Low-Fluence Q-Switched Nd: YAG Laser (LF-QSNY) May Be a Better Choice for the Treatment of Early Nevus of Ota: A Prospective Self-Controlled Trial of LFQS and Picosecond Alexandrite Laser

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Introduction
Nevus of Ota, a benign melanocytic nevus, mainly presents as speckled or mottled, brown to blue-green patches on the face, more specifcally, on where it is innervated by the branches of the trigeminal nerve [1].Nevus of Ota is most commonly found in Asian ethnicity and usually involves unilateral face.Pathologically, dendritic melanocytes appear in the dermis [2,3].Tough with a benign course, nevus of Ota brings cosmetic problems and many research studies have focused on the treatment.
Abundant research studies have proved the efcacy of the Q-switched Nd: YAG laser (QSNY) and Q-switched alexandrite laser (QSAL) on nevus of Ota [4].Recently, novel low-fuence QSNY has also been proved efective in the treatment of nevus of Ota with similar efect and minimal complication rates [5,6].Tis technique seems to be a promising method for patients, especially at young ages.
On the other side, the picosecond alexandrite laser (PSAL) has also proved higher clinical efcacy and lower adverse efects, especially compared with those of traditional QSAL [7].
However, a comparison between PSAL and LF-QSNY for nevus of Ota is lacking.Terefore, this study aims to compare the efcacy and safety of the two lasers for the treatment of nevus of Ota.

Materials and Methods
2.1.Study Design.Tis study was conducted in the Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, from June 2019 to July 2021.Patients were included if they were healthy subjects with untreated Nevus of Ota.Meanwhile, exclusion criteria were as follows: combined with other related diseases, during pregnancy or planning to be pregnant, wound or any skin complaint at treated site, allergic to local anesthetics, and participation in other clinical trials.Patients and/or their parents fully understood this clinical trial (Chinese Clinical Trial Registration Number: ChiCTR1900022690) and have signed the informed consent.Tis study has been approved by the institutional ethics committee of Shanghai Ninth People's Hospital (SH9H-2019-T48-1) (Figure 1).

Laser
Treatment.Each patient's nevus of Ota lesion was allocated to be treated with PSAL and LF-QSNY.Te sites for two treatments were selected by randomized sequences (https://www.random.org).Te patients who were assigned an odd number were treated by PSAL on the left or top test site and LF-QSNY on the right or bottom test site.Patients who were assigned an even number received contrary treatment [8].Topical anesthetic (EMLA cream: 2.5% lidocaine and 2.5% prilocaine) was applied 1 hour prior to laser treatments.Ice bag was applied for 15 min to reduce tissue edema and pain after the operation.
Treatment parameters are as follows: (1) PSAL group: 5.25-6.37J/cm Treatment has a two-stage process.First, each subject was treated with PSAL for one time and LF-QSNY for six times in a three-month comparative trial.Ten, each patient selected a preferred laser for after-treatment of the lesions.Te interval for PSAL and LF-QSNY is 3 months and 2 weeks.

Data Analysis.
GraphPad Prism 8 and SPSS 21.0 statistical software were used for statistical analysis.Te efcacy of two lasers was compared by the Wilcoxon test, and McNemar's test was used to compare the adverse event and recurrence rate.Te consistency of assessment among diferent observers was analyzed by the intraclass correlation coefcient (ICC) and was defned as follows: poor, ICC ≤ 0.50; moderate, 0.50 < ICC ≤ 0.75; good, 0.75 < ICC ≤ 0.9; excellent, ICC > 0.9.In addition, Fisher's exact test was used to analyze the correlation between efect and age, gender, lesion color, sclera pigmentation, and Tanino classifcation [9,10].Diference was defned as statistically signifcant when P < 0.05.

Patient Information.
Seventeen patients were enrolled, and 15 patients (three male and 12 female) with 34 lesions have fnished the trial (Table 1).Te mean age of treatment initiation was 8.02 ± 9.38 (0.4-29) years.Detailed clinical characteristics are shown in Table 1.

Visual Assessment.
All patients (15 cases with 34 lesions, two patients with two discontinued lesions) were treated with LF-QSNY six times and one PSAL treatment within three months (Figures 2 and 3).Te consistency of the evaluation results was good as the ICC reached 0.808 (P < 0.001).After the three-month treatment, the average VAS scores were 3.51 ± 0.87 and 3.47 ± 0.67 on the side treated by PSAL and LF-QSNY, respectively (P > 0.05).
In addition, as treatment mounted up, the efcacy of LF-QSNY gradually increased (VAS increased from 1.84 to 3.47) every two weeks.Most signifcant improvement in LF-QSNY was achieved after the frst session (VAS � 1.84).Meanwhile, VAS scores on the side which was received one PSAL treatment also steadily increased (2.69 to 3.51) within 12 weeks (Figure 4).

Safety Assessment.
During the frst three months, eight patients (53.33%) experienced PIHo on the side treated with PSAL (Figure 6).Te remission time for six of these patients ranged from 2 to 10 weeks, and one patient who had selected PSAL experienced PIHo for a half year, and the other one who had selected LF-QSNY still had PIHo 21 months after treatment.Meanwhile, three (20%) patients developed temporary PIH on the PSAL side and recovered in two to eight weeks.
On the LF-QSNY-treated side, one patient (6.67%) developed slight PIH and recovered in four weeks.No hypopigmentation had been observed.
No patient experienced relapse on the LF-QSNY-treated side, while one patient experienced a slight relapse on the PSAL-treated side with brown spots reappearing on the lesions at 12-month follow-up.
No patients showed scars.Patients who chose LF-QSNY were more satisfed, as all patients scored 5 (very satisfed), while only two patients who chose PSAL rated 5-score and six rated 4-score (satisfed) (P < 0.001).
Te Q-switched Nd: YAG (1064 nm) laser utilizes the concept of selective photothermolysis to target the melanin in Ota's nevus, and the wave length of 1064 nm can reach deeper targets as the abnormal melanocytes existed in the dermal layer.It is estimated that this wave length is the preferred choice for dark-skinned patients because of minimization of epidermal injury.Low-fuence QSNY with multipass and more sessions brings subcellular selective photothermolysis with minimal infammation [22].On the other hand, the ultrashort pulse equipped by a picosecond laser and additional photoacoustic efect makes it possible to reduce photothermal efects to the surrounding tissue and minimizing thermal damage [23].Tough both techniques have been successfully applied to nevus of Ota [5,6,24], recent studies only presented as retrospective, uncontrolled series.Terefore, our study frstly compared the efcacy of LF-QSNY and PSAL by prospective, evaluator-blinded, split-lesion-controlled design.
As shown, the overall efectiveness between LF-QSNY and PSAL within three months was not signifcantly different in the treatment of nevus of Ota.Further careful evaluation showed that fve patients (33.33%) responded signifcantly diferent to these two types of laser treatments (VAS diference ≥1 between the two laser treatments'  Te VAS score diferences before and after each laser treatment were 0.51, 0.32, 0.23, 0.27, and 0.30, respectively.Te diference between each two sessions was signifcant (P < 0.01 and P < 0.05).(b) Visual evaluation within 12 weeks after one treatment of PSAL.Te VAS score diferences were 0.21, 0.14, 0.06, 0.17, and 0.24, respectively.Te VAS score was steadily increased but was only signifcant at the fnal visit (P < 0.05).* means P < 0.05 and * * means P < 0.01.6 Dermatologic Terapy efcacy); among them, PSAL was superior in three patients, while LF-QSNY was superior in two patients.Te possible reason for the better efcacy of the picosecond laser may be that PSAL fuence was high enough to generate sufcient photothermolysis to damage those dermal melanocytes in nevus of Ota, thus leading to more lesion clearance.On the other hand, the possible reasons for the better efcacy of LF-QSNY may be that the photothermal damage for the picosecond laser was relatively high that PIH had been raised and not fully recovered by three months, or the damaged melanocytes had not achieved full degradation at threemonth follow-up since further improvement had been noted by some clinicians at six months to one year after the last treatment [7,25].Te results suggest that an initial test patch is necessary for subsequent treatment of nevus of Ota.
It was found that the efect of LF-QSNY gradually increased after each treatment; the most conspicuous improvement was observed after the frst session.Terefore, LF-QSNY steadily cleaned the lesion of nevus of Ota after each treatment, but the removal of the lesions would be more noticeable after the frst treatment, which was diferent to our previous study on its efcacy for café-au-lait macules (CALMs).Te diferent depths and features of pathological melanocytes in nevus of Ota and CALMs might be the reason of the diference of eliminating process.Te LFQS laser had obvious lesion clearance after the frst treatment.While both research studies indicated with the increase of LF-QSNY treatment sessions, the clearance of lesions gradually accumulated [26].
On the PSAL-treated side, lesions also steadily improved after treatment.Te VAS score improved from 2.69 to 3.51 for the PSAL-treated side between two weeks after treatment and three months after treatment.Te results indicated that the pigment particles would be gradually removed by the macrophages, which manifested very diferently from that of epidermal pigment disease.Te latter efcacy was stable from the time the scab was removed, which was about from two weeks to 12 weeks posttreatment [8].
For the PSAL-treated side, temporary depigmentation occurred on 53.33% of patients (n � 8), and the average resolving time for most cases was 2 to 12 weeks; however, one patient experienced PIHo for a half year; the other experienced for more than 21 months; and 20% of patients experienced temporary hyperpigmentation, which resolved in two to eight weeks.For the LF-QSNY-treated side, only one patient experienced slight PIH, which resolved within four weeks.Te higher PIHo rates reported by our study on the PSAL side may be due to the shorter follow-up time than that used in former studies, and the fuence used in our study is higher.In addition, we found more evenly pigmentation on the LF-QSNY-treated side during the early treatment, which resulted in more acceptable appearance improvement, though eventually, two lasers brought equal clearance on the lesion pigmentation.
PSAL therapy is preferred by older children and adults (50% among the further choices for PSAL) in order to get a better outcome (n � 4) or to balance their busy school or work lives (n � 4), while low-fuence technology was more popular among young patients for the following specifc benefts.First, the complication rates, including erythema, swelling, and scabbing on the LF-QSNY, would be signifcantly lower, which would reduce the caring time for the guardians.Faster pain and burning resolution will also reduce a child's symptoms of crying, restlessness, and fear, as reported by guardians.Also, adopting LF-QSNY leads to faster recovery.Te mean treatment sessions for the LF-QSNY were 15.62 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), which means patients can fnish the session within four months.While the mean treatment sessions for PSAL were two to fve, usually threeto-six-month intervals between sessions were recommended, which would take the mean at least 6 months for PSAL treatments and may even be longer than 30 months [27].Further treatments and shorter periods for overall recovery are ideal to limit psychosocial impacts in young patients [6].
During the follow-up, we found only one (6.67%)relapsed patient, which manifested as slight brown spots on the cured lesion at one-year follow-up after treatment.Tis patient chose the LF-QSNY laser, and the lesion was completely cleared; however, the relapse was on the PSAL side.Reported recurrence rate after high-fuence laser treatment was 0.6-1.2%[10], but higher recurrence was reported in younger patients with a rate of 15.4% [28].Te possible explanation for this relapse happened only on the PSAL side may be that the melanin-defcient melanocytes after the PSAL laser gradually accumulated melanin which would exaggerate pigment and Dermatologic Terapy trigger recurrence after complete clearance,while frequent and multiple LF-QSNY laser irradiation cumulates phototoxic damage on melanocytes, which causes a decrease in melanogenesis and atrophy of melanocyte dendrites [29,30].
In conclusion, based on patient's choice, LF-QSNY would be more preferred than PSAL among young patients due to the signifcantly reduced side efects and downtime.Also, LF-QSNY achieves good efcacy in younger children (less than fve years old) and requires a short recovery time; thus, patients can conduct more sessions of laser in the same period, and younger children can achieve complete lesion removal quicker with slighter wound healing processes.
Te limitations of our research were the lack of sample size and objective evaluation.Prospective clinical trials with objective evaluation and larger sample sizes are necessary to further confrm our conclusion and results.

Conclusion
Te diference between the LF-QSNY and the PSAL in the treatment of nevus of Ota within a three-month comparative trial was statistically insignifcant.However, LF-QSNY is more welcomed by young patients and their guardians; it is likely to bring the best outcome in a shorter period and cause less temporary adverse reactions in the meantime than PSAL.While PSAL may be a better choice for those preferring fewer visits and treatments, obvious lesion clearance might be observed after the frst treatment of LF-QSNY, an initial test patch is suggested.

Figure 2 :Figure 3 :
Figure 2: Male patient, 4.8 months old.(a) Before treatment; (b) two weeks after sixth treatments with LF-QSNY on the lower part; 12 weeks after one treatment with PSAL on the upper part; (c) after the comparative trial, the patient's guardian chose LF-QSNY for follow-up treatment.Two weeks after another 18 sessions of LF-QSNY treatments, the lesions were completely removed.

Figure 6 :
Figure 6: Female patient, 6 years old.(a) Before treatment; (b-g) 2, 4, 6, 8, 10, and 12 weeks after one treatment with PSAL on the left and two weeks after frst, second, third, fourth, ffth, and sixth treatments with LF-QSNY on the right; (h) two weeks after 12 additional treatments with LF-QSNY, the lesion has been completely removed.Slight hypopigmentation can be still observed on the PSAL treated side.