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Treatment of acquired bilateral nevus of Ota-like macules (Hori's nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser
LASER
SURGERY
Treatment of acquired bilateral nevus of Ota–like macules (Hori’s nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser Woraphong Manuskiatti, MD,a Apichati Sivayathorn, MD,a Panadda Leelaudomlipi, MD,a and Richard E. Fitzpatrick, MDb Bangkok, Thailand, and Encinitas, California Background: Acquired bilateral nevus of Ota-like macules (Hori’s nevus) is a dermal pigmented lesion commonly seen in middle-aged women of Asian descent. The Q-switched ruby laser (QSRL) has been used successfully to treat a variety of benign pigmented lesions. Multiple, sequential treatments are typically required for complete clearance of the dermal pigmented dermatoses. Objective: The purpose of this study was to determine the efficacy of QSRL in the treatment of Hori’s nevus and the beneficial effect of epidermal ablation using the scanned carbon dioxide (CO2) laser before QSRL. Methods: A total of 13 women from Thailand with Hori’s nevus were randomly treated with the scanned CO2 laser followed by QSRL on one side of their face, and QSRL alone on the other side. The same fluence of QSRL was used on both sides in individual patients. The treatment response was objectively evaluated by measuring the melanin index using a Mexameter (Courage & Khazaka Electronic GmbH, Ko¨ln, Germany), and subjectively assessed by the patients before treatment and 3 and 16 months after treatment. Adverse sequelae of the treatment and the patients’ tolerance were also evaluated at the same follow-up visit. Results: The 3- and 16-month posttreatment melanin index was significantly decreased compared with that of pretreatment on both treated sites and this corresponded to the patients’ subjective evaluations. The response rate, defined as “the percentage of reduction in melanin index,” was significantly higher on the sides treated with scanned CO2 laser followed by QSRL, compared with the sides irradiated with QSRL alone at both follow-up visits. At the 3-month follow-up, the most common adverse effect was hypopigmentation, found in 15% (2 of 13) of the patients on the sites treated with QSRL alone, and on the sites treated with scanned CO2 laser followed by QSRL (8%, 1/13). Erythema was observed in 15% (2/13) of the patients only on the sites that received combination treatment. However, no adverse sequelae were observed at the 16-month posttreatment follow-up. Conclusion: Epidermal ablation with scanned CO2 laser before the use of the pigment-specific laser may be an effective technique for increasing therapeutic efficacy in the treatment of dermal pigmented dermatoses. (J Am Acad Dermatol 2003;48:584-91.)
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cquired bilateral nevus of Ota–like macules (Hori’s nevus), a circumscribed dermal melanocytosis of the face, is commonly seen in middle-aged women of Asian descent.1,2 Clinically
From the Department of Dermatology, Siriraj Hospital, Mahidol University,a and Dermatology Associates/Cosmetic Laser Associates of San Diego County Inc.b Funding sources: None. Conflict of interest: None identified. Reprint requests: Woraphong Manuskiatti, MD, Department of Dermatology, Siriraj Hospital, 2 Pran-nok Rd, Bangkok 10700, Thailand. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.193
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Hori’s nevus is very similar to the congenital bilateral nevus of Ota (type IV nevus of Ota) characterized by blue-brown macules occurring bilaterally on the forehead, temples, eyelids, malar areas, nasal alae, and nasal root.3 Unlike the nevus of Ota, these pigmented lesions usually appear in the fourth or fifth decades of life in women (only rarely in men), and are not observed in the conjunctiva and mucous membranes of the mouth and nose. Histologically, in Hori’s nevus, actively melanin-synthesizing dermal melanocytes are dispersed in the papillary and middle portions of the dermis, whereas in the nevus of Ota, these melanin-laden cells are found diffusely throughout the entire dermis.4,5
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Melanin-targeting lasers have proven effective in the treatment of nevus of Ota.6-9 Although Hori’s nevus is a dermal melanocytic hyperpigmentation like the nevus of Ota, there have been very few reports concerning the treatment of Hori’s nevus. Dermabrasion,10 and laser irradiation using Q-switched (QS) ruby laser (QSRL)11 and QS Nd: YAG laser12,13 have been reported to be of benefit in this condition. Though dermabrasion has shown favorable results, the major disadvantages of this technique include a risk of bloodborne contamination and the uncontrollable depth of ablation. Although promising results in the treatment of Hori’s nevus with QSRL and QS Nd:YAG laser have been reported, the treatment responses have been noted to be less effective than that of the nevus of Ota13 and multiple sequential treatments are also required to achieve the desired improvement. This study was designed to objectively determine (1) the efficacy of QSRL in the treatment of Hori’s nevus and (2) whether epidermal ablation before QSRL provided a beneficial effect on treatment response.
PATIENTS AND METHODS Patients A total of 13 women from Thailand with a clinical diagnosis of Hori’s nevus were enrolled in the study. The age of the patients ranged from 22 to 55 years (mean age, 40.9 years). Skin phototypes III (5), IV (7), and V (1) were represented. Written informed consent was obtained from all patients after the investigational nature of the procedure had been explained fully. All 13 patients were followed up at 1 week, and 1, 3, and 4 months postoperatively. Of the 13 patients, 10 (77%) returned for office evaluations at an average follow-up period of 16 months postoperatively (range, 9-30 months). Lasers The QSRL (Lambda Photometrics, Hertfordshire, England) was a system delivered at 694 nm with a pulse width of 25 nsec using a 3-mm spot diameter. The scanned carbon dioxide (CO2) laser was a 20W continuous-wave CO2 laser (Sharplan Laser, Allendale, NJ) coupled to the optomechanic flash scanner (SilkTouch) with a 3-mm scan size. The scanner produced a spiral beam, the dwell time of which was approximately 1 millisecond. Laser procedure Preoperatively, the face was cleaned with chlorhexidine and wiped with isopropyl alcohol. Treatment areas were anesthetized with 1% lidocaine hydrochloride with 1:100,000 epinephrine intradermally. The patients were randomly treated with QSRL alone on one side of the lesion, and one pass
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of a scanned CO2 laser followed by another pass with the QSRL (CO2 ⫹ QSRL) on the other side. On the side treated with QSRL alone, the pulsed laser at a wavelength of 694 nm was delivered through a 3-mm spot diameter hand piece using an energy density (fluence) ranging from 4.5 to 6.5 J/cm2 (mean, 5.2 J/cm2) with 10% to 20% overlap. The fluence used on each patient was determined by the observation of a minimal “threshold” radiant exposure response that caused an immediate whitening of the nevus. On the side treated with CO2⫹QSRL, one pass of the scanned CO2 laser was used to ablate the epidermis, followed by another pass with the QSRL. The CO2 coupled to the flash scanner was set at a power of 7 W, 0.2-second pulse duration with a 3-mm scan size. Overlap was avoided. After one pass of the CO2 laser, the epidermis was wiped with saline-soaked gauze for debris removal, and immediately patted with dry gauze. Then the QSRL was delivered to the dermal pigmented lesions with the same fluence used on the side treated with the QSRL alone (Figs 1 and 2). During the treatment sessions, eye protection was provided to all patients and the clinical staff. The postoperative wounds were dressed with petroleum jelly. The patients were instructed to cleanse the areas gently at least twice daily. This consisted of debridement with vinegar soaks (1 tablespoon vinegar per cup of water) after which petrolatum was reapplied. All patients received Augmentin (SmithKline Beecham Pharmaceuticals, Brentford, England) (375 mg 3 times daily) orally for 7 days beginning the day before treatment. The patients were advised to avoid excessive sun exposure and to wear a broad-spectrum sunscreen with a sun protection factor of 15 or greater for at least 3 months postoperatively. No other topical agents were used before or after the procedure. Clinical evaluation Objective assessment. A Mexameter MX 16 (Courage & Khazaka Electronic GmbH, Ko¨ ln, Germany) was used to objectively quantify the degree of skin pigmentation measured as a melanin index.14 The melanin index was assessed preoperatively, and 3 and 16 months after the treatment in all patients on both sides of the lesions. An average value of 3 measurements on 3 representative points on each side of the lesion mapped with a permanent marker on a flexible, transparent sheet was obtained. The response rate, defined as “the percentage of melanin index” obtained at 3 and 16 months postoperatively compared with a baseline melanin index was determined for each method of treatment. Paired t tests were performed to determine the significance of the
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Fig 1. Representative patient with Hori’s nevus. Right side was treated with Q-switched ruby laser (QSRL) alone and left side was treated with carbon-dioxide laser and QSRL. Before (A and D), and 4 (B and E) and 24 (C and F) months after treatment.
Fig 2. Same patient as in Fig 1 demonstrating just after epidermal ablation with carbon-dioxide laser (A) and immediately after Q-switched ruby laser irradiation on dermal pigmented lesions (B).
improvements compared with a baseline for each treatment modality and to compare the percentage of clearing between the 2 treatment techniques. A P value less than or equal to .05 was considered statistically significant.
Subjective assessment. At month 16, 10 of the 13 patients (77%) who were available for the final evaluation were asked to grade the improvement of each treated side separately. The improvement was graded using a quartile system as poor (⬍25% clear-
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Table I. Summary of mean melanin index Treatment technique
Pre-QSRL 3-mo post-QSRL Pre-QSRL 16-mo post-QSRL Pre-CO2 ⫹ QSRL Post-CO2 ⫹ QSRL Pre-CO2 ⫹ QSRL 16-mo post-CO2 ⫹ QSRL Month 3 RR of QSRL RR of CO2 ⫹ QSRL Month 16 RR of QSRL RR of CO2 ⫹ QSRL
No. of patients
Mean (SD)
Mean difference (SD)
13 13 10 10 13 13 10 10
545.9 (21.57) 531.4 (23.91) 541.4 (19.52) 527.6 (17.56) 551.2 (28.38) 526.9 (19.65) 546.8 (26.10) 522.96 (19.36)
14.51 (22.20) 13.87 (18.65) 24.36 (27.22) 23.86 (26.62)
13 13
2.6% (3.91) 4.3% (4.55)
10 10
2.5% (3.28) 4.2% (4.47)
95% CI
P value
(1.09)-(27.92)
.036
(.53)-(27.21)
.043
(7.91)-(40.81)
.007
(4.82)-(42.90)
.02
⫺1.67 (1.94)
(⫺2.84)-(⫺0.50)
.009
⫺1.72 (2.39)
(⫺3.43)-(⫺1.15)
.05
CI, Confidence interval; CO2, carbon-dioxide laser; QSRL, Q-switched ruby laser; RR, response rate. P ⱕ .05 was statistically significant.
ance), fair (25%-50% clearance), good (50%-75% clearance), and excellent (75%-100% clearance). In addition, side effects from treatment were followed up by a dermatologist, who was familiar with laser operation but not involved with the treatment, at 1, 3, and 16 months after the treatment. Patients experiencing any side effects were followed up at monthly intervals until that adverse effect disappeared. These included the presence or absence of hypopigmentation, hyperpigmentation, erythema, and textural alteration. Histologic examination and ultrastructural evaluation. Preoperatively, 3-mm punch biopsy specimens were taken from 11 of the 13 patients and a further such specimen obtained from 1 patient 3 months after the treatment. These specimens were routinely processed for light and electron microscopy. Paraffin sections were stained with hematoxylin and eosin and Fontana-Masson. Sections for transmission electron microscopy were routinely processed, and stained with uranyl acetate and lead citrate.
RESULTS Objective clinical evaluation There was no statistically significant difference in the baseline melanin index of each side of the lesion in any individual patient (P ⫽ .214). Table I summarizes the mean melanin index of each treatment modality at pretreatment, and 3 and 16 months postoperatively. At 3 months, a significant reduction in the mean melanin index compared with the baseline melanin index was demonstrated on the side treated with QSRL alone (P ⫽ .036), and the side treated with CO2 ⫹ QSRL (P ⫽ .007). The significant reduc-
tion in the mean melanin index compared with that of the baseline persisted through month 16 on both treated sides (P ⫽ .043 and P ⫽ .02 on QSRL and CO2 ⫹ QSRL sides, respectively). For both treatment techniques, there was no significant difference in the mean melanin index at month 3 compared with that at month 16. However, a trend toward greater pigment lightening with a longer follow-up period was observed. At month 3, the response rate on the side treated with CO2⫹QSRL was significantly higher than the side treated with QSRL alone (P ⫽ .009). This significantly greater response rate on the CO2 ⫹ QSRL side compared with the QSRL side remained at the month-16 follow-up visit. Figs 1 and 2 demonstrate the clinical result of a representative patient side by side preoperatively, immediately after each treatment technique, at month 4 and 24. Patient self-assessment Of the 10 patients assessed at month 16, patient evaluation of the sites treated with QSRL alone showed that almost half the patients (40%, 4/10) graded the improvement as fair (25%-50% clearance), whereas the other half of the patients (6/10) reported the improvement as poor (⬍25% clearance). For patient evaluation of the sites treated with CO2 ⫹ QSRL, a majority of patients (70%, 7/10) judged the improvement as good (50%-75% clearance). Clearance grades of poor and fair were reported in 10% (1/10) and 20% (2/10) of the patients, respectively. More than half of the patients (60%, 6/10) noted further improvement of both treated sides at the longer follow-up visit.
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Fig 3. Adverse effects according to treatment techniques. CO2⫹QSRL, Scanned carbon dioxide laser followed by Q-switched ruby laser (QSRL).
Healing time and adverse sequelae There was no significant difference in healing time between the 2 treatment techniques. Complete re-epithelialization typically occurred by 7 to 10 days after the treatment. Adverse effects after the treatment are illustrated in Fig 3. The incidence of pigmentary changes on the sides treated with QSRL alone was comparable with that of CO2 ⫹ QSRL-treated sides at week 4 (54% [7/13] and 46% [6/13], respectively). These pigmentary alterations included hypopigmentation and hyperpigmentation, and all were substantially improved by month 3. All patients experiencing pigmentary alterations at month 3 showed complete clearing 1 month later (4 months postoperatively). At month 1, erythema was noted in all patients (100%) on the sides treated with CO2 ⫹ QSRL, whereas an incidence of 15% (2/13) was observed on the side treated with QSRL alone. However, by week 12 the erythema had completely disappeared on the side treated with QSRL alone and was found in only 15% (2 of 13) of the patients on the side treated with CO2 ⫹ QSRL. No textural alteration was
demonstrated in any of the treated areas in any patient. At month 16, of the 10 patients examined, none showed pigmentary changes on either of the sides treated. No cases of persistent erythema and textural change were observed in this group of patients. Histologic and ultrastructural findings Biopsy specimens taken from the pigmented lesions preoperatively revealed an overall thinning of the epidermis, along with sporadic dyskeratotic keratinocytes. All specimens demonstrated spindleshaped pigment-laden cells scattering diffusely along the collagen bundles of the dermis, particularly in the papillary dermis. These cells were positive for the Fontana-Masson stain. Electron microscopy showed dermal melanocytes that contained numerous melanosomes of various sizes. Most of the melanosomes were fully melanized and were in stage IV of melanization (Fig 4). With light microscopy, the biopsy specimen taken at week 12 in the treated area adjacent to the preoperative biopsy site on the side treated with CO2 ⫹ QSRL revealed a marked decrease in the
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Fig 5. Transmission electron micrograph of dermis 12 weeks postoperatively of same patient as in Fig 4, demonstrating apparent increase in density of normal collagen fibers (arrows) with normal periodicity. Marked decrease in number of dermal melanocytes is also seen. (Original magnification ⫻7700.)
Fig 4. Transmission electron micrograph of biopsy specimen before laser irradiation demonstrating dermal melanocytes containing fully melanized melanosomes of various sizes (arrows).(Original magnification ⫻3960 [A] and ⫻22,000 [B].)
number of dermal melanocytes. This was consistent with the observation on electron microscopy (Fig 5). Histologically, no increase in thickness of the subepidermal repair zone (zone of dermal fibrosis just deep to the dermoepidermal junction) was seen. However, ultrastructurally, an apparent increase in density of normal collagen fibers with normal banding periodicity was demonstrated (Fig 5). A multiplication of the basal lamina was also observed.
DISCUSSION The QS lasers have been generally accepted as the treatment of choice for nevus of Ota because of their high selectivity for dermal pigment.6-8 On the basis of a similar mechanism, the QSRL and QS Nd:YAG laser have been used to destroy pigmentladen melanosomes in Hori’s nevus.11-13 Though the QS lasers yield promising clinical results in treating dermal pigmented lesions, multiple sessions of laser operation are required to obtain the cosmetically desired improvement. In addition to the considerable expense of treatments, patients require substantial recovery time after each treatment session. This
often becomes a lengthy course of treatment because of the repeated treatments and subsequent healing time. Very few studies on the use of multiple lasers in the same treatment session to expedite the therapeutic responses have been reported.15-17 The current study objectively showed a significant beneficial effect on the degree of lesional lightening with epidermal ablation before the QSRL irradiation. This observation may be attributed to 3 factors. First, by using the CO2 laser to ablate the epidermis, competing epidermal melanin and melanocytes, and the epidermis itself will be eliminated, thereby reducing scattering of the beam and providing a greater amount of photons to the dermal target: dermal melanocytes.17 Second, the dermal pigment may possibly be eliminated through the denuded skin after the epidermal ablation.18 Third, the occurrence of an increased collagen fiber density may contribute to the cosmetic improvement by masking the residual underlying dermal melanocytes.19 This was evident by the findings of residual dermal melanocytes together with an apparent increase in density of collagen fiber noted on the electron microscopic evaluation and was akin to those described in previous studies of laser treatment of nevus of Ota.6,7,20 Variable responses of Hori’s nevus to laser treatments have been reported. Previous studies by Kunachak and Leelaudomlipi12 have demonstrated that complete clearance can be achieved in almost all patients with 2 to 3 treatment sessions of the QSRL11 or the QS Nd:YAG laser. In contrast, the current study and that of Polnikorn et al13 found that the therapeutic responses of Hori’s nevus to laser
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treatment was inferior to that of nevus of Ota. However, when evaluating the treatment response of a pigmented lesion to laser treatment many factors including the type of laser, treatment parameters, interval between treatments, and treatment technique need to be considered. Recently, the baseline color of the lesion has been shown to be an important determinant of the number of treatments required for complete eradication of nevus of Ota.19 A minimum of 3, 4, 5, and 6 laser treatments are required for complete clearance of the nevus depending on the baseline color. Similarly, we also noted an influence of the predominant color of Hori’s nevus on the therapeutic response. The question regarding the recurrence rate after laser treatment of Hori’s nevus remains unanswered. The finding of persistent deep dermal pigmentation in lesions of nevus of Ota that had clinically cleared has also been reported after ruby laser treatment. Whether the residual reticular pigment will lead to lesional recurrence is unknown. Recurrence of nevus of Ota 18 months to 2 years after successful QS laser treatments has recently been reported.21 For Hori’s nevus, no recurrence has been reported after a mean follow-up period of 42 months and 2.5 years after QS Nd:YAG laser12 and QSRL11 treatment, respectively. Of the 13 patients in this study, 4 were available for follow-up 2 to 3 years postoperatively (mean: 26 months). All of these patients have maintained a commensurate degree of clearance. The persistence of the clinical improvement observed in this series of the patients suggests that the underlying dermal hypermelanosis of Hori’s nevus may share a similar static nature to that of nevus of Ota22 but differs from the dynamic characteristic of melasma.23 Similar to previous studies,19,24 we have observed the continuous lightening of residual pigmentation many months after just 1 laser treatment. This may result from the constant clearing of the laser-demolished pigment particles by scavenger cells, together with dermal remodeling of fibrosis that masks the residual underlying dermal melanocytes.19 Complete clearance is the ideal clinical outcome when treating a pigmented lesion. A technique with better efficacy may reduce the number and increase the cost-effectiveness of the laser treatment. However, we have found that under some particular circumstances patients may withdraw from treatment once a good cosmetic result is achieved even in the absence of complete pigment removal. The healing time of the 2 different approaches was comparable. There were no long-term adverse sequelae noted in any patient. The only drawback of the combined CO2 ⫹ QSRL technique is the tran-
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sient erythema that is commonly seen after the CO2 resurfacing.25 Because only one pass of the scanned CO2 laser was performed, the degree of erythema was milder and resolved completely by 3 months postoperatively in almost all patients (85%). As demonstrated by the results of this and previous studies,15,16 the use of combined CO2 and QS lasers has been proven to be a safe and efficacious method for treating facial skin. However, the application of this combined laser technique to other anatomic areas is yet to be fully evaluated. A recent study18 using CO2 laser resurfacing before QS laser treatment for nonfacial tattoo removal has demonstrated that this method could enhance tattoo lightening in a minority of patients. However, there was a significant incidence of side effects including textural change, hyperpigmentation, increased pain and edema, delayed wound healing, and increased infection rate. The increase in healing time and side effects when treating the nonfacial skin may be attributed to the decreased vascularity and the sparse adnexal structures relative to the face. Thus, this combined laser technique is best reserved for privileged areas such as the face or for those patients who prove resistant to traditional QS laser treatment. This study demonstrates the effective use of CO2⫹QSRL to improve treatment efficacy. The absence of long-term adverse effects makes this technique an attractive treatment alternative. Whether long-term clearance can be expected will have to be determined. In addition, the efficacy of this technique in the treatment of other dermal melanocytic processes such as the nevus of Ota and blue nevus has yet to be established. REFERENCES 1. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol 1984;10:961-4. 2. Hori Y, Takayama O. Circumscribed dermal melanoses: classification and histologic features. Dermatol Clin 1988;6:315-26. 3. Kukita A, Hori Y, Ohhara K, Kawashima M, Takehara K. Nevus of Ota. In: Fitzpatrick TB, Kukita A, Morikawa F, Seiji M, Sober AJ, Toda K, editors. Biology and diseases of dermal pigmentation. Vol 1. 1st ed. Tokyo: University of Tokyo Press; 1981. p. 67-76. 4. Hori Y, Ohara K, Niimura M, Kukita A. Electron microscopy: ultrastructural observations of the extracellular sheath of dermal melanocytes in the nevus of Ota. Am J Dermatopathol 1982;4:24551. 5. Sun CC, Lu YC, Lee EF, Nakagawa H. Naevus fusco-caeruleus zygomaticus [published erratum appears in Br J Dermatol 1988; 118:314]. Br J Dermatol 1987;117:545-53. 6. Geronemus RG. Q-switched ruby laser therapy of nevus of Ota. Arch Dermatol 1992;128:1618-22. 7. Taylor CR, Flotte TJ, Gange RW, Anderson RR. Treatment of nevus of Ota by Q-switched ruby laser. J Am Acad Dermatol 1994; 30:743-51. 8. Alster TS, Williams CM. Treatment of nevus of Ota by the Qswitched alexandrite laser. Dermatol Surg 1995;21:592-6. 9. Chan HH, Ying SY, Ho WS, Kono T, King WW. An in vivo trial
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comparing the clinical efficacy and complications of Q-switched 755 nm alexandrite and Q-switched 1064 nm Nd:YAG lasers in the treatment of nevus of Ota. Dermatol Surg 2000;26:919-22. Kunachak S, Kunachak S, Sirikulchayanonta V, Leelaudomniti P. Dermabrasion is an effective treatment for acquired bilateral nevus of Ota-like macules. Dermatol Surg 1996;22:559-62. Kunachak S, Leelaudomlipi P, Sirikulchayanonta V. Q-switched ruby laser therapy of acquired bilateral nevus of Ota-like macules. Dermatol Surg 1999;25:938-41. Kunachak S, Leelaudomlipi P. Q-switched Nd:YAG laser treatment for acquired bilateral nevus of Ota-like maculae: a longterm follow-up. Lasers Surg Med 2000;26:376-9. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG laser. Dermatol Surg 2000; 26:477-80. Edwards C. The Mexameter MX 16TM. In: Berardesca E, Elsner P, Wilhelm K-P, Maibach HI, editors. Bioengineering of the skin: methods and instrumentation. 1st ed. Boca Raton (FL): CRC Press; 1995. p. 127-9. Choi EO. Combination therapy for nevus of Ota with the Q-switched ruby laser, CO2 laser, and dermabrader. J Kor Soc Laser Med 1998;2:46. Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. Combination treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: a pilot study. Dermatol Surg 1999; 25:494-7. Manuskiatti W, Fitzpatrick RE, Goldman MP. Treatment of facial
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skin using combinations of CO2, Q-switched alexandrite, flashlamp-pumped pulsed dye, and Er:YAG lasers in the same treatment session. Dermatol Surg 2000;26:114-20. Ort RJ, Anderson RR, Arndt KA, Dover JS. CO2 laser resurfacing of tattoos prior to Q-switched laser treatment. Lasers Surg Med 2000;Suppl 12:23. Ueda S, Isoda M, Imayama S. Response of naevus of Ota to Qswitched ruby laser treatment according to lesion colour. Br J Dermatol 2000;142:77-83. Hakozaki M, Masuda T, Oikawa H, Nara T. Light and electron microscopic investigation of the process of healing of the naevus of Ota by Q-switched alexandrite laser irradiation. Virchows Arch 1997;431:63-71. Chan HH, Leung RS, Ying SY, Lai CF, Chua J, Kono T. Recurrence of nevus of Ota after successful treatment with Q-switched lasers. Arch Dermatol 2000;136:1175-6. Hidano A, Kajima H, Ikeda S, Mizutani H, Miyasato H, Niimura M. Natural history of nevus of Ota. Arch Dermatol 1967;95:187-95. Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol 1995;131:1453-7. Chang CJ, Nelson JS, Achauer BM. Q-switched ruby laser treatment of oculodermal melanosis (nevus of Ota). Plast Reconstr Surg 1996;98:784-90. Bernstein LJ, Kauvar ANB, Grossman MC, Geronemus RG. The short- and long-term side effects of carbon dioxide laser resurfacing. Dermatol Surg 1997;23:519-25.
SURGERY
Treatment of acquired bilateral nevus of Ota–like macules (Hori’s nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser Woraphong Manuskiatti, MD,a Apichati Sivayathorn, MD,a Panadda Leelaudomlipi, MD,a and Richard E. Fitzpatrick, MDb Bangkok, Thailand, and Encinitas, California Background: Acquired bilateral nevus of Ota-like macules (Hori’s nevus) is a dermal pigmented lesion commonly seen in middle-aged women of Asian descent. The Q-switched ruby laser (QSRL) has been used successfully to treat a variety of benign pigmented lesions. Multiple, sequential treatments are typically required for complete clearance of the dermal pigmented dermatoses. Objective: The purpose of this study was to determine the efficacy of QSRL in the treatment of Hori’s nevus and the beneficial effect of epidermal ablation using the scanned carbon dioxide (CO2) laser before QSRL. Methods: A total of 13 women from Thailand with Hori’s nevus were randomly treated with the scanned CO2 laser followed by QSRL on one side of their face, and QSRL alone on the other side. The same fluence of QSRL was used on both sides in individual patients. The treatment response was objectively evaluated by measuring the melanin index using a Mexameter (Courage & Khazaka Electronic GmbH, Ko¨ln, Germany), and subjectively assessed by the patients before treatment and 3 and 16 months after treatment. Adverse sequelae of the treatment and the patients’ tolerance were also evaluated at the same follow-up visit. Results: The 3- and 16-month posttreatment melanin index was significantly decreased compared with that of pretreatment on both treated sites and this corresponded to the patients’ subjective evaluations. The response rate, defined as “the percentage of reduction in melanin index,” was significantly higher on the sides treated with scanned CO2 laser followed by QSRL, compared with the sides irradiated with QSRL alone at both follow-up visits. At the 3-month follow-up, the most common adverse effect was hypopigmentation, found in 15% (2 of 13) of the patients on the sites treated with QSRL alone, and on the sites treated with scanned CO2 laser followed by QSRL (8%, 1/13). Erythema was observed in 15% (2/13) of the patients only on the sites that received combination treatment. However, no adverse sequelae were observed at the 16-month posttreatment follow-up. Conclusion: Epidermal ablation with scanned CO2 laser before the use of the pigment-specific laser may be an effective technique for increasing therapeutic efficacy in the treatment of dermal pigmented dermatoses. (J Am Acad Dermatol 2003;48:584-91.)
A
cquired bilateral nevus of Ota–like macules (Hori’s nevus), a circumscribed dermal melanocytosis of the face, is commonly seen in middle-aged women of Asian descent.1,2 Clinically
From the Department of Dermatology, Siriraj Hospital, Mahidol University,a and Dermatology Associates/Cosmetic Laser Associates of San Diego County Inc.b Funding sources: None. Conflict of interest: None identified. Reprint requests: Woraphong Manuskiatti, MD, Department of Dermatology, Siriraj Hospital, 2 Pran-nok Rd, Bangkok 10700, Thailand. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.193
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Hori’s nevus is very similar to the congenital bilateral nevus of Ota (type IV nevus of Ota) characterized by blue-brown macules occurring bilaterally on the forehead, temples, eyelids, malar areas, nasal alae, and nasal root.3 Unlike the nevus of Ota, these pigmented lesions usually appear in the fourth or fifth decades of life in women (only rarely in men), and are not observed in the conjunctiva and mucous membranes of the mouth and nose. Histologically, in Hori’s nevus, actively melanin-synthesizing dermal melanocytes are dispersed in the papillary and middle portions of the dermis, whereas in the nevus of Ota, these melanin-laden cells are found diffusely throughout the entire dermis.4,5
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Melanin-targeting lasers have proven effective in the treatment of nevus of Ota.6-9 Although Hori’s nevus is a dermal melanocytic hyperpigmentation like the nevus of Ota, there have been very few reports concerning the treatment of Hori’s nevus. Dermabrasion,10 and laser irradiation using Q-switched (QS) ruby laser (QSRL)11 and QS Nd: YAG laser12,13 have been reported to be of benefit in this condition. Though dermabrasion has shown favorable results, the major disadvantages of this technique include a risk of bloodborne contamination and the uncontrollable depth of ablation. Although promising results in the treatment of Hori’s nevus with QSRL and QS Nd:YAG laser have been reported, the treatment responses have been noted to be less effective than that of the nevus of Ota13 and multiple sequential treatments are also required to achieve the desired improvement. This study was designed to objectively determine (1) the efficacy of QSRL in the treatment of Hori’s nevus and (2) whether epidermal ablation before QSRL provided a beneficial effect on treatment response.
PATIENTS AND METHODS Patients A total of 13 women from Thailand with a clinical diagnosis of Hori’s nevus were enrolled in the study. The age of the patients ranged from 22 to 55 years (mean age, 40.9 years). Skin phototypes III (5), IV (7), and V (1) were represented. Written informed consent was obtained from all patients after the investigational nature of the procedure had been explained fully. All 13 patients were followed up at 1 week, and 1, 3, and 4 months postoperatively. Of the 13 patients, 10 (77%) returned for office evaluations at an average follow-up period of 16 months postoperatively (range, 9-30 months). Lasers The QSRL (Lambda Photometrics, Hertfordshire, England) was a system delivered at 694 nm with a pulse width of 25 nsec using a 3-mm spot diameter. The scanned carbon dioxide (CO2) laser was a 20W continuous-wave CO2 laser (Sharplan Laser, Allendale, NJ) coupled to the optomechanic flash scanner (SilkTouch) with a 3-mm scan size. The scanner produced a spiral beam, the dwell time of which was approximately 1 millisecond. Laser procedure Preoperatively, the face was cleaned with chlorhexidine and wiped with isopropyl alcohol. Treatment areas were anesthetized with 1% lidocaine hydrochloride with 1:100,000 epinephrine intradermally. The patients were randomly treated with QSRL alone on one side of the lesion, and one pass
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of a scanned CO2 laser followed by another pass with the QSRL (CO2 ⫹ QSRL) on the other side. On the side treated with QSRL alone, the pulsed laser at a wavelength of 694 nm was delivered through a 3-mm spot diameter hand piece using an energy density (fluence) ranging from 4.5 to 6.5 J/cm2 (mean, 5.2 J/cm2) with 10% to 20% overlap. The fluence used on each patient was determined by the observation of a minimal “threshold” radiant exposure response that caused an immediate whitening of the nevus. On the side treated with CO2⫹QSRL, one pass of the scanned CO2 laser was used to ablate the epidermis, followed by another pass with the QSRL. The CO2 coupled to the flash scanner was set at a power of 7 W, 0.2-second pulse duration with a 3-mm scan size. Overlap was avoided. After one pass of the CO2 laser, the epidermis was wiped with saline-soaked gauze for debris removal, and immediately patted with dry gauze. Then the QSRL was delivered to the dermal pigmented lesions with the same fluence used on the side treated with the QSRL alone (Figs 1 and 2). During the treatment sessions, eye protection was provided to all patients and the clinical staff. The postoperative wounds were dressed with petroleum jelly. The patients were instructed to cleanse the areas gently at least twice daily. This consisted of debridement with vinegar soaks (1 tablespoon vinegar per cup of water) after which petrolatum was reapplied. All patients received Augmentin (SmithKline Beecham Pharmaceuticals, Brentford, England) (375 mg 3 times daily) orally for 7 days beginning the day before treatment. The patients were advised to avoid excessive sun exposure and to wear a broad-spectrum sunscreen with a sun protection factor of 15 or greater for at least 3 months postoperatively. No other topical agents were used before or after the procedure. Clinical evaluation Objective assessment. A Mexameter MX 16 (Courage & Khazaka Electronic GmbH, Ko¨ ln, Germany) was used to objectively quantify the degree of skin pigmentation measured as a melanin index.14 The melanin index was assessed preoperatively, and 3 and 16 months after the treatment in all patients on both sides of the lesions. An average value of 3 measurements on 3 representative points on each side of the lesion mapped with a permanent marker on a flexible, transparent sheet was obtained. The response rate, defined as “the percentage of melanin index” obtained at 3 and 16 months postoperatively compared with a baseline melanin index was determined for each method of treatment. Paired t tests were performed to determine the significance of the
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Fig 1. Representative patient with Hori’s nevus. Right side was treated with Q-switched ruby laser (QSRL) alone and left side was treated with carbon-dioxide laser and QSRL. Before (A and D), and 4 (B and E) and 24 (C and F) months after treatment.
Fig 2. Same patient as in Fig 1 demonstrating just after epidermal ablation with carbon-dioxide laser (A) and immediately after Q-switched ruby laser irradiation on dermal pigmented lesions (B).
improvements compared with a baseline for each treatment modality and to compare the percentage of clearing between the 2 treatment techniques. A P value less than or equal to .05 was considered statistically significant.
Subjective assessment. At month 16, 10 of the 13 patients (77%) who were available for the final evaluation were asked to grade the improvement of each treated side separately. The improvement was graded using a quartile system as poor (⬍25% clear-
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Table I. Summary of mean melanin index Treatment technique
Pre-QSRL 3-mo post-QSRL Pre-QSRL 16-mo post-QSRL Pre-CO2 ⫹ QSRL Post-CO2 ⫹ QSRL Pre-CO2 ⫹ QSRL 16-mo post-CO2 ⫹ QSRL Month 3 RR of QSRL RR of CO2 ⫹ QSRL Month 16 RR of QSRL RR of CO2 ⫹ QSRL
No. of patients
Mean (SD)
Mean difference (SD)
13 13 10 10 13 13 10 10
545.9 (21.57) 531.4 (23.91) 541.4 (19.52) 527.6 (17.56) 551.2 (28.38) 526.9 (19.65) 546.8 (26.10) 522.96 (19.36)
14.51 (22.20) 13.87 (18.65) 24.36 (27.22) 23.86 (26.62)
13 13
2.6% (3.91) 4.3% (4.55)
10 10
2.5% (3.28) 4.2% (4.47)
95% CI
P value
(1.09)-(27.92)
.036
(.53)-(27.21)
.043
(7.91)-(40.81)
.007
(4.82)-(42.90)
.02
⫺1.67 (1.94)
(⫺2.84)-(⫺0.50)
.009
⫺1.72 (2.39)
(⫺3.43)-(⫺1.15)
.05
CI, Confidence interval; CO2, carbon-dioxide laser; QSRL, Q-switched ruby laser; RR, response rate. P ⱕ .05 was statistically significant.
ance), fair (25%-50% clearance), good (50%-75% clearance), and excellent (75%-100% clearance). In addition, side effects from treatment were followed up by a dermatologist, who was familiar with laser operation but not involved with the treatment, at 1, 3, and 16 months after the treatment. Patients experiencing any side effects were followed up at monthly intervals until that adverse effect disappeared. These included the presence or absence of hypopigmentation, hyperpigmentation, erythema, and textural alteration. Histologic examination and ultrastructural evaluation. Preoperatively, 3-mm punch biopsy specimens were taken from 11 of the 13 patients and a further such specimen obtained from 1 patient 3 months after the treatment. These specimens were routinely processed for light and electron microscopy. Paraffin sections were stained with hematoxylin and eosin and Fontana-Masson. Sections for transmission electron microscopy were routinely processed, and stained with uranyl acetate and lead citrate.
RESULTS Objective clinical evaluation There was no statistically significant difference in the baseline melanin index of each side of the lesion in any individual patient (P ⫽ .214). Table I summarizes the mean melanin index of each treatment modality at pretreatment, and 3 and 16 months postoperatively. At 3 months, a significant reduction in the mean melanin index compared with the baseline melanin index was demonstrated on the side treated with QSRL alone (P ⫽ .036), and the side treated with CO2 ⫹ QSRL (P ⫽ .007). The significant reduc-
tion in the mean melanin index compared with that of the baseline persisted through month 16 on both treated sides (P ⫽ .043 and P ⫽ .02 on QSRL and CO2 ⫹ QSRL sides, respectively). For both treatment techniques, there was no significant difference in the mean melanin index at month 3 compared with that at month 16. However, a trend toward greater pigment lightening with a longer follow-up period was observed. At month 3, the response rate on the side treated with CO2⫹QSRL was significantly higher than the side treated with QSRL alone (P ⫽ .009). This significantly greater response rate on the CO2 ⫹ QSRL side compared with the QSRL side remained at the month-16 follow-up visit. Figs 1 and 2 demonstrate the clinical result of a representative patient side by side preoperatively, immediately after each treatment technique, at month 4 and 24. Patient self-assessment Of the 10 patients assessed at month 16, patient evaluation of the sites treated with QSRL alone showed that almost half the patients (40%, 4/10) graded the improvement as fair (25%-50% clearance), whereas the other half of the patients (6/10) reported the improvement as poor (⬍25% clearance). For patient evaluation of the sites treated with CO2 ⫹ QSRL, a majority of patients (70%, 7/10) judged the improvement as good (50%-75% clearance). Clearance grades of poor and fair were reported in 10% (1/10) and 20% (2/10) of the patients, respectively. More than half of the patients (60%, 6/10) noted further improvement of both treated sides at the longer follow-up visit.
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Fig 3. Adverse effects according to treatment techniques. CO2⫹QSRL, Scanned carbon dioxide laser followed by Q-switched ruby laser (QSRL).
Healing time and adverse sequelae There was no significant difference in healing time between the 2 treatment techniques. Complete re-epithelialization typically occurred by 7 to 10 days after the treatment. Adverse effects after the treatment are illustrated in Fig 3. The incidence of pigmentary changes on the sides treated with QSRL alone was comparable with that of CO2 ⫹ QSRL-treated sides at week 4 (54% [7/13] and 46% [6/13], respectively). These pigmentary alterations included hypopigmentation and hyperpigmentation, and all were substantially improved by month 3. All patients experiencing pigmentary alterations at month 3 showed complete clearing 1 month later (4 months postoperatively). At month 1, erythema was noted in all patients (100%) on the sides treated with CO2 ⫹ QSRL, whereas an incidence of 15% (2/13) was observed on the side treated with QSRL alone. However, by week 12 the erythema had completely disappeared on the side treated with QSRL alone and was found in only 15% (2 of 13) of the patients on the side treated with CO2 ⫹ QSRL. No textural alteration was
demonstrated in any of the treated areas in any patient. At month 16, of the 10 patients examined, none showed pigmentary changes on either of the sides treated. No cases of persistent erythema and textural change were observed in this group of patients. Histologic and ultrastructural findings Biopsy specimens taken from the pigmented lesions preoperatively revealed an overall thinning of the epidermis, along with sporadic dyskeratotic keratinocytes. All specimens demonstrated spindleshaped pigment-laden cells scattering diffusely along the collagen bundles of the dermis, particularly in the papillary dermis. These cells were positive for the Fontana-Masson stain. Electron microscopy showed dermal melanocytes that contained numerous melanosomes of various sizes. Most of the melanosomes were fully melanized and were in stage IV of melanization (Fig 4). With light microscopy, the biopsy specimen taken at week 12 in the treated area adjacent to the preoperative biopsy site on the side treated with CO2 ⫹ QSRL revealed a marked decrease in the
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Fig 5. Transmission electron micrograph of dermis 12 weeks postoperatively of same patient as in Fig 4, demonstrating apparent increase in density of normal collagen fibers (arrows) with normal periodicity. Marked decrease in number of dermal melanocytes is also seen. (Original magnification ⫻7700.)
Fig 4. Transmission electron micrograph of biopsy specimen before laser irradiation demonstrating dermal melanocytes containing fully melanized melanosomes of various sizes (arrows).(Original magnification ⫻3960 [A] and ⫻22,000 [B].)
number of dermal melanocytes. This was consistent with the observation on electron microscopy (Fig 5). Histologically, no increase in thickness of the subepidermal repair zone (zone of dermal fibrosis just deep to the dermoepidermal junction) was seen. However, ultrastructurally, an apparent increase in density of normal collagen fibers with normal banding periodicity was demonstrated (Fig 5). A multiplication of the basal lamina was also observed.
DISCUSSION The QS lasers have been generally accepted as the treatment of choice for nevus of Ota because of their high selectivity for dermal pigment.6-8 On the basis of a similar mechanism, the QSRL and QS Nd:YAG laser have been used to destroy pigmentladen melanosomes in Hori’s nevus.11-13 Though the QS lasers yield promising clinical results in treating dermal pigmented lesions, multiple sessions of laser operation are required to obtain the cosmetically desired improvement. In addition to the considerable expense of treatments, patients require substantial recovery time after each treatment session. This
often becomes a lengthy course of treatment because of the repeated treatments and subsequent healing time. Very few studies on the use of multiple lasers in the same treatment session to expedite the therapeutic responses have been reported.15-17 The current study objectively showed a significant beneficial effect on the degree of lesional lightening with epidermal ablation before the QSRL irradiation. This observation may be attributed to 3 factors. First, by using the CO2 laser to ablate the epidermis, competing epidermal melanin and melanocytes, and the epidermis itself will be eliminated, thereby reducing scattering of the beam and providing a greater amount of photons to the dermal target: dermal melanocytes.17 Second, the dermal pigment may possibly be eliminated through the denuded skin after the epidermal ablation.18 Third, the occurrence of an increased collagen fiber density may contribute to the cosmetic improvement by masking the residual underlying dermal melanocytes.19 This was evident by the findings of residual dermal melanocytes together with an apparent increase in density of collagen fiber noted on the electron microscopic evaluation and was akin to those described in previous studies of laser treatment of nevus of Ota.6,7,20 Variable responses of Hori’s nevus to laser treatments have been reported. Previous studies by Kunachak and Leelaudomlipi12 have demonstrated that complete clearance can be achieved in almost all patients with 2 to 3 treatment sessions of the QSRL11 or the QS Nd:YAG laser. In contrast, the current study and that of Polnikorn et al13 found that the therapeutic responses of Hori’s nevus to laser
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treatment was inferior to that of nevus of Ota. However, when evaluating the treatment response of a pigmented lesion to laser treatment many factors including the type of laser, treatment parameters, interval between treatments, and treatment technique need to be considered. Recently, the baseline color of the lesion has been shown to be an important determinant of the number of treatments required for complete eradication of nevus of Ota.19 A minimum of 3, 4, 5, and 6 laser treatments are required for complete clearance of the nevus depending on the baseline color. Similarly, we also noted an influence of the predominant color of Hori’s nevus on the therapeutic response. The question regarding the recurrence rate after laser treatment of Hori’s nevus remains unanswered. The finding of persistent deep dermal pigmentation in lesions of nevus of Ota that had clinically cleared has also been reported after ruby laser treatment. Whether the residual reticular pigment will lead to lesional recurrence is unknown. Recurrence of nevus of Ota 18 months to 2 years after successful QS laser treatments has recently been reported.21 For Hori’s nevus, no recurrence has been reported after a mean follow-up period of 42 months and 2.5 years after QS Nd:YAG laser12 and QSRL11 treatment, respectively. Of the 13 patients in this study, 4 were available for follow-up 2 to 3 years postoperatively (mean: 26 months). All of these patients have maintained a commensurate degree of clearance. The persistence of the clinical improvement observed in this series of the patients suggests that the underlying dermal hypermelanosis of Hori’s nevus may share a similar static nature to that of nevus of Ota22 but differs from the dynamic characteristic of melasma.23 Similar to previous studies,19,24 we have observed the continuous lightening of residual pigmentation many months after just 1 laser treatment. This may result from the constant clearing of the laser-demolished pigment particles by scavenger cells, together with dermal remodeling of fibrosis that masks the residual underlying dermal melanocytes.19 Complete clearance is the ideal clinical outcome when treating a pigmented lesion. A technique with better efficacy may reduce the number and increase the cost-effectiveness of the laser treatment. However, we have found that under some particular circumstances patients may withdraw from treatment once a good cosmetic result is achieved even in the absence of complete pigment removal. The healing time of the 2 different approaches was comparable. There were no long-term adverse sequelae noted in any patient. The only drawback of the combined CO2 ⫹ QSRL technique is the tran-
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sient erythema that is commonly seen after the CO2 resurfacing.25 Because only one pass of the scanned CO2 laser was performed, the degree of erythema was milder and resolved completely by 3 months postoperatively in almost all patients (85%). As demonstrated by the results of this and previous studies,15,16 the use of combined CO2 and QS lasers has been proven to be a safe and efficacious method for treating facial skin. However, the application of this combined laser technique to other anatomic areas is yet to be fully evaluated. A recent study18 using CO2 laser resurfacing before QS laser treatment for nonfacial tattoo removal has demonstrated that this method could enhance tattoo lightening in a minority of patients. However, there was a significant incidence of side effects including textural change, hyperpigmentation, increased pain and edema, delayed wound healing, and increased infection rate. The increase in healing time and side effects when treating the nonfacial skin may be attributed to the decreased vascularity and the sparse adnexal structures relative to the face. Thus, this combined laser technique is best reserved for privileged areas such as the face or for those patients who prove resistant to traditional QS laser treatment. This study demonstrates the effective use of CO2⫹QSRL to improve treatment efficacy. The absence of long-term adverse effects makes this technique an attractive treatment alternative. Whether long-term clearance can be expected will have to be determined. In addition, the efficacy of this technique in the treatment of other dermal melanocytic processes such as the nevus of Ota and blue nevus has yet to be established. REFERENCES 1. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol 1984;10:961-4. 2. Hori Y, Takayama O. Circumscribed dermal melanoses: classification and histologic features. Dermatol Clin 1988;6:315-26. 3. Kukita A, Hori Y, Ohhara K, Kawashima M, Takehara K. Nevus of Ota. In: Fitzpatrick TB, Kukita A, Morikawa F, Seiji M, Sober AJ, Toda K, editors. Biology and diseases of dermal pigmentation. Vol 1. 1st ed. Tokyo: University of Tokyo Press; 1981. p. 67-76. 4. Hori Y, Ohara K, Niimura M, Kukita A. Electron microscopy: ultrastructural observations of the extracellular sheath of dermal melanocytes in the nevus of Ota. Am J Dermatopathol 1982;4:24551. 5. Sun CC, Lu YC, Lee EF, Nakagawa H. Naevus fusco-caeruleus zygomaticus [published erratum appears in Br J Dermatol 1988; 118:314]. Br J Dermatol 1987;117:545-53. 6. Geronemus RG. Q-switched ruby laser therapy of nevus of Ota. Arch Dermatol 1992;128:1618-22. 7. Taylor CR, Flotte TJ, Gange RW, Anderson RR. Treatment of nevus of Ota by Q-switched ruby laser. J Am Acad Dermatol 1994; 30:743-51. 8. Alster TS, Williams CM. Treatment of nevus of Ota by the Qswitched alexandrite laser. Dermatol Surg 1995;21:592-6. 9. Chan HH, Ying SY, Ho WS, Kono T, King WW. An in vivo trial
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comparing the clinical efficacy and complications of Q-switched 755 nm alexandrite and Q-switched 1064 nm Nd:YAG lasers in the treatment of nevus of Ota. Dermatol Surg 2000;26:919-22. Kunachak S, Kunachak S, Sirikulchayanonta V, Leelaudomniti P. Dermabrasion is an effective treatment for acquired bilateral nevus of Ota-like macules. Dermatol Surg 1996;22:559-62. Kunachak S, Leelaudomlipi P, Sirikulchayanonta V. Q-switched ruby laser therapy of acquired bilateral nevus of Ota-like macules. Dermatol Surg 1999;25:938-41. Kunachak S, Leelaudomlipi P. Q-switched Nd:YAG laser treatment for acquired bilateral nevus of Ota-like maculae: a longterm follow-up. Lasers Surg Med 2000;26:376-9. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG laser. Dermatol Surg 2000; 26:477-80. Edwards C. The Mexameter MX 16TM. In: Berardesca E, Elsner P, Wilhelm K-P, Maibach HI, editors. Bioengineering of the skin: methods and instrumentation. 1st ed. Boca Raton (FL): CRC Press; 1995. p. 127-9. Choi EO. Combination therapy for nevus of Ota with the Q-switched ruby laser, CO2 laser, and dermabrader. J Kor Soc Laser Med 1998;2:46. Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. Combination treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: a pilot study. Dermatol Surg 1999; 25:494-7. Manuskiatti W, Fitzpatrick RE, Goldman MP. Treatment of facial
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skin using combinations of CO2, Q-switched alexandrite, flashlamp-pumped pulsed dye, and Er:YAG lasers in the same treatment session. Dermatol Surg 2000;26:114-20. Ort RJ, Anderson RR, Arndt KA, Dover JS. CO2 laser resurfacing of tattoos prior to Q-switched laser treatment. Lasers Surg Med 2000;Suppl 12:23. Ueda S, Isoda M, Imayama S. Response of naevus of Ota to Qswitched ruby laser treatment according to lesion colour. Br J Dermatol 2000;142:77-83. Hakozaki M, Masuda T, Oikawa H, Nara T. Light and electron microscopic investigation of the process of healing of the naevus of Ota by Q-switched alexandrite laser irradiation. Virchows Arch 1997;431:63-71. Chan HH, Leung RS, Ying SY, Lai CF, Chua J, Kono T. Recurrence of nevus of Ota after successful treatment with Q-switched lasers. Arch Dermatol 2000;136:1175-6. Hidano A, Kajima H, Ikeda S, Mizutani H, Miyasato H, Niimura M. Natural history of nevus of Ota. Arch Dermatol 1967;95:187-95. Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol 1995;131:1453-7. Chang CJ, Nelson JS, Achauer BM. Q-switched ruby laser treatment of oculodermal melanosis (nevus of Ota). Plast Reconstr Surg 1996;98:784-90. Bernstein LJ, Kauvar ANB, Grossman MC, Geronemus RG. The short- and long-term side effects of carbon dioxide laser resurfacing. Dermatol Surg 1997;23:519-25.