Nonaesthetic Applications for Botulinum Toxin in Plastic Surgery

Matthew D. Freeman, M.D.; Ilana G. Margulies, M.D., M.S.; Paymon Sanati-Mehrizy, M.D.; Nikki Burish, M.D.; Peter J. Taub, M.D., M.S.

Disclosures

Plast Reconstr Surg. 2020;146(1):157-170.

Abstract and Introduction

Abstract

Background: Since their introduction to clinical medicine in 1989, botulinum toxin injections have been used for many indications. First used for nonsurgical management of strabismus, botulinum toxin injections are now widely used in plastic and reconstructive surgery for aesthetic indications; however, nonaesthetic indications of botulinum toxin have grown tremendously over the past two decades and span numerous specialties, including urology, dermatology, ophthalmology, otolaryngology, gynecology, plastic surgery, general surgery, and neurology. The present review aims to highlight nonaesthetic indications of botulinum toxin that are most relevant to the plastic surgeon with an emphasis on evidence-based practice.

Methods: A PubMed search with manual reference checking was conducted to find the most relevant and influential articles on the nonaesthetic uses of botulinum toxin within the realm of adult plastic surgery. Studies were then categorized into areas of use, and quality of evidence for each category was highlighted.

Results: Botulinum toxin has numerous nonaesthetic indications in plastic surgery, including for select pain-related disorders, skeletal muscle activity disorders, exocrine gland hyperfunction, wound healing, Raynaud phenomenon, abdominal wall reconstruction, and prosthetic breast reconstruction and augmentation. Although these indications have been widely reported, high-quality evidence supporting efficacy, optimal dose, and injection protocol with randomized controlled trials is lacking in many areas.

Conclusions: Botulinum toxin is widely used in plastic surgery for a variety of nonaesthetic indications. Future studies should focus on investigating efficacy and best practice with high level of evidence research.

Introduction

Botulinum toxin is a potent neurotoxin produced by the bacterium Clostridium botulinum. It causes muscle paralysis by blocking the release of acetylcholine at the neuromuscular junction.^[1] Botulinum toxin also affects the release of other neurotransmitters and neuropeptides, which has increased its uses.^[2] Seven different botulinum toxin serotypes have been reported, with several subtypes that possess unique protein sequences and distinct molecular entities.^[3] Studies have shown that variability exists in potency,^[4] receptor occupancy,^[5] spread,^[6] and immunogenicity.^[7]

All botulinum toxin products on the market are composed of the A1 serotype (botulinum toxin type A), except for a single B serotype product [Myobloc (Solstice Neurosciences, Inc., South San Francisco, Calif.)/NeuroBloc (Eisai Manufacturing Limited, Herts, United Kingdom), botulinum toxin type B], which has been shown to have lower potency in humans than in experimental animal studies.^[8] The three most widely used botulinum toxin type A products, which differ in their final formulation and potency units, are onabotulinumtoxinA (Botox; Allergan, Inc., Dublin, Ireland), abobotulinumtoxinA (Dysport; Ipsen, Paris, France), and incobotulinumtoxinA (Xeomin; Merz, Frankfurt am Main, Germany).^[9]

At present, U.S. Food and Drug Administration–approved uses in aesthetic surgery include cosmetic improvement of lines in the glabellar and lateral canthal areas. Additional off-label aesthetic uses include lateral eyebrow elevation; treatment for gummy smile; and improving rhytides surrounding the forehead, nose, midface, lower face, and neck. Nonaesthetic on-label indications include treatment of chronic migraine, spasticity, detrusor activity, and strabismus (Table 1); however, numerous other off-label nonaesthetic indications have arisen over the past two decades.^[10,11] Although prior reviews have primarily explored indications for aesthetic botulinum toxin use,^[12–14] this article aims to provide a comprehensive yet succinct review of the most common nonaesthetic indications for botulinum toxin in the adult population relevant to plastic surgeons, with an emphasis on evidence-based practice using levels of evidence to summarize the studies included in each subsection (Figure 1).

(Enlarge Image)

Figure 1.

Overview of the wide scope of nonaesthetic botulinum toxin use. The following indications that are less commonly performed or outside the scope of plastic surgery are included in this diagram but are not further described in the text: vaginismus, prevention or treatment of salivary fistula in head and neck surgery, rhinitis, spastic entropion, and lacrimal hypersecretion. TMJ, temporomandibular joint. Printed with permission from © Mount Sinai Health System.

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Abstract and Introduction
Disorders
Conclusions
References

Table 1. U.S. Food and Drug Administration On-Label Indications for Botulinum Toxin
1. Urinary incontinence because of detrusor overactivity associated with neurologic disorder (SCI, MS) or nonresponse to anticholinergics
2. Prophylaxis of HA in adult patients with chronic migraine (≥15 days/mo with headache lasting 4 hr/day or longer)
3. Treatment of upper limb spasticity in adult patients
4. Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain
5. Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients
6. Treatment of blepharospasm associated with dystonia in patients aged 12 yr or older
7. Treatment of strabismus in patients aged 12 yr or older

SCI, spinal cord injury; MS, multiple sclerosis; HA, hyaluronic acid.

Table 2. Phase 3 Research Evaluating Migraine Prophylaxis Therapy Injection Protocol versus Targeted Injection Protocol*
	Total No. of Units	Total No. of Sites
Muscle target
Corrugator	10	2
Procerus	5	1
Frontalis	20	4
Temporalis	40–50	8–10
Occipitalis	30–40	6–8
Cervical paraspinal muscle group	20	4
Trapezius	30–50	6–10
Targeted injection protocol†
Peripheral nerve target
Supraorbital nerve/supratrochlear nerve	25	2
Zygomaticotemporal nerve	37.5	2
Greater occipital nerve	50	2

*All muscles should be injected bilaterally with the exception of the midline procerus. Dosages are in the form of onabotulinumtoxinA.
†Targeted botulinum toxin injection protocol as detailed in Janis JE, Barker JC, Palettas M. Targeted peripheral nerve-directed onabotulinumtoxin A injection for effective long-term therapy for migraine headache. Plast Reconstr Surg Glob Open 2017;5:e1270. 10.1097/GOX.0000000000001270

Table 3. OnabotulinumtoxinA Dosages and Injection Sites in Cervical Dystonia*
Muscle	Recommended Dosage (U)
Splenius capitis	15–100
Splenius cervicis	20–60
Sternocleidomastoid	15–100
Scalene complex	15–50
Semispinalis capitis	30–100
Trapezius	20–100
Longissimus	30–100
Levator scapulae	20–100

*All injections should be guided by results of electromyographic studies. As recommended dosages are provided in a wide range for each involved muscle, dosing should be individualized based on patient head and neck positioning, localization of pain, and muscular hypertrophy.

Table 4. Review of the Literature on Botulinum Toxin Use in Abdominal Wall Reconstruction*
Reference	Defect	Total Dose of BT per Patient	Time of Injection and Technical Considerations	Reported Outcomes	Level of Evidence
Elstner et al., 2017¹²⁴	Complex ventral hernia‡	300 U† or 150 U† if unilateral	• Injected 1–4 wk preoperatively	• Fascial closure achieved in all cases • Increase in mean abdominal wall length from 16.4 cm to 20.4 cm per side	II
Ibarra-Hurtado et al., 2009¹¹⁷	Midline incisional hernia	500 U§ injected through 5 points on each side between external and internal oblique muscles	• EMG instead of US guidance used • Injected at least 4 wk preoperatively	• Mean hernia reduction of 5.25 ± 2.32 cm before repair • No hernia recurrences at mean follow-up of 9.08 mo	II
Ibarra-Hurtado et al., 2014¹¹⁸	Midline incisional hernia	500 U§ injected through 5 points on each side in between external and internal oblique muscles	• Injected at least 4 wk preoperatively	• Reduction in muscle thickness and increase in muscle length • No hernia recurrences at mean follow-up of 49 mo	II
Farooque et al., 2016¹¹⁵	Midline or right-side incisional hernia	300 U† or 150 U† if unilateral	• Injected 2 wk preoperatively	• Fascial closure with mesh in all cases • Increase in mean abdominal wall length from 18.5 cm to 21.3 cm per side	II
Zielinski et al., 2013¹²³	Open abdomen	300 U†	• Injected when patients achieved hemodynamic stability after OA operation	• 83% primary fascial closure rate, 6% partial fascial closure rate, 11% planned ventral hernia rate	III
Rodriguez-Acevedo et al.,2018¹¹⁹	Complex ventral hernia\|\|	200–300 U†	• Injected 7–14 days preoperatively, with or without PPP	• Increase in mean lateral abdominal wall length from 16.1 cm to 20.1 cm per side • Primary closure achieved in all cases • 2% hernia recurrence	II
Bueno-Lledo et al., 2017¹²⁶	Large incisional hernia (VIH/VAC >20%)	500 U§ injected through 5 points on each side	• EMG guidance with US • Injected 40 days preoperatively, plus PPP	• 14% decrease in VIH/VAC ratio • 4.4% hernia recurrence after 40.5 ± 19 mo	II
Bueno-Lledo, 2018¹¹⁵	Incisional hernia with LOD	500 U§ injected through 5 points on each side	• EMG guidance with US • Injected 4 wk preoperatively, plus PPP	• 16.6% decrease of VIH-to-VAC ratio • 5.7% hernia recurrence after 34.5 ± 22.3 mo	II
Zendejas et al., 2013¹²²	Incisional hernia	300 U† injected through 5 points on each side	• 41% were injected at median of 6 days preoperatively, 59% were injected on the day of surgery	• Decreased postoperative opioid use and pain scores • No difference in hernia recurrence as compared to matched controls	III
Smoot et al., 2011¹²⁰	Ventral hernia	300 U†	• Injected >3 wk postoperatively	• Improvement of pain persisting to 3-mo follow-up	V

BT, botulinum toxin; EMG, electromyographic; US, ultrasound; OA, open abdomen; PPP, preoperative progression pneumoperitoneum; VIH,
volume of incisional hernia; VAC, volume of abdominal cavity; LOD, loss of domain.
*All injections of BT were performed under ultrasound guidance at three sites in external oblique, internal oblique, and transversus abdominis muscles unless otherwise specified. Timing of injection is described with respect to hernia repair.
†OnabotulinumtoxinA.
‡As defined by Slater NJ, Montgomery A, Berrevoet F, et al. Criteria for definition of a complex abdominal wall hernia. Hernia 2014;18:7–17. 10.1007/s10029-013-1168-6
§AbobotulinumtoxinA.
||As defined by >20% loss of domain or recurrent/traumatic defect(s) >6 cm.