Botulinum Toxin: Complications and Their Management
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In 2014, the International Society of Aesthetic Plastic Surgery published the numbers of non-surgical cosmetic procedures performed around the world, showing that the most popular procedure was botulinum toxin A (BTXA) injections. Although the most popular treatment, complications and adverse events relating to BTXA are rare as knowledge improves every day due to various anatomic studies, clinical studies, and the improvement of doctors’ skills. Due to the mechanism of action of BTXA, its adverse events tend to be transitory and short in duration, but have a negative impact on the patient’s quality of life that needs to be minimized or avoided. Knowledge of facial anatomy, injection techniques, complications, and adverse events is paramount. In this chapter we discuss the possible complications and adverse events of BTXA, how to avoid them, and how to minimize them when they do occur.
KeywordsBotulinum toxin Complications Adverse events Ptosis of the lids Asymmetry Hypersensitivity Onabotulinum toxin Abobotulinum toxin Incobotulinum toxin Pain
In the last 30 years few drugs have been studied and tested in relation to their efficacy and safety as much as botulinum toxin A (BTXA), both for its aesthetic and therapeutic indications (Coté et al. 2005). The efficacy of BTXA is well-established and unquestionable but, as with any other drug, its use may lead to adverse events and complications, which are well-accepted when treating diseases but not when related to cosmetic treatments (Cavallini et al. 2014). Although these effects have a short-term duration, they can impact negatively on the quality of life of patients, especially undesirable asymmetries. There are few alternatives for minimizing them but often there is no solution other than waiting for the improvement as the action of BTXA on the muscles fades away.
According to the International Society of Aesthetic Plastic Surgery (2014), BTXA injections are the most popular non-surgical cosmetic treatment around the world. Although used worldwide, complications and adverse events resulting from this therapeutic modality are very rare due to improvement of anatomy knowledge, clinical studies, and better training of the injectors. A recent publication has associated one-third of complications with off-label treatments in cosmetic use. On the other hand, in the same study, therapeutic injections were revealed to have complications seven times more frequently than cosmetic indications (Lolis et al. 2015).
Few papers in the scientific literature describe complications of BTXA used for aesthetic treatments and they are mostly related to injections in the superior third of the face. The number of articles describing complications of lower-face treatment is low, but they seem to be more frequent than in other regions of the face. Review articles consider similar adverse events with the use of onabotulinum toxin A, abobotulinum toxin or incobotulinum toxin, differing slightly in duration, severity, frequency, or dosage (Cavallini et al. 2014). Some of the adverse events and complications described in this chapter are from our everyday observations over many years of experience with BTX for cosmetic treatments.
Didactically, we could separate the adverse events into those related to the drug and puncture of the skin during the injection; and complications resulting from the effects of the BTXA, i.e., unexpected muscle relaxation or neural-sensitive complaints due to the BTXA action, the injection site, or the technique itself.
Another issue that can be considered a complication is any patient dissatisfaction with the results. The best way to prevent complaints is to begin with a correct and complete anamnesis and understand the patient’s expectations. Photographs should be taken of the patient with all facial mimics to be treated well documented. Frontal and lateral pictures should be taken – 45° pictures are also advised – with a resting face and showing all of the mimics the patient wants to treat. With patients who show any sign of doubts or psychological issues, a short film should be taken to ensure all different facial mimics and asymmetries are available for evaluation, since photographs can’t capture patients’ movements with accuracy. Previous asymmetries should be emphasized and the expected results should be discussed, with the aim of recognizing the patient’s desires and detecting false expectations, avoiding over-corrections, and planning the treatment to achieve a natural look, the result that most doctors recommend.
Adverse Events Related to the Drug
Adverse effects related to the drug are independent of the injection technique and are associated with an individual sensitivity to the chosen BTXA. It should be remembered that different brands have different excipients and they need to be diluted in different amounts of saline. The final solution used must be checked as doctors tend – sometimes following anecdotal publications – to use other diluents such as lidocaine and buffered saline solutions and also forget that there could be reactions due to the diluent or topical products applied before or after the procedure such as anesthetics creams or antiseptic solutions.
Cosmetic treatment almost always requires a low BTXA dosage in total and hypersensitivity for BTXA itself is very rare; when it does occur, it is generally related to the excipients. Lactose and gelatin have been described as sensitizers leading to drug reactions such as fixed pigmentary reaction, cutaneous rash, and urticaria, and other reactions could occur due to the toxoid (inactive part of the toxin).
Allergic reactions commonly occur a few minutes after the injection and affect, in general, previously BTXA-sensitized patients, especially those receiving frequent and premature touch-ups, rather than allergic reactions being related to the dosage itself. A reaction may present as an erythematous papule at the injection site or as a cutaneous rash (Tamura et al. 2008). Anaphylactic reactions can begin as a small urticaria lesion or generalized edema followed by dizziness and evolving to systemic shock (Ricciardi et al. 2013). If medical intervention is immediate, patients should recover well; cortisone, antihistamine, and adrenaline might be necessary. Incobotulinum toxin is a pure toxin that does not have protein complex added to it, only having albumins as the excipient, and it is described as the best choice for sensitized patients (Ricciardi et al. 2013). Albumins are not considered to be allergens but they can potentially be contaminated by various infectious viruses; however, the main trademarked products have proven trustworthy to date, with no cases of infection described.
Nausea and Flu-Like Symptoms
Nausea and flu-like sympoms might be observed in some patients; while their cause is not clear, they could be related to the excipients or toxin hypersensitivity. These symptoms only last a short time and there is no need to treat them (Coté et al. 2005).
Although BTXA has been used as an alternative treatment for migraine and tensional headache, mild to moderate headache can be considered an adverse effect and occurs in approximately 16% of patients receiving treatment for glabellar lines. Headache lasts a few hours to days, is poorly responsive to analgesics, and has spontaneous recovery. The etiology is still not understood but might be related to periosteal needle trauma, intramuscular hematoma, anxiety, and temporary muscle spasm (Vartanian and Dayan 2005); it has also been noted in patients who have had palmar BTXA injections (Cavallini et al. 2014).
Adverse Events Related to the Puncture
Puncture and injection pain can be alleviated with topical anesthetics, different formulations containing lidocaine, procaine and/or prilocaine in various concentrations, fresh pads, ice packs, vibration devices, massage, and the choice of very thin needles such as those produced specifically for BTXA injection. However, these methods will not alleviate the pain produced by the solution’s muscle distention, which shows almost no improvement with anything other than asking the patient to try to relax the muscle as much as he can and injecting slowly.
Ecchymosis and Hematoma
While hematoma is quite rare, ecchymosis is a very frequent adverse event as the areas that we treat with BTXA are fully vascularized (Cavallini et al. 2014). In addition to the worse aesthetic view of these effects, there is also the possibility of spreading BTXA to undesired areas, leading to the impairment of other muscles and resulting in asymmetries, paralysis, or ptosis and also of losing some BTXA with the blood reflux. It is important to always remember to check whether patients are using any drugs, medicines, or vitamins that change coagulation and use alternative tools such as cold pads and ice packs before the injections, firm local compression immediately after the injection, and intense pulsed light or other light-based devices that may be useful to minimize the ecchymosis or hematoma, especially at the inferior lid.
Although there are no concerns about emboli, frequent intravascular injections could potentially stimulate neutralizing antibodies or provoke systemic effects; however, to date, it seems that the amount of BTXA injected for cosmetic purposes is too insignificant to be clinically proven (Coté et al. 2005).
Edema and Erythema
Edema and erythema are generally transient, with a short recovery time. Edema is usually related to the volume of the injected solution, i.e., dilution with more than 1 mL of saline (Cavallini et al. 2014). If the signs are intense and do not reverse quickly, other causes such as allergy or dermographism due to a patient’s history of urticaria should be considered.
Local infection following BTXA is very rare and is related to inadequate antisepsis and the consequent contamination of the puncture sites (Lowe et al. 2005). In addition to correct local disinfection, the patient must be advised to avoid topical sunscreen, makeup, or creams that might contaminate the skin. Herpes simplex can follow any invasive skin treatment.
Dyschromia has also being described at the puncture site. In addition, a few authors have anecdotally described rare cases of bone hypertrophy at the injection site during the early use of BTXA, when the technique for forehead injection was inserting the needle until it touched the frontal bone and injecting the BTXA after pulling the needle back a few millimeters (Kim and Byrne 2007; Tamura 2007).
Muscle Motor Impairment
Undesirable motor muscle impairment is one of the most feared complications after BTXA treatment as it directly affects the quality of life and aesthetic results of the patients, being noticeable and evident to anyone in their social circle. This complication might be due to one of the following: injection of BTXA into the wrong muscle, individual anatomy, site of injection, incorrect dosage, poor training and knowledge of the injector, excessive volume of saline dilution, lack of familiarity with the chosen toxin, or diffusion of the product. Diffusion might occur because of the characteristics of the toxin, an ecchymosis or local hematoma, or edema, especially after skin ablative procedures such as medium or deep peelings, lasers, or collagen-stimulating fillers that are diluted and injected into areas already treated with BTXA (Lolis et al. 2015).
It should be noted that there are many articles and reviews regarding BTXA complications following cosmetic treatment for the lines of the upper third of the face but there are few for the medium and inferior third of the face and neck as most of the injections at these sites are still off-label; however, dysphasia, neck weakness, dry mouth, speech impairment, difficulty retaining food and liquids in the mouth, and pseudo-aneurysm of the superficial temporal artery have been described to date (Tamura 2010a, b; Skaf et al. 2012; Dayan 2013; Hassouneh and Newman 2013).
The solution to avoiding such complications is to determine the patient’s forehead muscle extension and strength prior to the procedure and carefully check the mimics of the eyebrow movements, and their relationship to the contraction and height of the eyebrows, and inject an appropriate number of units, usually a lower dosage, to relax the muscle enough to soften the lines but not so much as to paralyze it (Hexsel and De Almeida 2002; Gassia 2009).
To avoid such complications, we need to understand what to do, what not to do, and how to perform the treatment in the superior third of the face. Tamura (2007) and Tamura and Odo (2011) have described three easy ways to cause eyelid ptosis: injecting the BTXA inadvertently at what we ‘think’ is the corrugator; injecting in the periosteum; or neglecting the diffusion halo of different toxins. The suggestion of where and how to inject BTXA into the corrugators is to localize the muscle and the superior border of the orbit, hold the muscle between the fingers, directing the needle upward into the muscle, and not into the bone or the palpebral area, and be careful when injecting at the lateral extension of the muscle.
It should always be remembered that the eyebrow level is not a reference to localize a safe injection as the eyebrow might be located above, at, or under the orbital bone level. The orbit bone should be palpated and the corrugator pushed upward as it is held, injecting far from the levator palpebrae muscle. Avoid injection on the bone because the risk is higher at the level of the orbit rim as the solution might flow down at the layer of the periosteum, dissecting easily towards the rim and into the orbit at which the levator palpebrae is inserted. The characteristically larger abobotulinum toxin diffusion halo requires that the injection at the corrugators be higher and injections at the orbicularis muscle to elevate the brows be avoided or the dosage reduced drastically.
Apraclonidine, phenylephrine, or brimonidine eye drops could be used to contract the Müller’s muscle, which is located under the levator palpebrae muscle, without acetylcholine-mediated innervation (Kirkpatrick et al. 2016). In our experience, electrostimulation with microcurrents and/or facial aesthetic ultrasound towards the superior orbicular rim has also been helpful to stimulate the Muller’s muscle and the fibers of the levator palpebrae that are not affected by BTXA.
The upside-down medial and lateral ‘V’ shape and the ‘diabolical look’ are the most common complications of unnoticed frontal muscular localized strength. The upside-down ‘V’ shape can occur at the middle of the eyebrow or laterally, depending on the location of the stronger contraction area. It commonly occurs at the middle of the brow after the treatment of the forehead of Asian patients. The final effect results in a look somewhat like a clown’s eyebrow makeup; to avoid such a result we suggest that, for flat eyebrows and Asian patients, the injection be planned to begin at the forehead at the projection of an imaginary line from the pupil about 2 cm above the eyebrow. If at the first appointment the patient has an angular contour on the lateral sides, the injection marks should also begin at the strongest part of the frontalis that pulls the angle of the brow. After marking these key sites, we suggest marking the other areas within a distance of 1.5–2 cm apart, injecting at least 2 U at the strongest sites.
The ‘diabolical look’ was a very common result after forehead treatment in the early years of BTXA because doctors considered the frontal area lateral to the pupil to be a no BTXA injection zone. After some time, many doctors began to treat the lateral area of the frontal muscle if it is very active and strong to avoid this complication. We suggest injection of 1–2 U at a site higher than 1.5 cm above the eyebrow for a natural result without dropping the lateral aspect of the eyebrow.
Exacerbation of the Infraorbital or Nasojugal Sulcus Pads
Diplopia is a consequence of the injection of BTXA in one or more of the extrinsic motor muscles of the eye or the spread of the toxin to them. These muscles are responsible for the movement of the ocular globe and their paralysis is represented as ‘blurry vision’ or ‘double vision’ and diplopia might be seen clinically with divergent or convergent eyes. To avoid this complication, injections around the eye should respect the orbital rim, which is easily identified when we palpate the area, and when injecting BTXA in advanced and delicate sites, inject a small amount, less than 1 U per point, and very superficially. The palpation and identification of the orbital limits should never be neglected in any treatment as each patient has unique and personal small anatomical nuances. There is no treatment for diplopia at this time other than waiting for the effect of BTXA to end (Zagui et al. 2008; Gassia 2009).
‘Plateau Smile’ or ‘Topo Gigio’s Smile’
A ‘plateau smile’, or ‘Topo Gigio’s smile’, is very frequent when crow’s feet are treated with abobotulinum toxin or when an excessive quantity of units of another BTXA are injected to treat them. It is typical for the crow’s feet area to be very flat and the lines completely relaxed; when the patient smiles, only the malar structures rise up, creating a horizontal medial line, and the malar area becomes rounded like a ‘plateau smile’ or the cartoon character Topo Gigio’s face. We can minimize this undesirable effect injecting too many units at too many points in the crow’s feet area when the patient shows these kind of results. An easy test can be performed to predict this effect: hold both sides of the crow’s feet area simultaneously using pressure and ask the patient to force a smile; this gives an idea of the future results of the treatment. Patients with a rounded malar area are more prone to this effect than other patients.
All muscles of the face are susceptible to inadvertent treatment and one of the most adverse impacts is the paralysis of the zygomaticus m.; although all muscles are very important and are clinically visible, the relaxation of these muscles causes an almost hemifacial lack of expression. Clinically, it depends whether both zygomaticus muscles – minor and major – are relaxed or only one of them. If one side is affected, it results in an attenuation of the crow’s feet lines and an asymmetric smile with a drop of the buccal rima very similar to Bell’s paralysis. If both sides are paralyzed, the patient seems to have an emotionless face. Treatment of the lower crow’s feet with a third point too lateral to the zygomaticus bone or a fourth point lower than the classical lower site of injection to treat crow’s feet almost at the inferior border of the zygomaticus bone are the most common causes of undesirable zygomaticus m. relaxation. The best method to inject safely in this area would be to always localize the zygomaticus arch and the injections should be at the top of the arch, not on the side or under it (Hexsel and De Almeida 2002; Gassia 2009; Tamura and Odo 2011).
The most frequent complication of the treatment of the nasociliary area is a local, mainly unilateral asymmetry caused by the injection of BTXA at the periosteum and not at the orbicularis oculi m., which is quite thin at this region; to correct it, the BTXA should be reinjected at the location that the muscle still moves.
Injection of BTXA at the nasalis area might also lead to paralysis of the levator alaeque anguli oris m. as well as the levator anguli oris m. The best technique to avoid these complications is to inject BTXA by directing the needle to the middle line of the face, inserting it medially to an imaginary line from the lateral aspect of the nostrils.
There are different approaches to soften the peribuccal lines – the ‘bar code sign’ – by varying the number of injection sites and dosage, as well as their location. In our experience, 4 U at the upper lip and 2–4 U at the lower lip is more than enough to have some improvement without weakening the muscle to a point that the patient experiences complaints such as an incapacity to close the lips, inability to contain food in the mouth properly, or difficulties in pronouncing ‘b’ or ‘p’ or pursing the lips. Authors vary significantly in the recommended techniques but we reinforce the need for comprehensive anatomy knowledge. At the lateral area of the lips, fibers of the levator anguli oris m. and the alaeque nasi anguli oris m., and even in natural anatomical differences, fibers of the zygomaticus and risorius m. could be affected by BTXA, leading to a worse scenario with functional and aesthetic disability. We prefer to aim for a slight relaxation of the perioral muscle and to plan to inject fewer points and units. However, there is an exception for the indication of higher doses: when BTXA is injected as “prior” treatment to dermabrasion, phenol peelings, or even CO2 resurfacing for deep lines of the perioral zone.
Superior Lips Ptosis
Changes of the Smile
The patient’s smile characteristics may be changed when an intradermal BTXA injected using a ‘mini doses’ technique is chosen for the treatment of the peribuccal lines, as well as relaxing the zygomaticus, risorius levator labii, levator alaeque nasi and anguli oris, depressor labii, depressor anguli oris, and/or mental muscles. The relaxation of any of these will cause asymmetries and if relaxation occurs on both sides there will be almost no facial expression, leading to a sad linear and horizontal smile.
Oral Rim Deviation
Relaxation of the depressor anguli oris and sometimes the masseter muscle leads to food accumulation at the jugal mucosa between the teeth and inferior lips, and the patients need to use the tongue to remove the food to masticate it. To address this, fewer units should be injected at the next treatment or the balance between the side effect and the benefit of the treatment should be explained to the patient.
Weakness of the Masticatory Function and Speech Difficulties
Weakness of the masticatory function and speech difficulties can be a complication after the treatment of masseteric hypertrophy as a greater quantity of BTXA is required for an efficient result (Park et al. 2003).
Dysphagia, Cervical Muscles Weakness, and Respiratory Impairment
Treatment of the platysma m. with a high dosage of BTXA, different techniques, deep injections, or diffusion of the BTXA might result in dysphagia, cervical muscles weakness, and respiratory impairment (authors’ personal experience) (Cavallini et al. 2014; Tamura 2012). Injections at the cervical area should be very superficial and it is essential to be aware that the dangerous zone is at the anterior medial portion of the neck where the most important deglutition muscles are located (stylohyoid, sternohyod, thyrogloss, and hyoglossus muscles). Besides injecting BTXA very superficially in this area, lower doses and sites are advisable as well as chosing a smaller halo action BTXA.
Epiphora has also been described in a few papers as well as the current authors having seen it in their personal experience (Ozgur et al. 2012; Kim and Baek 2013). Epiphora resolves spontaneously in 1–2 weeks.
Dry Eye and Ocular Discomfort
Dry eye and ocular discomfort are related to an exaggerated amount of BTXA at the glabellar area as well as during treatment of the depressor cilia and nasociliary orbicular muscles. An excessive amount of BTXA in the muscles in this area might result in the entire glabellar area dropping, causing some difficulty in closing the eyes tightly (Ozgur et al. 2012; Cavallini et al. 2014). These effects are not common and tend to improve without treatment in few days. Ocular moisturizer drops could help to improve this problem and, technically, very superficial and tiny amounts of BTXA injected into the periocular area instead of a greater quantity should help to avoid such complications (Gassia 2009).
Other Sensitive Complications
Sensitive alterations including ‘burning’, paresthesia, or numbness along the sensitive nerve innervation area might occur when the puncture traumatizes the nerve. These symptoms are transitory and the best technique to avoid them is good anatomic knowledge. In addition, any patient complaints regarding unusual pain during the injection should be valued, and reinsertion of the needle more superficially or just beside the first site will prevent any future problems. In fact, in BTXA treatment for general aesthetics, superficial injections are required as the aim is to affect the mimic muscle and not the foramens and sensitive nerves located deeper in the muscular layer.
Injections at the wrong site, inadequate dosages, and lack of anatomy knowledge are less frequent among dermatologists and plastic surgeons today. The choice of BTXA brand is personal, although some papers suggest that abobotulinum toxin, due to its diffusion halo, should be avoided in the inferior portion of the face and neck. Understanding potential complications and side effects might drastically lower the number of post-procedure problems and increase patients’ confidence. Care should be taken with simultaneous procedures that cause edema, heat, and erythema as they can change the normal outcome of BTXA injection (Lorenc et al. 2013).
A total or partial lack of effect might happen ab initio or after several or a few treatments. The ab initio lack of BTXA response has some considerations, most of them theoretical or anedoctal case reports, or personal experience. In theory, this lack of effect might occur because of a previous botulism infection in a patient with mainly serotype A or a genetic enzymatic deficiency of any substance in the principal pathway between adhesion, internalization, and blockage of the acetylcholine in the neuromuscular plaque. The expected duration of the BTXA effects varies between 3 and 6 months, although the patient should know that the clinical results last an average of about 4 months (most studies are based on about 120 days). Other factors that are of extreme importance are variables such as injection dosage, muscle strength, number of injection points, and the muscle, but the duration should be around 4 months if the total dosage injected follows at least the minimum suggested in some good consensus papers (Lorenc et al. 2013).
A few patients might have short-duration results or even, rarely, no results at all after their first treatment, which could be explained by the presence of specific neutralizing antibodies against the BTXA due to previous exposure to Clostridium (Klein 2002) or, hypothetically, to a genetic-specific neuroreceptor enzyme deficiency or antibodies sensitized against the protein complex added to the active 150 kDa toxin (Tamura 2005). When the lack of response occurs after years of BTXA treatments, it should be investigated whether the cause is a real sensitization with antibodies against the toxin or the protein complex added to BTXA (Hefter et al. 2012). The recommendation to avoid shortening the duration of the effects or to stimulate antibodies is to respect a minimum interval of 1 month for touch-ups, even with very low doses, and 3 months for a new treatment. Recently, authors defended the choice of incobotulinum toxin due to its low antigenicity and purity and (Hefter et al. 2012) have published an interesting paper about the successful response to injection of this BTXA in the treatment of patients with detectable antibodies against BTXA and no clinical response to onabotulinum and abobotulinum toxin (Hefter et al. 2012). On the other hand, other authors claim that neutralizing or non-neutralizing antibodies have not been detected and that there is no therapeutic duration reduction with the long-term treatment with BTXA for cosmetic purposes (Schlessinger et al. 2014).
In theory, the effect of BTXA can be reduced when drugs such as 4-aminoquilones are prescribed as antimalarials and joint diseases and can be increased by antibiotics such as aminoglycosides (Santos et al. 1981; Molgó et al. 1987). Drugs that interfere with neural impulse transmissions to the muscle, such as tubocurarine due to its relaxant effect, can also interfere in theory, increasing the duration of the BTXA as well as the phytase enzyme intake.
Heat does seem to inactivate BTXA at the site of injection, although patients can be treated with light equipment or radiofrequency devices after BTXA injection without affecting its efficacy (West and Alster 1999).
In summary, we do not consider the adverse events or complications of the different halos of efficacy of abobotulinum toxin and its slight differences in technique to be reasons to avoid BTXA, rather being just a matter of knowledge and skills. This is a different issue to local edemas caused by the injection performed by the doctor leading to diffusion of BTXA and sometimes resulting in asymmetries. The recommendation for avoiding BTXA resistance is to not inject it frequently and to try and keep intervals between injections of at least 3 months.
Take Home Messages
Complications and adverse events relating to BTXA for aesthetic treatment are rare, transient, and of short duration but create a strong negative impact on the quality of life of the patient.
The incidence of complications might be lowered with improvement in the knowledge of the facial anatomy and proper training of the injector as most complications occur due to an incorrect injection site and depth, over- or under-correction, lack of awareness of the diffusion properties of the BTXA, and outdated knowledge of the evolution of techniques and local fashion, and the differences between the needs of women and men as well as patients of different ages and ethnicities.
Frequent touch-ups should be avoided and intervals between the injections kept to a minimum of at least 3 months to avoid possible sensitization against BTXA as much as possible (Naumann et al. 2013).
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