Cosmetic Botulinum Toxin Injections Complications; Treatment and Prevention

Aesthetic procedures using Botulinum Toxin Type A (BoNTA) have become widely popular for facial augmentation and anti-aging purposes. This review aims to provide a comprehensive overview of the complications associated with BoNTA injections, addressing their incidence, causes, treatment options, and preventive measures. A thorough literature search was conducted, focusing on studies reporting the complications following BoNTA injections. BoNTA injections are associated with various adverse events, including local reactions, headache, ocular complications, facial weakness, and hypersensitivity reactions. While BoNTA injections are generally considered safe, understanding the complications and available treatment options is crucial for mitigating risks and ensuring optimal outcomes in aesthetic procedures. Safe injection techniques, attention to anatomy, and proper patient selection remain paramount in preventing complications associated with BoNTA.

Keywords: Botulinum toxin, Cosmetic, Complication, Treatment, Prevention

Aesthetic procedures including botulinum toxin type A (BoNTA) have gained widespread popularity for their ability to enhance facial features and reduce the signs of aging. Since BoNTA’s approval by Food and Drug Administration (FDA) in 2002 BoNTA has become the most commonly performed non-surgical aesthetic procedure, accounting for 43.2% of all of the procedures [1]. Over the years, many companies have produced BoNTA using different methods, showing unique characteristics and clinical effects. These include (not limited to) OnabotulinumtoxinA (also known as BOTOX Cosmetic), AbobotulinumtoxinA (Dysport), Incobotulinum Toxin (Xeomin), PrabotulinumtoxinA (Jeuveau), and DaxibotulinumtoxinA (DAXXIFY).

While BoNTA is generally considered safe, it is not without complications. Understanding and addressing potential adverse events is crucial for both practitioners and patients. In this comprehensive overview, we delve into the various complications associated with BoNTA injections, shedding light on their incidence, causes, treatment options and potential preventive measures.

 Complications

Local adverse events

Pain has been reported by 9.3% of subjects who received BoNTA for skin cosmetic procedures. Injection site swelling, erythema, and bruising are fewer common events with the incidence rate of 6.4%, 1.8%, and 1.2%, respectively [2]. The incidence of injection site pain in cases that received DAXXIFY for glabellar lines has reported to be 2.4% [3], which is higher than what has been reported for older BoNTA compounds (0.86%) [4].

Many of local adverse events following BoNTA injection are self-resolving and do not require treatment. Injecting BoNTA in a subdermal plane (superficial) minimizes ecchymosis [5].

Headache

Headache is one of the most common adverse events of BoNTA injections with an incidence of 3–5.38% for cosmetic indications [4, 6]. When BoNTA injections were used for the treatment of glabellar lines, investigators found that the most common side effect was headache, with an incidence of 23.23%. Notably, headache after BoNTA injections may be related to the injection procedure instead of the botulinum toxin, although it is challenging to discern the source [4].

Blepharoptosis, eyebrow ptosis and diplopia

Eyelid and eyebrow ptosis occur either as a consequence of the toxin passing through the orbital septum, leading to eyelid ptosis, or due to the weakening of the lower fibers of the frontalis muscle, resulting in brow ptosis. In a case report series assessing complications after use of BoNTA for facial rejuvenation, Ferreira et. al suggest that ptosis and diplopia occurred due to the diffusion of botulinum toxin to the levator palpebrae superioris muscle and extrinsic muscles of the eye. For most patients, the symptoms were self-resolving [7]. One retrospective study found that blepharoptosis is a rare occurrence (0.2%) in patients receiving same-day combination treatment of periorbital BoNTA and full-face non-ablative fractional laser. The rarity of this complication may be due to the intrinsic properties of the laser, which could have some protective effects [8].

In a 2020 cross sectional review of the US FDA Adverse Event Reporting System, the most commonly reported events of BoNTA use among 10,577 reports were injection site pain (9.3%), swelling (6.4%), and eyelid/brow ptosis (6.1%) [2]. Upper lid ptosis is postulated to occur due to migration of the injected toxin to proximal muscles of the eye [9]. Eyebrow ptosis on the other hand can occur when the frontalis muscle is weakened. Eyebrow elevation is mainly due to frontalis muscle contraction and not the eyebrow depressors; therefore, frontalis muscle is the major determinant of eyebrow height [10].

There are different treatment options for BoNTA induced blepharoptosis; oxymetazoline HCl 0.1% (Upneeq, RVL Pharmaceuticals) received FDA approval for the treatment of acquired blepharoptosis in 2020. A pooled analysis of two randomized clinical trials showed significant improvement in peripheral visual field and marginal reflex distance1 (MRD1) in patients with acquired ptosis [11]. Other treatment options include apraclonidine ophthalmic drops and phenylephrine hydrochloride ophthalmic drops [12], although the side effects of pupillary dilation would not be ideal. In patients with an allergy to α‐adrenergic eye drops, anticholinesterases have proven effective [13].

To prevent eyebrow ptosis conservative doses of the injections should be placed in the upper half of the forehead to ensure preserving the role of the lower frontalis muscle and decreasing the chance of brow depression [10]. The recommended methods for forehead injections include remaining at least 2-3 cm above the supraorbital margin or 1.5-2 cm above the eyebrow. Furthermore, to prevent brow elevation as a result of BoNTA for brow depressors, Sethi et al. suggested treating the elevators and depressors simultaneously to avoid unopposed action of one muscle group [4].

Additionally, in the treatment of lateral canthal rhytids, injection guidelines include maintaining a 1.0 cm margin from the bony orbit and 1.5 cm margin from the lateral canthus. Failure to do so may result in diplopia [5].

Ocular pain and dry eye

BoNTA injection is used for the treatment of lateral canthal rhytids. Lateral canthal rhytids are characterized by hypertrophy of the lateral fibers of orbicularis oculi and are often considered an early sign of aging. In a 2002 case report, Matarasso discusses an abnormal Schirmer’s test of 5.0 mm (normal, 10-15 mm) following BoNTA injection for lateral canthal rhytids. This was explained as a result of inaccurate intramuscular injection of BoNTA onto the lacrimal gland [14].

Later it was hypothesized that ocular pain and dry eye syndrome were due to impairment of lacrimal gland innervation by BoNTA [7]. This hypothesis was later confirmed by detecting a significant reduction in tear film break up time and tear production (measured by Schrimer test) in subjects that received BoNTA for lateral canthal rhytids [15].

There are different mechanisms to explain the BoNTA induced dry eye:

• Blocking the function of the orbicularis oculi muscle and resultant disruption of the blinking reflex and eyelid laxity.
• Blocking the function of meibomian glands and decreasing secretion and delivery of meibomian oil.
• Blocking autonomic cholinergic transmission resulting in decreased aqueous production [15, 16].

Corticosteroid drops and physiologic solution have been cited for the treatment of ocular pain and dry eye secondary to BoNTA injection [7].

Lagophthalmos

Facial dystonia including blepharospasm and hemifacial spasms are commonly treated with BoNTA. Lagophthalmos is the most commonly found complication in patients with facial dystonias who receive BoNTA injections, with a 26.3% incidence rate [17]. In patients with benign essential blepharospasm (BEB), BoNTA injections can be given by either a preseptal (PST) or pretarsal (PTS) approach. In a randomized clinical trial of 24 patients with BEB, each participant received a PST injection in one eye and a PTS injection in the other eye. The results indicated that there were significantly higher rates of self-reported lagophthalmos on PTS injections as compared to PST (52.17%, 30.43%). Thus, to minimize lagophthalmos as an adverse outcome of BoNTA injection, a preseptal approach may be beneficial [18].

Facial weakness

BoNTA is implemented for masseter muscle reduction in efforts to achieve a slimmer lower face shape. Masseter muscle reduction is commonly performed in Asian populations. In a 2018 study of 2036 BoNTA injections for masseter muscle reduction, mastication force decrease was observed in 30% of the injections. The incidence of smile limitation, paradoxical bulging, sunken cheeks, and sagging were each less than 1% [19]. The complications are more common in older patients [20].

The facial muscle weaknesses have been reported in injections of BoNTA to other regions of the face. Matarasso et. al describes a temporary partial unilateral lip weakness in patients receiving BoNTA injections for lateral canthal rhytids. This is hypothesized to occur due to diffusion of the toxin from the orbicularis oculi to zygomaticus major leading to a drooping of the lateral aspect of the mouth [5].

To treat the facial flaccidity and sagging that may occur after BoNTA injection for masseter reduction, subsequent BoNTA injections can be applied to the platysma and depressor anguli oris to improve cheek curvature, elevate the lower face soft tissue, and tighten the mandibular skin [20].

When using BoNTA for masseter reduction, complications can be prevented through several mechanisms. To avoid sunken cheeks after the reduction, Wu et al. recommend lowering the dose of BoNTA and placing the injection over the lower portion of the masseter muscle and not too close to its anterior border. To avoid accidentally hitting risorius, the patient can clench their teeth to allow for proper injection to the masseter. Dosing adjustments can also be made to minimize asymmetry after treatment, and injection of BoNTA into the depressor muscles of the lower face and neck can prevent post-treatment sagging. Lastly, Wu et al. discusses the use of ultrasound imaging to guide injections to prevent paradoxical bulging [19]. When injecting BoNTA near the orbicularis oris, it is important to avoid the zygomatic arch and zygomaticus major to prevent lip ptosis [5, 14].

Hypersensitivity reaction

Hypersensitivity reactions to BoNTA has been reported in 2.9-3.4% of cosmetic injections [2, 4]. The immunogenicity of BoNTA products depends on factors like previous exposure, manufacturing process, antigenic protein load, toxin dose, and type of accessory proteins. While BoNTA proteins can stimulate the production of neutralizing host antibodies, true anaphylactic reactions are extremely uncommon. No single formulation seems to have an increased risk of causing hypersensitivity reactions [2]. Interestingly, the reported hypersensitivity reactions are higher in the placebo group [21]; thus, hypersensitivity reactions may occur due to antiseptic solutions that are used to disinfect the skin prior to the injection [4].

An uncommon complication following BoNTA injection in foreign body reaction. Pontes et al, reported a case of foreign body reaction after injections of BoNTA in the upper lip for gummy smile [22]. The foreign body reaction could be attributed to a delayed hypersensitivity reaction to botulinum toxin [23]. To prevent foreign body reactions following upper lip BoNTA injections, a single injection of BoNTA around the convergence of the levator labii superioris, levator labii superioris alaeque, and zygomaticus minor can be performed [22].

Exaggeration of wrinkles

Kang et al. reported the exaggeration of wrinkles as an adverse outcome of BoNTA injections for forehead horizontal lines in a series of four cases. In two patients, glabellar protrusion was seen by week 2 following the initial BoNTA injection. In another two patients, a deep wrinkle appeared unilaterally above the eyebrow by week 2. In all four patients, the exaggerated wrinkle disappeared by week 4 without any intervention [24]. To prevent the exaggeration of wrinkles after BoNTA treatment of facial rhytids, Kang et al. recommends placing the injection somewhere between 4-5 cm above the orbital rim [24].

The escalating popularity of botulinum toxin in aesthetic applications stems from its consistent clinical outcomes, along with minimal complications and rapid recovery compared to surgical interventions. With the growing prevalence of botulinum toxin usage, the spectrum of adverse events might expand. Hence, comprehensive understanding of potential complications across diverse indications and anatomical regions is essential for practitioners, fostering safer injection practices.

Funding/Support:

None.

Financial Disclosures:

Wendy Lee serves as a consultant for Allergan, Galderma, Revance and Evolus.

Conflict of Interest:

Wendy Lee serves as a consultant for Allergan, Galderma, Revance and Evolus.