Botox AEs

Am J Clin Dermatol 2005; 6 (3): 141-150 1175-0561/05/0003-0141/$34.95/0

LEADING ARTICLE

© 2005 Adis Data Information BV. All rights reserved.

Managing Adverse Events Associated with Botulinum Toxin Type A A Focus on Cosmetic Procedures Uwe Wollina and Helga Konrad Department of Dermatology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital, Dresden, Germany

Abstract

Botulinum toxin A (BTXA) has become a widely used drug in cosmetic dermatology, not only to treat focal hyperhidrosis but also hyperkinetic facial lines, platysma bands, d´ecollet´e bands, and other skin features. The spectrum of possible adverse effects of BTXA is broad but fortunately those that have been observed with cosmetic use of this product are generally mild and transient. The major tools for preventing adverse effects from BTXA are knowledge and skill. Use of correct injection techniques is mandatory since most unwanted effects are caused by incorrect technique. Knowledge of the target structures, e.g. the facial and extrafacial muscles, allows physicians to select the optimal dose, time and technique. The most common adverse effects are pain and hematoma. In the periocular region, lid and brow ptosis are important adverse effects. Adverse effects such as pain, hematoma, ecchymosis, and bruising may also occur in the upper and lower face and at extrafacial sites.

Other possible adverse effects seen in other indications that the user of BTXA in cosmetic dermatology should be wary of include induction headaches and possible interaction with concomitant medications. Induction of neutralizing antibodies due to cosmetic BTXA treatment has not been observed. This article also outlines recommendations regarding use of BTXA. Of these, the most important for avoiding most unwanted adverse effects are the proper techniques of dilution, storage, and injection, as well as the careful exclusion of patients with any contraindications. Pain, hematoma, ecchymosis, and bruising can be prevented by cooling the skin before and after BTXA injection. Upper lid ptosis may be partly corrected using apraclonidine or phenylephrine eyedrops. If simple rules relating to the indications for and application of BTXA are followed, this is a safe and effective drug in cosmetic dermatology.

Botulinum toxin (BTX) is produced by Clostridium botulinum.

This was discovered in 1905 by Tchitchikine, who described the substance as a neurotoxin.[1] BTX was purified by Sommer in California in 1920, and 36 years later Lamanna succeeded in further purifying BTX into crystalline form.[2] In 1949, it was demonstrated that BTX inhibits the release of acetylcholine from nerve endings.[3]

cle transport protein. In this way, it impedes proper binding of acetylcholine vesicles to, and fusion with, the cell membrane.

Neurotransmitter release to the muscle endplate is inhibited and muscle contraction prevented. The deadly dose for humans has been estimated to be 3000U of Botox® 1.[3,4]

BTX consists of two different chains, a heavy chain that is responsible for binding to the nerve ending and a light, toxifying chain. Following endocytosis, the molecule is cleaved by disruption of a disulfide bond. Seven different types of BTX are known, but only BTXA and very recently BTXB have been approved as drugs for human use. The target for BTXA is a 25kDa synaptosome-associated protein. The binding is rapid and stable.

BTXA, a zinc-dependent endopeptidase, cleaves the 25kDa vesi-

There are two different BTXA products on the international market – Botox® (Allergan) and Dysport® (Speywood/Ipsen). The two formulations have different biological potencies.[4] However, the exact relative potencies of the two products are still a matter of debate. While the potency of both BTXA products is expressed in LD50 mouse units (the amount of toxin required to kill 50% of test mice), the assays used for each are different. However, one vial of Botox® contains 100U, whereas one vial of Dysport® contains

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1. Botulinum Toxin A Brands

The use of trade names is for product identification purposes only and does not imply endorsement.

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500U, suggesting a conversion factor of 1 : 5 (Botox® vs Dysport®). Indeed, a single-blind, randomized, parallel study conducted in patients with blepharospasm or hemifacial spasm supported this conversion factor.[5] Other double-blind studies in cervical dystonia patients suggested a conversion factor of 1 : 3 to 1 : 4 (Botox® vs Dysport®).[6,7] Unfortunately, no comparative study in BTXA for hyperkinetic wrinkles or hyperhidrosis has been published as yet. Nor has it been proven that the abovementioned conversion factor for Botox® versus Dysport® is stable for all indications.

Because of the different potencies of the two available BTXA preparations, there is a risk of over- or under-treatment when different brands of BTXA are used in the same office. To minimize this risk, the reconstitution of lyophilized BTXA and the preparation of syringes for the individual patient should be carried out by the physician who administers the injections.

2. Use in Cosmetic Dermatology Use of BTXA in cosmetic medicine has arisen from observations that treatment of blepharospasm by BTXA also improved periocular lines.[8] Standard procedures for BTXA injection to improve mimic lines and wrinkles target frown lines, glabellar (horizontal) lines, and crow’s feet.

Evaluation of BTXA in double-blind, placebo-controlled studies of patients with glabellar folds[9,10] and crow’s feet[11,12] has resulted in recognition of this agent as an evidence-based cosmetic medicine for these indications. For other lines and wrinkles, the evidence for use of BTXA is based on uncontrolled studies.[8,13] More advanced techniques involve use of BTXA for perioral lines, sad lines, marionette lines, nasal (bunny) lines and the poppy chin.[8] BTXA has also been used for brow lift, eye opening (injection into the lower lid), gingival smile, platysmal bands, neck bands, sleeping lines and d´ecollet´e lines.[8] Knowledge of the pharmacology and toxicology of BTXA, and of the anatomy and physiology of treatment targets (i.e. the facial and extrafacial muscles), are the keys to successful use of BTXA. Development of expertise in the use of the appropriate injection techniques, dosages, and dilutions requires training. To avoid common mistakes, we recommend that practitioners who wish to administer BTXA attend at least a course and workshop given by an experienced user of BTXA. We advise that beginners in this field should not start with advanced techniques; rather, gradual progression from easier to more sophisticated applications is recommended. When basic guidelines are adhered to, use of BTXA for cosmetic reasons and hyperhidrosis is safe, predictable, has no serious complications, and delivers general patient satisfaction.[13,14] © 2005 Adis Data Information BV. All rights reserved.

Wollina & Konrad

3. Dosage and Administration BTXA should not be administered as large volumes of lowdose toxin. Dilutions should be as recommended in the product information. Higher dilutions are associated with a risk of instability since the protein concentrations are in the range of nanograms.

Furthermore, duration of response might be shortened with higher dilutions because of increased diffusion of BTXA and a lower effective concentration at the target site.[15] The use of concentrations according to the product information in small volumes (i.e.

0.1–0.2mL per injection site) will ensure that the toxin does not diffuse to unwanted sites.[15] In general, patients who have undergone previous facial surgery or show facial asymmetries require a dose adaption and probably modifications of the injection sites. The injection sites in general are placed in a symmetrical pattern, but any asymmetry of the facial musculature requires either a dose reduction on one site or an asymmetric placement of the injection sites.[8,13,15] Botox® must be used within 4 hours of reconstitution, and Dysport® within 8 hours, when kept at a temperature of between 2°C and 8°C.[16] 4. Contraindications and Precautions Patient selection is a crucial step toward prevention of patient dissatisfaction. Every patient needs an extensive informative consultation that covers not only the BTXA option but also all alternative methods and procedures. Patients should be made aware that facial asymmetry is common, and that use of BTXA cannot guarantee facial symmetry; however, asymmetry caused by hyperactive muscles can be smoothened.[17] BTXA should not be used for facial rejuvenation in patients that have a pre-existent lid ptosis or those who have undergone surgical procedures that may have repositioned or weakened the muscles.[18] Poor candidates for BTXA include patients with unrealistic expectations and psychiatric disease, in whom BXTA should be used with caution. There is also a small group of patients who fear the possibility of sustaining systemic botulism after BTXA injection and it should also be used with caution in these patients. In addition, patients who are normally rather demonstrative, such as politicians and actors, may fear that BTXA might leave them with a mask-like, non-emotive face.[15,19] In such cases, fillers might be a better alternative.

Contraindications to use of BTXA include pregnancy or lactation.[8,15] Patients with neuromuscular diseases such as LambertEaton syndrome, amyotrophic lateral sclerosis or myasthenia gravis are also not suitable for BTXA therapy since even low doses of the toxin may cause a neuromuscular crisis.[14] BTXA should not be used in patients taking concomitant aminoglycoside antibacterials, such as streptomycin, dihydrostreptomycin, gentamicin, neomycin, netilmicin, kanamycin or spectinoAm J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A

mycin, as these drugs can interfere with the metabolism of BTXA and prolong the half-life of the toxin.[4,19] When administered for cosmetic reasons or hyperhidrosis therapy, BTXA should also be avoided in patients taking one of the following medications, as these drugs may interfere with the action of BTXA at the target structures or increase the risk of infections, such as cyclosporin A: polymyxins, tetracyclines, lincomycin, penicillamine, quinine, cyclosporin, chloroquine and hydroxychloroquine, gallamine, pancuronium, tubocurarine, calcium channel antagonists, and local anesthetics.[4,14,19] These drugs may interfere with the action of BTXA at the target structures or increase the risk of infections such as cyclosporin A. The great importance of these precautions has been illustrated very recently by Li et al.,[20] who described a case of fatal anaphylaxis in a 43-year-old woman. She experienced chronic muscle pain and was treated several times with Botox®.

On the last occasion the patient received Botox® 100U, together with lidocaine 5mL injected into several muscular trigger points.

Mixtures of BTXA with local anesthetics should also be avoided since the mixture may change the tertiary structure of the BTXA molecule and interfere with pharmacokinetics.

Since conditions like diabetes, alcoholism, polymyositis and other immunocompromising conditions are risk factors for severe infectious disease, BTXA injections for either cosmetic reasons or hyperhidrosis should generally be avoided in patients with these conditions.

Every kind of septic and antiseptic care is necessary and recommended when handling and storing BTXA. Injection sites must be disinfected, and BTXA injection should not be given in any area of active infection.[10] 5. Adverse Effects The most common adverse effects of BTXA in cosmetic indications are listed in table I. 5.1 Allergies

Patients with known hypersensitivity to any of the components of commercially available BTXA, such as human albumin, lactose, saline and BTXA itself, are not suitable candidates for BTXA treatment. However, in two large studies involving >300 patients, most of whom received multiple treatments of BTXA, only four experienced generalized pruritus (n = 3) or an unspecified rash (n Table I. The most common adverse effects of botulinum toxin A (BTXA) in cosmetic indications Symptom

Management

Pain

Usually needs no treatment

Bruising

Pressure and cooling

Lid ptosis

Apraclonidine or phenylephrine eyedrops

Brow ptosis

BTXA for a brow lift

© 2005 Adis Data Information BV. All rights reserved.

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= 1).[21] As yet, there have been no published reports of BTXA allergy.

A single case of fixed drug eruption has been observed following BTXA injection.[22] However, the cause of the eruption was lactose, not the toxin or the non-toxic proteins. Lactose is a rare cause of fixed drug eruptions.[23] A so-called localized anaphylactic reaction was described following BTXA injection into leg muscles, although the allergic nature of the reaction was not proved.[24] To date, no anaphylaxis or deaths attributable to BTXA have been reported.[3] 5.2 Cardiovascular System

BTXA is a powerful presynaptic neuromuscular blocking agent which interferes with cholinergic parasympathetic terminals. In order to evaluate whether BTXA has an influence on the cardiovascular system, the short-term cardiovascular effects of BTXA were evaluated in 26 patients with torticollis.[25] The dosage was BTX (Dysport®) 12ng (almost 500U) administered intramuscularly. No significant influence on respiratory heart variation was observed after one injection. After a second injection, a significant attenuation of selected parameters was seen, and this response was noted with each subsequent injection over several months. However, no clinically manifest remote adverse effects or cardiac hypokinetic arrhythmias were seen over this period.[25] Nevertheless, fatal heart block has been described following treatment with BTXA for achalasia.[26] A 91-year-old man with pre-existent heart disease, first degree atrioventricular block, right bundle branch block, and incomplete left bundle branch block was treated for achalasia with Botox® 80U. He died 3 weeks later as a consequence of complete atrioventricular block and sepsis. It is rare for people of this age and with cardiovascular problems of this kind to ask for BTXA to treat cosmetic conditions. However, it is important to be aware of the possibility that BTXA may worsen a pre-existent bradycardia. In an animal model it was investigated whether BTXA injected into the sinoatrial fat pad inhibits decreases in heart rate induced by stimulation of the preganglionic parasympathetic nerves in the heart of the anesthetized dog.[27] Stimulation of the parasympathetic nerves in the sinoatrial fat pad (SAP stimulation) prolonged the atrial interval but not the atrioventricular interval, and cervical vagus nerve stimulation prolonged both atrial and atrioventricular intervals. After BTXA (Botox® 20U or 25U) was injected into the sinoatrial fat pad, it gradually inhibited the prolongation of the atrial interval evoked

by SAP and cervical vagus nerve stimulations but not the prolongation of the atrioventricular interval evoked by cervical vagus nerve stimulation. Conditioning successive stimulation of the cervical vagus nerves accelerated the inhibition by BTXA of the chronotropic response to cervical vagus nerve stimulation. These results indicate that selective injection of botulinum toxin into the Am J Clin Dermatol 2005; 6 (3)

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sinoatrial fat pad blocks bradycardia mediated by parasympathetic ganglionic activation in the dog heart.[27] Importantly, the doses of BTXA used in cosmetic procedures are in general much lower than those used in the treatment of achalasia, dystonia or spasticity. Furthermore, there has been no report of cardiovascular adverse effects following BTXA treatment for cosmetic reasons.

5.3 Generalized Reactions

As shown by electromyographic investigations conducted at sites distant from the BTXA injection site, small amounts of the toxin may diffuse into the circulation.[8] Generalized reactions have been observed in rare cases following intramuscular BTXA injection for spastic disorders and cosmetic reasons.[15] These reactions include nausea, fatigue, malaise, flu-like reactions, and rashes at distant sites. Symptomatic treatment only is required for these adverse effects.

5.4 Headaches

While headaches can be induced by injection of BTXA, especially in the forehead, it is more common for patients to report that chronic tension headaches have improved after injection of BTXA.[8,10,28] Furthermore, pericranial injection of BTXA has been found to be a safe and well tolerated treatment that reduces migraine frequency, severity, acute medication use, and associated vomiting.[29] In a study of 264 patients treated with BTXA (Botox®) for glabellar lines, 15.3% reported headaches. Of these, over 90% were rated as mild and two-thirds disappeared within a few hours.[10] In a prospective randomized trial of Botox® combined with collagen for glabellar furrows, no difference in headache rate was observed between Botox®/collagen and placebo recipients.[30] No specific therapy is generally required in patients who report headaches following Botox® injection. Local application of cold compresses is beneficial in most cases.[8,15] Recently, severe headache after BTXA application for cosmetic reasons or palmar hyperhidrosis was reported in five patients.[31] The headaches lasted for 1–4 weeks. No infection or any other sign of adverse reaction to BTXA was documented. The reason for these headaches is not known and risk factors have not been defined. Painkillers are necessary in these rare cases.

5.5 Hematoma, Ecchymosis and Bruising

Intramuscular injections may cause hematomas. Ecchymosis of mucous membranes is another possible adverse effect of BTXA injection. However, the available evidence suggests that hematoma and ecchymosis at injection sites occur in less than 1% of BTXA injections.[32,33] Nevertheless, patients with bleeding disor© 2005 Adis Data Information BV. All rights reserved.

ders or medications that affect hemostasis and thrombostasis should not be treated with intramuscular (BTXA) injections.

Even with proper technique, ecchymosis occurs easily in the soft eyelid tissue and the periorbital tissue of patients receiving BTXA injections in these areas. In a placebo-controlled trial of BTXA for crow’s feet, bruising was seen in 11–25% of patients, with similar rates being seen in the placebo group.[11] This adverse effect can be minimized by immediately applying pressure at the injection site after every injection, alone or in combination with a cold compress.

Patients should discontinue nonsteroidal anti-inflammatory agents such as aspirin, but also tocopherol (vitamin E) or gingko biloba, 10 days before BTXA injections.[19,33] Furthermore, because smokers tend to have more bruising after BTXA injection, it has been recommended that smoking should be stopped at least 7 days before injection.[33] 5.6 Infection

To date, infections have not been reported in patients seeking cosmetic treatment with BTXA.[31] 5.7 Interactions with Concomitant Medications

BXTA should not be used in patients taking the medications listed in section 4. In addition, Fiacchino et al.[34] reported that BTXA interferes with other neuromuscular blockers like vecuronium and may cause tolerance to the effects of vecuronium.

5.8 Muscles

In general, the main adverse effects of BTXA in cosmetic dermatology and the treatment of hyperhidrosis are a loss of facial expression, incomplete muscle paralysis with residual rhytides, and unwanted muscle paralysis resulting from spread of toxin to adjacent sites.[35] Asymmetry can result from either using excessively high (loss of facial expression) or excessively low (incomplete muscle paralysis with residual rhytides) doses of injected BXTA.[36] Unwanted paralysis can be due to incorrect injection site or high-volume, low-concentration injections. Patients with previous facial surgery or palsy need special attention (see section 3).

Muscular weakness at the site of BTXA injection is a desirable effect when treating lines and wrinkles. Correct injection technique will ensure that this weakness is limited to those muscles where the effect is needed. Local spread of BTXA occurs by diffusion up to 3cm in diameter from the injection point.[4] There is one published report of a 70-year-old woman who developed esotropia, hypertropia, ptosis of the upper lid, and double vision after BTXA injections around the eyelids.[37] The adverse effects described mimicked myasthenia gravis. Muscular adverse effects in indications other than cosmetic use have also Am J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A

been reported. Recently, two patients with paraplegia or tetraplegia who were treated with BTXA for neurogenic detrusor overactivity were reported to have developed muscular weakness at distant sites lasting for approximately 3 months.[38] One patient received Dysport® (total dosage 1500U), the other Botox® (total dosage 300U). The authors suggested that these two patients did not develop the expected tight binding of BTXA locally, which would normally prevent passage of BTXA into the circulatory system.[38] Another study of patients with cervical dystonia suggested that Dysport® was associated with more swallowing problems than Botox®.[39] These types of adverse effects have not been observed in cases of cosmetic use of BTXA. However, we recommend that participation in any activity that increases local blood flow, such as massage, sauna, steam bath or sun bath, should be avoided within a few hours of BTXA injection.[8,15,19] 5.8.1 Upper Face

Transient eyelid ptosis is the most significant complication of BTXA injection in the glabellar area and occurs in about 2% of injections.[40] Lid ptosis was seen in 5.4% of 264 patients treated for glabellar lines in one study.[10] The upper eyelid levator muscle can be affected as BTXA migrates through the orbital septum, leading to ptosis within 2 to 10 days of injection.[14] When frown lines are being treated with BTXA, a distance of at least 1cm above the bony supraorbital margin at the lateral injection site should be left to avoid brow or lid ptosis.[41] Lid ptosis can also occur if injection of the nasal bridge is too lateral.

The lateral brow lift is performed by injection in the outer third of the brow about 0.5cm above the upper orbital margin. Brow lift by injection at the level of the lateral canthus can produce lid ptosis if it is not directed above the orbital rim.[42,43] The medial brow lift is performed by injecting below the medial part of the brow. The dosage of BTXA used should be as little as Botox® 2–6U or Dysport® ≤6U for medial brow lift and about Botox® 3.5U or Dysport® 5–10U for lateral brow lift.[44] At a recent German consensus conference on BTXA, a single injection point was recommended for brow lift procedures.[44] However, previously, Ahn et al.[45] had suggested injection of a total of 7–10U of Botox® at three injection points into the superolateral part of the orbicularis oculi below the lateral third of the brow. Again, injection should be superior and lateral to the orbital rim to minimize the risk of diffusion of toxin through the orbital septum. Based on published data from open studies, the risk of lid ptosis seems to be higher for Dysport® (6.6%) than for Botox® (1.4%).[46,47] Several investigators have noted that caution is warranted when treating older patients who may have reduced or absent orbital septum as this causes the risk of a wider spreading of BTXA and thereby an increased risk of lid ptosis.[14,18,48] In patients with lid ptosis, apraclonidine 0.5% (Iopidine®) or phenylephrine hydrochloride 2.5% (Neosynephrine®) stimulate © 2005 Adis Data Information BV. All rights reserved.

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Mueller’s muscle and thereby elevate the upper eyelid; apraclonidine has the advantage of not affecting the pupil.[14] Over-treatment of horizontal lines with BTXA can cause a mask-like appearance and brow ptosis. Indeed, transient brow ptosis, particularly involving the lateral brow, has been reported in up to 5% of patients treated with BTXA for horizontal lines.[49,50] Brow ptosis can also be aggravated by injection of the forehead, as documented in 22 of 25 patients in a study by Bulstrode and Grobbelaar.[51] Patients with pre-existent brow ptosis should not be treated with BTXA because of the possibility of developing a hooded appearance.[15] Injections for horizontal lines should be made at least 2.5cm distant from the upper brow line.[14] The injections should also be within the midpupillary lines of both eyes. If the lateral part of the venter frontalis is well developed, a quizzical brow lift known as ‘Spock’s’ or ‘Jack Nicholson’s’ brows might occur. Some patients like this type of brow lift, but not everybody is happy with it.[42] In the latter case, correction can be performed by injecting Botox® 1–2U or Dysport® 5U into the more lateral frontal fibers, i.e. above the outer third of the eyebrow.[19,44] Appearance or aggravation of nasal lines after glabellar BTXA injection can become obvious when the patient smiles. This is known as the ‘botulinum toxin sign’ and can be corrected by the application of Botox® 2U or Dysport® 10U into the lateral face of the nose, i.e. the levator nasi muscle.[32,33] We do not recommend that beginners in the field treat horizontal and frowning lines at the same time. In the authors’ opinion, this would tend to result in use of a higher volume and dose of BTXA than would be used in sequential therapy. Use of higher volumes of BTXA is more likely to result in brow or lid ptosis.[15] For the experienced user, the risk benefit ratio is balanced. Therefore, some authors recommend that experienced physicians use a combined approach of glabella and forehead injection to maximize effects.[44] 5.8.2 Mid-Face

Lateral brow ptosis was reported to occur in about 5% of patients who were injected for crow’s feet with BTXA.[52] The cause is denervation of the lateral frontalis muscle, which can be avoided by injecting below the eyebrow. It is also important to respect the horizontal line between the cheeks (os zygomaticus) when treating crow’s feet; not staying above this line can result in lip or cheek ptosis.[15] In addition, paralysis of the zygomaticus muscles can cause a Bell palsy appearance.[42] To ensure the treatment of crow’s lines is safe, the volumes injected should be small (0.1–0.2mL per injection point). The needle should be placed at least 1–2cm lateral to the lateral bony margin of the orbita to avoid lid ptosis, diplopia and strabismus.[14,18] Lateral rectus palsy is a potential complication of BTXA for crow’s feet when the injection is too medial and deep.[52] Zygomatic lines that accompany periorbital wrinkles may persist Am J Clin Dermatol 2005; 6 (3)

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or worsen when only the crow’s feet are treated.[15,42] To improve appearance, tissue augmentation using fillers or skin resurfacing techniques can be utilized.[18] Injection of crow’s feet with a lateral canthus injection has been used to lessen rhytides and widen the eyes.[53] Some authors have found that intradermal injections are helpful for decreasing spread of BTXA, especially in the periorbital region.[53] Caution is necessary when treating patients who have had previous eye surgery, particularly lower eyelid blepharoplasty. In these patients, the balance between the tarsoligamentous complex and pretarsal orbicularis of the lower lid can be tipped in favor of the tarsoligamentous complex. The muscular pumping action of the lower lid is weakened, resulting in transient localized lymphedema and festooning that disappears within 3–4 weeks.[54] BTXA injections into the lower eyelid to improve the puffy appearance caused by horizontal bands due to the pretarsal inferior orbicularis muscle should be given only in patients with normal skin elasticity to avoid an ectropium of the lower lid.[44,55] This can be demonstrated using a simple snap test. The dosage of BTXA should be as low as Botox® ≤2U or Dysport® 2–6U.[41,55] There is a synergistic effect when treatment of the lower lid is combined with injection for crow’s feet (optimal dosage Botox® 12U for crow’s feet plus Botox® ≤4U for the lower eyelid).[55] Lower eyelid injections in the midpupillary line about 3mm distant to the lid margin are used to open the eyes. The results of the snap test can be used to identify patients with impaired skin elasticity, who should not receive the injection. Patients who have had previous surgery of the eyelids should also be excluded.

Dosages used may be as low as Botox® 1U or Dysport® 2U.[44] Because patients with fat herniation will develop a prominence of pseudoherniating infraorbital fat pads following BTXA injections of the lower eyelid, infraorbital injections are best avoided in these patients.[53] Some authors do not recommend BTXA for the lower eyelid at all because of the risk of subsequent ectropium, entropium, and pupillary changes like Adie’s pupil.[49] The latter is thought to be due to ciliary ganglion damage.[49] Injections too distant from the recommended injection sites for bunny lines or lower eyelids can compromise the levator labii superioris and zygomaticus major muscles. This may lead to lip ptosis. In a study involving 485 patients treated with BTXA for cosmetic reasons, lip ptosis was seen in two patients injected in the upper lip for attenuation of the nasolabial sulcus.[56] In the authors’ opinion, treatment of a mental crease is more successful using a filler than BTXA.

injection technique, this can impair the function of orbicularis oris, which is undesirable in actors and musicians.[44,50] Fillers may be more appropriate in such patients.

Sad lines (with ptosis of the oral margins) can be improved by injection into depressor anguli oris about 1cm laterally and caudal from the lip margin.[18,44] Injections too close to the mouth should be avoided because of the danger of producing a flaccid cheek, an incompetent mouth, or an asymmetric smile.[57] The poppy chin can easily be treated with a single or double injection into the mentalis muscle. The usual dosage should not exceed Botox® 5U or Dysport® 10–15U.[18,44] Application closer to the mouth may induce a lower lip ptosis. Injections into the mental fold may induce an incompetent mouth.[57] Asian women tend to prefer almond-shaped faces. However, masseter hypertrophy, which is recognized as an asymptomatic enlargement of one or both masseter muscles, may lead to a square jaw contour. Masseter hypertrophy can be treated with BTXA injections. To contour the lower face, injections are given 1cm below and above a reference line drawn from the tragus of the ear to the corner of mouth. The usual dosage is Botox® 25–30U.[58,59] A common adverse effect is reduction of mastication strength, which is seen in up to 44% of patients treated.[59] 5.8.4 Extrafacial Sites

Platysma bands can be improved by BTXA.[8] Serial injections for platysma bands should be given directly into the anterior part of the muscle belly in a superficial way and not directed to the throat (median part of the neck). Three to five injections should be spaced at 1–2cm intervals from the jawline to the lower neck. The sternocleidomastoid muscle and the pharynx region should be spared. The dosage should be limited to Botox® ≤40U because even Botox® 60U can affect swallowing.[41] Horizontal neck lines can be softened with injections of Botox® 1–2U administered along the lines.[41] If injections are given too deeply and the dosages are too high (Botox® >40U), dysphagia and neck muscle weakness may develop.[14] A floppy neck may develop when fibers of the sternocleidomastoid muscle are affected by BTXA.[19] Therefore, it is recommended that, in general, the dosage should not exceed Botox® 100U.[57] Decollet´e wrinkles can be improved by injection of BTXA either in a V-shape along the upper, medium, and lower decollet´e or in a half-moon shape in the upper part alone, depending on the topography of the muscles and wrinkles.[44] A dosage of about Botox® 5U or Dysport® 10U should be used at each injection site.

5.9 Neurologic Adverse Effects

5.8.3 Lower Face

Treatment of the vermilion line to improve vertical rhytides is achieved by injecting low-dose BTXA (Botox® 1U or Dysport® 2U) about 1mm above the upper lip. However, even with proper © 2005 Adis Data Information BV. All rights reserved.

In animal studies, BTXA injection into the sympathetic ganglia of rabbits resulted in a sympathetic ganglion effect for more than 1 month without causing considerable pathologic changes.[60] InjecAm J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A

tion of BTXA in the sciatic nerves of rats also did not cause inflammation or damage.[61] In theory, three types of nerve injury can take place when injecting BTXA into the glabellar area: neuropraxia, axontomesis, and neurontomesis. For example, when a 40-year-old man with cervical dystonia was treated with BTXA, he developed an acute inflammatory demyelinating polyradiculoneuritis.[62] While no causal relationship between BTXA and this adverse event could be firmly established, patients with such an adverse effect should not be treated with BTXA again. In another case report, Cobb et al.[63] reported the first instance of botulism-like syndrome with respiratory arrest after intramuscular injection of BTXA for muscular spasm. The probable explanation was incomplete receptor binding or arrested pinocytosis of BTXA-receptor complexes. However, hard data have not been published to explain this phenomenon.

Importantly, no nerve injuries have been observed with cosmetic use of BTXA. Furthermore, BTXA does not cross the blood-brain barrier and therefore has no CNS effects.[64,65] There has been a single case report of a 44-year-old nonsmoker who, after treatment for glabellar frown and crow’s feet with Botox® 49U, repeatedly reported a metallic taste after injections; these disappeared within 2 weeks.[66] Other reports of dysgeusia due to BTXA have also been published after injection into the masseter muscle.[58] The pathogenesis of such adverse reactions remains unclear.

5.10 Neutralizing Antibodies

It is well known from BTXA treatment of patients with muscle spasm that neutralizing antibodies may develop during a course of repeated injections.[3] The frequency of neutralizing antibodies in patients with cervical dystonia treated with BTXA has been estimated to be as high as 6.5%.[3] Increasing the dose of BTXA cannot overcome secondary therapy failure due to the presence of neutralizing antibodies.[67] The incidence of secondary resistance to the effect of the toxin has been dramatically diminished by the reduction of non-toxic proteins in current batches of Botox®.[68] To date, induction of neutralizing antibodies has not been observed with use of BTXA for cosmetic purposes.

5.11 Ophthalmologic Adverse Effects

Diplopia has been reported in 3% of patients treated for facial muscle spasm with BTXA.[69] It was suggested that the extraocular muscles of some patients may be more susceptible to BTXA than others, or that BTXA may diffuse more easily in some patients.

To maintain the safety of treating crow’s lines, only small volumes (0.1–0.2mL per injection point) of BTXA should be injected and dosages should not exceed Botox® 4U or Dysport® 10U. The needle should be placed at least 1–2cm lateral to the © 2005 Adis Data Information BV. All rights reserved.

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lateral bony margin of the orbita to avoid lid ptosis, diplopia and strabismus.[44,70] Because injections of BTXA for blepharospasm can also induce lid ptosis,[15,71] Scott[71] investigated whether injection of human botulinum immune globulin could prevent this adverse effect. He found that 3.2 × 10–3 IU of human botulinum immune globulin per 1U of Botox® was effective in blocking the toxin effect when injected into the same tissue site within 4 hours. The limited temporary lid ptosis seen with use of BTXA for cosmetic indications may be improved with apraclonidine 0.5% (Iopidine®) or phenylephrine 2.5% (Neosynephrine®) eyedrops. These act on the Mueller muscle of the upper lid and can lift the lid up to 1.0mm.[14] Injections around the eye should always be performed laterally with the needle pointing away from the eyeball. There have been reports of blindness after centripetal injection of fat and collagen in this area.[72,73] Theoretically, needle penetration of the orbit can occur, leading to retrobulbar hemorrhage.[49] Injections of BTXA into the medial part of the lower eyelid decrease the mean blink-out rate (a measure of the frequency of lid movement).[49] This can cause a problem in patients exposed to dust or other airborne material that may necessitate rapid lid closure. On the other hand, this effect may be beneficial in patients with dry eye conditions, since every movement may cause burning or even pain.[74,75] However, reduced blinking can also lead to corneal exposure and corneal ulcers.[49] According to a recent report, incorrect injection of BTXA into the pretarsal portion of the orbicularis oculi muscle in an attempt to correct lateral canthal rhytides resulted in abnormal lacrimation, as shown by Schirmer‘s test.[75] The condition was treated with ocular lubrication. However, use of the correct injection technique should have prevented this adverse effect.

When treating horizontal lines, it is important to avoid causing brow ptosis and asymmetry. These adverse effects were seen in 22 of 25 and 2 of 25 patients, respectively, in a study by Bulstrode and Grobbelaar.[51] We recommend maintaining a distance of at least 2.5cm between the upper line of the brow and any injection point.

Bilateral ptosis has been reported after injections of BTXA into neck muscles.[57] 5.12 Pain

Adverse effects that can occur at any injection site (not only with BTXA) include pain, burning sensations, edema, redness, and short-time hypoesthesia.[15] Pain during BTXA injection is variable and depends on individual sensitivity.[32] However, the smaller the needles used, the better the tolerance. We recommend use of 30–34 gauge needles. The injection should be delivered slowly while pinching the skin to reduce injection-related pain.[14] In some countries, isotonic sodium chloride can contain preservatives. It has been shown that preservatives in the solution Am J Clin Dermatol 2005; 6 (3)

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used for reconstitution of BTXA can significantly decrease patient discomfort on injection.[76] However, in their package leaflets, both Speywood/Ipsen and Allergan recommend against use of preservative-containing isotonic sodium chloride solutions for reconstituting BTXA. Topical application of anesthetic EMLA® cream may help decrease injection pain.[77] Application of ice or a frozen gel-filled mask 5 minutes before BTXA injection also decreases pain in about 45% of recipients.[78] In special cases, local analgesia is helpful.[15] 5.13 Psychiatric Disorders

Botulinophilia is a dysmorphic disorder, in which patients seem to be obsessed about getting BTXA treatment for complaints that are either non-existent or still in remission, so they objectively do not need a (repeat of) treatment. Botulinophilia is not caused by BTXA but rather should be considered a contraindication for the use of BTXA.[79] Acute anxiety and depression have been observed in a spastic patient after intramuscular injection of BTXA, but it is doubtful whether these mood disturbances were caused by BTXA.[80] 5.14 Skin

Cutaneous adverse effects of BTXA are extremely rare.[4,8,13,15] Only case reports of dermatologic adverse events have been published and the causative role of BTXA in these conditions remains mostly speculative.

In dark-skinned patients, injection-related inflammation may cause pigmentation changes.[81] However, in a study of 26 African American patients receiving repeated periocular BTXA injections, no evidence of any pigmentary disorder was noted.[81] Persistent rash arising from (lactose) allergy may develop at the site of repeated BTXA injections.[22] Repeated BTXA injections to the forehead have been reported to cause dryness and flakiness of the frontal area in 2 of 52 patients.[49] This can be explained by the antihydrotic activity of BTXA, even in the case of intramuscular injection. Most female patients will not experience this mild adverse effect if they usually use facial moisturizers. However, some male patients may suffer from this minor discomfort. Regular use of a moisturizer will diminish BTXA-induced dryness.[57] A case of human herpes virus type 8-positive facial angiosarcoma developing at the site of BTXA injection for blepharospasm has been reported.[82] The role of BTXA in this case remains unclear.

An 80-year-old woman with chronic myeloid leukemia who underwent BTXA injections for blepharospasm developed a necrotizing fasciitis.[83] © 2005 Adis Data Information BV. All rights reserved.

A psoriasiform eruption has been observed after intramuscular injection of BTSA.[84] In patients with skin diseases likely to show Koebnerization, such as psoriasis, lichen planus etc, patients should be informed that skin lesions may develop at the site of injection.

5.15 Therapeutic Failure

Although sporadic, there is anecdotal evidence that some patients do not respond to BTXA. For example, patients with severe actinic damage and poorly developed musculature will not benefit greatly from BTXA.[70] In patients who develop neutralizing antibodies as a result of non-cosmetic use of BTXA, a change to BTXB may be necessary.

However, there is no standardized commercially available assay for testing neutralizing antibodies. Not all patients with neutralizing antibodies experience a loss of activity of the compound.

Furthermore, there is an imprecise correlation between antibody levels and the number of injections, length of treatment, or cumulative BTXA dose.[3,4] Although immunologic and treatment resistance have yet to be reported in patients treated for cosmetic reasons or hyperhidrosis, it may be necessary to warn patients of this as one of the possible complications of BTXA therapy.

However, this adverse effect can be avoided by keeping injected volumes low, avoiding intravascular injections, and spacing injections at intervals of at least 1 month.[14] Administration of suboptimal doses and use of incorrect injection techniques will lead to treatment failure. Electromyography has been recommended by some authors as a means of improving localization of injection points for hyperkinetic facial lines.[85] 6. Conclusions BTXA is safe for cosmetic indications and treatment of hyperhidrosis when simple treatment guidelines are followed. The main complications are technique-dependent. They can be minimized by adequate training, detailed knowledge of the anatomy and physiology of injection targets, and an understanding of the pharmacology and toxicology of BTXA. To ensure a safe and satisfying treatment outcome, serious attention needs to be paid to the following points: • obtaining a detailed medical history from the patient; • performing a careful physical examination; • excluding contraindications, if necessary by laboratory and other investigations; • using accurate techniques of injection, dilution, and storage of BTXA; • injecting concentrated small volumes; • avoiding injections in unsuitable areas; • educating the patient and providing complete documentation about how BTXA works, when it is indicated, its potential Am J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A

risks, the nature of the procedure, and your recommendations about use of the drug; • obtaining the patient’s written consent.

We believe that BTXA therapy is a medical procedure that should be administered only by skilled, experienced and well trained physicians. Application of BTXA by non-medical personnel is unethical and dangerous. Adherence to these recommendations listed above can only increase the chance that patients receiving BTXA injections will benefit from the procedure.

Acknowledgments No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Correspondence and offprints: Dr Uwe Wollina, Department of Dermatology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital, Friedrichstrasse 41, Dresden, 01067, Germany.

E-mail: Wollina-Uw@khdf.de

Am J Clin Dermatol 2005; 6 (3)