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Effect of Botulinum Toxin Pretreatment on Laser Resurfacing Results
A Prospective, Randomized, Blinded Trial
Marc S. Zimbler, MD;
John B. Holds, MD;
Mimi S. Kokoska, MD;
Dee Anna Glaser, MD;
Stephen Prendiville, MD;
Christopher S. Hollenbeak, PhD;
J. Regan Thomas, MD
Arch Facial Plast Surg. 2001;3:165-169.
ABSTRACT
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Background Facial laser resurfacing and chemodenervation with botulinum toxin type
A are used independently as means of nonsurgical facial rejuvenation. Recent
reports in the literature have described combining these 2 therapies, claiming
improved and longer-lasting laser resurfacing results. To date, no scientific
investigation has been undertaken to prove or disprove this theory.
Design Institutional review board–approved, prospective, randomized,
blinded study at university-affiliated outpatient cosmetic surgery offices.
Intervention Patients had one side of their face injected, at specific anatomic subsites
(crow's feet, horizontal forehead furrows, and glabellar frown lines), with
botulinum toxin 1 week before laser resurfacing. After receiving an injection,
patients underwent cutaneous laser exfoliation on both sides of the face with
either a carbon dioxide or an erbium dual-mode laser.
Main Outcome Measures Patients' injected (experimental) and noninjected (control) sides were
compared after laser resurfacing. Follow-up was documented at 6 weeks, 3 months,
and 6 months after laser resurfacing. Subjective evaluation, based on a visual
analog scale, was performed in person by a blinded observer. Furthermore,
a blinded panel of 3 expert judges (1 facial plastic surgeon, 1 oculoplastic
surgeon, and 1 cosmetic dermatologist) graded 35-mm photographs taken during
postoperative follow-up visits.
Results Ten female patients were enrolled in the study. A 2-tailed t test showed that all sites that were pretreated with botulinum toxin
showed statistically significant improvement (P .05)
over the nontreated side, with the crow's feet region showing the greatest
improvement. Comparing results between the carbon dioxide and erbium lasers
did not result in any statistically significant differences.
Conclusions Hyperdynamic facial lines, pretreated with botulinum toxin before laser
resurfacing, heal in a smoother rhytid-diminished fashion. These results were
clinically most significant in the crow's feet region. We recommend pretreatment
of movement-associated rhytides with botulinum toxin before laser resurfacing.
For optimum results, we further recommend continued maintenance therapy with
botulinum toxin postoperatively.
INTRODUCTION
CURRENT nonsurgical rejuvenative therapy for the aging face includes
injectable soft-tissue augmentation, chemical exfoliation, dermabrasion, laser
resurfacing, and chemodenervation. The last 2 treatment modalities have been
the focus of the cosmetic surgical community during the past decade. Advances
in technology, as well as our detailed understanding of facial anatomy, have
led to their popularity and predictable aesthetic results.
In 1983, Anderson and Parrish1 described
the theory of selective photothermolysis that revolutionized cutaneous laser
therapy by producing localized thermal damage. Carbon dioxide lasers were
now able to deliver char-free ablation with site-specific target injury within
tissue. The CO2 laser, with a wavelength of 10 600 nm, is
strongly absorbed by skin's water, which allows tissue ablation with minimal
diffusion of thermal damage. During the past few years, the erbium:YAG laser
has gained popularity as a method of facial skin resurfacing. The erbium laser's
shorter wavelength, at 2940 nm, is 10 times more selectively absorbed by water.
Consequently, the residual thermal damage is much less than with CO2 lasers, resulting in decreased postoperative erythema. However, erbium
laser resurfacing does not provide the same degree of clinical improvement
as do CO2 lasers, especially in terms of collagen shrinkage and
tissue tightening effects.2 Erbium lasers require
3 to 4 times more passes to reach appropriate ablation depth, resulting in
substantially more postoperative oozing. However, recent developments in erbium
laser technology3 have led to the combination
of ablative and coagulative pulses, a method called dual
mode, which allows for deeper vaporization with hemostasis and controlled
tissue coagulation.
The areas shown to be most amenable to laser resurfacing include the
cheek and periorbital regions.4 However, many
patients who undergo laser resurfacing experience premature recurrence of
rhytides at specific anatomic subsites5: crow's
feet, horizontal forehead furrows, and glabellar frown lines. Such subsites
are areas of long-term muscle animation and produce hyperdynamic facial lines.
Although histologic studies have confirmed neocollagen formation associated
with laser resurfacing,6-7 it
appears that fibroplasia cannot overcome the forces of long-term animation
on these movement-associated rhytides.
The anaerobic bacterium Clostridium botulinum
produces 8 serologically distinct exotoxins. However, botulinum toxin type
A (Botox; Allergan Inc, Irvine, Calif) is presently the only Food and Drug
Administration–approved purified neurotoxin. Botulinum toxin acts at
the neuromuscular junction by inhibiting the release of acetylcholine from
nerve terminals. When injected locally at therapeutic doses, botulinum toxin
produces a localized chemical denervation paralysis lasting from 2 to 6 months.
The presumption that specific facial lines result from forces generated by
local muscle action was first observed on a microanatomic basis by Pierard
and Lapiere in 1989.8 In 1993, Blitzer et al9 were the first to describe the use of botulinum toxin
treating hyperdynamic facial lines. Cosmetic denervation of hyperfunctional
facial lines by means of intramuscular botulinum toxin injections has proved
an excellent method of nonsurgical facial rejuvenation. Focal denervation
of particular facial muscles has been shown to improve overall facial appearance
by not only temporarily eliminating rhytides but also improving malposition
changes.10 Today, botulinum toxin is a well-established
method for treating hyperdynamic facial lines and furrows and has firmly established
its role in facial plastic surgery.
Facial laser resurfacing and chemodenervation with botulinum toxin are
used independently as means of facial rejuvenation. Anecdotal clinical experience10-14
suggests that skin pretreated with botulinum toxin before laser resurfacing
heals in a smoother wrinkle-free fashion. It is postulated that paralysis
of specific facial muscles could result in reepithelialization and the remodeling
of collagen in an adynamic wound healing environment. Thus, botulinum toxin
pretreatment could prevent recurrence and/or severity of movement-associated
rhytides after laser resurfacing.
The purpose of this investigation was to evaluate the effect of botulinum
toxin on hyperdynamic facial rhytides after cutaneous laser resurfacing. A
1-time unilateral botulinum toxin injection was administered to specific anatomic
subsites of the face before laser resurfacing. The injected and noninjected
sides were compared at 6 weeks, 3 months, and 6 months after facial laser
resurfacing.
PATIENTS AND METHODS
A Saint Louis University (St Louis, Mo) Human Research Protocol was
approved by the institutional review board, and 10 patients (all female) were
entered in the study. The null hypothesis was that the experimental (botulinum
toxin–pretreated) side of the face would not be smoother after healing
than the control side after laser skin resurfacing. The study was conducted
as a randomized, prospective, blinded study in patients undergoing facial
laser resurfacing for aesthetic indications. All procedures were performed
at a university-affiliated cosmetic plastic surgery clinic after informed
consent was obtained.
Patients were examined preoperatively to determine Fitzpatrick skin
type and to grade the degree of facial skin actinic damage and rhytidosis
by means of the Glogau scale. Exclusion criteria included active acne, psoriasis,
eczema, allergic dermatitis, isotretinoin use within the previous 12 months,
and facial skin resurfacing or botulinum toxin therapy within the past 6 months.
To remove confounding variables, such as severity of preoperative facial rhytides
and differences in skin types and wound-healing abilities, each patient served
as her own control.
Lyophilized botulinum toxin type A (Botox) was obtained in vials containing
100 U and stored at -5°C until reconstitution. The toxin was reconstituted
with 2.0 mL of sterile nonpreserved isotonic sodium chloride solution, resulting
in a concentration of 5.0 U/0.1 mL. All patients received injections 1 week
before laser resurfacing and within 48 hours after toxin reconstitution. The
patients' skin was prepared with an alcohol wipe, and injections were performed
with a 1-mL syringe equipped with a 30-gauge needle. The side chosen for injection
was randomized by coin toss, and the physician (M.S.K.) who performed the
injections was not involved in postoperative evaluation, to maintain the blinded
nature of the study. Patients were examined at the time of laser resurfacing
to determine that appropriate chemodenervation was obtained. Injected subsite
doses were as follows: for crow's feet, 2 injections of 5.0 U (0.2 mL); for
the corrugator region, 1 injection of 7.5 U (0.15 mL); and for the frontalis
region, 2 paramedian injections of 5.0 U (0.2 mL).
The 2 lasers used in the study were the Sharplan CO2 Silk
Laser (ECS Sharplan Corp, Norwood, Mass) and the dual-mode Sciton Erbium Contour
Laser (Sciton, Palo Alto, Calif). Laser selection was based on patient's request
and Fitzpatrick skin type. All laser resurfacing was performed with the patient
under local anesthesia. For the CO2 laser, 2 standardized settings
were used (both with a 200-mm handpiece and a 6- to 8-mm2 computer
pattern generator; one used 18 W and the other, 36 W). For treatment of the
periocular region, all patients underwent 1 pass with 18 W followed by a second
pass with 36 W. The corrugator and frontalis regions were treated with 2 passes
of 18 W. For the erbium laser, the periocular region was treated with a first
pass of ablation only at 60 µm (15 J/cm2) with 20% overlap,
a second pass of ablative and coagulative modes at 60 and 50 µm, respectively,
and a final ablative pass at 60 µm. The corrugator and frontalis regions
were treated in a similar fashion; however, the settings were increased to
80 µm; followed by a second pass of ablative and coagulative modes at
80 and 100 µm, respectively; and ending with an 80-µm ablation
only.
Postoperative care included an occlusive hydrogel dressing (Vigilon;
CR Bard Inc, Covington, Ga) for the first 24 hours followed by application
of a thick layer of ointment (Aquaphor; Beiersdorf Inc, Norwalk, Conn) until
epithelialization was complete (5-10 days). Routine postoperative medications
included cefadroxil, 500 mg twice daily, and valacyclovir hydrochloride, 250
mg twice daily (starting 48 hours before surgery) for 7 days. After reepithelialization,
a UV-A and UV-B sunscreen with sun protective factor greater than 15 was applied.
Beginning at 4 weeks postoperatively, 3% hydroquinone was prescribed as needed
for early signs of hyperpigmentation.
Results were evaluated in person by a blinded observer (M.S.Z.) at 6
weeks, 3 months, and 6 months postoperatively. Standardized photography was
performed at each of the postoperative visits (Nikon N2000 SLR camera; Nikon
Corp, Tokyo, Japan; Tamron SP 90-mm macro lens; Tamron USA, Inc, Commack,
NY; and Sunpak automatic DX-12R ring flash; Sunpak, Osaka, Japan) with 2 slave-triggered
strobe studio lights; 35-mm slide film was used (Ektachrome ISO 100; Eastman
Kodak Co, Rochester, NY). The photographs were shown to a panel of 3 blinded
observers (a facial plastic surgeon [J.R.T.], an oculoplastic surgeon [J.B.H.],
and a cosmetic dermatologist [D.A.G.]). A visual analog scale graded 0 to
3 was used to compare sides treated with and without botulinum toxin, where
0 indicated no difference; 1, subtle improvement; 2, moderate improvement;
and 3, marked improvement.
After averaging across reviewers, scores were tested against an alternative
hypothesis of no effect by means of a 2-tailed t
test. All analyses were performed with SAS statistical software (version 8.0;
SAS Institute Inc, Cary, NC), with statistical significance defined as P.05.
RESULTS
The ages of the 10 female patients ranged from 37 to 50 years (mean
± SD, 42.9 ± 4.6 years). Fitzpatrick skin type and Glogau rhytidosis
scores are seen in Table 1. Five
patients underwent resurfacing with the CO2 laser and 5 with the
erbium dual-mode laser. Twenty anatomic subsites were treated and evaluated
for the study.
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Table 1. Patient Participation Data*
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Examination for the paralytic effects of botulinum toxin showed complete
resolution by 3 months in all patients. Both the blinded in-person observer
and the blinded panel of 3 expert judges (using 35-mm photographs) were able
to identify greater improvement in the botulinum toxin–pretreated side
in all subsites analyzed. Site-specific analysis is given in Table 2, with all subsites showing statistically significant improvement
(P.05). Figure
1 demonstrates that the crow's feet subsite showed the highest level
of improvement. Moreover, this improvement was sustained at the 6-month visit
after the paralytic effects of the botulinum toxin had worn off. No perioperative
complications were observed, and only 1 patient maintained mild hyperpigmentation
after 3 months.
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Table 2. Injection Site-Specific Analysis
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Figure 1. Average improvement score by region
and follow-up time. A score of 0 indicates no improvement; 1, subtle improvement;
2, moderate improvement; and 3, marked improvement.
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Figure 2 illustrates a patient's
preoperative and 6-month follow-up photographs. The patient's right glabellar
frown line was pretreated with botulinum toxin before laser resurfacing. Figure 3 illustrates another patient's preoperative
and 6-month follow-up photographs. The patient's right crow's feet were pretreated
with botulinum toxin before laser resurfacing.
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Figure 2. A, Glabellar frown lines before
treatment. B, Six months after laser resurfacing. Patient's right glabellar
frown lines (arrow) were pretreated with botulinum toxin.
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Figure 3. A and B, Crow's feet before treatment.
C and D, Six months after laser resurfacing. Patient's right inferior crow's
feet (C) were pretreated with botulinum toxin.
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COMMENT
Immediately after laser resurfacing, hyperdynamic facial rhytides as
well as fine rhytides associated with photoaging often resolve. Studies have
shown4, 15 clinical improvement
of non–movement-associated rhytides to be as high as 94%, whereas hyperdynamic
facial lines average improvement between 45% and 85% and generally recur within
6 to 12 months. Pretreatment with botulinum toxin has been anecdotally reported10-14
to improve results after laser resurfacing. To date, however, no published
studies are available that prove or disprove this theory.
Wound immobilization is a basic concept for proper wound healing. Casts,
plates, and sutures minimize the negative effect of muscle tension on healing
tissue. The dynamic musculature of the face is in constant movement and can
impede healing after facial surgery. It is postulated that paralysis of specific
facial muscles could result in reepithelialization and the remodeling of collagen
in an adynamic wound-healing environment. This, in theory, could prevent recurrence
and/or severity of movement-associated rhytides after laser resurfacing. Choi
et al16 described 11 patients who underwent
botulinum toxin therapy to promote wound immobilization for high-risk patients
undergoing complex eyelid reconstruction. They found improved wound-healing
results in the botulinum toxin–treated wounds compared with simple tarsorrhaphy
alone. Recently, Gassner et al17 examined the
cosmetic results of facial wounds in primates treated with botulinum toxin.
They found that the cosmetic appearance of unfavorably oriented cutaneous
scars were improved by pharmacologic chemodenervation of the surrounding tissue.
Fagien10, 12 reported "enhanced"
laser results, especially in the crow's feet region, in patients pretreated
with botulinum toxin before resurfacing. He suggested that the pretreatment
with botulinum toxin may improve the smoothing of newly resurfaced skin long
enough to effect "more permanent eradication of wrinkles." Carruthers and
Carruthers13-14 treated 4 female
patients asymmetrically with botulinum toxin before CO2 laser resurfacing.
They reported that patient "satisfaction" was highest in the botulinum toxin–pretreated
side. Furthermore, they stated that the recurrent crow's feet were "coarser,
thicker and more obvious" in the nonpretreated side. However, they did note
deterioration of the botulinum toxin–pretreated side at approximately
10 months. West and Alster18 reported the effects
of botulinum toxin on movement-associated rhytides after CO2 laser
resurfacing. They studied 20 patients who underwent botulinum toxin therapy
1 to 3 months after resurfacing was complete. They found prolonged correction
of laser resurfacing if botulinum toxin treatment was instituted during the
postoperative period. Without such treatment, they claimed return of most
movement-associated rhytides within 6 to 12 months. Unfortunately, their control
population (patients who did not receive botulinum toxin therapy after laser
resurfacing) consisted of a separate random group of 20 patients who underwent
laser resurfacing and did not account for differences in preoperative rhytidosis
severity.
The most important finding in our study was that all of the blinded
judges were able to identify the botulinum toxin–pretreated side with
some level of improvement. This improvement was clinically most marked for
the crow's feet subsite. Even though the improvement seen was statistically
significant, clinical correlation shows that this was only "subtle" improvement.
The visual analog scale that was graded 0 to 3 showed that the average (±SD)
improvement for the crow's feet subsite was 1.10 ± 0.74 at 6 weeks
postoperatively and 0.85 ± 0.48 at 6 months postoperatively. This improvement
was sustained after the major effects of botulinum toxin had worn off, implying
that the effects of the botulinum toxin pretreatment were more than merely
simultaneous effects of the 2 treatment modalities. Six-month follow-up of
the forehead and glabellar region did show statistically significant results.
However, clinical examination of these data shows that most blinded observers
graded these patients between "no improvement" and "subtle improvement" when
compared with the control side. One could argue that the amount of toxin injected
preoperatively was not sufficient to cause complete paralysis of the anatomic
subsite. However, these conservative doses were chosen so as not to create
severe asymmetries for the patient. Of further interest was that no statistical
difference was found when results were compared between the CO2
and erbium lasers. Perhaps this is the result of the newer dual-mode erbium
technology.
Botulinum toxin pretreatment did enhance laser resurfacing results of
hyperdynamic facial rhytides, resulting in the rejection of the null hypothesis.
Six-month follow-up suggested that the improvement obtained was more than
merely the simultaneous effects of the botulinum toxin therapy. As West and
Alster18 suggested in treating movement-associated
rhytides, laser improvement could be maintained if botulinum toxin therapy
were begun in the postoperative period. It would seem from our study, and
the results by West and Alster, that optimum results could be obtained by
pretreating patients with botulinum toxin and then continuing treatment well
into the postoperative period.
CONCLUSIONS
Facial laser resurfacing and chemodenervation with botulinum toxin are
used independently as means of facial rejuvenation. Laser exfoliation is the
treatment of choice for fine to medium rhytides, while chemodenervation appears
to be superior for the treatment of glabellar frown lines, crow's feet, and
horizontal forehead furrows. Our study showed that hyperdynamic facial rhytides,
pretreated with botulinum toxin before laser resurfacing, heal in a smoother
rhytid-diminished fashion. We recommend pretreatment of movement-associated
rhytides with botulinum toxin before laser resurfacing. For optimum results,
we also recommend continued maintenance with botulinum toxin therapy postoperatively.
AUTHOR INFORMATION
Accepted for publication January 4, 2001.
Corresponding author and reprints: Marc S. Zimbler, MD, Division
of Facial Plastic Surgery, Department of Otolaryngology–Head and Neck
Surgery, Beth Israel Medical Center, 10 Union Square E, Suite 4J, New York,
NY 10003 (e-mail: mzimbler{at}bethisraelny.org).
From the Division of Facial Plastic Surgery, Department of Otolaryngology–Head
and Neck Surgery, Beth Israel Medical Center, New York, NY (Dr Zimbler); Departments
of Ophthalmology (Dr Holds), Otolaryngology–Head and Neck Surgery (Dr
Holds), and Dermatology (Dr Glaser) and Division of Facial Plastic Surgery
of the Department of Otolaryngology–Head and Neck Surgery (Drs Kokoska
and Prendiville), Saint Louis University Hospital, St Louis, Mo; Departments
of Surgery and Health Evaluation Sciences, Penn State College of Medicine,
Hershey, Pa (Dr Hollenbeak); and Division of Facial Plastic Surgery, Department
of Otolaryngology–Head and Neck Surgery, University of Illinois at Chicago
School of Medicine (Dr Thomas).
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