin is prone to hyperpigmentation after laser therapy.21 Intense pulsed light

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therapy using the variables used in this study had minimal adverse effects and is safe to treat pigmented lesions in Asian persons. Although no correlation between the skin phototypes and treatment efcacy was noted, both patients with transient postinammatory hyperpigmentation had darker skin color. For darker skin, a lower uence should be used with caution. Other supercial pigmentary anomalies, such as freckles or lentigines, intermingled with melasma is common in Asian women. Prolonged postinammatory hyperpigmentation, especially in Asian women with melasma, decreases the efcacy of laser treatment. intense pulsed light can improve the irregularity of dyschromia without the possibility of postinammatory hyperpigmentation. Two patients in our intense pulsed light group had superimposed pigmentary lesions in addition to melasma and both had excellent improvement after the treatment. Furthermore, most patients in our intense pulsed light group also had additional benets of brighter skin color, smoother skin texture, and uniform pigmentation. These ndings supported the safety of photorejuvenation using intense pulsed light, even in patients with melasma. Based on videomicroscopic and histopathologic ndings, Kawada et al.22 proposed that the light energy of intense pulsed light induced the injury of melanin-containing epidermal cells via photothermal effects. Clinical improvement of pigmented lesions was seen when microcrusts were formed and dropped off with melanin pigment. The effects of intense pulsed light for melasma may be associated with a similar mechanism, including the destruction of dermal melanin. More than half of our patients experienced microcrusts, which appeared 2 to 3 days after irradiation and disappeared within 1 to 2 weeks. The crusts formed on pigmented areas, not on normal skin, indicating that intense pulsed light was specific for melanin under our conditions. Intense pulsed light may achieve selective photothermolysis of pigmented lesions even though the pulse duration is longer than the thermal relaxation time of melanosome (70250 ns). The disappearance of the crusts led to the clinical improvement of the melasma. The pigments gradually reappeared, however, possibly because deeper pigment remained or repigmentation was induced by persistent trigger factors.

maintenance therapy. Additional studies are needed to establish the optimal treatment parameters and to determine the biologic mechanisms of the treatment.

References
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Conclusion
Intense pulsed light is a safe and effective treatment for refractory melasma in Asian persons, with minimal side effects under our conditions. Partial repigmentation is noted in the long-term follow-up, indicating that additional treatment sessions are required for