Lasers in Medical Science

https://doi.org/10.1007/s10103-020-03125-9

ORIGINAL ARTICLE

Comparing the efficacy and safety of Q-switched and picosecond

lasers in the treatment of nevus of Ota: a systematic
review and meta-analysis
Natalie M. Williams 1 & Pooja Gurnani 1 & Jun Long 1 & John Reynolds 2 & Yue Pan 3 & Takahiro Suzuki 1 &
Ghadah I. Alhetheli 1,4 & Keyvan Nouri 1

Received: 15 July 2020 / Accepted: 10 August 2020

# Springer-Verlag London Ltd., part of Springer Nature 2020

Abstract
Nevus of Ota is cosmetically burdensome and often prompts patients to seek treatment. Lasers are commonly used in removing
these lesions; however, no systemic analysis has been conducted to support a gold standard laser. To conduct a meta-analysis of
the efficacy and safety of Q-switched Nd:YAG lasers (QSNL), Q-switched ruby lasers (QSRL), Q-switched alexandrite lasers
(QSAL), and picosecond alexandrite lasers (PSAL) in removing nevus of Ota. Inclusion criteria were nevus of Ota patients
treated with QSNL, QSRL, QSAL, or PSAL and documentation of percent clearance and the rate of at least one adverse event.
Articles in English, Chinese, or Japanese were included. The prespecified outcome measures were efficacy (percent clearance)
and safety (rates of hyperpigmentation, hypopigmentation, scarring, and recurrence). The review included 57 studies and 13,417
patients. The pooled success rate was 64% for QSNL (95% CI 52–76%), 54% for QSRL (95% CI 39–69%), 58% for QSAL
(95% CI 44–72%), and 100% for PSAL (95% CI 98–102%). The pooled adverse event rate was 5% for QSNL (95% CI 4–6%),
14% for QSRL (95% CI 9–19%), 9% for QSAL (95% CI 6–12%), and 44% (95% CI 31–57%) for PSAL. QSNL has the most
evidence for effectively and safely treating nevus of Ota. PSAL potentially has a superior efficacy; however, further studies are
needed to elucidate its side effect profile when treating nevus of Ota.

Keywords Dermatology . Pigmented lesions . Nevus of Ota . Q-switched lasers . Picosecond lasers

Introduction hyperpigmented macules and patches on the face, generally

Nevus of Ota, or oculodermal melanocytosis, is a benign der-
mal melanocytic nevus. It typically presents as blue-gray
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s10103-020-03125-9) contains supplementary
material, which is available to authorized users.
* Natalie M. Williams
nmw50@med.miami.edu
1
Dr. Phillip Frost Department of Dermatology and Cutaneous
Surgery, University of Miami Miller School of Medicine, 1150 NW
14th Street, Miami, FL 33136, USA
2
University of Miami Miller School of Medicine, Miami, FL, USA
3
Department of Public Health Sciences, University of Miami Miller
School of Medicine, Miami, Florida, USA
4
Department of Dermatology and Cutaneous Surgery, College of
Medicine, Qassim University, Buraydah, Saudi Arabia
distributed along the ophthalmic and maxillary divisions of
the trigeminal nerve. The majority of cases affect unilateral
facial regions such as the forehead, zygoma, and periorbital
areas, with only 5–10% of lesions demonstrating bilateral in-
volvement [1]. The condition is more common in Asian wom-
en, with a 5:1 female-to-male ratio [2].
Although these are benign lesions, patients with nevus of
Ota may suffer psychologic distress given the cosmetic ap-
pearance. Previously used treatment options included cryo-
therapy, dermabrasion, and skin-grafting. Due to side effects
and poor patient satisfaction, these options have been super-
seded by laser therapy. Presently, Q-switched lasers are the
most widely used and well-studied lasers for treating nevus of
Ota, and include Q-switched ruby lasers (QSRL), Q-switched
neodymium-doped yttrium aluminum garnet (Nd:YAG) la-
sers (QSNL), and Q-switched alexandrite lasers (QSAL), each
with advantages and shortcomings. QSRL has a relatively
short wavelength (694 nm), allowing for greater absorption
of dermal melanin. QSNL has a longer wavelength (1064

nm) and penetrates 4–6 mm into the skin before dispersing
energy. Finally, QSAL has a wavelength (755 nm) that is ideal
for targeting deep melanin but has decreased absorption of
superficial melanin when compared with shorter wavelengths.
Recently, the European Society of Laser in Dermatology
recommended the 1064 nm QSNL as the gold standard treat-
ment for nevus of Ota [3]. However, no systematic review
comparing this laser with both the QSRL and QSAL exists.
In 2016, a meta-analysis compared QSAL and QSNL for
treating nevus of Ota, finding that QSAL had higher success
rates with lower complication rates [4]. Given these contradic-
tory conclusions and the lack of a systematic comparison of
each Q-switched laser used in nevus of Ota, further evaluation
is warranted. Likewise, treatment is no longer limited to Q-
switched lasers. The picosecond laser became available in
2013 for its use in tattoo removal. Reports of the picosecond
alexandrite laser (PSAL) in treating nevus of Ota lesions are
promising and may be more effective than Q-switched lasers
[5]. Thus, PSAL should also be methodically compared with
Q-switched lasers.
Given the cosmetic burden of this lesion, the most effective
laser should be used. While lasers are generally safe, they carry
risks such as dyspigmentation and scarring. Therefore, selecting
a laser with the lowest side effect profile is essential. The objec-
tive of this study is to systematically review and quantitatively
analyze the efficacy and safety of laser therapy for nevus of Ota,
specifically comparing QSNL, QSRL, QSAL, and PSAL.
Materials and methods
Search strategy
Our review was conducted according to the Methodological
Expectations for Cochrane Intervention Reviews (MECIR)
and reported following preferred reporting items for system-
atic reviews and meta-analyses (PRISMA) and meta-analysis
of observational studies in epidemiology (MOOSE) guide-
lines. We registered a protocol for the review with
PROSPERO (CRD42019147243). We searched Ovid
Medline (1946 to present, including Epub Ahead of Print,
In-Process & Other Non-Indexed Citations and Daily),
Embase (Elsevier Embase.com, 1947 to present), CINAHL
Plus (EBSCO, 1937 to present), Cochrane Central
(Cochrane Library, Wiley, no date limits), and Scopus
(Elsevier, 1788 to present). We searched the foreign
language databases CiNii Articles (National Institute of
Informatics, Japan, 1906 to present), J-STAGE (Japan
Science and Technology Agency, without date limits),
CNKI Overseas, (China Knowledge Resource Integrated
Database, China Academic Journals, Professional Search,
1994 to present), and the VHL Regional Portal (BIREME-
PAHO-WHO, The Latin American and Caribbean Center on
Lasers Med Sci
Health Sciences Information, Pan American Health
Organization, and World Health Organization, 1982 to pres-
ent) using English language interfaces. We searched trial reg-
istries Clinicaltrials.gov and the World Health Organization
International Clinical Trials Registry Platform (ICTRP) for
trials with reported results. We incorporated studies cited in
previous systematic reviews and guidelines into the search
strategy, and we searched the online tables of contents of four
journals, British Journal of Dermatology, Journal of the
American Academy of Dermatology, JAMA Dermatology,
and Lasers in Surgery and Medicine, in lieu of handsearching.
The search strategy was developed by an academic health
science librarian (J.R.) in consultation with the project lead
(N.W.) and was reviewed using the Peer Review for
Electronic Search Strategies tool through the PRESSforum
(pressforum.pbworks.com) [6]. The search strategy was
written for Ovid Medline and translated using each
database’s syntax, controlled vocabulary, and search fields.
MeSH terms, EMTREE terms, CINAHL headings, and text
words were used for the search concepts of laser therapy and
nevus of Ota and their synonyms. No language or date limits
were applied. We searched all databases on September 13,
2019. Journal table of content searches was completed on
October 10, 2019. A final search of Ovid Medline, Embase,
CINAHL, Cochrane Central, and Scopus was run on
March 23, 2020. For full search strategies, see Appendix 1.
All database records were downloaded to EndNote X9, then
uploaded to Covidence web-based software for deduplication,
screening, and data extraction. We contacted one study author
directly for clarification of methods. After study selection, two
authors (J.R. and J.L.) checked for retractions at The
Retraction Watch Database and individual journal websites.
Eligibility criteria
Patients of all ages, ethnicities, and skin types with cutaneous
nevus of Ota treated with QSNL, QSRL, QSAL, or PSAL
were included. Studies were required to document a percent
clearance of the lesion after treatment, with the rate of at least
one of the following adverse events recorded: hyperpigmen-
tation, hypopigmentation, scarring, and/or recurrence. Articles
of human studies in English, Chinese, or Japanese were in-
cluded. Exclusion criteria were as follows: studies with < 5
patients, animal studies, articles in languages other than those
mentioned in the inclusion criteria, narrative reviews, combi-
nations of lasers, prior laser treatment, combinations of lasers
with surgical or medical management, studies not reporting
outcomes per laser modality, and studies comprised only of
patients with bilateral lesions (or phrased acquired nevus of
Ota-like macules [ABNOM] and/or Hori’s nevus), as bilateral
nevus of Ota lesions is infrequent (5–10% of cases) and more
resistant to laser therapy [7]. Studies that included patients
with bilateral lesions, but were predominantly comprised of
Lasers Med Sci
unilateral lesions in proportions similar to the general popula-
tion (> 85%), were included. Our prespecified outcome mea-
sures were as follows: (i) percent clearance; (ii) hyperpigmen-
tation; (iii) hypopigmentation; (iv) scarring; and (v)
recurrence.
Risk of bias and quality assessment
Risk of bias of randomized controlled trials (RCTs) was
assessed with the Revised Cochrane risk-of-bias tool for ran-
domized trials [8]. For the quality assessment of case series,
we used the quality appraisal tool for case series, which con-
sists of an 18-criteria checklist [9]. Prior to extraction, we
predefined the most relevant items to generate five key items
required to indicate sufficient quality. If at least 14 of the 18
items and all five key items were scored “yes,” the study was
labeled “good quality.” If either 14 of the 18 items or all five
key items were met, the study was considered “moderate qual-
ity,” and if neither criterion was met, the study was labeled
“low quality.”
Reference determination
Two authors (N.W. and P.G.) independently screened the ti-
tles and abstracts of all English citations generated via the
search strategy and used the aforementioned inclusion and
exclusion criteria to vet the articles that would move on to
full-text screening. For Chinese articles, N.W. and J.L. com-
pleted the same process with translation provided by a native
speaker (J.L.). For Japanese articles, N.W. and T.S. underwent
the same process with translation provided by a native speaker
(T.S.). The full texts of all potentially eligible studies were
then scrutinized by authors independently. Disagreements
were resolved by reevaluation and consensus discussion. A
flow diagram is explained in Fig. 1.
Data extraction
The data was extracted using a combined spreadsheet by each
author independently, and risk-of-bias and quality assess-
ments were carried out. The following information from each
eligible study was recorded: author, year, location, study de-
sign, number of patients, loss to follow-up, patient ethnicities
and skin types, ages, nevus of Ota features (location, color),
laser modality, number of sessions, treatment intervals, length
of follow-up, laser parameters, percent clearance rate, and
rates of adverse effects (hyperpigmentation,
hypopigmentation, scarring, and recurrence).
Statistical analysis
All statistical analyses were completed using the Package
“meta” 4.11-0 in R-3.6.3 [10, 11]. The success, failure, and
total adverse event rates (including hyperpigmentation,
hypopigmentation rate, and scarring) were evaluated by
meta-analytic techniques. For each meta-analysis, the
Cochrane’s Q statistic test (Q test) was calculated to assess
the heterogeneity of studies, which was defined by the value
of I2. When I2 was less than 30%, studies were considered to
have acceptable heterogeneity, and the fixed-effects model
was used. The random-effects model was applied to studies
with significant heterogeneity, and forest plots were created
demonstrating the pooled value with its 95% confidence in-
terval (CI). A two-tailed P value less than 0.05 was deemed
statistically significant.
Results
Included studies
The database search retrieved a total of 680 unique hits,
and 176 studies had the full text screened. The majority of
eligible studies were case series, with only three RCTs. In
the 57 included studies, a total of 13,417 patients with
nevus of Ota were evaluated. The characteristics of includ-
ed studies for QSNL, QSRL, QSAL, and PSAL are shown
in Tables S1–S4, respectively. The number of participants
varied between studies (range 5–1496 patients), as did the
ages of participants (range 4 months to 72 years). Overall,
QSNL was the most studied modality (28 studies) [12–39],
followed by QSAL (18) [13, 16, 32, 35, 40–53], QSRL
(17) [22, 30, 54–68], and PSAL (2) [43, 69]. Laser param-
eters, such as fluence, spot size, and pulse duration, varied
strongly between and within studies, as did the number of
treatments (single treatment up to 46 times), interval be-
tween treatments (2 weeks to over 3 years) and duration of
follow-up (weeks to 6 years). Owing to the heterogeneity
and incomparability of laser settings, treatment timing, and
follow-up, it was not possible to incorporate these features
into the meta-analysis. Furthermore, while we extracted
information on patient characteristics (i.e., ethnicity,
Fitzpatrick type, nevus features), the overwhelming major-
ity of studies did not document this.
Quality assessment
The risk of bias of NRCTs and quality assessment of case
series are summarized in Fig. 2. All RCTs were assessed as
having a high risk of bias, largely due to performance bias and
detection bias. The overall quality of the case series was low,
often due to unclear eligibility criteria, no reporting of loss to
follow-up and follow-up duration, and the lack of statistical
tests.
 Lasers Med Sci

Records idenfied through database

searching (n = 1,050)

Idenficaon
- Embase (n=343)
- Scopus (n=224)
- Ovid MEDLINE (n=207)
- CKNI Overseas (n=131)
- CiNii Arcles (n=56)
- Cochrane Central (n=46) Addional records idenfied through
- CINAHL (n=46)
Table of Contents searching
- WHO PAHO VHL (n=8)
- J-Stage (n=7) (n = 91)

Total records idenfied through database

searching
(n = 1,141)
Screening

Excluded duplicates
(n = 448)

Records screened on tle/abstract Records excluded

(n = 693) (n = 517)

Studies screened on full-text Full-text arcles excluded

Eligibility

eligibility (n = 119)
(n = 176) - Wrong outcome (n=31)
- Unable to retrieve full text (n=24)
- Outcomes not specified per lesion
type (n=12)
- Duplicate or overlapped data
(n=11)
Studies included in - Review, expert opinion, or
comment (n=8)
qualitave synthesis - <5 paents (n=7)
(n = 57) - Abstract only (n=6)
- Outcomes not specified per laser
type (n=5)
- Non-English/Chinese/Japanese
language (n=4)
Included

Studies included in - Prior laser treatment (n=4)

- Study not completed (n=3)
quantave synthesis (meta- - ABNOM, Hori’s nevus, or excessive
analysis) bilateral cases (n=2)
(n = 55) - Combined with surgical or medical
treatment (n=2)

Fig. 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of screening and selection procedure

Meta-analyzed results improvement,” 25–49% as “moderate improvement,”

The success rate, failure rate, and total adverse event rate
(including hyperpigmentation, hypopigmentation, and scar-
ring) were analyzed by meta-techniques.
Percent clearance
In this systematic review, the primary outcome was laser
efficacy, specifically measured by the percent clearance.
The majority of studies measured percent clearance using
a quartile system, defining < 25% clearance as “poor
50–74% as “good improvement,” and > 75% as “excellent
improvement.” Several studies set > 70% clearance as
“excellent,” with < 30% as “poor” [31, 49, 51, 65]. To
maximize inclusivity, we defined the success rate to be >
70% and the failure rate to be < 30%. Therefore, studies
using different percentage cutoffs that could not be incor-
porated into this system were not included in the meta-
analysis [30].
The success rate of QSNL (χ2 = 8402.54, p < 0.001, I2 =
99.7%), QSRL (χ2 = 648.32, p < 0.001, I2 = 97.8%), and
QSAL (χ2 = 3074.56, p < 0.001, I2 = 99.4%) demonstrated
Lasers Med Sci

(a) (b) Author Year Items scored 'yes' Key items scored Quality

Blinding of participants and personnel (performance bias)

Alster 1995 10/18 4/5 Low
Aurangabadkar 2008 11/18 4/5 Low

Blinding of outcome assessment (detection bias)

Chan 2000 15/18 5/5 Good

Random sequence generation (selection bias)

Chang 1996 12/18 4/5 Low
Chang 2011 12/18 4/5 Low

Incomplete outcome data (attrition bias)

Allocation concealment (selection bias)
Chen 2000 8/18 4/5 Low
Choi 2014 12/18 3/5 Low

Selecve reporng (reporng bias)

Choi 2015 12/18 4/5 Low
Chu 2012 13/18 5/5 Moderate
Deng 2000 8/18 3/5 Low
Gao 2015 8/18 3/5 Low
Gao 2001 8/18 3/5 Low
Geronemus 1992 9/18 4/5 Low
Hao 2010 8/18 4/5 Low
Kang 1999 13/18 4/5 Low
Kar 2011 13/18 4/5 Low
Kasai 2001 9/18 3/5 Low
Ge + + - - + - Konda 2000 10/18 4/5 Low
Kono 2001 15/18 5/5 Good
Pan + ? - - + ? Li 2011 10/18 4/5 Low
Yang + ? - - + ? Liu 2016 11/18 3/5 Low
Liu 2018 12/18 4/5 Low
Liu 2000 7/18 3/5 Low
Liu 2013 14/18 5/5 Good
Lowe 1993 9/18 3/5 Low
Lu 2002 14/18 5/5 Good
Lu 2002 11/18 4/5 Low
Miyamoto 1996 10/18 3/5 Low
Moreno-Arias 2001 10/18 4/5 Low
Rong 2014 8/18 4/5 Low
Sakio 2018 11/18 5/5 Moderate
Sami 2016 13/18 5/5 Moderate
Sethuram 2013 15/18 5/5 Good
Shimbashi 1997 8/18 4/5 Low
Suh 2000 11/18 4/5 Low
Suzuki 1995 9/18 4/5 Low
Suzuki 1996 9/18 4/5 Low
Taylor 1994 12/18 4/5 Low
Tsai 2000 8/18 4/5 Low
Ueda 2000 9/18 3/5 Low
Wang 2016 12/18 5/5 Moderate
Wang 2006 9/18 4/5 Low
Watanabe 1994 10/18 3/5 Low
Xu 2011 11/18 3/5 Low
Yamashita 1998 8/18 3/5 Low
Yan 2018 12/18 3/5 Low
Yan 2016 7/18 2/5 Low
Yang 1996 10/18 4/5 Low
Yongqian 2017 14/18 4/5 Low
Yuan 2002 8/18 3/5 Low
Zeng 2003 10/18 3/5 Low
Zhao 2009 8/18 3/5 Low
Zhong 2017 9/10 4/5 Low
Zhou 2004 8/18 3/5 Low
Fig. 2 a Risk-of-bias assessment of randomized controlled studies. b Quality assessment of case series

significant heterogeneity by Q test. Thus, the random-effects
model was applied. PSAL (χ2 = 1.25, p = 0.264) demonstrat-
ed acceptable heterogeneity; therefore, the fixed-effects model
was used. The pooled success rate was 64% for QSNL (95%
CI 52–76%), 54% for QSRL (95% CI 39–69%), 58% for
QSAL (95% CI 44–72%), and 100% for PSAL (95% CI
98–102%) (Fig. 3).
Similarly, the failure rate of QSNL (χ2 = 270.33, p <
0.001, I2 = 91.1%), QSRL (χ2 = 98.14, p < 0.001, I2 =
86.8%), and QSAL (χ2 = 266.40, p < 0.001, I2 = 95.5%)
demonstrated significant heterogeneity. The pooled failure
rate was 3% for QSNL (95% CI 2–4%), 5% for QSRL (95%
CI 1–8%), 12% for QSAL (95% CI 7–16%), and 0% for
PSAL (95% CI−7%–7%) (Figure S1).
a QSNL ES (95% CI)
c QSAL ES (95% CI)
Fig. 3 a–d Annotated forest plot for meta-analysis of success rate (> 70%
clearance) calculated using a random-effects model for QSNL, QSRL,
QSAL, and the fixed-effects model for PSAL. Size of square is directly
Lasers Med Sci
Adverse event rate
In this review, adverse events included hyperpigmentation,
hypopigmentation, or scarring. The total adverse event rate
in the QSNL (χ2 = 406.01, p < 0.001, I2 = 94.3%), QSRL
(χ2 = 105.66, p < 0.001, I2 = 87.7%), and QSAL (χ2 =
371.08, p < 0.001, I2 = 95.7%) groups demonstrated signifi-
cant heterogeneity by Q test, requiring the use of the random-
effects model. The fixed-effects model was used for PSAL (χ2
= 2.94, p = 0.086). The pooled adverse event rate was 5% for
QSNL (95% CI 4–6%), 14% for QSRL (95% CI 9–19%), 9%
for QSAL (95% CI 6–12%), and 44% for PSAL (95% CI 31–
57%) (Fig. 4). Outcomes per laser type are demonstrated in
Table 1.
b
QSRL ES (95% CI)
d
PSAL
ES (95% CI)
proportional to amount of information available. a QSNL, b QSRL, c
QSAL, and d PSAL
Lasers Med Sci

Discussion recommend 1064-nm QS lasers as the gold standard treatment

We systematically reviewed 57 studies with four different
lasers in 13,417 patients to examine the efficacy and safety
of these options in removing nevus of Ota. Overall, the QSNL
was the most studied device. In general, all lasers were effec-
tive in removing pigment; however, the quality of evidence
was very low.
With regard to efficacy, PSAL appears superior to Q-
switched lasers, with a pooled success rate of 100% and fail-
ure rate of 0%. However, these values were derived from only
two studies and were not statistically significant. Although we
cannot conclude that PSAL is the most effective laser based
on this limited information, the results of the RCT with PSAL
demonstrated the most promise of all included studies [43]. To
understand why picosecond lasers may be superior, it is im-
portant to recognize how they differ from Q-switched lasers.
Q-switched lasers function on the principle of selective
photothermolysis, or the specific targeting of chromophores
by a particular wavelength. In contrast, picosecond lasers
eliminate pigment primarily via a photomechanical effect
rather than a photothermal process [70]. The sudden increase
in temperature generates a pressure wave that surpasses the
tensile strength of the pigment, fragmenting it into pieces. To
minimize collateral damage, a pulse duration that is less than
or equal to the target’s thermal relaxation time (TRT) should
be selected. Dermal melanosomes, such as those deposited in
nevus of Ota, have a TRT of around 50–250 ns, and therefore
seem to be ideal targets for Q-switched lasers that function on
the level of nanoseconds [71]. However, a pulse duration in
the picosecond range may actually be superior due to the
higher maximum temperatures and greater photomechanical
effect [72, 73].
Overall, QSNL has the most evidence to support its effica-
cy in removing nevus of Ota, with a pooled success rate of
64% and a failure rate of only 3%. This is compared with
success and failure rates of 54% and 5% for QSRL, and
58% and 12% for QSAL. The superior efficacy of the
QSNL is likely related to its longer wavelength (1064 nm),
which allows for deeper penetration into the skin to eradicate
dermal melanocytes. These results support the European
Society of Laser in Dermatology’s guidelines, which
for nevus of Ota [3].
While the success rates of QSAL and QSRL are similar, the
failure rate of QSAL is strikingly higher (12 vs. 5%). These
results were partly influenced by studies by Chan and Chen,
which documented failure rates of 57% and 37%, respectively
[13, 41]. The latter study’s failure rate may be related to the
increased proportion of Tanino type III lesions (38%), which
indicate extensive nevus of Ota involvement and normally
account for about 16% of lesions [74]. While there is no ob-
vious choice for the least efficacious laser of these options,
QSRL appears to be an overall more effective laser than
QSAL given its more acceptable failure rate.
In terms of safety, QSNL again proved to be the most
impressive, with an adverse event rate of 5%. The side effects
included in this number were hyperpigmentation,
hypopigmentation, and scarring. Transient side effects such
as burning and edema were not included as they are common
and expected events. As with efficacy, the safety of QSNL is
likely due to its longer wavelength, which allows for de-
creased melanin light absorption and thus a lesser risk of
dyspigmentation. This is particularly important in individuals
with darker skin types whose higher concentrations of epider-
mal melanin put them at a greater risk of side effects. Of the
other Q-switched options, QSRL demonstrated the highest
adverse event rate at 14%. This relatively high rate was influ-
enced by an article in which all patients demonstrated both
hyperpigmentation and hypopigmentation after laser treat-
ment [62]. However, this study was carried out in adults (ages
25–47) with relatively darker skin types, including Fitzpatrick
VI, which are both demographics associated with higher risks
of complications [58].
Finally, PSAL displayed the highest adverse event rate at
44%. Of note, this was from hyperpigmentation and
hypopigmentation, with no cases of scarring reported. The
study that led to this high rate was by Ge and colleagues,
who conducted an RCT comparing PSAL and QSAL, finding
that both hyper- and hypopigmentation rates were significant-
ly higher among patients treated with QSAL [43]. They attrib-
uted the overall high rates of dyspigmentation to the short
follow-up time (3 months) in which some patients may not
have fully recovered. Theoretically, picosecond lasers should

Table 1 Comparison of success rate (> 70% clearance), failure rate (< 30% clearance), and total adverse event rate (hyperpigmentation,
hypopigmentation, scarring) between QSNL, QSRL, QSAL, and PSAL

Success rate (with 95% CI) Failure rate (with 95% CI) Total adverse event rate (with 95% CI)

QSNL 64% (52–76%) 3% (2–4%) 5% (4–6%)

QSRL 54% (39–69%) 5% (1–8%) 14% (9–19%)
QSAL 58% (44–72%) 12% (7–16%) 9% (6–12%)
PSAL 100% (98–102%) 0% (− 7 to 7%) 44% (31–57%)

CI confidence interval

a QSNL ES (95% CI)
c QSAL ES (95% CI)
Fig. 4 a–d Annotated forest plot for meta-analysis of adverse event rate
(hyperpigmentation, hypopigmentation, scarring) calculated using a
random-effects model for QSNL, QSRL, QSAL, and the fixed-effects
be safe given their short energy pulses that allow for less heat
diffusion into surrounding structures, which should therefore
lead to fewer side effects [75]. Various studies comparing
picosecond lasers with Q-switched lasers for ABNOM and
tattoo removal have demonstrated a significantly lower side
effect profile with picosecond lasers [76]. Therefore, the lim-
ited sample size for PSAL in our analysis likely skews the
adverse event rate. Ultimately, more studies on the use of
picosecond lasers for nevus of Ota are needed to better eluci-
date its side effects.
It is important to note that a multitude of variables may
factor into these results. For example, the outcomes are likely
related to patient factors (i.e., age, skin type, ethnicity) or
features intrinsic to the nevus (i.e., location, color). In
Lasers Med Sci
b
QSRL ES (95% CI)
d
PSAL ES (95% CI)
model for PSAL. Size of square is directly proportional to amount of
information available. a QSNL, b QSRL, c QSAL, and d PSAL
addition, a wide range of laser parameters were used between
and within individual studies. While the nature of procedural
studies limits RCTs to being single-blinded, it is nevertheless
important to standardize laser parameters, patient characteris-
tics, and treatment timing in future studies to fully interpret the
effect.
To our knowledge, this is the first systematic review and
meta-analysis of the efficacy and safety of Q-switched and
picosecond lasers in treating nevus of Ota. While a 2016
meta-analysis compared QSNL and QSAL [4], our study fur-
ther compared these lasers with QSRL and PSAL.
Furthermore, we investigated articles from a wider range of
databases and years, in addition to those in Chinese and
Japanese, which resulted in a different outcome. Including
Lasers Med Sci
Chinese and Japanese articles was a particular strength of our
study, as nevus of Ota is relatively common in these popula-
tions. However, one limitation was our decision to omit
Chinese and Japanese articles when re-running the search in
March 2020 due to the difficulties acquiring non-English
articles.
Overall, QSNL has the most evidence for effectively and
safely treating nevus of Ota; however, the quality of evidence
is low. While PSAL is emerging as a highly effective option,
there is limited data on its side effect profile when treating
nevus of Ota and should therefore be further studied before
recommending it as a first-line treatment option.
Acknowledgments We would like to acknowledge the hardworking in-
terlibrary loan staff at the University of Miami Calder Memorial Library
and Otto G. Richter Library who assisted in retrieving the full-text articles
for this study. We would also like to thank Rachel Couban, MA, MISt,
from the DeGroote Institute for Pain Research and Care at McMaster
University, Hamilton, ON, for peer review of the Medline search strategy.
Availability of data and material Provided in the supplemental
materials.
Authors’ contributions
• NW: project design, title/abstract screening, full-text screening, quality
appraisal, data extraction, wrote manuscript
• PG: title/abstract screening, English full-text screening, quality apprais-
al, data extraction, edited manuscript
• JL: title/abstract screening, Chinese full-text screening, quality appraisal,
data extraction
• JR: creation of search strategy, completion of in-depth literature search
• TS: title/abstract screening, Japanese full-text screening, quality apprais-
al, data extraction
• YP: statistical analysis, edited manuscript
• GA: third person for title/abstract and full-text screening to resolve
conflicts
• KN: project design, edited manuscript
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
Code availability N/A
Informed consent/ethics approval N/A
References
1. Mosher D (1993) Disorders of pigmentation. Dermatol Gen Med.
In: Fitzpatrick T, Eisen A, Wolff K, et al. (eds) Dermatology in
general medicine, 4th edn
2. Hidano A, Kajima H, Ikeda S, Mizutani H, Miyasato H, Niimura M
(1967) Natural history of nevus of Ota. Arch Dermatol 95(2):187–
195
3. Passeron T, Genedy R, Salah L, Fusade T, Kositratna G, Laubach
HJ et al (2019) Laser treatment of hyperpigmented lesions: position
statement of the European Society of Laser in Dermatology. J Eur
Acad Dermatol Venereol 33(6):987–1005. https://doi.org/10.1111/
jdv.15497
4. Yu P, Yu N, Diao W, Yang X, Feng Y, Qi Z (2016) Comparison of
clinical efficacy and complications between Q-switched alexandrite
laser and Q-switched Nd:YAG laser on nevus of Ota: a systematic
review and meta-analysis. Lasers Med Sci 31(3):581–591. https://
doi.org/10.1007/s10103-016-1885-z
5. Chan JC, Shek SY, Kono T, Yeung CK, Chan HH (2016) A retro-
spective analysis on the management of pigmented lesions using a
picosecond 755-nm alexandrite laser in Asians. Lasers Surg Med
48(1):23–29. https://doi.org/10.1002/lsm.22443
6. McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V,
Lefebvre C (2016) PRESS Peer Review of Electronic Search
Strategies: 2015 Guideline Statement. J Clin Epidemiol 75:40–46.
https://doi.org/10.1016/j.jclinepi.2016.01.021
7. Lee B, Kim YC, Kang WH, Lee ES (2004) Comparison of charac-
teristics of acquired bilateral nevus of Ota-like macules and nevus
of Ota according to therapeutic outcome. J Korean Med Sci 19(4):
554–559. https://doi.org/10.3346/jkms.2004.19.4.554
8. Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron
I et al (2019) RoB 2: a revised tool for assessing risk of bias in
randomised trials. BMJ:366
9. Moga C, Guo B, Schopflocher D, Harstall C (2012) In: Edmonton
AB (ed) Development of a quality appraisal tool for case series
studies using a modified Delphi technique. Institute of Health
Economics
10. Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-
analysis with R: a practical tutorial. Evid-Based Ment Health 22(4):
153–160
11. Schwarzer G (2007) meta: an R package for meta-analysis. R News
7(3):40–45
12. Aurangabadkar S (2008) QYAG5 Q-switched Nd:YAG laser
treatment of nevus of Ota: an Indian study of 50 patients. J
Cutan Aesthet Surg 1(2):80–84. https://doi.org/10.4103/0974-
2077.44164
13. Chan HH, Leung RS, Ying SY, Lai CF, Kono T, Chua JK et al
(2000) A retrospective analysis of complications in the treatment of
nevus of Ota with the Q-switched alexandrite and Q-switched Nd:
YAG lasers. Dermatol Surg 26(11):1000–1006. https://doi.org/10.
1046/j.1524-4725.2000.0260111000.x
14. Chang CJ, Kou CS (2011) Comparing the effectiveness of Q-
switched Ruby laser treatment with that of Q-switched Nd:YAG
laser for oculodermal melanosis (Nevus of Ota). J Plast Reconstr
Aesthet Surg 64(3):339–345. https://doi.org/10.1016/j.bjps.2010.
05.036
15. Choi CW, Kim HJ, Lee HJ, Kim YH, Kim WS (2014) Treatment of
nevus of Ota using low fluence Q-switched Nd:YAG laser. Int J
Dermatol 53(7):861–865. https://doi.org/10.1111/ijd.12085
16. Choi JE, Lee JB, Park KB, Kim BS, Yeo UC, Huh CH et al (2015)
A retrospective analysis of the clinical efficacies of Q-switched
Alexandrite and Q-switched Nd:YAG lasers in the treatment of
nevus of Ota in Korean patients. J Dermatol Treat 26(3):240–245.
https://doi.org/10.3109/09546634.2014.930409
17. Deng LCLJ, Chen QF, Li ZH, Li XH (2000) Comparison of Q-
switched Alexandrite laser and Q-Switched Nd: YAG laser in the
treatment of nevus of Ota (Chinese). Chin J Dermatol 33(6):430
18. Gao Y, Ye X (2001) Clinical effect of Q-switched Nd:YAG dye
laser surgery in treatment of 209 patients with nevus of Ota.
Southern China Journal of Dermato-Venereology 8(2):81–82
19. Gao W (2015) Clinical analysis of Q switch laser in treatment of
nevus of Ota. China Health Stand Manag 6(17):43–44
20. Hao Y, Hu Y, Zhang M (2010) Clinical experience on Q-switch
1064 nm Nd YAG laser in treatment of 52 cases of nevus of Ota on
the face. Occup Health 26(14):1657–1658
21. Kar HK, Gupta L (2011) 1064 nm Q switched Nd: YAG laser
treatment of nevus of Ota: an Indian open label prospective study
of 50 patients. Indian J Dermatol Venereol Leprol 77(5):565

22. Kasai K, Sakai M, Hisano A, Asada Y, Yamamura Y (2001) Laser
treatment of nevus of Ota. Jpn Plast Reconstr Surg 44(12):1175–
1183
23. Li C, Yin R, Deng J, Cheng L, Huang Y, Yang L (2011) The
therapeautic effect analysis of 1496 cases in the treatment of nevus
of Ota by Q-switch Nd:YAG laser. Chin J Aesthet Med 20(12):
1934–1935
24. Liu X, Yuan K, Zhang T, Wu S (2013) Analysis on therapeautic
efficacy of Q-switching 1064 nm laser on nevus of Ota. Chin J
Laser Med Surg 22(3):151–155
25. Liu Y, Zeng W, Geng S (2016) A retrospective study on the char-
acteristics of treating nevus of Ota by 1064-nm Q-switched
neodymium-doped yttrium aluminum garnet laser. Indian J
Dermatol 61(3):347. https://doi.org/10.4103/0019-5154.182470
26. Liu Y, Zeng W, Li D, Wang W, Liu F (2018) A retrospective
analysis of the clinical efficacies and recurrence of Q-switched
Nd:YAG laser treatment of nevus of Ota in 224 Chinese patients.
J Cosmet Laser Ther 20(7-8):410–414. https://doi.org/10.1080/
14764172.2018.1444772
27. Pan Z (2010) The observations of effects and complications on
YAG laser with nevus of ota. Med Innov China 7(11):63–64
28. Sethuraman G, Sharma VK, Sreenivas V (2013) Melanin index in
assessing the treatment efficacy of 1064 nm Q switched Nd-Yag
laser in nevus of Ota. J Cutan Aesthet Surg 6(4):189–193. https://
doi.org/10.4103/0974-2077.123398
29. Suzuki T (1995) Q-switched Nd:YAG laser treatment of Ota’s ne-
vus. J Jpn PRS 15(4):238–252
30. Suzuki T, Hosaka K, Aihara K (1996) Comparative study of Q-
switched Nd:YAG laser and Q-switched ruby laser treatments for
deep-seated Ota’s nevus. 日本レ ザ 学会誌;16(Supplement):301-8.
31. Wang C, Shao L, Hu F (2016) The curative effect and safety of Q-
switched Nd:YAG laser in the treatment of the dermis pigmented
dermatosis. Chin J Modern Oper Surg 20(4):316–320
32. Xu C, Zhang X, Chen Y, Wen L (2011) The treatment effect of
different bandwidths laser on nevus of Ota. Acta Laser Biol Sin (激
光生物学报) 20(4):564–568
33. Yan F, Zhou B, Lu Y (2016) Efficacy of the pigmented dermatosis
treated with Q-switched Nd:YAG laser. Chin J Aesthet Med
25(10):88–89
34. Yan L, Di L, Weihua W, Feng L, Ruilian L, Jun Z et al (2018) A
study on the clinical characteristics of treating nevus of Ota by Q-
switched Nd:YAG laser. Lasers Med Sci 33(1):89–93. https://doi.
org/10.1007/s10103-017-2342-3
35. Yang J, Zhang J, Huang H, Tang Y, Cen L (2019) Comparative
study on Q1064nm laser and Q755nm laser treatment of infant
Taitian nevus of Ota. Chin J Aesthet Med 28(1):70–72
36. Yongqian C, Li L, Jianhai B, Ran H, Li G, Hao W et al (2017) A
split-face comparison of Q-switched Nd:YAG 1064-nm laser for
facial rejuvenation in nevus of Ota patients. Lasers Med Sci 32(4):
765–769. https://doi.org/10.1007/s10103-017-2161-6
37. Yuan L, Yu L, Chen F (2002) Q-switched Nd:YAG laser in treat-
ment of nevus of Ota: report of 326 cases. Chin J Med Aesth
Cosmet 8(3):5–7
38. Zeng W, Wang Y (2003) Analysis of therapeautic effect and the
correlative influencing factors of nevus of Ota treated with Q-
switched Nd:YAG laser. Chin J Aesthet Med 12(5):481–483
39. Zhao W, Ye J, Yang E, Ouyang X (2009) Clinical survey of the
pigmented dermatosis treated by Q-switched Nd: YAG laser. Chin J
Aesthet Med 1:43
40. Alster TS, Williams CM (1995) Treatment of nevus of Ota by the
Q-switched alexandrite laser. Dermatol Surg 21(7):592–596.
https://doi.org/10.1111/j.1524-4725.1995.tb00512.x
41. Chen L, Qingzhen W, Huansheng Z, Shuyu Y, Hui W, Huifeng D
et al (2000) The clinical analysis of 246 cases of Ota nevus with Q-
switched Alexandrite Laser. Appl Laser 2:14
Lasers Med Sci
42. Chu Y, Xu Z, Sun Y (2012) Therapeautic effect of Q-switched
alexandrite laser on nevus of Ota: a report of 180 cases in children.
J Prac Dermatol 5(2):102–104
43. Ge Y, Yang Y, Guo L, Zhang M, Wu Q, Zeng R et al (2019)
Comparison of a picosecond alexandrite laser versus a Q-
switched alexandrite laser for the treatment of nevus of Ota: a ran-
domized, split-lesion, controlled trial. J Am Acad Dermatol. https://
doi.org/10.1016/j.jaad.2019.03.016
44. Kang W, Lee E, Choi GS (1999) Treatment of Ota’s nevus by Q-
switched alexandrite laser: therapeutic outcome in relation to clin-
ical and histopathological findings. Eur J Dermatol 9(8):639–643
45. Lu Z, Fang L-H, Jiao S (2002) Study on the treatment interval in Q-
switched Alexandrite laser therapy of nevus of Ota. Journal-Fudan
University Medical Science 29(2):125–128
46. Lu Z, Fang L, Jiao S, Huang W, Chen J, Wang X (2002) Q-
switched Alexandrite laser therapy in 522 patients with nevus of
Ota. J Clin Dermatol 31(7):434–436
47. Miyamoto H, Nakanishi H, Nakagawa K, Seike T, Takiwaki H
(1996) Quantitative evaluation of laser treatment for nevus of Ota
based on the color analysis of the skin surface image. Jpn J
Dermatol 106(4):415–419
48. Moreno-Arias GA, Camps-Fresneda A (2001) Treatment of nevus
of Ota with the Q-switched alexandrite laser. Lasers Surg Med
28(5):451–455. https://doi.org/10.1002/lsm.1073
49. Rong L, Ding T (2014) The observe of recent and future date
therapeutic effect that Q-switched alexandrite treated the skin
pigmented. SiChuan Med J 35(5):530–532
50. Sami L, Changzheng H, Yan L (2016) Factors affecting response,
number of laser sessions and complications in nevus of Ota treated
by Q-switched alexandrite laser: a retrospective study. G Ital
Dermatol Venereol 151(2):160–168
51. Suh DH, Hwang JH, Lee HS, Youn JI, Kim PM (2000) Clinical
features of Ota’s naevus in Koreans and its treatment with Q-
switched alexandrite laser. Clin Exp Dermatol 25(4):269–273
52. Wang H, Wang J, Liu Y, Zuo Y, Jin H, Jiang G, Li H, Ma D (2006)
Clinical efficacy of Q-switched Alexandrite laser for pigmentary
skin diseases in 4656 patients. Acta Acad Med Sin 28(2):202–205
53. Zhou H, Wang X, Sheng Z, An Y (2004) Treating nevus of Ota
using Q-switch alexandrite laser. Chin J Aesthet Med 13(1):29–30
54. Chang CJ, Nelson JS, Achauer BM (1996) Q-switched ruby laser
treatment of oculodermal melanosis (nevus of Ota). Plast Reconstr
Surg 98(5):784–790. https://doi.org/10.1097/00006534-
199610000-00004
55. Geronemus RG (1992) Q-switched ruby laser therapy of nevus of
Ota. Arch Dermatol 128(12):1618–1622
56. Kim C-S, Yang H-Y, Kim J-H (1996) Q-switched ruby laser in the
treatment of nevus of Ota. Ann Dermatol 8(1):6–13
57. KONDA T, SASAKI M, SHIMIZU T (2000) Q-switched ruby
laser therapy for nevus Ota. Skin Res 42(4):452–459
58. Kono T, Chan HH, Ercocen AR, Kikuchi Y, Uezono S, Iwasaka S
et al (2003) Use of Q-switched ruby laser in the treatment of nevus
of ota in different age groups. Lasers Surg Med 32(5):391–395.
https://doi.org/10.1002/lsm.10171
59. Liu J, Zuo W, Qian H (2000) Q-switched ruby laser in the treatment
of nevus of Ota: report of 246 Cases. Chin J Dermatol 33(1):26–28
60. Lowe NJ, Wieder JM, Sawcer D, Burrows P, Chalet M (1993)
Nevus of Ota: treatment with high energy fluences of the Q-
switched ruby laser. J Am Acad Dermatol 29(6):997–1001.
https://doi.org/10.1016/0190-9622(93)70280-7
61. Shimbashi T, Hyakusoku H, Okinaga M (1997) Treatment of nevus
of Ota by Q-switched ruby laser. Aesthet Plast Surg 21(2):118–121.
https://doi.org/10.1007/s002669900096
62. Taylor CR, Flotte TJ, Gange RW, Anderson RR (1994) Treatment
of nevus of Ota by Q-switched ruby laser. J Am Acad Dermatol
30(5 Pt 1):743–751. https://doi.org/10.1016/s0190-9622(08)
81505-8
Lasers Med Sci
63. Tsai Y-C, Lin H-C, Tseng F-Y, Young S-Y (2000) Treatment of
nevus of Ota using ruby lasers: six years of experience and review
of the literature. Formos J Surg 33(5):209–214
64. Ueda S, Isoda M, Imayama S (2000) Response of naevus of Ota to
Q-switched ruby laser treatment according to lesion colour. Br J
Dermatol 142(1):77–83. https://doi.org/10.1046/j.1365-2133.
2000.03264.x
65. Watanabe S, Takahashi H (1994) Treatment of nevus of Ota with
the Q-switched ruby laser. N Engl J Med 331(26):1745–1750.
https://doi.org/10.1056/NEJM199412293312604
66. YAMASHITA Y, TAMURA T, ENDOH H, TEZUKA T (1998)
Treatment of nevus Ota with Q-switched ruby laser. Skin Res 40(3):
296–300
67. Yang HY, Lee CW, Ro YS, Yu HJ, Kim YT, Kim JH et al (1996)
Q-switched ruby laser in the treatment of nevus of Ota. J Korean
Med Sci 11(2):165–170. https://doi.org/10.3346/jkms.1996.11.2.
165
68. Zhong W (2017) Clinical observation of Q-switched ruby laser in
treating facial pigmented dermatosis. Chin J Aesthet Med 26(9):
78–79
69. Sakio R, Ohshiro T, Sasaki K, Ohshiro T (2018) Usefulness of
picosecond pulse alexandrite laser treatment for nevus of Ota.
Laser Ther 27(4):251–255. https://doi.org/10.5978/islsm.27_18-
OR-22
70. Ho DD, London R, Zimmerman GB, Young DA (2002) Laser-
tattoo removal–a study of the mechanism and the optimal treatment
strategy via computer simulations. Lasers Surg Med 30(5):389–
397. https://doi.org/10.1002/lsm.10065
71. Felton SJ, Al-Niaimi F, Ferguson JE, Madan V (2014) Our per-
spective of the treatment of naevus of Ota with 1,064-, 755- and
532-nm wavelength lasers. Lasers Med Sci 29(5):1745–1749.
https://doi.org/10.1007/s10103-013-1332-3
72. Herd RM, Alora MB, Smoller B, Arndt KA, Dover JS (1999) A
clinical and histologic prospective controlled comparative study of
the picosecond titanium:sapphire (795 nm) laser versus the Q-
switched alexandrite (752 nm) laser for removing tattoo pigment.
J Am Acad Dermatol 40(4):603–606. https://doi.org/10.1016/
s0190-9622(99)70444-5
73. Ross V, Naseef G, Lin G, Kelly M, Michaud N, Flotte TJ et al
(1998) Comparison of responses of tattoos to picosecond and nano-
second Q-switched neodymium: YAG lasers. Arch Dermatol
134(2):167–171. https://doi.org/10.1001/archderm.134.2.167
74. Huang WH, Wang HW, Sun QN, Jin HZ, Liu YH, Ma DL et al
(2013) A new classification of nevus of Ota. Chin Med J 126(20):
3910–3914
75. Lee SH, Lee MH, Noh TK, Choi KH, Won CH, Chang SE et al
(2016) Successful treatment of tattoos with a picosecond 755-nm
Alexandrite laser in Asian skin. Ann Dermatol 28(5):673–675.
https://doi.org/10.5021/ad.2016.28.5.673
76. Yu W, Zhu J, Yu W, Lyu D, Lin X, Zhang Z (2018) A split-face,
single-blinded, randomized controlled comparison of alexandrite
755-nm picosecond laser versus alexandrite 755-nm nanosecond
laser in the treatment of acquired bilateral nevus of Ota-like mac-
ules. J Am Acad Dermatol 79(3):479–486. https://doi.org/10.1016/
j.jaad.2017.12.053
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.