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

© 2005 Adis Data Information BV. All rights reserved.

Managing Adverse Events Associated withBotulinum Toxin Type AA Focus on Cosmetic Procedures

Uwe Wollina and Helga Konrad

Department of Dermatology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital, Dresden, Germany

Botulinum toxin A (BTXA) has become a widely used drug in cosmetic dermatology, not only to treat focalAbstracthyperhidrosis but also hyperkinetic facial lines, platysma bands, decollete bands, and other skin features. Thespectrum of possible adverse effects of BTXA is broad but fortunately those that have been observed withcosmetic use of this product are generally mild and transient. The major tools for preventing adverse effects fromBTXA are knowledge and skill. Use of correct injection techniques is mandatory since most unwanted effects arecaused by incorrect technique. Knowledge of the target structures, e.g. the facial and extrafacial muscles, allowsphysicians to select the optimal dose, time and technique. The most common adverse effects are pain andhematoma. In the periocular region, lid and brow ptosis are important adverse effects. Adverse effects such aspain, 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 bewary of include induction headaches and possible interaction with concomitant medications. Induction ofneutralizing antibodies due to cosmetic BTXA treatment has not been observed. This article also outlinesrecommendations regarding use of BTXA. Of these, the most important for avoiding most unwanted adverseeffects are the proper techniques of dilution, storage, and injection, as well as the careful exclusion of patientswith any contraindications. Pain, hematoma, ecchymosis, and bruising can be prevented by cooling the skinbefore and after BTXA injection. Upper lid ptosis may be partly corrected using apraclonidine or phenylephrineeyedrops. If simple rules relating to the indications for and application of BTXA are followed, this is a safe andeffective drug in cosmetic dermatology.

Botulinum toxin (BTX) is produced by Clostridium botulinum. cle transport protein. In this way, it impedes proper binding ofacetylcholine vesicles to, and fusion with, the cell membrane.This was discovered in 1905 by Tchitchikine, who described theNeurotransmitter release to the muscle endplate is inhibited andsubstance as a neurotoxin.[1] BTX was purified by Sommer inmuscle contraction prevented. The deadly dose for humans hasCalifornia in 1920, and 36 years later Lamanna succeeded inbeen estimated to be 3000U of Botox® 1.[3,4]further purifying BTX into crystalline form.[2] In 1949, it was

demonstrated that BTX inhibits the release of acetylcholine from1. Botulinum Toxin A Brandsnerve endings.[3]

BTX consists of two different chains, a heavy chain that is There are two different BTXA products on the internationalresponsible for binding to the nerve ending and a light, toxifying market – Botox® (Allergan) and Dysport® (Speywood/Ipsen). Thechain. Following endocytosis, the molecule is cleaved by disrup- two formulations have different biological potencies.[4] However,tion of a disulfide bond. Seven different types of BTX are known, the exact relative potencies of the two products are still a matter ofbut only BTXA and very recently BTXB have been approved as debate. While the potency of both BTXA products is expressed indrugs for human use. The target for BTXA is a 25kDa LD50 mouse units (the amount of toxin required to kill 50% of testsynaptosome-associated protein. The binding is rapid and stable. mice), the assays used for each are different. However, one vial ofBTXA, a zinc-dependent endopeptidase, cleaves the 25kDa vesi- Botox® contains 100U, whereas one vial of Dysport® contains

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

142 Wollina & Konrad

500U, suggesting a conversion factor of 1 : 5 (Botox® vs 3. Dosage and AdministrationDysport®). Indeed, a single-blind, randomized, parallel study con-

BTXA should not be administered as large volumes of low-ducted in patients with blepharospasm or hemifacial spasm sup-dose toxin. Dilutions should be as recommended in the productported this conversion factor.[5] Other double-blind studies ininformation. Higher dilutions are associated with a risk of instabil-cervical dystonia patients suggested a conversion factor of 1 : 3 toity since the protein concentrations are in the range of nanograms.1 : 4 (Botox® vs Dysport®).[6,7] Unfortunately, no comparativeFurthermore, duration of response might be shortened with higher

study in BTXA for hyperkinetic wrinkles or hyperhidrosis hasdilutions because of increased diffusion of BTXA and a lower

been published as yet. Nor has it been proven that the above-effective concentration at the target site.[15] The use of concentra-

mentioned conversion factor for Botox® versus Dysport® is stabletions according to the product information in small volumes (i.e.

for all indications.0.1–0.2mL per injection site) will ensure that the toxin does not

Because of the different potencies of the two available BTXA diffuse to unwanted sites.[15]

preparations, there is a risk of over- or under-treatment when In general, patients who have undergone previous facial sur-different brands of BTXA are used in the same office. To mini- gery or show facial asymmetries require a dose adaption andmize this risk, the reconstitution of lyophilized BTXA and the probably modifications of the injection sites. The injection sites inpreparation of syringes for the individual patient should be carried general are placed in a symmetrical pattern, but any asymmetry ofout by the physician who administers the injections. 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, and2. Use in Cosmetic DermatologyDysport® within 8 hours, when kept at a temperature of between2°C and 8°C.[16]

Use of BTXA in cosmetic medicine has arisen from observa-tions that treatment of blepharospasm by BTXA also improved 4. Contraindications and Precautionsperiocular lines.[8] Standard procedures for BTXA injection toimprove mimic lines and wrinkles target frown lines, glabellar Patient selection is a crucial step toward prevention of patient(horizontal) lines, and crow’s feet. dissatisfaction. Every patient needs an extensive informative con-

sultation that covers not only the BTXA option but also allEvaluation of BTXA in double-blind, placebo-controlled stud-alternative methods and procedures. Patients should be madeies of patients with glabellar folds[9,10] and crow’s feet[11,12] hasaware that facial asymmetry is common, and that use of BTXAresulted in recognition of this agent as an evidence-based cosmeticcannot guarantee facial symmetry; however, asymmetry caused bymedicine for these indications. For other lines and wrinkles, thehyperactive muscles can be smoothened.[17] BTXA should not beevidence for use of BTXA is based on uncontrolled studies.[8,13]

used for facial rejuvenation in patients that have a pre-existent lidMore advanced techniques involve use of BTXA for perioral lines,ptosis or those who have undergone surgical procedures that maysad lines, marionette lines, nasal (bunny) lines and the poppyhave repositioned or weakened the muscles.[18]

chin.[8] BTXA has also been used for brow lift, eye openingPoor candidates for BTXA include patients with unrealistic(injection into the lower lid), gingival smile, platysmal bands, neck

expectations and psychiatric disease, in whom BXTA should bebands, sleeping lines and decollete lines.[8]

used with caution. There is also a small group of patients who fearKnowledge of the pharmacology and toxicology of BTXA, and the possibility of sustaining systemic botulism after BTXA injec-

of the anatomy and physiology of treatment targets (i.e. the facial tion and it should also be used with caution in these patients. Inand extrafacial muscles), are the keys to successful use of BTXA. addition, patients who are normally rather demonstrative, such asDevelopment of expertise in the use of the appropriate injection politicians and actors, may fear that BTXA might leave them withtechniques, dosages, and dilutions requires training. To avoid a mask-like, non-emotive face.[15,19] In such cases, fillers might becommon mistakes, we recommend that practitioners who wish to a better alternative.administer BTXA attend at least a course and workshop given by Contraindications to use of BTXA include pregnancy or lacta-an experienced user of BTXA. We advise that beginners in this tion.[8,15] Patients with neuromuscular diseases such as Lambert-field should not start with advanced techniques; rather, gradual Eaton syndrome, amyotrophic lateral sclerosis or myastheniaprogression from easier to more sophisticated applications is rec- gravis are also not suitable for BTXA therapy since even lowommended. When basic guidelines are adhered to, use of BTXA doses of the toxin may cause a neuromuscular crisis.[14]

for cosmetic reasons and hyperhidrosis is safe, predictable, has no BTXA should not be used in patients taking concomitant ami-serious complications, and delivers general patient satisfac- noglycoside antibacterials, such as streptomycin, dihydrostrepto-tion.[13,14] mycin, gentamicin, neomycin, netilmicin, kanamycin or spectino-

© 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A 143

mycin, as these drugs can interfere with the metabolism of BTXA = 1).[21] As yet, there have been no published reports of BTXAand prolong the half-life of the toxin.[4,19] When administered for allergy.cosmetic reasons or hyperhidrosis therapy, BTXA should also be A single case of fixed drug eruption has been observed follow-avoided in patients taking one of the following medications, as ing BTXA injection.[22] However, the cause of the eruption wasthese drugs may interfere with the action of BTXA at the target lactose, not the toxin or the non-toxic proteins. Lactose is a rarestructures or increase the risk of infections, such as cyclosporin A: cause of fixed drug eruptions.[23]

polymyxins, tetracyclines, lincomycin, penicillamine, quinine, A so-called localized anaphylactic reaction was described fol-cyclosporin, chloroquine and hydroxychloroquine, gallamine, lowing BTXA injection into leg muscles, although the allergicpancuronium, tubocurarine, calcium channel antagonists, and lo- nature of the reaction was not proved.[24] To date, no anaphylaxiscal anesthetics.[4,14,19] These drugs may interfere with the action of or deaths attributable to BTXA have been reported.[3]

BTXA at the target structures or increase the risk of infectionssuch as cyclosporin A. The great importance of these precautions

5.2 Cardiovascular Systemhas been illustrated very recently by Li et al.,[20] who described acase of fatal anaphylaxis in a 43-year-old woman. She experienced

BTXA is a powerful presynaptic neuromuscular blocking agentchronic muscle pain and was treated several times with Botox®.which interferes with cholinergic parasympathetic terminals. InOn the last occasion the patient received Botox® 100U, togetherorder to evaluate whether BTXA has an influence on the cardio-with lidocaine 5mL injected into several muscular trigger points.vascular system, the short-term cardiovascular effects of BTXAMixtures of BTXA with local anesthetics should also be avoidedwere evaluated in 26 patients with torticollis.[25] The dosage wassince the mixture may change the tertiary structure of the BTXABTX (Dysport®) 12ng (almost 500U) administered intramuscular-molecule and interfere with pharmacokinetics.ly. No significant influence on respiratory heart variation was

Since conditions like diabetes, alcoholism, polymyositis andobserved after one injection. After a second injection, a significant

other immunocompromising conditions are risk factors for severeattenuation of selected parameters was seen, and this response was

infectious disease, BTXA injections for either cosmetic reasons ornoted with each subsequent injection over several months. How-

hyperhidrosis should generally be avoided in patients with theseever, no clinically manifest remote adverse effects or cardiac

conditions.hypokinetic arrhythmias were seen over this period.[25]

Every kind of septic and antiseptic care is necessary andNevertheless, fatal heart block has been described following

recommended when handling and storing BTXA. Injection sitestreatment with BTXA for achalasia.[26] A 91-year-old man with

must be disinfected, and BTXA injection should not be given inpre-existent heart disease, first degree atrioventricular block, right

any area of active infection.[10]

bundle branch block, and incomplete left bundle branch block wastreated for achalasia with Botox® 80U. He died 3 weeks later as a5. Adverse Effectsconsequence of complete atrioventricular block and sepsis. It is

The most common adverse effects of BTXA in cosmetic indica- rare for people of this age and with cardiovascular problems of thistions are listed in table I. kind to ask for BTXA to treat cosmetic conditions. However, it is

important to be aware of the possibility that BTXA may worsen a5.1 Allergies pre-existent bradycardia. In an animal model it was investigated

whether BTXA injected into the sinoatrial fat pad inhibits de-Patients with known hypersensitivity to any of the componentscreases in heart rate induced by stimulation of the preganglionicof commercially available BTXA, such as human albumin, lac-parasympathetic nerves in the heart of the anesthetized dog.[27]

tose, saline and BTXA itself, are not suitable candidates for BTXAStimulation of the parasympathetic nerves in the sinoatrial fat padtreatment. However, in two large studies involving >300 patients,(SAP stimulation) prolonged the atrial interval but not the atrio-most of whom received multiple treatments of BTXA, only fourventricular interval, and cervical vagus nerve stimulation pro-experienced generalized pruritus (n = 3) or an unspecified rash (nlonged both atrial and atrioventricular intervals. After BTXA(Botox® 20U or 25U) was injected into the sinoatrial fat pad, itgradually inhibited the prolongation of the atrial interval evokedby SAP and cervical vagus nerve stimulations but not the prolon-gation of the atrioventricular interval evoked by cervical vagusnerve stimulation. Conditioning successive stimulation of the cer-vical vagus nerves accelerated the inhibition by BTXA of thechronotropic response to cervical vagus nerve stimulation. Theseresults indicate that selective injection of botulinum toxin into the

Table I. The most common adverse effects of botulinum toxin A (BTXA) incosmetic 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. Am J Clin Dermatol 2005; 6 (3)

144 Wollina & Konrad

sinoatrial fat pad blocks bradycardia mediated by parasympathetic ders or medications that affect hemostasis and thrombostasisganglionic activation in the dog heart.[27] should not be treated with intramuscular (BTXA) injections.

Even with proper technique, ecchymosis occurs easily in theImportantly, the doses of BTXA used in cosmetic proceduressoft eyelid tissue and the periorbital tissue of patients receivingare in general much lower than those used in the treatment ofBTXA injections in these areas. In a placebo-controlled trial ofachalasia, dystonia or spasticity. Furthermore, there has been noBTXA for crow’s feet, bruising was seen in 11–25% of patients,report of cardiovascular adverse effects following BTXA treat-with similar rates being seen in the placebo group.[11] This adversement for cosmetic reasons.effect can be minimized by immediately applying pressure at theinjection site after every injection, alone or in combination with a5.3 Generalized Reactionscold compress.

As shown by electromyographic investigations conducted at Patients should discontinue nonsteroidal anti-inflammatorysites distant from the BTXA injection site, small amounts of the agents such as aspirin, but also tocopherol (vitamin E) or gingkotoxin may diffuse into the circulation.[8] Generalized reactions biloba, 10 days before BTXA injections.[19,33] Furthermore, be-have been observed in rare cases following intramuscular BTXA cause smokers tend to have more bruising after BTXA injection, itinjection for spastic disorders and cosmetic reasons.[15] These has been recommended that smoking should be stopped at least 7reactions include nausea, fatigue, malaise, flu-like reactions, and days before injection.[33]

rashes at distant sites. Symptomatic treatment only is required forthese adverse effects. 5.6 Infection

To date, infections have not been reported in patients seeking5.4 Headachescosmetic treatment with BTXA.[31]

While headaches can be induced by injection of BTXA, espe-5.7 Interactions with Concomitant Medicationscially in the forehead, it is more common for patients to report that

chronic tension headaches have improved after injection of BXTA should not be used in patients taking the medicationsBTXA.[8,10,28] Furthermore, pericranial injection of BTXA has listed in section 4. In addition, Fiacchino et al.[34] reported thatbeen found to be a safe and well tolerated treatment that reduces BTXA interferes with other neuromuscular blockers like vecuroni-migraine frequency, severity, acute medication use, and associated um and may cause tolerance to the effects of vecuronium.vomiting.[29]

In a study of 264 patients treated with BTXA (Botox®) for 5.8 Musclesglabellar lines, 15.3% reported headaches. Of these, over 90%

In general, the main adverse effects of BTXA in cosmeticwere rated as mild and two-thirds disappeared within a fewdermatology and the treatment of hyperhidrosis are a loss of facialhours.[10] In a prospective randomized trial of Botox® combinedexpression, incomplete muscle paralysis with residual rhytides,with collagen for glabellar furrows, no difference in headache rateand unwanted muscle paralysis resulting from spread of toxin towas observed between Botox®/collagen and placebo recipients.[30]

adjacent sites.[35] Asymmetry can result from either using exces-No specific therapy is generally required in patients who reportsively high (loss of facial expression) or excessively low (incom-headaches following Botox® injection. Local application of coldplete muscle paralysis with residual rhytides) doses of injectedcompresses is beneficial in most cases.[8,15]

BXTA.[36] Unwanted paralysis can be due to incorrect injectionRecently, severe headache after BTXA application for cosmeticsite or high-volume, low-concentration injections. Patients withreasons or palmar hyperhidrosis was reported in five patients.[31]

previous facial surgery or palsy need special attention (see sectionThe headaches lasted for 1–4 weeks. No infection or any other sign3).of adverse reaction to BTXA was documented. The reason for

Muscular weakness at the site of BTXA injection is a desirablethese headaches is not known and risk factors have not beeneffect when treating lines and wrinkles. Correct injection tech-defined. Painkillers are necessary in these rare cases.nique will ensure that this weakness is limited to those muscleswhere the effect is needed. Local spread of BTXA occurs by5.5 Hematoma, Ecchymosis and Bruisingdiffusion up to 3cm in diameter from the injection point.[4]

Intramuscular injections may cause hematomas. Ecchymosis of There is one published report of a 70-year-old woman whomucous membranes is another possible adverse effect of BTXA developed esotropia, hypertropia, ptosis of the upper lid, andinjection. However, the available evidence suggests that hemato- double vision after BTXA injections around the eyelids.[37] Thema and ecchymosis at injection sites occur in less than 1% of adverse effects described mimicked myasthenia gravis. MuscularBTXA injections.[32,33] Nevertheless, patients with bleeding disor- adverse effects in indications other than cosmetic use have also

© 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A 145

been reported. Recently, two patients with paraplegia or te- Mueller’s muscle and thereby elevate the upper eyelid;traplegia who were treated with BTXA for neurogenic detrusor apraclonidine has the advantage of not affecting the pupil.[14]

overactivity were reported to have developed muscular weakness Over-treatment of horizontal lines with BTXA can cause aat distant sites lasting for approximately 3 months.[38] One patient mask-like appearance and brow ptosis. Indeed, transient browreceived Dysport® (total dosage 1500U), the other Botox® (total ptosis, particularly involving the lateral brow, has been reported indosage 300U). The authors suggested that these two patients did up to 5% of patients treated with BTXA for horizontal lines.[49,50]

not develop the expected tight binding of BTXA locally, which Brow ptosis can also be aggravated by injection of the forehead, aswould normally prevent passage of BTXA into the circulatory documented in 22 of 25 patients in a study by Bulstrode andsystem.[38] Another study of patients with cervical dystonia sug- Grobbelaar.[51] Patients with pre-existent brow ptosis should not begested that Dysport® was associated with more swallowing treated with BTXA because of the possibility of developing aproblems than Botox®.[39] These types of adverse effects have not hooded appearance.[15] Injections for horizontal lines should bebeen observed in cases of cosmetic use of BTXA. However, we made at least 2.5cm distant from the upper brow line.[14] Therecommend that participation in any activity that increases local injections should also be within the midpupillary lines of bothblood flow, such as massage, sauna, steam bath or sun bath, should eyes. If the lateral part of the venter frontalis is well developed, abe avoided within a few hours of BTXA injection.[8,15,19] quizzical brow lift known as ‘Spock’s’ or ‘Jack Nicholson’s’

brows might occur. Some patients like this type of brow lift, but5.8.1 Upper Face not everybody is happy with it.[42] In the latter case, correction can

be performed by injecting Botox® 1–2U or Dysport® 5U into theTransient eyelid ptosis is the most significant complication ofmore lateral frontal fibers, i.e. above the outer third of the eye-BTXA injection in the glabellar area and occurs in about 2% ofbrow.[19,44]

injections.[40] Lid ptosis was seen in 5.4% of 264 patients treatedAppearance or aggravation of nasal lines after glabellar BTXAfor glabellar lines in one study.[10] The upper eyelid levator muscle

injection can become obvious when the patient smiles. This iscan be affected as BTXA migrates through the orbital septum,known as the ‘botulinum toxin sign’ and can be corrected by theleading to ptosis within 2 to 10 days of injection.[14] When frownapplication of Botox® 2U or Dysport® 10U into the lateral face oflines are being treated with BTXA, a distance of at least 1cmthe nose, i.e. the levator nasi muscle.[32,33]above the bony supraorbital margin at the lateral injection site

We do not recommend that beginners in the field treat horizon-should be left to avoid brow or lid ptosis.[41] Lid ptosis can alsotal and frowning lines at the same time. In the authors’ opinion,occur if injection of the nasal bridge is too lateral.this would tend to result in use of a higher volume and dose ofThe lateral brow lift is performed by injection in the outer thirdBTXA than would be used in sequential therapy. Use of higherof the brow about 0.5cm above the upper orbital margin. Brow liftvolumes of BTXA is more likely to result in brow or lid ptosis.[15]

by injection at the level of the lateral canthus can produce lid ptosisFor the experienced user, the risk benefit ratio is balanced. There-if it is not directed above the orbital rim.[42,43] The medial brow liftfore, some authors recommend that experienced physicians use ais performed by injecting below the medial part of the brow. Thecombined approach of glabella and forehead injection to maximizedosage of BTXA used should be as little as Botox® 2–6U oreffects.[44]

Dysport® ≤6U for medial brow lift and about Botox® 3.5U orDysport® 5–10U for lateral brow lift.[44] At a recent German 5.8.2 Mid-Faceconsensus conference on BTXA, a single injection point was Lateral brow ptosis was reported to occur in about 5% ofrecommended for brow lift procedures.[44] However, previously, patients who were injected for crow’s feet with BTXA.[52] TheAhn et al.[45] had suggested injection of a total of 7–10U of Botox® cause is denervation of the lateral frontalis muscle, which can beat three injection points into the superolateral part of the orbicu- avoided by injecting below the eyebrow. It is also important tolaris oculi below the lateral third of the brow. Again, injection respect the horizontal line between the cheeks (os zygomaticus)should be superior and lateral to the orbital rim to minimize the when treating crow’s feet; not staying above this line can result inrisk of diffusion of toxin through the orbital septum. Based on lip or cheek ptosis.[15] In addition, paralysis of the zygomaticuspublished data from open studies, the risk of lid ptosis seems to be muscles can cause a Bell palsy appearance.[42]

higher for Dysport® (6.6%) than for Botox® (1.4%).[46,47] Several To ensure the treatment of crow’s lines is safe, the volumesinvestigators have noted that caution is warranted when treating injected should be small (0.1–0.2mL per injection point). Theolder patients who may have reduced or absent orbital septum as needle should be placed at least 1–2cm lateral to the lateral bonythis causes the risk of a wider spreading of BTXA and thereby an margin of the orbita to avoid lid ptosis, diplopia and strabis-increased risk of lid ptosis.[14,18,48]

mus.[14,18] Lateral rectus palsy is a potential complication of BTXAIn patients with lid ptosis, apraclonidine 0.5% (Iopidine®) or for crow’s feet when the injection is too medial and deep.[52]

phenylephrine hydrochloride 2.5% (Neosynephrine®) stimulate Zygomatic lines that accompany periorbital wrinkles may persist

© 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)

146 Wollina & Konrad

or worsen when only the crow’s feet are treated.[15,42] To improve injection technique, this can impair the function of orbicularis oris,appearance, tissue augmentation using fillers or skin resurfacing which is undesirable in actors and musicians.[44,50] Fillers may betechniques can be utilized.[18] Injection of crow’s feet with a lateral more appropriate in such patients.canthus injection has been used to lessen rhytides and widen the Sad lines (with ptosis of the oral margins) can be improved byeyes.[53] Some authors have found that intradermal injections are injection into depressor anguli oris about 1cm laterally and caudalhelpful for decreasing spread of BTXA, especially in the peri- from the lip margin.[18,44] Injections too close to the mouth shouldorbital region.[53] be avoided because of the danger of producing a flaccid cheek, an

incompetent mouth, or an asymmetric smile.[57]Caution is necessary when treating patients who have hadprevious eye surgery, particularly lower eyelid blepharoplasty. In The poppy chin can easily be treated with a single or doublethese patients, the balance between the tarsoligamentous complex injection into the mentalis muscle. The usual dosage should notand pretarsal orbicularis of the lower lid can be tipped in favor of exceed Botox® 5U or Dysport® 10–15U.[18,44] Application closerthe tarsoligamentous complex. The muscular pumping action of to the mouth may induce a lower lip ptosis. Injections into thethe lower lid is weakened, resulting in transient localized mental fold may induce an incompetent mouth.[57]

lymphedema and festooning that disappears within 3–4 weeks.[54] Asian women tend to prefer almond-shaped faces. However,masseter hypertrophy, which is recognized as an asymptomaticBTXA injections into the lower eyelid to improve the puffyenlargement of one or both masseter muscles, may lead to a squareappearance caused by horizontal bands due to the pretarsal inferiorjaw contour. Masseter hypertrophy can be treated with BTXAorbicularis muscle should be given only in patients with normalinjections. To contour the lower face, injections are given 1cmskin elasticity to avoid an ectropium of the lower lid.[44,55] This canbelow and above a reference line drawn from the tragus of the earbe demonstrated using a simple snap test. The dosage of BTXAto the corner of mouth. The usual dosage is Botox® 25–30U.[58,59]should be as low as Botox® ≤2U or Dysport® 2–6U.[41,55] There isA common adverse effect is reduction of mastication strength,a synergistic effect when treatment of the lower lid is combinedwhich is seen in up to 44% of patients treated.[59]with injection for crow’s feet (optimal dosage Botox® 12U for

crow’s feet plus Botox® ≤4U for the lower eyelid).[55]

5.8.4 Extrafacial SitesLower eyelid injections in the midpupillary line about 3mmPlatysma bands can be improved by BTXA.[8] Serial injectionsdistant to the lid margin are used to open the eyes. The results of

for platysma bands should be given directly into the anterior partthe snap test can be used to identify patients with impaired skinof the muscle belly in a superficial way and not directed to theelasticity, who should not receive the injection. Patients who havethroat (median part of the neck). Three to five injections should behad previous surgery of the eyelids should also be excluded.spaced at 1–2cm intervals from the jawline to the lower neck. TheDosages used may be as low as Botox® 1U or Dysport® 2U.[44]

sternocleidomastoid muscle and the pharynx region should beBecause patients with fat herniation will develop a prominencespared. The dosage should be limited to Botox® ≤40U becauseof pseudoherniating infraorbital fat pads following BTXA injec-even Botox® 60U can affect swallowing.[41]

tions of the lower eyelid, infraorbital injections are best avoided inHorizontal neck lines can be softened with injections of Botox®these patients.[53]

1–2U administered along the lines.[41] If injections are given tooSome authors do not recommend BTXA for the lower eyelid atdeeply and the dosages are too high (Botox® >40U), dysphagiaall because of the risk of subsequent ectropium, entropium, andand neck muscle weakness may develop.[14] A floppy neck maypupillary changes like Adie’s pupil.[49] The latter is thought to bedevelop when fibers of the sternocleidomastoid muscle are affect-due to ciliary ganglion damage.[49]

ed by BTXA.[19] Therefore, it is recommended that, in general, theInjections too distant from the recommended injection sites fordosage should not exceed Botox® 100U.[57]

bunny lines or lower eyelids can compromise the levator labiiDecollete wrinkles can be improved by injection of BTXAsuperioris and zygomaticus major muscles. This may lead to lip

either in a V-shape along the upper, medium, and lower decolleteptosis. In a study involving 485 patients treated with BTXA foror in a half-moon shape in the upper part alone, depending on thecosmetic reasons, lip ptosis was seen in two patients injected in thetopography of the muscles and wrinkles.[44] A dosage of aboutupper lip for attenuation of the nasolabial sulcus.[56] In the authors’Botox® 5U or Dysport® 10U should be used at each injection site.opinion, treatment of a mental crease is more successful using a

filler than BTXA.5.9 Neurologic Adverse Effects

5.8.3 Lower Face

Treatment of the vermilion line to improve vertical rhytides is In animal studies, BTXA injection into the sympathetic gangliaachieved by injecting low-dose BTXA (Botox® 1U or Dysport® of rabbits resulted in a sympathetic ganglion effect for more than 12U) about 1mm above the upper lip. However, even with proper month without causing considerable pathologic changes.[60] Injec-

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Managing Adverse Events of Botulinum Toxin Type A 147

tion of BTXA in the sciatic nerves of rats also did not cause lateral bony margin of the orbita to avoid lid ptosis, diplopia andinflammation or damage.[61] strabismus.[44,70]

In theory, three types of nerve injury can take place when Because injections of BTXA for blepharospasm can also in-injecting BTXA into the glabellar area: neuropraxia, axontomesis, duce lid ptosis,[15,71] Scott[71] investigated whether injection ofand neurontomesis. For example, when a 40-year-old man with human botulinum immune globulin could prevent this adversecervical dystonia was treated with BTXA, he developed an acute effect. He found that 3.2 × 10–3 IU of human botulinum immuneinflammatory demyelinating polyradiculoneuritis.[62] While no globulin per 1U of Botox® was effective in blocking the toxincausal relationship between BTXA and this adverse event could be effect when injected into the same tissue site within 4 hours. Thefirmly established, patients with such an adverse effect should not limited temporary lid ptosis seen with use of BTXA for cosmeticbe treated with BTXA again. In another case report, Cobb et al.[63] indications may be improved with apraclonidine 0.5% (Iopidine®)reported the first instance of botulism-like syndrome with respira- or phenylephrine 2.5% (Neosynephrine®) eyedrops. These act ontory arrest after intramuscular injection of BTXA for muscular the Mueller muscle of the upper lid and can lift the lid up tospasm. The probable explanation was incomplete receptor binding 1.0mm.[14]

or arrested pinocytosis of BTXA-receptor complexes. However, Injections around the eye should always be performed laterallyhard data have not been published to explain this phenomenon. with the needle pointing away from the eyeball. There have beenImportantly, no nerve injuries have been observed with cosmetic reports of blindness after centripetal injection of fat and collagenuse of BTXA. Furthermore, BTXA does not cross the blood-brain in this area.[72,73] Theoretically, needle penetration of the orbit canbarrier and therefore has no CNS effects.[64,65] occur, leading to retrobulbar hemorrhage.[49]

There has been a single case report of a 44-year-old non- Injections of BTXA into the medial part of the lower eyelidsmoker who, after treatment for glabellar frown and crow’s feet decrease the mean blink-out rate (a measure of the frequency of lidwith Botox® 49U, repeatedly reported a metallic taste after injec- movement).[49] This can cause a problem in patients exposed totions; these disappeared within 2 weeks.[66] Other reports of dys- dust or other airborne material that may necessitate rapid lidgeusia due to BTXA have also been published after injection into closure. On the other hand, this effect may be beneficial in patientsthe masseter muscle.[58] The pathogenesis of such adverse reac- with dry eye conditions, since every movement may cause burningtions remains unclear. 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 into5.10 Neutralizing Antibodiesthe pretarsal portion of the orbicularis oculi muscle in an attemptto correct lateral canthal rhytides resulted in abnormal lacrimation,It is well known from BTXA treatment of patients with muscleas shown by Schirmer‘s test.[75] The condition was treated withspasm that neutralizing antibodies may develop during a course ofocular lubrication. However, use of the correct injection techniquerepeated injections.[3] The frequency of neutralizing antibodies inshould have prevented this adverse effect.patients with cervical dystonia treated with BTXA has been esti-

When treating horizontal lines, it is important to avoid causingmated to be as high as 6.5%.[3] Increasing the dose of BTXAbrow ptosis and asymmetry. These adverse effects were seen in 22cannot overcome secondary therapy failure due to the presence ofof 25 and 2 of 25 patients, respectively, in a study by Bulstrode andneutralizing antibodies.[67] The incidence of secondary resistanceGrobbelaar.[51] We recommend maintaining a distance of at leastto the effect of the toxin has been dramatically diminished by the2.5cm between the upper line of the brow and any injection point.reduction of non-toxic proteins in current batches of Botox®.[68]

Bilateral ptosis has been reported after injections of BTXA intoTo date, induction of neutralizing antibodies has not beenneck muscles.[57]observed with use of BTXA for cosmetic purposes.

5.12 Pain5.11 Ophthalmologic Adverse Effects

Adverse effects that can occur at any injection site (not onlyDiplopia has been reported in 3% of patients treated for facial with BTXA) include pain, burning sensations, edema, redness, and

muscle spasm with BTXA.[69] It was suggested that the extraocular short-time hypoesthesia.[15] Pain during BTXA injection is varia-muscles of some patients may be more susceptible to BTXA than ble and depends on individual sensitivity.[32] However, the smallerothers, or that BTXA may diffuse more easily in some patients. the needles used, the better the tolerance. We recommend use of

30–34 gauge needles. The injection should be delivered slowlyTo maintain the safety of treating crow’s lines, only smallwhile pinching the skin to reduce injection-related pain.[14]volumes (0.1–0.2mL per injection point) of BTXA should be

injected and dosages should not exceed Botox® 4U or Dysport® In some countries, isotonic sodium chloride can contain pre-10U. The needle should be placed at least 1–2cm lateral to the servatives. It has been shown that preservatives in the solution

© 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)

148 Wollina & Konrad

used for reconstitution of BTXA can significantly decrease patient A psoriasiform eruption has been observed after intramusculardiscomfort on injection.[76] However, in their package leaflets, injection of BTSA.[84] In patients with skin diseases likely to showboth Speywood/Ipsen and Allergan recommend against use of Koebnerization, such as psoriasis, lichen planus etc, patientspreservative-containing isotonic sodium chloride solutions for should be informed that skin lesions may develop at the site ofreconstituting BTXA. injection.

Topical application of anesthetic EMLA® cream may help5.15 Therapeutic Failuredecrease injection pain.[77] Application of ice or a frozen gel-filled

mask 5 minutes before BTXA injection also decreases pain inAlthough sporadic, there is anecdotal evidence that some pa-about 45% of recipients.[78] In special cases, local analgesia is

tients do not respond to BTXA. For example, patients with severehelpful.[15]

actinic damage and poorly developed musculature will not benefitgreatly from BTXA.[70]

5.13 Psychiatric Disorders In patients who develop neutralizing antibodies as a result ofnon-cosmetic use of BTXA, a change to BTXB may be necessary.

Botulinophilia is a dysmorphic disorder, in which patients seem However, there is no standardized commercially available assayto be obsessed about getting BTXA treatment for complaints that for testing neutralizing antibodies. Not all patients with neutraliz-are either non-existent or still in remission, so they objectively do ing antibodies experience a loss of activity of the compound.not need a (repeat of) treatment. Botulinophilia is not caused by Furthermore, there is an imprecise correlation between antibodyBTXA but rather should be considered a contraindication for the levels and the number of injections, length of treatment, or cumu-use of BTXA.[79] Acute anxiety and depression have been ob- lative BTXA dose.[3,4] Although immunologic and treatment resis-served in a spastic patient after intramuscular injection of BTXA, tance have yet to be reported in patients treated for cosmeticbut it is doubtful whether these mood disturbances were caused by reasons or hyperhidrosis, it may be necessary to warn patients ofBTXA.[80]

this as one of the possible complications of BTXA therapy.However, this adverse effect can be avoided by keeping injected

5.14 Skin volumes low, avoiding intravascular injections, and spacing injec-tions at intervals of at least 1 month.[14]

Cutaneous adverse effects of BTXA are extremely rare.[4,8,13,15]Administration of suboptimal doses and use of incorrect injec-

Only case reports of dermatologic adverse events have been pub- tion techniques will lead to treatment failure. Electromyographylished and the causative role of BTXA in these conditions remains has been recommended by some authors as a means of improvingmostly speculative. localization of injection points for hyperkinetic facial lines.[85]

In dark-skinned patients, injection-related inflammation maycause pigmentation changes.[81] However, in a study of 26 African 6. ConclusionsAmerican patients receiving repeated periocular BTXA injections,

BTXA is safe for cosmetic indications and treatment of hyper-no evidence of any pigmentary disorder was noted.[81] Persistenthidrosis when simple treatment guidelines are followed. The mainrash arising from (lactose) allergy may develop at the site ofcomplications are technique-dependent. They can be minimizedrepeated BTXA injections.[22]

by adequate training, detailed knowledge of the anatomy andRepeated BTXA injections to the forehead have been reportedphysiology of injection targets, and an understanding of the phar-to cause dryness and flakiness of the frontal area in 2 of 52macology and toxicology of BTXA. To ensure a safe and satisfy-patients.[49] This can be explained by the antihydrotic activity ofing treatment outcome, serious attention needs to be paid to theBTXA, even in the case of intramuscular injection. Most femalefollowing points:patients will not experience this mild adverse effect if they usually• obtaining a detailed medical history from the patient;use facial moisturizers. However, some male patients may suffer• performing a careful physical examination;from this minor discomfort. Regular use of a moisturizer will• excluding contraindications, if necessary by laboratory anddiminish BTXA-induced dryness.[57]

other investigations;A case of human herpes virus type 8-positive facial angi-• using accurate techniques of injection, dilution, and storage ofosarcoma developing at the site of BTXA injection for blepharos-

BTXA;pasm has been reported.[82] The role of BTXA in this case remains

• injecting concentrated small volumes;unclear.

• avoiding injections in unsuitable areas;An 80-year-old woman with chronic myeloid leukemia whounderwent BTXA injections for blepharospasm developed a nec- • educating the patient and providing complete documentationrotizing fasciitis.[83] about how BTXA works, when it is indicated, its potential

© 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)

Managing Adverse Events of Botulinum Toxin Type A 149

20. Li M, Goldberger BA, Hopkins C. Fatal case of BOTOX (R)-related anaphylaxis? Jrisks, the nature of the procedure, and your recommendationsForensic Sci. In press

about use of the drug; 21. Cohen DE, Kaufmann JM. Hypersensitivity reactions to products and devices inplastic surgery. Facial Plast Surg Clin N Am 2003; 11: 253-65• obtaining the patient’s written consent.

22. Cox NH, Duffey P, Royle J. Fixed drug eruption caused by lactose in an injectedWe believe that BTXA therapy is a medical procedure that botulinum toxin preparation. J Am Acad Dermatol 1999; 40: 263-4

23. Taylor SL, Hefle SL. Ingredient and labeling issues associated with allergenicshould be administered only by skilled, experienced and wellfoods. Allergy 2001; 56 Suppl. 67: 64-9trained physicians. Application of BTXA by non-medical person-

24. LeWitt PA, Trosch RM. Idiosyncratic reactions to intramuscular botulinum toxinnel is unethical and dangerous. Adherence to these recommenda- type A injection. Mov Disord 1997; 12: 1064-7

25. Claus D, Druschky A, Erbguth F. Botulinum toxin: influence on respiratory hearttions listed above can only increase the chance that patientsrate variation. Mov Disord 1995; 10: 574-9receiving BTXA injections will benefit from the procedure.

26. Malnick SD, Metchnik L, Somin M, et al. Fatal heart block following treatmentwith botulinum toxin for achalasia. Am J Gastroenterol 2000; 95: 3333-4

27. Tsuboi M, Furukawa Y, Kurogouchi F, et al. Botulinum neurotoxin A blocksAcknowledgmentscholinergic ganglionic neurotransmission in the dog heart. Jpn J Pharmacol2002; 89: 249-54No sources of funding were used to assist in the preparation of this

28. Wollina U. Botulinum A toxin for wrinkles: release from tension headache. J Eurmanuscript. The authors have no conflicts of interest that are directly relevant Acad Dermatol Venereol 2000; 14: 142-3to the content of this manuscript. 29. Silberstein S, Mathew N, Saper J, et al. Botulinum toxin type A as a safe migraine

preventive treatment. Headache 2000; 40: 445-5030. Patel MP, Talmor M, Nolan WB. Botox and collagen for glabellar furrows:

References advantages of combination therapy. Ann Plast Surg 2004; 52: 442-71. Tchitchikine A. Essai d’immunisation par la voie gastrointestinale contre la toxine 31. Alam M, Arndt KA, Dover JS. Severe, intractable headache after injection with

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