Dermatol Clin 22 (2004) ix

Preface

The clinical use of botulinum toxin

Arnold W. Klein, MD

Guest Editor

The interest in botulinum toxin and its many uses In addition to its previously noted off-label cos-

has increased exponentially in recent years; especially

since the approval of Botox Cosmetic for the treatment

of glabellar lines. In fact, Botox, which was virtually

unheard of to many just 5 years ago, has become a

household name. This increased popularity has been a

truly amazing process to behold. Facial wrinkles are

frequently caused by repeated muscle contraction.

Botulinum A exotoxin can produce weakness or

paralysis of these muscles and offers a novel approach

for the treatment of certain facial rhytides. The disap-

pearance of wrinkles through the paralysis of these

muscles, although temporary, is extremely popular

with both patients and physicians. There is a very

low incidence of side effects and it is a relatively easy

technique to acquire. For these reasons, botulinum

toxin A has gained rapid and enthusiastic acceptance.

Experience since the worldwide approval of the

first therapeutic botulinum-neurotoxin based product

in 1989, Botox, has shown that this therapeutic agent

is safe and effective for numerous indications, includ-

ing movement disorders. Subsequently, another botu-

linum toxin type A complex, Dysport, was approved

in the United Kingdom in 1991, but is not currently

available in the United States. There is also a type B

complex preparation, Myobloc, which is approved by

the Food and Drug Administration for cervical dys-

tonia patients.

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doi:10.1016/j.det.2004.01.001

metic indication, Botox in all likelihood will be shown

to be safe and effective in placebo-controlled studies

for a wide range of medical conditions including

achalasia, dysphonia, cervical dystonia, cerebral palsy,

chronic anal fissures, migraines, and hyperhidrosis.

There are numerous reasons for this phenomenal

explosion of interest. The rapid thrust of Botox into

the limelight has brought with it an influx of novice

injectors, increasing the possibility of unwanted com-

plications. It has also brought a plethora of new uses,

which are being discovered everyday. I believe it is

important to bring together many of the most experi-

enced and knowledgeable people in the field to share

their experience and knowledge with those who are

just beginning to get involved with this material. This

issue of Dermatologic Clinics comprises a compre-

hensive look at the subject. All of us, the novice user

and the highly experienced, can increase our knowl-

edge from reading these articles.

Arnold W. Klein, MD

David Geffen School of Medicine at UCLA

435 North Roxbury Drive

Suite 204

Beverly Hills, CA 90210, USA

E-mail address: awkmd1@aol.com

s reserved.

Dermatol Clin 22 (2004) 131–133

Development of botulinum toxin therapy

Alan B. Scott, MD

Smith-Kettlewell Eye Research Institute, 2318 Fillmore Street, San Francisco, CA 94115, USA

Botulism occurs mostly from eating improperly Animals vary in their susceptibility—in particular,

preserved food. In the eighteenth and nineteenth cen-

turies in Bavaria, botulismwas caused by sausages that

were preserved with inadequate boiling, smoking, and

salting. Justinius Kerner collected data on 230 cases of

botulism and published two important monographs in

1820 and 1822. Kerner gave a remarkably complete

and accurate description of clinical botulism: its symp-

toms, time course, and physical findings, especially

that the tear fluid disappears, the pupil dilates, the eye

muscles are paralyzed, mucus and saliva secretion is

suppressed, the skin is dry, the skeletal muscles and gut

are paralyzed, and until the last, cognition is preserved.

Finally, Kerner suggested the potential therapeutic use

of toxin to block abnormal motor movements, such as

chorea, and speculated on its use in other disorders

with hypersecretion, for example. However, he

stopped there. Kerner was an important romantic poet

and a busy medical officer; lacking a university

appointment, he went off in these directions at

age 37, after remarkably insightful and creative

research on botulism. His work is summarized in

further detail by Smith [1] and more recently by

Erbguth and Naumann [2].

Seventy-five years later, van Ermengem, professor

of bacteriology and a student of Koch, correctly

described the bacterial basis of botulism. Of 34 indi-

viduals who had attended a funeral and ate some raw,

partially salted ham, 23 were paralyzed and three died.

van Ermengem found extracts of the ham to be toxic to

laboratory animals, producing a paralytic disease akin

to botulism. The toxicity in the animals, as well as in

those who had eaten the ham, was related to the

amount consumed, with only a small amount needed.

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doi:10.1016/S0733-8635(03)00019-6

E-mail address: abs@ski.org

carrion eaters, such as dogs, are resistant. From the

ham and from the spleen of a man who had died, van

Ermengem isolated the anaerobic bacterium, grew it,

named it, characterized its culture requirements, and

described its toxin.

Over the next three decades, food canning and

botulism grew together. K.F. Myer, a Swiss veterinar-

ian, developed a major focus of botulinum investiga-

tion at the Hooper Foundation in San Francisco. New

strains of the organism and toxin were characterized.

Techniques for reliably killing the spores in the can-

ning process and knowledge of the correct pH (<4.0)

and salt concentration to prevent organism growth and

toxin production were defined. The requirements for

toxin inactivation by heating were also defined. The

California canning industry was saved, and knowledge

of how to grow the organism and extract the toxin was

developed. Type F toxin was recognized later in 1960

and type G in 1970.

Swords into plowshares

The potential for botulinum toxin as a warfare

agent was a second focus of investigation from the

1930s onward. The bacteria are remarkably easy

to grow in culture, with tremendous toxin yields in a

5-gallon container after just 3 or 4 days. It is easy to

concentrate (although not so easy to crystallize), and

quantities to paralyze whole cities or armies have been

made by several nations—the United States, the

United Kingdom, Russia, Iraq, and perhaps many

others. But distribution for ingestion is not easy, as

the toxin loses potency with time in dilute without

protein-buffering solutions, as might occur in a water

supply. Inhalation of the dried toxin as an aerosol is

frightening to contemplate but was never developed.

s reserved.

A.B. Scott / Dermatol Clin 22 (2004) 131–133132

Development of concentration and crystallization

techniques at Fort Detrick by Lamanna and Duff in

1946–7, using acid precipitation techniques, became

the basis of the clinical product. The breakup of the

Army’s Chemical Corps at Fort Detrick led to the

move by Edward Schantz to the Food Research

Institute in Wisconsin. There, he continued to manu-

facture toxin in concentrated form for experimental use

and gave it out generously to the academic community.

Among these experimenters was Drachman [3],

at Johns Hopkins, who used small doses of toxin

to paralyze the hind limb in chicks. At that time,

techniques had been developed to accurately inject

extraocular muscles with local anesthetics to assess

their contribution to the eye movement performance.

Because strabismus surgery had high reoperative rates

in many categories, other alternatives to strabismus

surgical treatment were being sought systematically by

injecting various anesthetics, alcohol, enzymes, en-

zyme blockers, snake neurotoxins, and finally, moti-

vated by Drachman’s work, botulinum toxin. The

effect was remarkable. An injection of a few pico-

grams would induce paralysis confined to the target

muscle, long in duration, and with no side effects

whatsoever. The results of these animal experiments

on strabismus were published in 1973, and an appli-

cation was sent to the Food and Drug Administration

(FDA) for human use after working out techniques

for freeze-drying, buffering with albumin, and assur-

ing sterility, potency, and safety. Human experimenta-

tion began first in strabismus in 1977. By 1982, the eye

muscles were injected for strabismus and nystagmus,

the lid muscles for retraction, hemifacial spasm, and

blepharospasm, and the limbs and neck for dystonia,

all as predicted in the 1973 study. It was astonishing

that none of the local neurology, orthopedic, and

rehabilitation physicians at the Children’s Hospital,

University of California at San Francisco, Stanford,

and the Shriner’s Hospital would try toxin for muscle

contractures with stroke, dystonia, torticollis, or cere-

bral palsy. This strong aversion to the idea of toxin use

makes it possible to grasp why no one in the century

and a half since the time of Kerner had tried this.

Without local support, I had no possibility of trying out

the wide spectrum of toxin uses and, therefore, enlisted

others. My cases of torticollis, the first three injected,

were later published by Dr. Tsui of Vancouver [4], and

many others undertook to expand the use in dystonia

and muscular disorders. It was only in the late 1980s

that Dr. Koman of Wake Forest University would

pioneer the use of toxin in pediatric treatment of leg

spasm and cerebral palsy. The use gradually expanded,

because there was no adequate alternative treatment

for manymotility disorders. With active patient groups

and Internet access, blepharospasm patients rapidly

disseminated information of good results. Torticollis

patients likewise came soon to know that pain was

markedly decreased by toxin injection, motility in-

creased, head position improved a little, and tremor

was not changedmuch. And so on through the range of

motor and muscle disorders such as spasmodic dys-

phonia, spasm in various gastroenteric and urinary

sphincters, muscle spasm in stroke, and pretty well

every muscle, including those producing low back

pain. With data from thousands of patients and

240 investigators, the FDA approved use in adult

strabismus and blepharospasm in December 1989.

The use to reduce hyperhidrosis came from the

original and creative application of botulinum toxin by

Drobic and Laskawi in 1994 [5] to treat Frey’s Syn-

drome, gustatory sweating usually occurring after

parotid gland surgery with subsequent anomalous

connection of nerves in that region. It was an easy

transfer of this concept of blocking cholinergic inner-

vation to sweat glands as a treatment for hyperhidrosis

in the axilla, hands, and elsewhere. Remarkable in this

application in Frey’s Syndrome is the extraordinary

duration of toxin effect, sometimes more than 1 year,

much longer than the typical 3 to 4 months seen after

injection of muscles. An extension of this approach is

the use to diminish salivation by parotid gland injec-

tion to ameliorate the poorly handled secretions

in amyotrophic lateral sclerosis and to decrease exces-

sive lacrimal gland secretion effects, which harkens

directly back to clinical findings of dryness so promi-

nent in Kerner’s patients of 1820.

Cosmetic use of botulinum toxin, probably its

greatest single application, is the creation of Alistair

and Jean Carruthers. For many years, a few blepharo-

spasm patients injected at intervals of 3 or 4 months

around the eyes and upper face would mention as a

joke upon return that they were ‘‘back to get the

wrinkles out.’’ But only somebody working in aes-

thetic dermatology and ophthalmology could grasp the

potential for this application of botulinum toxin. The

Carruthers’ thoughtful and rational application of

toxin to selective agonist-antagonistic muscle groups

in the face, to lift the brow, flatten folds, is probably

overtaken now by less discriminate use. The idea that

toxin use in young people may prevent skin wrinkle

development is an intriguing prospect. It is from

widespread use around the face that the beneficial

effect of toxin on headache has emerged. Direct release

of muscle tension by the paralytic effect at neuromus-

cular junctions is the principal mechanism. Intriguing

theories on toxin operating by effect on propriocep-

tors, thus altering centrally controlled muscle tonus in

migraine, are speculative.

A.B. Scott / Dermatol Clin 22 (2004) 131–133 133

An important historical event is the appearance of

toxin type B, Myobloc. In choosing the toxin type to

concentrate on in our original studies, we looked at

epidemics and found that type A typically produced

extensive muscle paralysis, and type B was often

associated with autonomic disorders. This has been

proved by the high degree of autonomic side effects of

type B toxin, where use for torticollis brought about

good paralytic effects, but in a sizable percentage

also dryness of the mouth, difficulty in accommoda-

tion, reduced sweating, constipation, and so on [6]. If

limited for muscle paralysis in higher doses because of

side effects, type B toxin would seem superior for

injection into lacrimal or salivary glands and in the GI

tract. Type B is essential in those patients for whom

type A toxin is impossible because of antibody

development, although the development of resistance

to type B toxin in five of 21 patients resistant to type A

toxin is a high and troubling occurrence rate [7]. A

drawback for cosmetic use of type B is the stinging of

the current low pH solution when injected subcuta-

neously. This can be ameliorated by dilution with

bicarbonate buffer, but then higher volume injection

at each site is needed. Type C is under development in

Italy, and types D, E, and G will certainly be future

alternatives. Type F toxin developed in Japan and used

in clinical experimental series had a shorter duration of

effect than type A toxin and is not available.

Antibodies to botulinum toxin should become

increasingly less of a problem. The initial lot of

type A (79-11) licensed to me by the FDA and later

used by Allergan to formulate Botox in the United

States had a relatively low potency, and thus a higher

antigenic protein content. This resulted in antibody

production in doses > 200 U or even lesser doses at

injection intervals of < 30 days. The lot used in Europe

for Botox (88-4), had a much higher potency and

probably fewer antibodies developed. Both of these

have now been replaced by still higher potencies for

the Allergan product, Botox. In the future, we might

hope for cheaper toxin as competition develops,

but high regulatory costs in the United States will

prevent this.

References

[1] Smith Louis DS, Thomas Charles C. Botulism. Spring-

field (IL): Charles C. Thomas; 1977.

[2] Erbguth FJ, Naumann M. Historical aspects of botuli-

num toxin: Justinus Kerner (1786–1862) and the ‘‘sau-

sage poison’’. Neurology 1999;53:1850–3.

[3] Drachman DB. Neuropoisons. In: Simpson LL, editor.

New York: Plenum Press; 1971. p. 315–39.

[4] Tsui JK, Eisen A, Mak E, Carruthers J, Scott A, Calne

DB. A pilot study on the use of botulinum toxin in spas-

modic torticollis. Can J Neurol Sci 1985;12(4):314–6.

[5] Drobik C, Laskawi R. Frey-Syndrom: Behandlung mit

Botulinum-Toxin. HNO Aktuell 1994;2:142–4.

[6] Dressler D, Benecke R. Initial experiences with clinical

use of botulinum toxin type B. Nervenarzt 2002;73(2):

194–8.

[7] Kumar R, Seeberger L. Long-term safety, efficacy, and

dosing of botulinum toxin B (Myobloc) in cervical dys-

tonia (CD) and other movement disorders. Mov Disord

2002;17(Suppl 5):S292–3.

Dermatol Clin 22 (2004) 135–136

Dilution, storage, and electromyographic guidance

in the use of botulinum toxins

Alan M. Mantell, MD

1818 Verdugo Boulevard, Suite 304, Glendale, CA 91208-1403, USA

To use botulinim toxin A (BTX-A) successfully for tuted using preservative-free solutions, recent studies

cosmetic purposes, it is important to understand the

basic principles of BTX-A therapy and the specific

guidelines for its use, including dilution and storage.

BTX-A is available commercially in two formulations,

BOTOX, (Allergan Inc., Irvine, CA) and Dysport

(Ipsen Limited, Berkshire, England). BOTOX is avail-

able in the United States, Canada, and many other

countries, whereas Dysport is available in Britain,

France, Germany, and other countries, but not in the

United States or Canada. Both are sold in a lyophilized

form andmust be reconstituted with physiologic saline

before use. Botulinim toxin type B, MYOBLOC,

which is currently available only in the United States

but may become available in Europe soon, is sold in an

aqueous solution. The dosages of each of these vary

greatly, and it is essential to use the correct dosage for

the specific product used. Incorrect dosages are very

likely to result in severe adverse effects. This is

particularly significant when using BOTOX at Dys-

port or MYOBLOC dosages. The Dysport dosages are

typically 3 to 6 times higher than the BOTOX dosages,

and the MYOBLOC dosages are typically 50 to

100 times higher than the typical BOTOX dosages.

Using Dysport or MYOBLOC at BOTOX dosages

will result in inadequate therapeutic benefit.

Dilution and storage

Although the manufacturers of both BOTOX and

Dysport recommend that their products be reconsti-

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E-mail address: dralan@pacbell.net

[1] have shown that preservative-containing normal

saline is just as effective and retains its potency when

refrigerated for a week or more after reconstitution.

When using preservative-free solutions, the botulinum

toxin should be used within 4 hours of reconstitution.

A significant number of patients have reported that

injections with preservative-containing saline are less

painful. Dr. Murad Alam performed a double-blind,

randomized trial to validate the findings from a botu-

linum toxin study [1]. He concluded that botulinum

toxin A that has been reconstituted with benzyl alco-

hol–preserved saline maintains its potency for a week

or more when refrigerated and appears to be just as

effective in results and duration as preservative-free

saline. He found no adverse effects associated with

using preservative-containing saline. Most patients

noted a significant reduction in the pain associated

with the injection [1].

Depending on how the BTX-A is to be used, the

dilution may vary. Two studies have shown that higher

doses delivered in smaller volumes tend to keep the

toxin and its effect more localized [2,3]. For BOTOX,

dilutions range from 2.5 U/mL to 100 U/mL with most

investigators using about 25 U/mL or 100 mL [4–10].

Higher concentrations allow for low-volume injec-

tions with more precise placement of the toxin and

with little spread to other areas. Low concentrations

may be useful in some cases, but increasing the

concentration and decreasing the volume injected will

limit the possibility of adverse effects resulting from

the unintended spread of the toxins to other areas. The

manufacturer’s guidelines should be adhered to for

storage and handling of all botulinum products. When

BTX-A has been diluted with preservative-free

saline, it should be refrigerated at 2 �Centigrade to

s reserved.

A.M. Mantell / Dermatol Clin 22 (2004) 135–136136

8 �Centigrade for a maximum of 4 hours to ensure that

it remains sterile [11].

Electromyographic guidance in the use of

botulinum toxins

Injection using electromyographic (EMG) guid-

ance is helpful in achieving correct placement of

BTX-A by locating the most active part of the muscle

responsible for a particular facial line. For this purpose,

a combined EMG injection needle (available through

Allergan Inc., Irvine, CA) is used. The EMG-guided

technique is helpful until a thorough understanding of

the facial anatomy is attained. However, it requires the

use of a larger needle, and many clinicians feel it has

little benefit to the experienced physician except when

dealing with patients who are difficult to treat or who

have not had a satisfactory result. Some clinicians use

EMG to increase the accuracy of the injections because

the effect of BTX-A is muscular. Nevertheless, EMG

is useful in locating the muscle, especially when

injecting a patient for the first time because the pattern

of muscle activity varies from patient to patient.

Some clinicians feel that the anatomy of the glabela

is so reliable that EMGguidance is not necessary. They

use EMG guidance only for reinjection in cases where

they have produced a partial response. It may be a

better idea to use EMG guidance the first time so that

the muscle is located more accurately, rendering rein-

jection unnecessary. Furthermore, the pattern of mus-

cle activity is not uniform from patient to patient and

EMG can obviate these variables. The EMG apparatus

can be used to determine which muscles are contract-

ing during the frowning process and contributing to the

frown. The use of 0.5-inch, 30-gauge metal needles for

patient comfort in place of the hollow-bore 27-gauge

needles supplied with the EMG machine is highly

recommended. Although the 30-gauge needles trans-

mit electrical impulses from their entire length rather

than only at needle tip, they are still more user friendly

for both the physician and patient. Additionally,

patients who fear the use of botulinum toxin may be

calmed by the knowledge that the physician is locating

the target muscles accurately [12].

The recommended technique for injecting using

EMG guidance is to first cleanse the area with alcohol

and allow the alcohol to evaporate completely. The

target muscles should be at rest. The patient is directed

to frown, squint, or raise the eyebrows to activate the

targeted muscle. One-half to one-third of a 0.5-inch

metal hub needle, which is connected to the EMG unit,

is placed in the muscle. After placement, if no sound is

heard upon activation of the muscle, the needle is

reinserted until a sound is heard from the EMG

machine [12].

References

[1] Alam M. Pain associated with injection of botulinum

toxin A exotoxin reconstituted using isotinic sodium

chloride with and without preservative. Arch Dermatol

2002;138:510–4.

[2] Borodic GE, Ferrante R, Pierce B, et al. Histologic as-

sessment of dose related diffusion and muscle fiber re-

sponse after therapeutic botulinum-A. toxin injection.

Mov Disord 1994;9:31–9.

[3] Shaari CM, Sander SI. Quantifying how location and

dose of botulinum toxin injection affect muscle paraly-

sis. Muscle Nerve 1993;16:964–9.

[4] Blitzer A, Binder WJ, Aviv JE, et al. The management

of hyperfunctional facial lines with botulinum toxin.

Arch Otolaryngol Head Neck Surg 1997;123:389–92.

[5] Lowe NJ, Maxwell A, Harper H. Botulinum a exotoxin

for glabellar folds: a double blind, vehicle controlled

study with an electromyographic injection technique.

J Am Acad Dermatol 1996;35:569–72.

[6] Carruthers A, Carruthers J. Cosmetic uses of botulinum

A exotoxin. In: Klein AW, editor. Tissue augmentation

in clinical practice. New York: Marcel Dekker; 1998.

p. 207–36.

[7] Klein AW. Dilution and storage of botulinum toxin.

Dermatol Surg 1998;24:1179–80.

[8] Pribitkin EA, Greco TM, Goode RL, et al. Patient

selection in the treatment of glabellar wrinkles with

botulinumtoxin type a injection. Arch Otolaryngol

Head Neck Surg 1997;123:321–6.

[9] Ahn K-Y, Park M-Y, Park D-H, et al. Botulinum

toxin A for the treatment of facial hyperkinetic wrin-

kle lines in Koreans. Plast Reconstr Surg 2000;105:

778–84.

[10] Guerrissi JO. Intraoperative injection of botulinum

toxin A into orbicularis oculi muscle for the treatment

of crow’s feet. Plast Reconstr Surg 2000;105:2219–28.

[11] Carruthers A, Carruthers J. Botulinum toxin type A:

history and current cosmetic use in the upper face.

Semin Cutan Med Surg 2001;20(2):71–84.

[12] Klein AW, Mantell A. Electromyographic guidance

in injecting botulinum toxin. Am Soc Dermatol Surg

1998;24:1184–6.

Dermatol Clin 22 (2004) 137–144

Botulinum toxin type A for the treatment

of glabellar rhytides

Alastair Carruthers, MDa,*, Jean Carruthers, MDb

aDivision of Dermatology, University of British Columbia, Vancouver, BC, CanadabDepartment of Ophthalmology, University of British Columbia, Vancouver, BC, Canada

Since the introduction of botulinum toxin type A what clinicians already knew: that BTX-A was an

(BTX-A) more than 20 years ago, its use has expanded

to include a wide range of clinical applications for the

aging face. Although its use in facial rejuvenation

initially provoked amazement in the general popula-

tion, BTX-A injections have become an accepted part

of cosmetic practice. Glabellar frown lines, which give

the impression of anger, frustration, or general unhap-

piness, especially in women [1], were the focus of

the initial cosmetic investigations and are still the

most common site for BTX-A injections. This article

reviews the start of this process (BTX-A for the

treatment of glabellar lines) and reviews current clini-

cal procedures and experience.

Initial clinical trials

One of the authors (JC) was one of the early co-

investigators with Alan Scott of the management of

blepharospasm with BTX-A. When patients pointed

out that they were unable to frown as much as they had

before as a result of treatment, we were intrigued and

developed the first systematic study of BTX-A (Botox,

Botox Cosmetic; Allergan, Irvine, CA) in treating

glabellar lines. The first report was published in

1992 [2]; two small, double-blind, placebo-controlled

trials followed, reporting benefits in 42 patients [3,4].

Trials continued until 2001, when the results of a

large, randomized, placebo-controlled trial cemented

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00071-8

* Corresponding author. 943 West Broadway, Suite 820,

Vancouver, BC V5Z 4E1, Canada.

E-mail address: alastair@carruthers.net (A. Carruthers).

impressively effective and safe treatment for facial

rhytides. In this trial, 264 patients with moderate to

severe glabellar lines at maximum frown received

20 U BTX-A or placebo into five glabellar sites and

were followed for 120 days after injection [5]. Patients

receiving BTX-A experienced a significantly greater

reduction in glabellar line severity than patients re-

ceiving placebo, as measured by physician rating of

glabellar line severity at maximum frown and rest and

patient assessment of improvement. Clinical results

lasted 3 to 6 months and were greater in magnitude and

duration in patients less than 50 years of age.

The cumulative result of these trials led to the

official approval of BTX-A for the treatment of gla-

bellar rhytides by Health Canada in 2001 and the US

Food and Drug Administration in 2002.

Anatomy

Mastering the use of BTX-A for any indication

requires a thorough understanding of the relevant mus-

cular anatomy (Fig. 1). Any discussion of anatomy,

however, must be prefaced with a warning about the

enormous variability in facial features and muscula-

ture. In addition, although each muscle functions

individually, it is important to remember that most

work in conjunction with others. Treatment of one

muscle invariably affects others.

Frontalis

Understanding the anatomy of the frontalis (a

large, quadrilateral muscle that originates from the

s reserved.

Fig. 1. Facial anatomy.

Fig. 2. Glabellar frown lines.

A. Carruthers, J. Carruthers / Derm138

galea aponeurotica and inserts inferiorly into the

procerus, orbicularis oculi, corrugator supercilii, de-

pressor supercilii, and the skin of the brow) is crucial.

The frontalis muscle resting tone suspends the lateral

eyebrow segment medial to the temporal fusion line

of the skull [6]. Contraction of the frontalis produces

a series of primarily horizontal forehead wrinkles,

which appear in the late 20s to early 40s; thicker

musculature contributes to increased, overlying, cu-

taneous rhytides. The frontalis, which has no bony

attachments and is adherent to the superficial fascia,

raises the eyebrows and skin over the root of the nose

and draws the scalp forward. The lower 2 cm of the

frontalis is thought to be largely responsible for

elevation of the eyebrows.

The paired frontalis muscles are described as

forming a large quadrilateral muscle with a distinct

mid-line separation. In the authors’ experience, many

individuals do not have this mid-line separation. The

superior margins of these muscles originate from the

galea aponeurotica just anterior to the coronal suture

line of the skull, with the lateral aspects extending

more cephalad. Many fibrous septae pass from the

muscle anterior surface up to the dermis. The lateral

margin of the frontalis always ends or becomes

severely attenuated at the temporal fusion line.

Glabellar complex

The glabella is the smooth elevation of the frontal

bone just above the bridge of the nose. The ‘‘glabellar

complex’’ refers to a group of brow-associated mus-

cles that are used primarily for facial expression,

especially concern, anger, unhappiness, and pleasure.

Muscles of the glabellar complex include the orbicu-

laris oculi and corrugator muscles (which move the

eyebrows medially or inferomedially), and the proce-

rus and depressor supercilii muscles (which move the

eyebrows inferiorly).

The strength and size of the glabellar complex

varies significantly from patient to patient, and cadaver

dissection and forehead lift surgery show that there

is variation of muscle mass between individuals. In

general, men have a larger glabellar complex com-

pared with women, and many patients with deeper

wrinkles have a hypertrophic glabellar complex com-

pared with those with fewer wrinkles. Glabellar frown

lines (vertical creases seen adjacent to or in between

the medial aspects of the eyebrows) arise naturally

from the activity of the glabellar complex (Fig. 2).

Corrugator supercilii

Corrugator supercilii muscles arise from the medial

end of the superciliary arch and run at an angle to insert

along and above the skin of the eyebrow, with most of

the muscle passing through the fibers of the orbicularis

oculi and the frontalis [7]. Hyperactivity of the corru-

gator supercilii, in conjunction with the lateral orbicu-

laris oculi and the depressor supercilii, can antagonize

the frontalis and facilitate the descent of the eyebrow

and contribute to the formation of the oblique glabellar

skin line [8].

atol Clin 22 (2004) 137–144

Dermatol Clin 22 (2004) 137–144 139

Procerus and depressor supercilii

The procerus and depressor supercilii, which lie ad-

jacent to one another and may be an extension of the

frontalis, originate from the nasal bone and extend up-

ward to insert into the skin of the brow intertwining

with fibers of the orbicularis oculi and frontalis.

The procerus draws the medial angle of the eyebrows

down and produces transverse wrinkles over the

nasal bridge.

Orbicularis oculi

The orbicularis oculi is the sphincter muscle of the

eyelids. The palpebral portion of this muscle is thin

and close to the skin, ringing around the palpebral

opening and acting largely involuntarily, whereas

the orbital portion is thicker, with horizontal and

oblique fibers. Orbicularis oculi muscles move the

brow inferomedially and run at an angle, penetrating

the frontalis and orbicularis muscles to insert into

the dermis above the middle third of the eyebrow,

whereas the procerus and depressor supercilii pull the

brow inferiorly, creating a frown or furrowed brow.

A. Carruthers, J. Carruthers /

Fig. 3. The male brow, associated with a greater muscle mass,

often requires more toxin to produce paresis, compared with

the female brow.

Procedures

Injections of BTX-A for glabellar rhytides are

rapid, can be performed on an outpatient basis, and

do not require a lengthy recovery period, unlike more

invasive procedures [5]. The best outcomes arise from

individualizing treatment sites and doses to match

each patient’s needs [9]. Although there are currently

two commercially available sources of BTX-A, all

references in this article refer to the Botox, Botox

Cosmetic, or Vistabel formulations, unless otherwise

specified. The clinician should be aware, however, of

the significant clinical differences between the sources

of BTX-A, and adjust dosages accordingly.

Patient assessment and education

In preparing patients for treatment, it is important to

address their safety concerns. Ensure that they under-

stand the procedures, what to expect before and after

treatment, potential side effects (including ptosis or

bruising), the typical time course of the clinical effects,

and the need for retreatment after 3 to 6 months. All

of the authors’ patients sign an informed consent

form, which outlines the treatment, the reasons for

treatment, the expected outcomes, and the potential

risks and benefits for the average patient. Informed

consent forms also ensure that patients understand

what treatments and indications are and are not offi-

cially approved by Health Canada or the Food and

Drug Administration.

Not all patients respond well to BTX-A injections,

especially older patients with existing brow ptosis or

extensive photodamage. BTX-Aworks by relaxing the

underlying musculature that causes dynamic facial

rhytides; nondynamic rhytides may improve from

BTX-A treatment but rarely disappear completely.

Before treatment, standardized, same-magnifi-

cation, color photographs of the muscles at rest and

maximum frown determine individual patient charac-

teristics. Document each patient’s current anatomy

with careful photographs that provide ‘‘before’’ and

‘‘after’’ comparisons and note any atypical features.

Sites and dosages

The type of brow arch, asymmetry, ptosis, and

regional muscle mass can be important factors in de-

termining injection sites and dosages. The male brow,

associated with greater muscle bulk, requires more

toxin to produce paresis (Fig. 3).

A variety of injection sites and dosages have been

reported in the literature, ranging from a single injec-

tion of 10 U into each corrugator to total doses of

20 to 50 U spread over seven sites [9]. For women, the

authors’ current dose is a total of 25 to 40 U BTX-A.

Although they previously reported lower total doses of

20 U [9], current dose-ranging studies suggest that

higher doses of 30 and 40 U produce significantly

greater responses with the longer duration on glabellar

lines than 10 or 20 U [10]. Most patients injected with

higher doses report benefits lasting 3 to 4 months;

although some continue to benefit for as long as 6 to

8 months, these patients usually have experienced a

series of injections over a year or more. In addition, the

Fig. 4. Injection sites for the treatment of glabellar rhytides.

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137–144140

authors found that injecting total doses of 30 to 40 U

leads to a significant lateral, central, and medial

eyebrow elevation that peaks 12 weeks following

injection [11,12]. Although few studies have been

conducted in men, it is known that greater doses are

required to produce a satisfactory response in the

glabellar region, more than double the amount re-

quired in women. Data show that men injected with

60 and 80 U BTX-A achieve a better response rate and

no increase in adverse effects than men injected with

lower doses [13].

In the authors’ clinic, initial doses are 30 U (in

women) and 60 U (in men). Simply halving the

volume of saline used to reconstitute the vial is an

easy method of doubling the injected dose for men. If

patients fail to experience a sufficient response after

the first treatment, the dose is increased to 40 and

80 U in women and men, respectively.

Injection techniques

Injection techniques vary by clinic and injecting

physician. The following injection techniques are

used in the authors’ clinic with the Botox or Botox

Cosmetic formulations.

1. Follow all usual precautions of sterility and

skin preparation before injection.

2. Reconstitute the BTX-A with sterile, preserved

saline. The authors find that it is more effi-

cient to apply low-volume, concentrated toxin

(100 U/mL).

3. Use a bottle opener to remove the vial’s rubber

stopper gently so that the injecting needle re-

mains sharp. Draw up the appropriate dose of

BTX-A into the syringe and express the air. The

authors’ clinic uses the Becton-Dickinson Ultra-

Fine II short needle 0.3 insulin syringe (Becton-

Dickinson Inc., Franklin Lakes, NJ), which has

an integrated 30-gauge, silicon-coated needle

to minimize patient discomfort [14]. The needle

dulls after approximately six injections and

should then be discarded.

4. Seat the patient with chin down and head

slightly lower than the physician’s. The authors

always begin by injecting the central area (pro-

cerus), because that area is less painful and can

be massaged. This helps the patient to become

accustomed to the injection procedure. Five to

10 U are injected into the procerus at a point

below a line joining the brows and above the

crossing point of the X formed by joining

the medial eyebrow to the contralateral inner

canthus (Fig. 4).

5. Next, insert the needle directly in the medial

corrugator above the caruncle of the inner can-

thus (at the bony supraorbital ridge) and inject

4 to 10 U. Always place the injection site

above the bony supraorbital ridge, regardless

of eyebrow position, at a point where it is pos-

sible to apply postinjection pressure if bleeding

is encountered. Injectors should keep their

nondominant thumb on the orbital rim to avoid

injection within the orbit.

6. Partially withdraw the needle, keeping it be-

neath the skin, and reposition it until it an-

gles superiorly.

7. Advance the tip until it is approximately 1 cm

above the previous injection site in the orbi-

cularis oculi; inject another 4 to 10 U.

8. Repeat the injection on the contralateral side to

achieve a balanced look.

9. Finally, inject an additional 3 to 10 U into a point

1 cm above the supraorbital rim in the mid-

pupillary line in those with horizontal brows.

After the injections are complete, instruct the

patient to remain vertical for the next 2 hours and

frown as much as possible while the toxin is binding.

Patients should not press or manipulate the injected

areas. Typically, neuromodulation of the injected

muscles begins to occur 1 to 2 days after injection,

increasing in intensity during the first week [15].

At 2 weeks, patients are asked to return for a

follow-up visit, at which time photographs are taken

and treatment responses are assessed. Patients with

deep furrows at 2 weeks may require the addition of a

filler. BTX-A is used routinely as adjunctive therapy

with soft tissue augmentation to achieve more effec-

tive, longer lasting results. BTX-A often eliminates or

reduces the muscular activity responsible for the

wrinkles, improves the response, and increases the

longevity of the filling agent [16–18].

Injection intervals should be no more frequent than

every 2 weeks, and injections should be performed

using the optimum dose. Further injections at 3- to

4-month intervals over a period of 1 year in those with

deep glabellar lines are recommended to keep the

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137–144 141

musculature paralyzed and allow the furrows to drop

out. After 1 year, patients return as desired.

Results

The safety and efficacy of BTX-A as a treatment

for glabellar lines have been well documented. In the

authors’ first published study, glabellar rhytides in

18 patients were treated with BTX-A; 16 out of

17 patients showed improvement for periods ranging

from 3 to 11 months [2]. In a much larger prospec-

tive, double-blind, randomized, placebo-controlled,

clinical trial, 264 patients with moderate to severe gla-

bellar lines at maximum frown received 20 U BTX-A

or placebo into five glabellar sites and were followed

for 120 days after injection [5]. Patients receiving

BTX-A experienced a significantly greater reduction

in glabellar line severity than patients receiving

placebo, as measured by physician rating of glabellar

line severity at maximum frown and rest and patient

assessment of improvement (Fig. 5). These clinical

effects lasted from 3 to 6 months, although the

magnitude and duration of effect were somewhat

lower in patients greater than or equal to 51 years

than in patients younger than 50 years. In the authors’

experience, maximum clinical effects typically last

around 3 to 4 months. Although some patients

continue to benefit for as long as 6 to 8 months or

longer, these patients usually have received a series of

treatments over the period of a year or more.

Fig. 5. Before (A) and after (B) treatment

Combination therapy with BTX-A and a filling

agent provides superior benefits for severe glabellar

rhytides than BTX-A alone. The authors reported a

retrospective study of the improved treatment of com-

bined BTX-Awith hylan B (Hylaform) compared with

BTX-A alone in patients with moderate or severe

glabellar rhytides at rest [17]. After treatment, no

patients treated with BTX-A alone achieved a reduc-

tion in rhytides to none or mild, whereas 94% of those

treated with both BTX-A and hylan B achieved mild

rhytides. In a prospective, randomized study of

38 patients with moderate-to-severe glabellar rhytides,

BTX-A plus nonanimal stabilized hyaluronic acid led

to a better response both at rest and onmaximum frown

than nonanimal stabilized hyaluronic acid (Restylane)

alone (Fig. 6) [18]. In addition, combination therapy

led to a longer duration of response: the median time

for return to preinjection furrow status occurred at 18

weeks in the nonanimal stabilized hyaluronic acid

alone or BTX-A alone groups, compared with

32 weeks in patients treated with BTX-A plus non-

animal stabilized hyaluronic acid.

Complications

Most complications are relatively uncommon and

are related to poor injection techniques [19]. The

authors have used BTX-A for over 20 years, and

none of their patients has suffered a serious, irrevers-

ible complication.

of glabellar rhytides with BTX-A.

Fig. 6. (A–H) Severe glabellar rhytides before and after nonanimal stabilized hyaluronic acid alone (R306). Severe glabellar

rhytides before and after BTX-A plus nonanimal stabilized hyaluronic acid (RB304). Both subjects photographed using Canfield

photography at rest and on maximum frown before treatment and after treatment.

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137–144142

Dermatol Clin 22 (2004) 137–144 143

Brow ptosis

One of the most undesirable adverse events, brow

ptosis occurs when the injected toxin affects the

frontalis during glabellar or brow treatment and is

related to poor injection technique. Avoiding brow

ptosis begins with proper patient selection and pre-

injecting the brow depressors in patients with low-set

brows, mild brow ptosis, and patients over the age of

50 years [19]. Using a higher concentration allows for

more accurate placement of injections, greater dura-

tion of effect, and fewer side effects, because of toxin

spread of 1 to 1.5 cm (2 to 3 cm diameter) associated

with each point of injection. Injecting the glabella and

the whole forehead in one session is also more likely to

produce brow ptosis [19]. Patients must be advised to

remain upright for 2 hours, exercise the treated

muscles as much as possible for the first 4 hours, and

avoid rubbing or massaging the injected area for

2 hours following treatment. Mild brow ptosis re-

sponds to aproclonidine (Iopidine 0.5%) a-adrenergicagonist ophthalmic eye drops.

Eyelid ptosis

Ptosis of the upper eyelid occurs when the injected

toxin migrates to the upper eyelid levator muscle,

producing a weak paralytic effect as early as 48 hours

or as late as 14 days after injection and persisting from

2 to 12 weeks. The incidence of ptosis in the authors’

clinic is low (0% to 1%). Accurate dose dilution and

injecting the toxin no closer than 1 cm above the

central eyebrow decreases the chances of ptosis, as

does advising patients to remain upright for 2 to

3 hours following treatment and to refrain from ma-

nipulating the injection site. Bothersome ptosis can be

treated with aproclonidine [19].

A. Carruthers, J. Carruthers /

Summary

Injections of BTX-A improve the appearance of

glabellar rhytides by relaxing the underlying muscu-

lature in a quick and relatively painless procedure that

can be performed over the lunch hour and causes few

adverse effects. Alone or in combination with filling

agents, BTX-A has become one of the most popular

cosmetic procedures performed. Cosmetic facial aes-

thetics is a dynamic, rapidly evolving field, however,

and producing the most optimal benefits means under-

standing the dynamics of facial musculature and prin-

ciples of BTX-A therapy and remaining abreast of the

latest clinical developments.

References

[1] Carruthers J, Carruthers A. Botox treatment for expres-

sive facial lines and wrinkles. Curr Opin Otolaryngol

Head Neck Surg 2000;8:357–61.

[2] Carruthers JDA, Carruthers JA. Treatment of glabellar

frown lines with C. botulinum-A exotoxin. J Derm

Surg Oncol 1992;18:17–21.

[3] Keen M, Blitzer A, Aviv J. Botulinum toxin A for

hyperkinetic facial lines: results of a double-blind, ve-

hicle-controlled study. Plast Reconstr Surg 1994;94:

94–9.

[4] Lowe NJ, Maxwell A, Harper A. Botulinum A exotox-

in for glabellar folds: a double-blind, vehicle controlled

study with an electromyographic injection technique.

J Am Acad Dermatol 1996;35:569–72.

[5] Carruthers JA, Lowe NJ, Menter MA, et al. A multi-

center, double-blind, randomized, placebo-controlled

study of the efficacy and safety of botulinum toxin type

A in the treatment of glabellar lines. J Am Acad Der-

matol 2002;46:840–9.

[6] Knize DM. An anatomically-based study of the mecha-

nism of eyebrow ptosis. Plast Reconstr Surg 1996;97:

1321–33.

[7] Isse NG, Elahi MM. The corrugator supercilii muscle

revisited. Aesthetic Surg J 2001;21:209–15.

[8] Knize DM. Muscles that act on the glabellar skin:

a closer look. Plast Reconstr Surg 2000;105:350–61.

[9] Carruthers A, Carruthers J. Botulinum toxin type A:

history and current cosmetic use in the upper face.

Semin Cutan Med Surg 2001;20:71–84.

[10] Carruthers A, Carruthers J, Said S. Dose-ranging study

of botulinum toxin type A in the treatment of glabellar

lines. Presented at the 20th World Congress of Derma-

tology. Paris, France, July 1–5, 2002.

[11] Carruthers A, Carruthers J. Botulinum toxin type A

(BTX-A) in the treatment of glabellar rhytides: an ob-

jective analysis of treatment response. Presented at the

American Academy of Dermatology 2002WinterMeet-

ing. New Orleans, LA, February 22–27, 2002.

[12] Carruthers A, Carruthers J. Glabella BTX-A injec-

tion and eyebrow height: a further photographic analy-

sis. Presented at the Annual Meeting of the American

Academy of Dermatology. San Francisco, March

21–26, 2003.

[13] Carruthers A, Carruthers J. Botulinum toxin type A

for treating glabellar lines in men: a dose-ranging

study. Presented at the Annual Meeting of the Ameri-

can Academy of Dermatology. San Francisco, March

21–26, 2003.

[14] Flynn TC, Carruthers A, et al. Surgical pearl: the use of

the Ultra-Fine II short needle 0.3-cc insulin syringe for

botulinum toxin injections. J Am Acad Dermatol 2002;

46:931–3.

[15] Product monograph. Botox cosmetic (botulinum toxin

type A for injection) purified neurotoxin complex.

Irvine, CA: Allergan; 2002.

[16] Fagien S, Brandt FS. Primary and adjunctive use of

botulinum toxin type A (Botox) in facial aesthetic

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surgery: beyond the glabella. Clin Plast Surg 2001;28:

127–48.

[17] Carruthers J, Carruthers A, Maberley D. Deep resting

glabellar rhytides respond to BTX-A and hylan B.

Dermatol Surg 2003;29:1–6.

[18] Carruthers J, Carruthers A. A prospective, randomized,

parallel group study analyzing the effect of BTX-A

(Botox) and non animal sourced hyaluronic acid (Na-

sha, Restylane) in combination compared to Nasha

(Restylane) alone in severe glabellar rhytides in adult

female subjects. Dermatol Surg, in press.

[19] Klein AW. Complications and adverse reactions with

the use of botulinum toxin. Dermatol Surg, in press.

Dermatol Clin 22 (2004) 145–149

Botox for the eyes and eyebrows

Arnold W. Klein, MD

Department of Dermatology, David Geffen School of Medicine at UCLA, 435 North Roxbury Drive,

Suite 204 Beverly Hills, CA 90210, USA

The forehead and crow’s-feet (periorbital wrin- plete lack of expressiveness. The goal is to soften the

kles) are among areas where Botox has been quite

helpful. This cosmetic use is not approved by the

Food and Drug Administration and is considered off-

label. The effect, although temporary, is extremely

popular with patients, has a very low incidence of side

effects, and is a relatively easy technique to acquire.

One of the primary tenets to remember when

injecting botulinum toxin is that one is injecting

muscles, not wrinkles. It is the underlying pull of

the musculature that causes the wrinkles and it is the

relaxation of those muscles that alleviates the wrin-

kles. It is incumbent on the injecting physician to

understand thoroughly the musculature of the face

and the interaction of these muscles (Fig. 1). The

occipitofrontalis (frontal belly) raises the eyebrows

and produces transverse wrinkles of the forehead.

The orbicularis oculi functions as the sphincter of the

eye. The orbital portion acts primarily to depress the

eyebrow. The palpebral portion pertains to the eye-

brow and the eyelid. The depressor supercilii de-

presses the eyebrow. The procerus pulls the forehead

skin in an inferior direction and is determinant of

medial eyebrow height [1].

Horizontal forehead lines are produced by the

action of the frontalis. This is a large, vertically ori-

ented muscle that inserts superiorly into the galea

aponeurotica and inferiorly into procerus, orbicularis

oculi, corrugator supercilii, depressor supercilli, and

the skin of the brow.

The brow is the aesthetic center of the upper face

just as the lips are the aesthetic center of the lower

face. The objective in treating this area is to lessen the

forehead lines without causing brow ptosis or a com-

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/j.det.2004.02.001

E-mail address: melissa.hollis@doctorklein.md

forehead lines without eliminating them completely.

Before injecting the forehead of a patient for the

first time, it is best to determine the anatomic bound-

aries. Pre-existing or anatomic changes in the under-

lying musculature can alter the effects of Botox, and

modifications in injection technique should be made.

The width of the forehead and location of the temporal

fusion line vary from patient to patient. Botulinum

toxin treatment of the forehead needs to be individu-

alized. The high-narrow forehead must be treated

differently than the short and wide forehead. When

treating the forehead, one must consider the aesthetic

effects it will have on brow shape and position.

For the forehead, six injections of 0.10 mL (3.3 U)

are placed across the forehead in a uniform grid

(using a 3-mL per vial dilution). Electromyogram

assistance is used and in this area visible blebs are

temporarily produced on injection. It must be remem-

bered that the brow shape can be changed because the

major muscles responsible for elevating the brow

are being eliminated. The characteristics of a well-

proportioned female eyebrow are well established.

The medial aspect of the brow should begin at a point

defined by a straight line drawn from the lateral nose

upward. The eyebrow should arch maximally at a

point defined by a line drawn from the lateral nose

through the pupil. The eyebrow should end at a point

defined by a line from the lateral nose through the

lateral aspect of the eyeball (Fig. 2). John Pershing

from Yale has shown that altering brow shape or

position has a dramatic effect on others’ perception of

mood. Thirty-five versions of facial images were

viewed by 20 participants. Surprise, anger, sadness,

disgust, happiness, and tiredness were evaluated. The

greatest variable was found to be brow shape.

The lateral-most injection should be vertically

above the mid-pupil, although with wider foreheads

s reserved.

Fig. 1. Understanding facial anatomy is critical to the successful use of Botox.

A.W. Klein / Dermatol Clin 22 (2004) 145–149146

this can be extended beyond the pupil to the iris.

Lack of expressivity may be caused by injection of

frontalis lateral to the mid-pupillary line. It must be

remembered that the brow shape can be changed be-

cause one is relaxing the major muscle responsible for

elevating the brow. If the patient has a low eyebrow,

treatment of the forehead lines should be avoided, or

limited to that portion of the forehead 4 cm or more

above the brow. The glabella and the entire forehead

should not be injected during the same session. This

invariably produces brow ptosis. Frequently, only the

upper half of the forehead should be injected to avoid

the possibility of brow ptosis. The upper half of the

forehead and the frown can be done at the same time.

It is important always to remember the brow dynamics

of the opposing muscles (Fig. 3). Injections in the

forehead should always be above the lowest fold

Fig. 2. The feminine eyebrow. The well-proportioned eye-

brow should begin at point A, maximally arch at point B,

and end at point C.

produced when the subject is asked to elevate their

forehead (frontalis). The beneficial effects typically

last from 4 to 6 months.

The lower 2.5 to 4 cm of the frontalis muscle

moves cephalad to elevate the eyebrows. Older peo-

ple use this to raise their eyebrows to see. One must

always cautiously address the lower frontalis and stay

2 cm above the brow in all individuals. Weakening

the frontalis muscle rather than completely immobi-

lizing it can achieve the desirable goal of reducing the

folds while maintaining some forehead movement.

In individuals who have significant brow ptosis,

the possible effects of frontalis injection should be

discussed with the individual and injection of the

brow depressors (the glabellar complex) performed.

There is upward diffusion of toxin, which addresses

the lower forehead lines.

The frontalis muscle ends midway between the

lateral and the mid-brow. The orbicularis oculi de-

presses the portion of the brow lateral to this. Injec-

tion of 3 U of Botox just below the lateral brow and

lateral to the temporal fusion line can raise the lateral

brow, giving the patient a ‘‘chemical’’ brow-lift of up

to 2 mm [2].

Treatment of the brow depressors alone may be

indicated. This can be accomplished without totally

eliminating the frown. This produces brow elevation,

especially medially, and a more open-eyed look.

Treated individuals also frown less because of weak

treatment of the brow opposers, but can frown if

required. This form of treatment is more successful in

women, especially those who do not have heavy

horizontal brows.

Fig. 3. Brow dynamics.

A.W. Klein / Dermatol Clin 22 (2004) 145–149 147

Many of the complications that occur in the brow

can be mitigated if, before injection, the full range of

motion of the frontalis muscle is noted and the

proposed injection sites are marked. Patients should

also be reminded that most of the population (roughly

90%) has some degree of brow asymmetry and

warned that this can be diminished or, conversely,

may be accentuated by the treatment.

An alternative method is the injection of large

volumes of low-dose toxin to smooth crow’s-feet and

brow area. This method works by weakening, but not

paralyzing, underlying facial muscles. Many have

found, however, that these large dilutions result in

paralysis of unacceptably short duration [3]. Large

dilutions have also, naturally, resulted in larger areas

of paralysis as an associated side effect.

In general, a higher concentration allows for more

accurate placement and greater duration of effect and

fewer side effects. Lower concentrations encourage

the spread of the toxin. It should be remembered that

there is an area of denervation associated with each

point of injection because of toxin spread of about

2.5 to 3 cm. The concentration of the toxin is highest

at the point of injection and the concentration gradi-

ent decreases rapidly with distance from this point.

With higher dilutions and more volume of solution

injected, this area of diffusion naturally increases and

the concentration gradient is much less steep.

The most significant complication of treatment of

the frontalis is brow ptosis. Botox should not be

injected above the middle brow so as to avoid brow

ptosis. Injection should also be avoided within 1 cm

of the bony superior orbital rim for the same reason.

Botox works best in younger female patients (20–

45 years of age). In some older patients and in some

male patients, redundant skin can be created under

the brow (pseudoptosis), so these patients should be

approached with caution. Treatment of the brow de-

pressors may be necessary, however, after brow ptosis

has become manifest.

Untoward sequelae that can occur at any site

because of percutaneous injection of Botox include

pain, edema, erythema, ecchymosis, headache, and

short-term hypesthesia. Discomfort can be decreased

by use of topical anesthetics (EMLA, Astra Pharma-

ceuticals, Westborough, MA) before injection, and

the use of smaller-gauge needles. Local anesthesia

injections are also helpful in reducing pain. Ice

applied immediately before and after injection further

reduces the pain and the edema and erythema asso-

ciated with an intramuscular injection. Ecchymosis

can be minimized by avoiding aspirin, aspirin-

containing products, and products that inhibit platelet

function (nonsteroidal anti-inflammatory agents) for

7 to 10 days before injection. Limiting the number of

injections and postinjection digital pressure without

manipulation assists in reducing the number and

severity of bruising

Ecchymosis occurs easily in the soft eyelid tissue

and can be minimized by applying pressure at the

injection site immediately following needle with-

drawal. More importantly, injecting superficially in

this area greatly reduces this occurrence.

An equally aesthetically unfavorable outcome is

the brow that assumes a quizzical or ‘‘cockeyed’’

appearance [4]. That is, the lateral eyebrows may arch

A.W. Klein / Dermatol Clin 22 (2004) 145–149148

upward to an excessive extent because of the unop-

posed pull of the frontalis. This occurs when the lat-

eral fibers of the frontalis muscle have not been

appropriately injected. This may be corrected by

injecting 3 U about 2 cm above each brow medial

to the temporal fusion line. For this reason most

individuals have moved their lateral-most forehead

injections laterally.

Ptosis of the upper eyelid, although less likely,

also can occur. This is secondary to downward

diffusion of the injected material and often caused

by poor technique. Eyelid ptosis is a significant risk if

injections are placed at or under the middle of the

eyebrows in the vicinity of the mid-pupillary line.

Diffusion of the toxin downward can induce levator

ptosis requiring correction by recurrent use of apra-

clonidine eye drops. The baseline rate of diffusion of

botulinum toxin may be amplified by rapid or force-

ful injection, or excessively deep injection at the level

of the periosteum, which can disperse botulinum

toxin far from the injection site and may increase the

risk of eyelid ptosis. Use of very dilute solutions of

toxin may also result in diffusion of the material

to areas distant from the injection site.

The female brow is normally positioned above the

bony orbital margin, rising in its central and lateral

portions to resemble a wing. Ptosis of the brow

occurs with photodamage and with the inherent

and habitual use of the brows in thinking, working,

and speaking. The resulting interpretation of this ex-

pression is one of fatigue, depression, frustration, or

anger—all negative emotions. The normal male brow

is situated below the orbital margin but this is

perceived as a vital part of masculine presentation.

An injection directly under the lateral eyebrows

into the lateral brow depressors can make the eye

appear more open and create an aesthetically desir-

able eyebrow arch. Injections that are incorrectly

placed too far medial to the lateral edge of the brow

can result in brow ptosis or even lid ptosis. Small

quantities should be used because diffusion from

larger injections can further contribute to the risk of

ptosis. Precautions can also be taken to reduce the

likelihood of overcorrection in those who would

benefit from this technique. Limiting the quantity of

botulinum toxin injected and concurrently injecting

the medial depressors in the glabellar complex to

raise the medial brow may help avoid aesthetically

displeasing overcorrection.

Crow’s-feet in the lateral canthal area are pro-

duced by the action of the orbicularis oculi, whose

fibers are arranged in a circular pattern around the

eyes, and also by the elevators of the corner of the

mouth, risorius, and zygomaticus. Contraction of

orbicularis is needed for forceful closure of the eye-

lids. The goal of treatment is to produce a weakening

just in the area of the crow’s-feet lines.

Treatment of the lateral orbital (crow’s-feet) areas

with Botox produces satisfactory amelioration of

wrinkling in this area. Younger individuals have no

wrinkling in this area, so that if an individual just

has the crow’s-feet area treated, this does not produce

any detectable change apart from a more youthful

appearance. This is distinct from treatment of the

glabellar area, which produces an inability to frown.

When treating this area it is important to treat only

the area that shows wrinkling. In addressing the

periocular area with botulinum toxin, it is possible

to erase crow’s-feet, soften lateral oblique lines on

the forehead, smooth the inferior oblique lines of

the cheek, soften the suborbital area, and elevate the

lateral eyebrow.

To treat the periorbital wrinkles, measure 1.5 cm

from the lateral canthus (or 1 cm lateral to the bony

margin) and inject at this site. Again, the electromyo-

gram should be used. The observance of such a

boundary is more important if very dilute, large-

volume injections are performed. Consequently, injec-

tion of large volumes should be avoided. Oculoplastic

surgeons using small, concentrated volumes often

inject right at the lateral canthus. This dose should

be repeated 1 cm inferior and slightly medial to the

first injection site. The dose should also be repeated

1 cm superior and slightly medial to the first injection

site. These sites can be massaged gently, but firmly,

away from the orbital rim. Some believe that this

produces a more even result and reduces the bruising,

which is more common in this location. Nevertheless,

one should always stay above the zygomatic arch for

the inferior injection.

At each site, 0.1 mL (3.3 U) is used for a total of

3 � 3.3 or 9.9 U per side. A total dose of 6 to 18 U

per side is satisfactory for most individuals but can be

increased if necessary. Similarly, if the wrinkled area

is larger, appropriately spaced injection sites can be

used, bearing in mind that the effect of the toxin

seems to spread at least 1 cm radius from the injection

site in this area. Injection should follow the pattern of

the wrinkling. There are four basic wrinkle patterns of

crow’s-feet: (1) full fan from the upper eyelid to the

upper cheek, (2) lower lid and upper eyelid to the

upper cheek, (3) upward sweeping crow’s-feet, and

(4) central zone of crow’s-feet at the lateral canthus

only. These should be directed at the site of the

wrinkles only. It is important to keep the periorbital

injections as superficial as possible to avoid blood

vessels around the eyes. This technique is best for

lateral and upper crow’s-feet at rest.

A.W. Klein / Dermatol Clin 22 (2004) 145–149 149

If a patient has redundant skin, one should be

careful because the skin can end up folding on the

zygomatic arch, producing an undesirable cosmetic

result. This technique is best for lateral and upper

crow’s-feet at rest. Ecchymoses are common when

treating periorbital wrinkles, so ice compresses are

advised after each side is treated [5]. This can be

almost totally avoided by injecting the Botox in a

wheal or a series of continuous blebs with each

injection at the advancing border of the previous

injection to avoid hitting blood vessels. All Botox

patients are told to stay upright for at least 4 hours.

Immediately after injection, movement of the treated

muscles is encouraged so that the toxin is taken-up by

the involved neural end plates.

Deeper zygomaticus lines often connect to the

lower crow’s-feet lines. Treatment of the crow’s-feet

can paradoxically worsen the zygomaticus lines be-

cause the redundant cheek skin gravitates downward.

Anatomically, many facial muscles do not insert

into bone (eg, the frontalis). When the treating

physician has the patient smile to see the crow’s-feet,

the lower crow’s-feet are really created by the zygo-

maticus major, not the obicularis oculi. If the crow’s-

feet are treated, one quite large lower crow’s-foot

remains when the patient smiles. This is why Botox

is best balanced by fillers in the lower areas.

A more wide-eyed look can be obtained for the

patient by injecting the lower eyelid at the lash

margin. Two Units of Botox are injected at the mid-

pupil and 2 U midway between the pupil and the

outer canthus. Some injectors only use the single

injection at mid-pupil. This procedure also helps to

smooth out fine lines under the eyes. This must be

approached cautiously and should not be attempted

if the patient exhibits a significant degree of scleral

show pretreatment; if the patient has had significant

surgery under the eye previously; or if the patient has

a great deal of redundant skin under the eye as

exhibited by a snap test of the lower eyelid (ie, if

the lid does not return to its previous position when

manually pulled down). Lateral rounding of the eye,

however, may result when 4 U or more are injected.

Although many patients are delighted by the round-

ing, some may complain that it makes the pre-exist-

ing oval contour of their eyes rather too round.

Injections into the soft skin under the lateral eyes

can cause ecchymoses. Tissue should be handled

gently, and superficial vessels identified and avoided.

Blebs should be placed immediately under the epi-

dermis because the periocular muscles are extremely

superficial at this site. Pressure should be applied

immediately following injection in the event of

incipient purpura to mitigate the risk of a full-

fledged bruise.

Reported complications in this area are bruising,

diplopia, ectropion or a drooping lateral lower eyelid,

and an asymmetric smile caused by the toxin diffus-

ing to the zygomaticus major. To avoid these com-

plications one should inject at least 1 cm outside the

bony orbit or 1.5 cm lateral to the lateral canthus and

not inject close to the inferior margin of the zygoma.

Violating these boundaries has on occasion also

resulted in diplopia caused by medial migration of

Botox and resultant paralysis of the lateral rectus

muscle. If diplopia occurs covering or patching the

eye alleviates some of the double vision. Injecting

below the lateral margin of the zygoma and deeply

can affect the zygomaticus major.

Strabismus can also occur. Both diplopia and

strabismus are exceedingly uncommon side effects.

If they manifest, referral to an ophthalmologist is

imperative for appropriate management.

References

[1] Toledo LS. Facial rejuvination: technique and rationale.

In: Fodor PB, Nicanor GI, Hengst TC, editors. Endo-

scopically assisted aesthetic plastic surgery. St. Louis:

Mosby-Year Book; 1996. p. 91–105.

[2] Fraenkel AS, Kamer FM. Chemical brow lift. Arch Oto-

laryngol Head Neck Surg 1998;124:321–3.

[3] Guyuron B, Huddleston S. Aesthetic indications for

botulinum toxin. Plast Reconstr Surg 1994;93:913–8.

[4] Burns RL. Complications of botulinum exotoxin. Pre-

sented at the 25th Annual Clinical and Scientific Meet-

ing of the ASDS. Portland, OR, May 13–17, 1998.

[5] Keen M, Kopelman J, et al. Botulinum toxin A: a novel

method to remove periorbital wrinkles. Facial Plast Surg

1994;10:141–6.

Dermatol Clin 22 (2004) 151–158

Botulinum toxin A in the mid and lower face and neck

Jean Carruthers, MDa,*, Alastair Carruthers, MDb

aDepartment of Ophthalmology, University of British Columbia, 943 West Broadway, Suite 720,

Vancouver, BC V5M 4E1, CanadabDivision of Dermatology, University of British Columbia, Vancouver, BC V5M 4E1, Canada

Although once considered a novel concept, the At this time in North America there are two

use of botulinum neurotoxins, primarily botulinum

types A (BTX-A) and B (BTX-B), to smooth hyper-

kinetic lines in the upper face has become an accepted

and successful procedure in facial rejuvenation. In the

mid and lower face and neck, botulinum toxin injec-

tions diminish rhytides and sculpt the face into more

aesthetically pleasing lines. The doses used in the mid

and lower face and neck differ greatly from those in

the upper face, however, and only experienced clini-

cians with a detailed understanding of the under-

lying muscular anatomy and tissue relationships

should inject in areas associated with more risk of

potential complications. This article reviews current

approaches to botulinum toxins as primary and ad-

junctive therapies in the mid and lower face and neck.

Botulinum toxins

Botulinum neurotoxins derive from the bacterium

Clostridium botulinum and include seven distinct

serotypes, identified as A, B, C1, D, E, F, and G

[1]. These serotypes share the ability to block neuro-

transmission at the neuromuscular junction by block-

ing acetylcholine release, producing denervation and

atrophy of cholinergic skeletal muscles. Because the

neurotoxin serotypes differ in their cellular mecha-

nisms of action and in the size of the neurotoxin

complex, however, they are not interchangeable

and their clinical profiles vary. BTX-A is the most

powerful toxin and was the first to be developed for

clinical use.

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00118-9

* Corresponding author.

E-mail address: drjean@carruthers.net (J. Carruthers).

commercially available toxins: Botox (BTX-A) and

Myobloc (BTX-B). Botox is the only botulinum

toxin currently approved for cosmetic use in North

America, although Dysport (BTX-A) is available in

Europe and is under consideration for licensing by

the US Food and Drug Administration. Because each

preparation differs in terms of the C botulinum strain,

potency, and manufacturing, the biologic behaviors

of each are not interchangeable, and the dosages

for each product vary. For most procedures, 1 U of

Botox has efficacy equivalent to 3 to 5 U of Dysport.

Botox is distributed in a crystalline form with

approximately 100 U per vial. The package insert

recommends reconstitution with sterile, nonpreserved

saline [2]. Recent data, however, suggest that recon-

stitution with preserved saline does not impair the

stability of BTX-A [3,4] and is less painful than

nonpreserved saline [5]. The optimum concentration

depends on the procedure. Although the package

insert suggests that the reconstituted toxin should be

used within 4 hours, evidence now indicates that the

reconstituted product can be stored refrigerated for a

week or longer without any loss of efficacy [6].

Myobloc is available in a liquid formulation con-

taining BTX-B, 5000 U/mL, and is available in 0.5-,

1-, and 2-mL vials containing BTX-B, saline, human

serum albumin, and sodium succinate, with a pH of

approximately 5.6 (accounting for the stinging sensa-

tion reported on injection) [7]. Reconstitution is not

required and is hampered by ‘‘overfill’’ of the vials.

Clinicians with the desire to add saline are advised to

do so in the syringe. The unopened vial is stable for

months or years; once opened, the labeling is similar

to BTX-A.

Dysport is available as a lyophilized vial contain-

ing 500 U of BTX-A and sodium chloride, lactose,

s reserved.

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151–158152

and human serum albumin [8]. In Europe, Dysport

is labeled for transport at ambient temperature and

storage at 2�C to 8�C, and the guidelines for recon-

stitution and use are similar to those for Botox.

Clinical application of botulinum type A

Intramuscular injections of BTX-A have become

the treatment of choice for most forms of focal

dystonia. The ability of botulinum toxin to block ace-

tylcholine release from autonomic nerve endings

innervating glandular tissue or smooth muscle has

led to investigation of its use for other indications

including hyperhidrosis [9,10] and gastrointestinal

disorders [11–14]. More recently, BTX-A has been

reported to have beneficial effects in relieving myo-

fascial pain [15,16] and tension and migraine head-

ache [17–22], and for the treatment of obesity [23].

Because most of the authors’ clinical experience re-

sides with Botox, all references hereafter refer to the

Botox or Botox Cosmetic formulations, unless other-

wise specified. Clinicians should be aware, however,

of the significant clinical differences between the

sources of BTX-A and adjust dosages accordingly.

Contraindications

Botulinum type A is contraindicated in patients

with neuromuscular disease, such as myasthenia

gravis and amyotrophic lateral sclerosis [2]. Experi-

ence with BTX-A in pregnant and lactating women is

extremely limited, so caution is warranted in these

cases (the authors believe that use in pregnancy is

contraindicated). Other contraindications include in-

fection at the injection site, or a known hypersensi-

tivity to any of the product contents. The possibility

of drug interactions exists, and patients taking amino-

glycoside antibiotics should receive smaller doses.

Dosing

The effects of BTX-A injections begin to appear

within 1 to 2 days and typically last for 3 or 4 months

or longer. There is a tendency for repeated injections

to show a longer duration of effect. Larger muscles

require larger unit doses of BTX-A. The volume of the

dose should be adjusted according to the desired

diffusion of toxin: more concentrated doses diffuse

less and should be used to target small muscles.

Among cosmetic users, the average volume of dilutant

has been reported to be 2.5 mL [3], but the authors

typically dilute the vial in 1 mL. In general, higher

doses of BTX-A delivered in smaller volumes keep

the effects more localized and allow for the precise

placement of the toxin with little diffusion, whereas

smaller doses in larger volumes tend to cause more

widespread effects [24].

One of the greatest concerns with the use of

BTX-A is the formation of neutralizing antibodies.

The total protein concentration and number of units

injected are critical in determining potential immu-

nogenicity, and some studies suggest that BTX-A

injections at more frequent intervals or at higher

doses may lead to a greater incidence of antibody

formation [2]. The protein concentration in the cur-

rent lots of Botox is significantly lower than in

previous lots, however, and has been shown to be

less antigenic than the original product. The overall

risk of antibody formation using BTX-A at recom-

mended doses for cosmetic applications is low, and

injecting the lowest effective dose with the longest

feasible intervals between injections minimizes the

potential for immunogenicity.

Midface indications

Hypertrophic orbicularis

Widening the palpebral aperture is part of the new

‘‘artistry’’ of BTX-A in facial contouring and sculpt-

ing. Hypertrophy of the pretarsal portion of the

orbicularis oculi can give a ‘‘jelly roll’’ appearance.

In some patients, the act of smiling transiently dimin-

ishes the perceived size of the palpebral aperture,

especially in Asian patients, who sometimes desire

a more round-eyed appearance. Flynn et al [25] in-

jected 2 U subdermally, 3 mm inferior to the lower

pretarsal orbicularis, in addition to three injections of

4 U placed 1.5 cm from the lateral canthus, each 1 cm

apart and found a mean palpebral aperture increase

in 86% of patients of 1.8 mm at rest and 2.9 mm at

full smile [25]. One must be careful, however, to se-

lect patients who have a good preinjection snap test

and who have not had previous lower eyelid ablative

resurfacing or infralash blepharoplasties without a

coexisting canthopexy to support the normal position

of the lower eyelid. Goldman [26] reports one case

in which a patient developed festooning of the

infraocular area 2 to 3 days following injections of

10 and 2 U BTX-A in the midlateral canthal region

and 2 to 3 mm below the ciliary margin in the mid-

papillary line, respectively.

Dermatol Clin 22 (2004) 151–158 153

Bunny lines and nasal flare

Contraction of the muscular fibers of the upper

nasalis across the bony dorsum of the nose causes

fanning rhytides (bunny lines) at the radix of the

nose. Weakening of the underlying mimetic muscu-

lature with botulinum toxin effectively and dramati-

cally softens these lines. The authors inject 2 to 4 U

of botulinum toxin into the belly of the upper nasalis

as it transverses the nasal bone. The injection should

be given high on the lateral nasal wall, inferior to the

angular vein. Care must be taken to give the injection

well above the nasofacial groove to avoid relaxing the

levator labii superioris and causing upper lip ptosis.

Gentle massage should follow the injection to diffuse

the toxin.

Some individuals repeatedly dilate their nostrils in

social situations, revealing the sides of the columella

and septum. Injecting 5 to 10 U BTX-A bilaterally

into the lower nasalis fibers draped over the lateral

nasal ala, at the most active area of muscle contrac-

tion, can decrease involuntary nostril flare in some

patients for 3 to 4 months [24].

Nasolabial folds

Nasolabial (melolabial) folds extend from the

lateral nasal ala to a point lateral to the external angle

of the mouth. Older individuals who have sustained

photodamage or who smile excessively develop a

permanent, deep crevice. The most common treatment

for these folds has been soft tissue fillers and laser

resurfacing. Injecting BTX-A directly into the area

of the fold is most likely to produce an asymmetric

smile and upper lip ptosis. Weakening the lip eleva-

tor muscles and zygomaticus and risorius muscles,

tempting although it may be, flattens the midface and

elongates the upper lip. In patients who have a

naturally shorter upper lip, however, very small doses

(1 U) into each lip elevator complex in the nasofacial

groove collapses the upper extent of the nasolabial

fold but also elongates the upper lip. Because the

effect is long lasting (F 6 months), one should select

patients carefully and be sure to explain fully the

aesthetic result of the procedure.

Perioral rhytides

The orbicularis oris is the sphincter muscle that

encircles the mouth, lying between the skin and

mucous membranes of the lips and extending upward

to the nose and down to the region between the lower

lip and chin. Sometimes called the ‘‘kissing’’ muscle,

it causes the lips to close and pucker. Overactive

J. Carruthers, A. Carruthers /

orbicularis oris causes vertical perioral rhytides that

are commonly labeled as ‘‘smokers’ lines’’ but can

also result from heredity, photodamage, playing a

musical instrument that requires embouchure, or even

whistling. Patients often are disturbed by the increased

vertical length of the cutaneous lip and by the radial

upper lip lines that can cause lipstick to bleed upward

from the lip and blur the outline of the lip. Although

multiple fine wrinkles of the upper lip can be treated

effectively with fillers, such as collagen, or with

ablative or nonablative resurfacing, deeper wrinkles

may be resistant to these treatments. Tiny doses (1 to

2 U per lip quadrant) are usually sufficient to result in

localized microparesis of the orbicularis oris, espe-

cially when used adjunctively with a soft tissue

augmenting agent, such as collagen, hylaruronan, or

Artecol, and can greatly improve the appearance of

the lip without creating a paresis that might interfere

with elocution and suction.

To maintain competence of the mouth it is impor-

tant to be conservative with dosing and to use su-

perficial, rather than deep, injections [24]. Even low

doses, however, may result in lip sphincter weak-

ening that affects the ability of the individual to play

musical instruments or whistle. Patients should be

screened carefully; musicians who play wind instru-

ments, professional singers or speakers, and patients

with unrealistic expectations are not ideal candidates

for this procedure.

Lower face indications

Botulinum toxin should be used with caution for

cosmetic indications in the area of the mouth. Dos-

ages are much reduced in comparison with those used

for the upper face, and the underlying muscular

anatomy varies from patient to patient.

Mouth frown and melomental fold

The frowning expression created when the lateral

corners of the mouth are permanently angled down-

ward gives an impression of disapproval and unpleas-

antness, even in the absence of a discrete melomental

fold or ‘‘drool groove.’’ The depressor anguli oris

(DAO) pulls down the corner of the mouth in oppo-

sition to the zygomaticus major and minor muscles.

BTX-A injections can weaken the DAO and reset the

muscular balance, allowing the zygomaticus to ele-

vate the corners of the mouth and return them to a

horizontal position (Fig. 1) [24]. In the authors’ clinic,

2 to 3 U of botulinum toxin are injected .directly into

the DAO on each side of the mouth

Fig. 1. Treatment of depressor anguli oris with botulinum type A.

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151–158154

Melomental folds (drool grooves or marionette

lines) extending from the downturned corner of the

mouth to the lateral mentum involuntarily produces a

sad expression and reinforces the negative impression

produced by the inverted smile. They also give the

appearance of advancing age and decrepitude. Tradi-

tionally, soft tissue augmentation has been used alone

to rebuild the soft tissue support of the lateral mouth

corner and the melomental fold, but the effects are

short term. Injections of BTX-A are useful adjuncts to

soft tissue augmentation, relaxing the muscles and

lengthening the duration of the filling-agent effect,

such as Zyplast, Hylaform, Restylane, Perlane, or

Artecol, by preventing the repeated molding of the

implant [27]. BTX-A in combination with laser resur-

facing produces the most satisfactory results. The

authors inject 2 to 5 U BTX-A into each DAO

immediately above the angle of the mandible and

1 cm lateral to the lateral oral commissure.

Caution must be used when placing injections

close to the mouth. Injections too medial can cause

an ipsilateral weakness of the depressor labii and

flattening of the lower lip contour when the mouth

attempts to form an ‘‘O,’’ and injections placed too

high can interfere with the sphincter function of the

orbicularis oris, leading to difficulties with speech and

suction. Other possible complications include flaccid

cheek, incompetent mouth, difficulty with elocution,

and asymmetric smile. Injections are not recom-

mended for singers or musicians, or for patients who

use their perioral muscles with intensity.

Mental crease and peau d’orange chin

Contraction of the mentalis produces a deep

groove, or mental crease, between the lower lip and

the prominence of the chin. Soft tissue augmentation

in the mental crease leads to visible beading and poor

results. Injections into the mentalis at the bony men-

tum softens the crease while avoiding an incompetent

mouth, which can occur from BTX-A injections at the

level of the crease. The authors usually inject 3 to 5 U

BTX-A per mentalis band.

The mentalis serves to raise and protrude the

lower lip and wrinkles the skin of the chin, producing

horizontal or multiple dimple rhytides called the

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151–158 155

‘‘apple dumpling’’ or ‘‘peau d’orange’’ chin. Previ-

ously treated with soft tissue augmentation and la-

ser resurfacing, chin dimpling responds well either

to BTX-A plus soft tissue augmentation or BTX-A

alone. The authors inject 5 to 10 U BTX-A into the

mentalis at the most distal point from the orbicu-

laris oris, the prominence of the chin. Following the

injection, massage of the chin is recommended to aid

in the diffusion of toxin.

Smile lines

Deep smile lines, produced by contraction of the

zygomaticus and often connected to lower crow’s

feet lines, are best treated with carbon dioxide laser

resurfacing. One to 2 U BTX-A injected into each

side of the zygomaticus before resurfacing, however,

enhances the effects of the procedure [28].

Upper gum show

In some patients, the levator labii superioris

alaeque nasi retracts the upper lip and produces

excessive upper gum exposure, revealing the gum

line, upper incisors, and canines. Injecting 1 to 2 U

BTX-A into the levator labii superioris on each side

of the bony nasal prominence drops the upper lip

enough to correct the upper gum show [27]. Because

vertical elongation of the cutaneous lip can occur

after injections (a process that occurs naturally with

aging), treatment produces optimal results in younger

patients. The best results are often obtained when

BTX-A is used in combination with soft tissue aug-

mentation in the lip margins.

Facial asymmetry

Correction of midfacial asymmetry, which may

have bony tissue, soft tissue, or muscular etiology, is

another artistic indication for BTX-A that requires a

thorough knowledge of muscular anatomy and func-

tion. Physicians not comfortable with facial surface

anatomy are advised to use the aid of an electromyog-

raphy system for accurate placement of injections.

In hemifacial spasm, in which repeated clonic and

tonic facial movements draw the facial midline over

toward the hyperfunctional side, relaxing the hyper-

functional zygomaticus, risorius, and masseter with

BTX-A injections allows the face to be centered at

rest. Likewise, hypofunctional asymmetry, such as

Bell’s palsy, can be alleviated by small injections

(1 to 2 U into the zygomaticus, risorius, and orbicu-

laris and 5 to 10 U in the masseter) on the normo-

functional side [29].

Botulinum type A can be used to relax the jaw

and relieve discomfort in patients who experience

asymmetric jaw movements. Injections (10 to 15 U)

are placed intraorally into the internal pterygoid on

the hyperfunctional side.

Surgical cutting or traumatic lesion of the orbicu-

laris oris or the risorius muscle can result in an off-

centered mouth caused by the unopposed action of

the partner muscles in the normally innervated side.

Correction can be achieved by treatment of the ri-

sorius immediately lateral to the corner of the mouth

on the normally innervated side. In patients with

congenital or acquired unilateral weakness, who can-

not depress the corner of one side of the mouth,

BTX-A injected into the partner muscle restores func-

tional balance.

Masseteric hypertrophy

Preliminary investigations show that BTX-A may

be a simple alternative with a short recovery period for

facial contouring in patients with masseteric hyper-

trophy. To et al [30] injected 200 to 300 U of Dys-

port per side in five patients with unilateral and

bilateral hypertrophy of the masseter. All five patients

showed a good response, with the maximal effect of a

31% reduction in muscle bulk 3 months after treat-

ment. Three out of nine hypertrophic muscles needed

a secondary injection within 1 year to maintain

atrophy. Von Lindern et al [31] reported a reduction

of the masseter muscles by half in seven patients with

unilateral and bilateral hypertrophy of the masseter

and temporalis muscles treated with an average of

100 U of Dysport. Four patients considered the result

satisfactory after a single injection. More recently,

Park et al [32] injected 25 to 30 U BTX-A per side in

five to six sites in 45 patients. Masseter thickness

was gradually reduced during the first 3 months fol-

lowing injection (average change in masseter thick-

ness, 1.5 to 2.9 mm, equivalent to 17% to 19% of

the original muscle thickness). Clinical effects lasted

6 to 7 months following injection before the muscle

thickness retreated to its initial size; at 10 months,

36 patients expressed satisfaction with the results.

Main transient side effects included mastication diffi-

culty, muscle pain, and verbal difficulty during speech

and lasted from 1 to 4 weeks.

Cervical indications

The platysma is a large muscle arising from upper

parts of pectoralis major and deltoid that slants up-

ward along the full length of the neck. Some platysmal

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151–158156

fibers extend to the mandible, whereas others insert

into the skin and subcutaneous tissue of the lower part

of the face or blend into the muscles of expression

above the angle and lower corner of the mouth and

lower lip. As with all facial muscles, there is enor-

mous variability from one individual to another. Two

types of lines can be produced from the platysma:

horizontal ‘‘necklace’’ lines (transverse lines in the

neck that run perpendicular to the contraction of the

platysma) and vertical platysmal bands.

Horizontal neck lines

Horizontal necklace lines of skin indentation,

caused by the superficial musculoaponeurotic system

attachments in the neck, often grace the chubbier

neck. To treat with BTX-A, the authors ‘‘dance’’

along the lines, injecting small doses over multiple

sites, for a total of 15 to 20 U per treatment session.

Gentle massage following treatment helps alleviate

potential bruising. Physicians are advised to use deep

dermal, rather than subcutaneous, injections because

of deeper venous perforators that can bleed and under-

lying muscles of deglutition that can be affected.

Vertical platysmal bands

When cervical skin loses its elasticity, the anat-

omy of the submental space changes: more submen-

tal fat becomes visible, and the platysma separates

into two diverging vertical bands [33]. These bands

tighten and become prominent when the patient

speaks or otherwise animates the neck.

Botulinum type A injections can soften vertical

platysmal bands in some patients [24,34]; however,

careful patient selection of those with obvious platys-

mal bands, good cervical skin elasticity, and minimal

fat descent are essential. In necks with jowl formation

and bone resorption, treatment with BTX-A may

worsen the appearance of the bands. To some, tradi-

tional rhytidectomy surgery remains the gold standard

treatment for most aging necks [35]. Used as an

adjunct to rhytidectomy, BTX-A reduces the residual

muscular banding that becomes apparent in the post-

operative phase. In addition, some patients may prefer

to use botulinum toxin treatment as a kind of rehearsal

for regular surgery.

Because the platysma is external to the muscles of

deglutition and neck flexion, large doses of BTX-A

(ie, 75 or 100 U) have been known to cause profound

dysphagia [24] and must be used cautiously. The

authors typically inject 5 U in three sites for each

band (with sites that are 1 to 1.5 cm apart) and no

more than 25 to 30 U over multiple sites per treatment

session. It is far better to undertreat; additional touch-

up treatments can always be given if necessary during

a subsequent treatment session.

Side effects and complications

Side effects that may occur with BTX-A injections

include transient swelling or bruising at the injection

site, mild headache, and flulike symptoms. To mini-

mize ecchymosis, patients are instructed to avoid

aspirin, nonsteroidal anti-inflammatory drugs, and

vitamin E. Smaller doses of BTX-A are less likely

to cause problems than larger doses, which supports a

conservative approach in most patients. Most compli-

cations are relatively uncommon and are related to

poor injection techniques [36].

Most side effects result from undesired muscle

weakening caused by diffusion of the toxin to adjacent

muscles and can be avoided by using concentrated

doses. No long-term adverse effects have been re-

ported, and no other systemic safety problems have

been associated with botulinum toxin treatment.

Studies of the lower face report complications,

such as effects on muscle function and facial ex-

pression, usually caused by overenthusiastic use of

BTX-A in large doses [36]. Starting with low doses

and injecting more superficially rather than deeply

limits the potential for complications (such as drool-

ing and asymmetry), and injections should be sym-

metric to ensure uniform postinjection movement.

Avoid injections in singers, musicians, or other

patients who use their perioral muscles with intensity.

When injecting the DAO, avoid areas too close to the

mouth, injection into the mental fold, and interaction

with the orbicularis oris, all of which can result in a

flaccid cheek, incompetent mouth, or asymmetric

smile. Large doses (> 100 U) of BTX-A in the pla-

tysma have resulted in reports of dysphagia and

weakness of the neck flexors.

Summary

Botulinum toxins have been smoothing hyperki-

netic lines in the upper face for over 15 years. More

recently, their use has widened to include applications

in the mid and lower face and neck to smooth, shape,

and sculpt, blurring the line between science and

art. Their use in the lower face, however, requires a

thorough and detailed knowledge of not only facial

and cervical anatomy, but also the complex interac-

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151–158 157

tions of muscles and the aesthetic and implications of

a misplaced injection. Although proper patient selec-

tion and injection techniques do not guarantee optimal

results, poor selection and techniques almost certainly

guarantee disappointing results. In addition to its use

as primary procedure, botulinum toxin is also an

effective adjunct to other cosmetic procedures, en-

hancing and prolonging the benefits of surgery, soft

tissue augmentation, and laser resurfacing.

References

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[5] Alam M, Dover JS, Arndt KA. Pain associated with

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[9] Naumann M, Hofmann U, Bergmann I, Hamm H,

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[12] Albanese A, Bentivoglio AR, Cassetta E, Viggiano A,

Maria G, Gup D. Review article: the use of botuli-

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sphincteric botulinum toxin injection in the treatment

of chagasic achalasia. Dis Esophagus 2003;16:33–8.

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[17] Carruthers A, Langtry JAA, Carruthers J, Robinson

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ing wrinkles with botulinum toxin A injections. Head-

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[18] Klapper JA, Klapper A. Use of botulinum toxin in

chronic daily headaches associated with migraine.

Headache Q 1999;10:141–3.

[19] Silberstein S, Mathew N, Saper J, Jenkins S. Botuli-

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[20] Barrientos N, Chana P. Efficacy and safety of botu-

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[21] Mauskop A. Long-term use of botulinum toxin type

A (Botox) in the treatment of episodic and chronic

migraine headaches. Presented at the American Head-

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[22] Blumenfeld A. Botulinum toxin type a as an effective

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Headache 2003;43:853–60.

[23] Gui D, de Gaetano A, Spade PL, et al. Botulinum toxin

injected in the gastric wall reduces body weight and

food intake in rats. Aliment Pharmacol Ther 2000;14:

829–34.

[24] Carruthers A, Carruthers J. Botulinum toxin type A:

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Semin Cutan Med Surg 2001;20:71–84.

[25] Flynn TC, Carruthers JA, Carruthers JA. Botulinum A

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27:703–8.

[26] Goldman MP. Festoon formation after infraorbital

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2003;29:560–1.

[27] Carruthers J, Carruthers A. Botox treatment for expres-

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Head Neck Surg 2000;8:357–61.

[28] Carruthers J, Carruthers A. The adjunctive usage of

botulinum toxin. Dermatol Surg 1998;24:1244–7.

[29] Carruthers JDA, Carruthers JA. Botulinum toxin in

clinical ophthalmology. Can Ophthalmol 1996;31:

389–400.

[30] To EW, Ahuja AT, Ho WS, et al. A prospective study

of the effect of botulinum toxin A on masseteric

muscle hypertrophy with ultrasonographic and electro-

myographic measurement. Br J Plast Surg 2001;54:

197–200.

[31] von Lindern JJ, Niederhagen B, Appel T, Berge S,

Reich RH. Type A botulinum toxin for the treatment

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of hypertrophy of the masseter and temporal muscle:

an alternative treatment. Plast Reconstr Surg 2001;

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[32] Park MY, Ahn KY, Jung DS. Application of botuli-

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lower face. Dermatol Surg 2003;29:477–83.

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[34] Matarasso A, Matarasso SL, Brandt FS, Bellman B.

Botulinum A exotoxin for the management of pla-

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[35] Kane MAC. Nonsurgical treatment of platysmal

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Dermatol Clin 22 (2004) 159–166

Botulinum toxin for the treatment of neck lines

and neck bands

Fredric S. Brandt, MDa,b,*, Andres Boker, MDb

aDepartment of Dermatology, University of Miami School of Medicine, 4425 Ponce de Leon Boulevard, Suite 200,

Coral Gables, FL 33146, USAbClinical Research, Frederic S. Brandt, MD, PA, 4425 Ponce de Leon Boulevard, Suite 200, Coral Gables, FL 33146, USA

The recent upheaval caused by the new ‘‘wonder The aging neck

drug,’’ in part prompted by the Food and Drug Admin-

istration’s (FDA) recent approval of botulinum toxin

type A for cosmetic purposes, has sent the popularity

and use of this remedy soaring. Botulinum toxin type

A (BOTOX, Allergan, Inc., Irvine, CA) has become

a household name, and the procedure is now part

of virtually every cosmetic and general dermatology

practice in the nation.

With an ever-increasing demand for the procedure

and the number of treated patients steadily growing, so

are the experience and knowledge of the physicians

administering the drug. The resulting better under-

standing of its mechanism of action, clinical effective-

ness, and potential side effects is gradually helping

establish the cosmetic use of botulinum toxin as a

safer, better, and more predictable practice.

Nowadays, the importance of health maintenance

and beauty preservation is higher than ever before, and

as a result, cosmetic procedures have become a per-

fectly acceptable means of rejuvenation. The advent of

botulinum toxin injections as an outpatient ‘‘quick fix’’

for the temporary treatment of facial wrinkles has

unquestionably changed the concept of cosmetic pro-

cedures and the way people perceive them.

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00021-4

* Corresponding author. Department of Dermatology,

University of Miami School of Medicine, 4425 Ponce de

Leon Boulevard, Suite 200, Coral Gables, FL 33146.

E-mail address: dermbrandt@aol.com (F.S. Brandt).

As the human body ages, the vitality of all organs

and tissues decreases, and there is a progressive loss of

optimal function throughout. In the skin, these changes

are especially apparent and are therefore a common

complaint of the aging population. This process is

the result of the combination of two distinct patho-

physiologic phenomena. Chronologic (intrinsic) aging

affects the skin in a manner similar to other organs in

which a reduced collagen deposition resulting from

diminished biosynthesis and reduced proliferative

capacity of fibroblasts yields an atrophy and apparent

tissue volume loss in the dermal layer of the skin [1].

Furthermore, the coexisting loss of elastin fibers, the

oxidative stress imposed upon the lipid bilayer of cell

membranes and dermal proteins, the nonenzymatic

glycosilation of proteins, and the reduced repair ca-

pacity to resynthesize both collagen and elastin fibers

all contribute to and accelerate the degenerative

changes occurring in the senescent skin [2,3]. Super-

imposed on this inherent process is the injury resulting

from environmental factors, mainly ultraviolet-in-

duced photodamage to the dermal connective tissue

of the exposed skin from sunlight [4,5]. This may be

the most important contributing factor responsible

for the premature senescence of the skin and is

therefore the main target of preventive measures for

cutaneous health preservation.

In the neck, the aging process is no different and in

the long run is manifested by increased laxity, thin-

ning, and loss of elasticity of the cervical skin. Fur-

thermore, the downward pull exerted by the platysma

s reserved.

Fig. 1. Age-related changes of the human face and neck. (A) Physical effects of age on facial structures. (B) Topographic changes

in the cervical region related to advancing age.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166160

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166 161

muscle complex and the ptosis of the facial portion of

the muscle itself creates jowls, with loss of definition

of the chin and jawline. Gravity, too, has a profound

effect on the thin, lax, and dehydrated skin of the aged

neck and contributes to the accentuation of horizontal

and radial neck lines (Fig. 1). All facial soft tissue

descends and pushes down on the cervical structures,

bringing the skin, soft tissue, and even the hyoid bone

and larynx caudally and more visibly noticeable [6].

The vertical fibrous bands classically noted in a

senescent neck are the result of a persistently active

platysma muscle trying to support the sagging deeper

neck and floor of the mouth structures. In addition, the

anterior edges of the muscle separate over time, lose

tone, and protrude anteriorly, creating the anterior

banding or ‘‘turkey neck’’ deformity. These changes

become particularly apparent in people who use this

muscular complex habitually during facial animation

and expression. In addition, the loss of tone of the

platysma muscle allows for a large subplatysmal fat

pad to herniate through the free borders of the muscle

and create a central fullness of the neck [7].

Until recently, the only treatment options people

had to rejuvenate their necks involved an invasive

surgical procedure (eg, liposuction, superficial mus-

culoaponeurotic system (SMAS) facelift), which was

often highly risky and required a prolonged recupera-

tion time [8,9]. In addition, numerous potential candi-

dates are precluded from surgical procedures because

of medical problems, psychological instability, or

suboptimal previous rhytidectomy results.

The recent application of botulinum toxin injec-

tions to the neck to help reduce both rhytids and

prominent banding has given a myriad of patients

the chance to look better quickly with virtually no

down time.

Fig. 2. Schematic representation of the superficial and mid-

depth anatomic relations of the neck. (1) Platysmamuscle. (2)

External jugular vein. (3) Sternocleidomastoid muscle. (4)

Orbiculris oris muscle. (5) Depressor anguli oris muscle.

Relevant anatomy

When injecting the neck with botulinum toxin, it is

important to keep inmind the neck’s intricate anatomic

composition, thereby avoiding injury to important

blood vessels, nerves, and deeper cervical structures

and minimizing complications.

The platysma complex is a broad muscular sheet

that stretches over the anterolateral aspect of the neck.

It has its origin on the fascia covering the upper parts

of the pectoralis major and deltoid muscles including

clavicular and acromial subcutaneous insertions on

each side. Its fibers arise as two separate sheets and

cross the clavicle and proceed obliquely upward and

medially along the side of the neck. Both muscular

sheets are joined at the anterosuperior portion of the

neck and continue upward in a decussated fashion

(Fig. 2). Cadaver studies have identified three different

variants of the platysma muscle based on the decussa-

tion of its fibers (Table 1). The most common variant,

or type I, seen in f 75% of patients, is where the

platysma fibers interface with those of the opposite

side 1 to 2 cm below the chin. In the second category,

or type II, found in f 15% of the patients, the

decussation of fibers occurs at the level of the thyroid

cartilage and covers the submental region confluently

in one band. In the third variant (type III), the do not

interdigitate with those of the opposite side and run as

two separate muscle sheets toward their insertions in

the mandible and the skin. This is the least common

presentation and occurs in only f 10% of patients

[10] (Fig. 3). After descussation, some fibers are then

inserted into the mandibular bone below the oblique

line, others into the skin and subcutaneous tissue of the

lower part of the face. Many of these fibers blend in

with the perioral muscles at the angle and lower part of

the mouth (Fig. 2) [11]. Above the mandible the fibers

continue cephalically as the SMAS. When the entire

platysma complex is contracted, it produces a slight

wrinkling of the skin of the neck in an oblique

Table 1

Anatomical variants of the platysma muscle complex

Type Description

I The medial fibers of the platysma muscle are

separated in the suprahyoid region. They interlace

with those of the opposite side below the chin.

II The medial fibers of the platysma muscle decussate

at the level of the thyroid cartilage, forming

a single muscular layer covering the

submental region.

III Fibers do not interlace, they run separately toward

their cutaneous and body insertions in the chin.

Data from Cardoso de Castro C. The changing role of pla-

tysma in face lifting. Plast Reconstr Surg 2000;105:764–75.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166162

direction. Its anterior portion, the thickest part of the

muscle, depresses the lower jaw and also serves to

depress slightly the lower lip and angle of the mouth.

The platysma muscle receives its innervation from

the cervical motor branch of the facial nerve. The sen-

sory component of the nerve surfaces at the junction of

the sternocleidomastoid and platysma muscles at Erb’s

point. The major blood vessels in the cervical area are

the two anterior jugular veins, running in a cephalo-

caudal manner on each side lateral to the thyroid

cartilage, and the external jugular veins, also running

cephalocaudally along the anterior edge of the sterno-

cleidomastoid muscles.

There are two distinct fat depositions that play an

important role in the aging pathophysiology of the

neck: the submental fat pad, which lies directly ante-

rior to the platysma muscle, and the subplatysmal

fat pad, which lies deep and posterior to the muscle.

Depending on the anatomic variant of the platysma

muscle, the protrusion of the subplatymsal herniated

fat pad becomes more or less clinically evident. As

Fig. 3. Schematic representation of the three anatomic variants

(C) Type III.

such, patients with submental fullness classified as the

type II anatomic variant, with the platysma covering

the entire submental region, will respond almost com-

pletely with botulinum toxin treatment, as relaxation

of the protruded anterior bands will tighten the mus-

cular fibers overlying the fat pad and push it back into

place. Conversely, if the submental platysma muscle is

absent as seen in the third anatomic variant of the

muscle (type III), a herniated fat pad will be especially

noticeable, and injections with botulinum toxin alone

will not suffice to correct the abnormality. In these

cases, liposuction can be performed to enhance the

cosmetic outcome.

Classification

The aging neck can be classified into four distinct

categories (Table 2). Category I describes the earliest

phase of cervical cutaneous degeneration and category

IV the most severe [12].

Injection technique

Patients are treated in an upright sitting position,

and the cervical skin is cleansed with a rubbing alcohol

swab. To identify properly the platysmal bands,

patients are asked to forcefully contract their necks

by clenching their teeth. Each band is grasped indi-

vidually and held firmly between the thumb and index

fingers. Injections are placed directly into the platys-

mal band at 1.0- to 1.5-cm intervals along the band,

starting at the jawline and descending all the way to the

clavicular border (Figs. 4, 5). Injections should be

placed into the deep dermis and not subcutaneously

as the risk of hitting deep venous perforations or

of the platysma muscle complex. (A) Type I. (B) Type II.

Table 2

Categories of age-related neck degeneration

Category Description

I Platysmal bands only detectable with

neck contraction

Subtle horizontal neck rhytides

No laxity of the skin

No submental fat pads

II Thin platysmal bands at rest

Mild horizontal neck rhytides

Mild laxity of the skin

Minimal jowls

III Moderate platysmal bands at rest

Moderate horizontal neck rhytides

Moderate laxity of the skin

Moderate jowls

Submental fat pads

IV Severe hyperthrophy of platysmal bands

Deep horizontal neck rhytides

Severe laxity of the skin

Prominent jowls and loss of the

mandibular contour

Prominent submental fat pads/drooping

of the chin

From Brandt FS, Bellman B. Cosmetic use of botulinum

A exotoxin for the aging neck. Dermatol Surg 1998;24:

1232–4; with permission.

Fig.5. Treating physician’s perspective of platysmal band

injection.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166 163

other cervical muscles increases as injections are

situated in more profound planes. Our technique

using botulinum toxin type A at a dilution of 2.0 cc

per 100-U vial involves placing 3 to 10 U into each

injection point using a 0.5-inch, 30-gauge metal

Fig. 4. Schematic representation of the approximate injection

points of botulinum toxin into the platysma muscle.

hubbed needle. The decision on how many U to inject

depends on the thickness of the band at the injection

site. Upon injection, one can feel the resistance of the

platysma muscle, indicating the correct injection

depth. Although the total injected dose of botulinum

toxin type A has occasionally been as high as 200 U

per treatment session,most patients need a total of 50 to

100 U to achieve optimal correction, depending on the

category of their age-related neck degeneration.

Immediately after the injection of the toxin, one can

observe relaxation of the platysma muscle and eleva-

tion of the SMAS complex. The onset of striated

muscle weakness usually begins 3 to 5 days after the

treatment session and continues to improve over the

next couple of weeks.

Most of our experience treating the aged neck has

been using botulinum toxin type A. However, recent

experience using botulinum toxin type B (MYO-

BLOC, Elan Pharmaceuticals, San Diego, CA) for this

particular indication has shed some light on some of the

differences between the two formulations. Whereas

the doses for botulinum toxin type A are well estab-

lished and the results quite predictable, the doses

needed for botulinum toxin type B still need to be

established. However, a recent clinical trial comparing

three different dose groups of botulinum toxin type B

(2500, 5000, and 7500 U) showed that the best results

were obtained when using the highest doses. Further-

more, as a general rule, botulinum toxin type B has an

earlier onset of action and clinical results can be

observed 2 to 3 days after injection. Also, the botuli-

num toxin type B appears to diffuse more extensively,

and care must be exercised when placing the injections

so that they are not too close to each other and there is

not too much overlap between the treated regions.

Gentle massage and icing the skin after the injections

will prevent the skin from bruising

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166164

Results

An acceptable cosmetic result when treating the

aged neck with botulinum toxin can be achieved after a

singe treatment session. Most patients treated with the

botulinum toxin type A exotoxin report the onset of a

favorable cosmetic result f 5 to 7 days after injec-

tions, whereas patients treated with botulinum toxin

type B notice the changes occurring f 3 to 5 days

after being treated. The duration of effect is also

variable, even when the appropriate dose and injection

technique are used, and depends on several factors,

including the individual’s age and biological catabo-

lism of the toxin.

It is likely that gradually increasing doses of

botulinum toxin type Awill yield exponentially better

subjective results in the majority of patients. However,

the fixed number of SNARE-complex receptors in the

neuromuscular junction and their saturation with max-

imal doses of exotoxin make very high doses unlikely

to be beneficial after a certain point, also increasing the

risk of prompting unwanted adverse reactions. Thus,

as mentioned before, dosing of the toxin should be

Fig. 6. Frontal view of the cervical region before (A, B) and

estimated individually and according to the thickness

of the bands and degree of sagginess of the overlying

skin. As such, patients with very thick hypertrophied

bands obtain significant improvement after injection

of up to 30 U of botulinum toxin type A per band,

whereas patients with thinner, less fibrous bands

respond well with doses up to 15 to 20 U per band

(Figs. 6, 7). Younger patients yield noticeably better

results than their older counterpart, as do older patients

with previous facelift surgery.

Complications

Treating platysma muscle banding and horizontal

lines of the neck with botulinum toxin is a fairly safe

procedure. Complications are minimal and, as a gen-

eral rule, technique dependent. It is therefore para-

mount to have a complete understanding of the

toxin’s pharmacologic properties and the anatomic

relations of the neck to perform the therapy optimally

andminimize complications. Commonly observed and

expected side effects include transient edema and

after (C, D) treatment with botulinum toxin type A.

Fig. 7. Frontal view of the cervical region before (A, B) and after (C, D) treatment with botulinum toxin type B.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166 165

ecchymoses, both of which usually resolve within 1 to

2 days. Other less common adverse reactions include

muscle soreness or neck discomfort, difficulty lifting

the head off a pillow from the decubital position, and

headaches. Rare complications include hoarseness and

difficulty swallowing. The latter must be prevented at

all costs by exercising care during injection to not

place the toxin too deeply where it can affect other

cholinergic muscular structures.

As mentioned earlier, the experience with botuli-

num toxin type B is somewhat limited in treating this

area in part because the optimal doses have yet to be

determined correctly. This also makes the true and

objective description of commonly observed side

effects more challenging. But generally speaking,

some common complaints observed in a fair amount

of patients being treated with botulinum toxin type B

are drymouth and headache. The drymouth can last up

to 3 weeks after injection, and the headaches usually

disappear after 1 or 2 days.

So far, no reports have been made of allergic

reaction to any type of botulinum toxin preparations,

and although the incidence of antibody formation to

the botulinum protein complex has been reported to be

between 3% and 5%, when treating the neck region

alone we have not observed resistance to botulinum

toxin secondary to antibody neutralization [13]

Summary

Rejuvenation of the aging neck with botulinum

toxin injections is a minimally invasive, safe, and

effective treatment modality with a very high patient

satisfaction rate. Treatments are usually started early

in the aging process of the neck to prevent further

degenerative changes and are performed thereafter at

4- to 6-month intervals. It is the ideal alternative to

rhytidectomy when the patient is too young for face-

lift surgery or for patients unwilling to take recupera-

tion time. Furthermore, botulinum toxin therapy can

be used to correct jowl and platysmal band asymme-

try occurring after suboptimal rhytidectomy.

Botulinum exotoxin should not be used in preg-

nant or lactating women or in patients with a known

sensitivity to human albumin or with a history of

neuromuscular disorders.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159–166166

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Dermatol Clin 22 (2004) 167–175

Botulinum neurotoxin for the treatment of migraine and

other primary headache disorders

Andrew M. Blumenfeld, MDa,*, David W. Dodick, MD, FRCP(C), FACPb,c,Stephen D. Silberstein, MD, FACPd

aDepartment of Neurology, Kaiser Permanente, 4405 Vandever Avenue, San Diego, CA 92120, USAbDepartment of Neurology, Mayo Medical School, USA

cDepartment of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USAdJefferson Headache Center, Thomas Jefferson University Hospital, 111 South 11th Street, Suite 8130,

Philadelphia, PA 19107, USA

Migraine is a chronic neurovascular disorder that [6]. There is a significant need to develop more

afflicts 2% to 15% of the world’s population. In the

United States there are an estimated 28 million mi-

graine sufferers, with women being affected three

times as often as men [1]. It is characterized by severe

headaches and is often associated with nausea, vomit-

ing, and heightened sensitivity to sound and light at the

peak of the attack. Migraine is considered to cause

more disability than epilepsy, and severe migraine has

been judged by theWorld Health Organization to be as

disabling as quadriplegia, psychosis, and dementia [2].

Most sufferers are in their most socially active and

productive years (25 to 55) [1]. Not only is migraine

painful and disabling for the sufferer, but it exerts

a significant economic burden on society. It causes

112 million bedridden days each year and costs

$14 billion in reduced productivity and missed work-

days [3]. The economic burden of migraine is com-

parable with that of diabetes [4] and higher than that

of asthma [5].

Even among migraineurs who consult a physician,

many are not satisfied with their therapy and report that

prescribedmedications are not always optimal. Triptan

medications, the most effective therapy for acute

migraine attacks, are only effective in improving the

pain and associated migraine symptoms, such as

photophobia and nausea, in up to two thirds of patients

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00105-0

* Corresponding author.

E-mail address: Andrew.m.Blumenfeld@kp.org

(A.M. Blumenfeld).

effective therapies for migraine prevention because

35% of migraineurs suffer from two to three severe

attacks per month, whereas 25% suffer frommore than

four attacks per month [6]. Furthermore, more than 4%

of the United States population suffers from chronic

daily headache [7].

Patients with frequent, disabling, or refractory

migraine should be considered for prophylactic treat-

ment. Current United States guidelines recommend

preventive therapy in one or more of the following

situations: (1) frequent headaches; (2) recurring mi-

graines that significantly interfere with daily routine;

(3) failure of, a contraindication to, overuse of, or ad-

verse events (AEs) with acute migraine therapies;

(4) cost of acute and preventive therapies; (5) patient

preference; and (6) the presence of uncommon mi-

graine conditions, including hemiplegic migraine,

basilar migraine, migraine with prolonged aura, or

migrainous infraction [8]. Although numerous thera-

pies are currently available for the prevention and

treatment of migraine, most of these agents have sig-

nificant side effects.

Commonly used agents for migraine prophy-

laxis include b-adrenergic blockers, calcium channel

blockers, tricyclic antidepressants, and anticonvul-

sants (Table 1). Moderate to severe AEs are not un-

common with all available prophylactic medications.

b-Blockers are known to produce a wide array of

AEs, including drowsiness, fatigue, lethargy, sleep

disorders, and depression. AEs typically associated

with the calcium channel blockers include constipa-

s reserved.

Table 1

Preventive therapeutics commonly prescribed for migraine

Quality of

EvidenceaScientific

EffectbClinical

Impressionc

Anticonvulsants

Divalproex sodium A +++ + + +

Topiramate A ++ + + + +

Gabapentin B ++ + +

Antidepressants

Amitriptyline A ++ + + + +

Fluoxetine B + +

b-blockersPropranolol A ++ + + +

Metoprolol B ++ + + +

Timolol A ++ + + +

Atenolol B ++ + +

Calcium channel blockers

Verapamil B + +

Nimodipine B + +

a A, Multiple well-designed randomized clinical trials,

directly relevant to the recommendation, yielded a consistent

pattern of findings; B, some evidence from randomized cli-

nical trials supported the recommendation, but scientific sup-

port was not optimal.b +, Effect of medication is either statistically or not

clinically significant; ++, effect of medication is statistically

significant and exceeds the minimally clinically significant

benefit; +++, effect is statistically significant and far exceeds

the minimally clinically significant benefit.c +, Somewhat effective: few people get clinically sig-

nificant improvement; ++, effective: some people get cli-

nically significant improvement; +++, very effective: most

people get clinically significant improvement.

Adapted from Silberstein SD, Goadsby PJ. Migraine:

Preventive treatment. Cephalalgia 2002;22:491–512.

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175168

tion, peripheral edema, and weight gain [9], whereas

the tricyclic antidepressants commonly are associated

with a variety of AEs, including sedation, weight

gain, dry mouth, constipation, dizziness, mental con-

fusion, palpitations, blurred vision, and urinary reten-

tion. The AEs associated with antiepileptic drugs are

unique to each medication, but the most common AEs

include nausea, vomiting, and gastrointestinal distress

[9]. Because of the AE profile and limited efficacy of

currently available preventive therapies, there is a

need for novel and improved prophylactic therapies.

Recently, the potent neurotoxin botulinum toxin

type-A (BoNT-A) has been under intensive clinical

investigation for the treatment of migraine and other

types of headache. Over the last 20 years, BoNT-A has

been used to treat a variety of disorders characterized

by inappropriate and involuntary muscle contraction

[10]. BNT-A is currently approved for blepharospasm,

strabismus, cervical dystonia, and, more recently, for

the treatment of glabellar lines [11]. Although not

currently indicated, it has also been safely used for

spasticity; hyperkinetic disorders, such as tremor;

autonomic disorders, such as hyperhidrosis; and cos-

metically troublesome hyperfunctional facial lines

(crow’s feet, forehead lines) [12,13].

The analgesic effect of BoNT-A has long been

observed in the treatment of dystonia and spasticity

[14,15]. This led to further investigation of the efficacy

of BoNT-A for other painful conditions, including

migraine and tension-type headaches. Because most

clinical experience with the use of BoNT for the

treatment of headache has been with BoNT-A, this

article describes the potential antinociceptive mecha-

nism of action of BoNT-A, summarizes the clinical

evidence to date for BoNT-A as effective migraine

prophylactic therapy, and reviews the injection tech-

nique and strategies used in treating headache and

cervical myofascial pain.

Mechanism of action

Botulinum toxins are exotoxins of the anaerobic

bacterium Clostridium botulinum. This bacterium has

eight serotypes: A, B, C-alpha, C-beta, D, E, F, and G.

Seven serologically separate exotoxins are produced.

The intracellular targets of each of these toxins vary;

however, their biologic activity at the neuromuscular

junction is similar [16].

Injection of BoNT-A directly affects neuromuscu-

lar signaling processes. On injection, the toxin enters

the nerve terminals by endocytosis; interacts with

intracellular proteins (snare proteins); and inhibits

the vesicular release of the acetylcholine neurotrans-

mitter at the neuromuscular junction. Inhibition of

acetylcholine produces chemical denervation and

paralysis of the striated muscles. Paralysis usually

peaks 2 weeks postinjection. Because of molecular

turnover within the neuromuscular junction and neu-

ronal sprouting, neuronal activity begins to return at

3 months, with complete function at approximately

6 months [17].

Although neuromuscular activity inhibition may

alleviate a portion of the pain associated with headache

disorders, it does not fully explain the pain relief

mechanisms mediated by BoNT-A. Intensive research

on BoNT-A has begun to suggest that this toxin may

interact with several other neuronal signaling path-

ways, although the exact mechanisms remain elusive.

Current data suggest that BoNT-A modifies the sen-

sory feedback loop to the central nervous system by

blocking intrafusal fibers, resulting in decreased acti-

vation of muscle spindles. This effectively alters the

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 169

sensory afferent system by reducing the traffic along Ia

spindle afferent fibers [18]. This toxin also seems to

inhibit the release of glutamate from primary afferent

nociceptive fibers, reduce the firing of wide dynamic

range neurons within the dorsal horn of the spinal cord,

and reduce the activity of central nociceptive neurons

as measured by a reduction in the expression of

immediate early genes (c-Fos) after nociceptor stimu-

lation [19]. A reduction in afferent sensory activity

coming from pericranial and cervical muscles, and

inhibition of peripheral and central trigeminal sensi-

tization, may represent the potential mechanisms by

which BoNT-A exerts its therapeutic effect in mi-

graine, tension-type headache, and other primary

headache disorders [20].

Fig. 2. Injection site: temporalis and masseter muscles.

Clinical efficacy: retrospective reviews and open-

label trial

Historically, while conducting the initial clinical

trials of BoNT-A for the treatment of hyperfunctional

facial lines, Binder et al [21] noted a correlation

between pericranial BoNT-A injections and alleviation

ofmigraine headache symptoms. Based on these initial

findings, the authors conducted a combined, multicen-

ter, open-label trial that evaluated the efficacy of

Fig. 1. Injection sites: glabellar and frontal regions.

Fig. 3. Injection site: occipital, suboccipital, and trapezius

muscles.

Table 2

Retrospective/open-label and placebo-controlled trials of botulinum toxin A treatment for migraine

Study Design (N) and Patient Typea Dose Injection site Primary result reported

Retrospective Reviews/Prospective Open-label Trials

Binder et al (2000) Retrospective chart

review (N=77)

Mean dose 31 units

(range 5–110 units)

Fixed injection sites

Glabellar

Frontal

Temporal

51% of migraine patients reported

complete response

Mauskop and Basedo (2000) Retrospective chart

review (N=27)

25–100 units Fixed injection sites

(frontalis, glabellar,

and temporalis)

85% (23 of 27) of patients reported significant

reduction in frequency and intensity

Some patients received

a combination of fixed

injections and

‘‘follow-the-pain’’ injections

Mauskop (2002) Retrospective chart review (N=78)

Episodic migraine, N=32

Chronic migraine, N=46

Varying dose from

25–200 units

‘‘Follow-the-pain’’ protocol Most patients reported partial to complete

response (no percentage improvement given

in this study)

Miller and Denny (2002) Retrospective chart review (N=48)

All patients were chronic headache

patients who had failed

previous therapy

Varying dose from

50–300 units

Fixed injection site

(frontalis, corrugator,

temporalis, splenius captis)

with ‘‘follow-the-pain’’

as needed

86% of patients treated with BTX-A reported

nominal benefit with 35% reporting good and

27% very good benefits

Blumenfeld (2002) Retrospective chart

review (N=271)

Headache types includeb

Chronic daily

Episodic-tension

Episodic-migraine

Mixed

Average dose 63.2 units Injection sites were

either ‘‘fixed’’ or

‘‘follow-the-pain’’

25% reduction in headache intensity ( P < .001)

56% reduction in headache days per month

( P< .0001)

85.6% of patients reported symptomatic improvement

Mathew et al (2002) Retrospective chart

review (N=112)

All patients diagnosed with

chronic migraine

50–100 units Combination of fixed

injection sites (frontal/

glabellar/ temporal/

occipital/ suboccipital)

and ‘‘follow-the-pain’’

Three months after third injection a significant

decrease in the number of headache days

( P< .05) and a decrease in mean MIDAS scores

( P< .01) were observed

A.M

.Blumenfeld

etal/Derm

atolClin

22(2004)167–175

170

Smuts and Barnard (2000) Prospective, open-label

(N=19)

100 units Variable sites

(no specific protocol

mentioned in abstract)

68% (13 of 19) of migraine patients reported

positive response

Eross and Dodick (2002) Prospective, open-label

(N=73)

Episodic migraine, N=12

Chronic migraine, N=36

25 units

If required based on

pain, 25–75 additional

units injected into

cervical paraspinals

Fixed injection sites

Frontalis

Temporalis

Procerus

Corrugator

Of patients who responded > 50% reported an

improvement in disability

61% of responders reported decrease in headache

frequency and 27% reported decrease in

headache severity

Placebo-Controlled Trials

Barrientos and Chana (2002) Placebo-controlled (N=30) 50 units Fixed injection sites

Glabellar

Frontal

Temporal

Procerus

Trapezius

Splenium capitis

Significant reduction in frequency (P< .001),

severity (P < .02), and adjunct medications

(P < .001) compared with placebo

Silberstein et al (2000) Placebo-controlled/

double-blind (N=123)

25 units (low dose)

75 units (high dose)

Fixed injection sites

Glabellar

Frontal

Temporal

45% of patients in low-dose group (25 units)

reported a >50% decrease in frequency

Brin et al (2000) Placebo-controlled/

double-blind (N=56)

Dose not given

in study

Fixed injection sites

Frontal

Temporal

BTX-A was superior than placebo in reducing

severity (P=.04)

Ondo et al (2002) Placebo-controlled/

double-blind (N=60)

Chronic migraine, N=19

Chronic tension headache,

N=22

Features of both types of

headache, N=19

200 units Individual injection

choice using ‘‘follow-

the-pain’’ protocol

10% of patients reported a ‘‘dramatic’’ improvement

and 24% a ‘‘marked’’ improvement.

Significant reduction in the number of headache

days (weeks 8–12) compared with placebo

(P < .05)

a Unless specified, patient population consists of migraine headache.b Number of patients in each headache not specified.

A.M

.Blumenfeld

etal/Derm

atolClin

22(2004)167–175

171

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175172

BoNT-A for migraine management. Efficacy was

categorized as either complete response with total

symptom elimination, partial response with greater

than 50% reduction in headache severity and fre-

quency, or no beneficial response. In this study, 51%

of patients treated with BoNT-A as migraine pro-

phylaxis reported a complete response to localized

head and neck BoNT-A injections with a mean dura-

tion of 4.1 months. An additional 38% reported par-

tial improvement with a mean response period of

2.7 months [21].

Since then, many researchers have reported their

experience with BoNT-A. Mauskop and Basedo [22]

reviewed chart records of 27 patients treated with

BoNT-A for migraine prophylaxis by injections in

the pericranium. A decrease in headache frequency

and severity was reported in 85% (N = 23) of patients.

Rather than focusing solely on the end point of severity

and frequency of headache, Eross and Dodick [23]

evaluated the effect of BoNT-A (25 to 100 units) on

reducing disability in 47 patients with either episodic

or chronic migraine. Using a well-validated tool to

assess migraine-related disability (the MIDAS ques-

tionnaire), 58% of all patients reported a decrease in

migraine-associated disability. Episodic migraine

patients (N = 12) seemed to show the most benefit,

with 75% reporting a decrease in migraine frequency

compared with 53% of chronic migraine patients [23].

Other retrospective reviews [24–28] further sup-

port the beneficial role of BoNT-A for the preventive

treatment of episodic migraine, chronic tension-type

headache, and treatment-refractory chronic migraine

headaches. Aside from the obvious limitation of a

retrospective review or open-label design, the weak-

nesses of many of these study reports include small

patient number; poorly defined end points; and often

heterogeneous patient populations (episodic-chronic

migraine, tension-type or chronic headaches).

Clinical efficacy: placebo-controlled trials

Currently, few well-conducted clinical trials of

BoNT-A in migraine prevention exist. The first

double-blind, placebo-controlled, randomized clinical

trial was published by Silberstein et al [8]. In this study,

123 patients who had experienced between two to

eight moderate-to-severe migraine headaches over a

3-month period were randomized to receive a single

injection of either placebo, low-dose (25 units), or

high-dose (75 units) BoNT-A. This single dose was

injected into multiple sites of pericranial muscles

during the injection visit. Injections were performed

anteriorly, in the frontalis, glabellar region, and tem-

poralis muscle. At the end of the 3-month follow-up

period postinjection, the low-dose BoNT-A group

experienced a mean decrease of 1.88 moderate-to-

severe migraines compared with the placebo group

(P = .042). Furthermore, patients in the low-dose

group had a significant reduction in the incidence of

migraine-associated vomiting compared with placebo

(P = .012). The high-dose BoNT-A group, however,

did not have a significant effect on migraine pain and

associated symptoms. In fact, at the higher dose, there

was an increase in AEs. The authors suggest that the

lack of BoNT-A activity at this higher concentration

may actually be caused by a lower number of migraine

headaches at baseline compared with the low-dose

BoNT-A group [8]. In this trial, BoNT-A was well

tolerated with no AEs observed in the low-dose group

compared with placebo.

Barrientos and Chana [29] also conducted a ran-

domized, placebo-controlled trial (no indication of

being double-blinded) that evaluated the efficacy and

tolerability of BoNT-A as prophylaxis for episodic

migraine. Thirty patients with a history of two to

eight migraine attacks per month were enrolled and

randomized to receive placebo or 50 units of BoNT-A

injected in 15 pericranial muscle sites. During the

3-month study, when compared with baseline, patients

treated with BoNT-A experienced fewer attacks at

day 30 (3.7 versus 5.8, P< .02); day 60 (3.2 versus

5.8, P < .2); and day 90 (2.5 versus 5.8, P < .01). In

comparison, no significant reduction from baseline

was observed in the placebo group. Severity and

duration of migraine attacks also were significantly

reduced in the BoNT-A group compared with placebo.

At the end of the 3-month study, the BoNT-A–treated

group reported a significant decrease in the use of

nonsteroidal anti-inflammatory drugs and triptan

medications for acute headache treatment compared

with placebo. This supports the previous clinical data

that BoNT-A is effective and well tolerated for pre-

ventive migraine treatment.

A small, double-blind, placebo-controlled study of

BoNT-A conducted by Brin et al [30] further supports

the efficacy of BoNT-A in migraine. In this trial,

56 subjects with a history of two to six migraines per

month were randomized into four groups receiving (1)

BoNT-A in frontal-temporal regions, (2) BoNT-A in

frontal and placebo in temporal, (3) placebo in frontal

and BoNT-A in temporal, and (4) placebo in frontal-

temporal regions. Migraine frequency was reduced by

a median of 1.8 headaches per month in BoNT-A–

treated groups (groups 1 to 3) compared with a median

reduction of 0.2 headaches per month in the placebo

group (group 4). This study is limited, however, by its

small population size.

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 173

Recently, Ondo et al [31] conducted a randomized,

double-blind, placebo-controlled, parallel clinical trial

that examined the effect of BoNT-A treatment on pa-

tients with chronic daily headache, including chronic

tension-type headache and chronic migraine. Sixty

patients who experienced chronic headache more than

15 days each month were enrolled and randomized to

receive, based on the ‘‘follow-the-pain’’ rationale,

either 200 units of BoNT-A or matching placebo and

at 12 weeks, if patient consented, a second open-label

BoNT-A injection. Following the first injection,

patients treated with BoNT-A had significantly fewer

headache days from week 8 to 12 compared with

placebo. In addition, 10% of patients treated with

BoNT-A reported a dramatic improvement and 24%

reported a marked improvement compared with 3%

and 7%, respectively, in the placebo-treated group. At

week 24, patients who had received two BoNT-A

injections had significantly fewer headache days over

the second 12-week period than those receiving one

injection (40 versus 19 days, P < .05).

Use of botulinum toxin A: dosage and

administration

The most common sites of injections include the

glabellar (procerus and corrugators), frontal, temporal,

and sometimes the occipital regions (Figs. 1–3).

BoNT-A is administered either at fixed injection sites;

at sites of pain or tenderness (‘‘follow the pain’’); or a

combination of both. The total dosage of toxin, the

number of units per site of injection, dilution of toxin,

and sites of injection varied widely, however, between

studies (Table 2). The total dosage ranged from 25 to

300 units over several injection sites.

The fixed-site approach consists of bilateral in-

jections, even if the patient has strictly unilateral

headaches. The muscles injected are the procerus,

corrugators, frontalis, and temporalis. Follow-the-pain

injection sites are identified by history (‘‘Where does it

hurt when you have a headache’’? and ’’ Showmewith

your hands where the pain is’’) and by examination of

the cervical-shoulder girdle and temporomandibular

musculature. These sites include the frontalis, tempo-

ralis, occipitalis, trapezius, splenius capitus, suboccipi-

tal, and cervical paraspinal muscles.

For patients with migraine or migrainous headache

features by history, treatment with a fixed-site ap-

proach may be required for successful results. When

only a follow-the-pain approach is used in patients

with migraine or migrainous headache, two problems

arise: first, a poor cosmetic outcome; and second, the

headaches often shift to the previously unaffected side.

For patients with only tension-type headaches, the

follow-the-pain approach is used. Even in these cases,

cosmetic effects in the frontal region need to be

obtained, but asymmetric injections can be given in

the temporalis, occipitalis, splenius capitus, cervical,

and subcervical paraspinal muscles. The doses injected

in the cervical-shoulder girdle muscles are low to pre-

vent any possible weakness, which could cause head-

ache. Patients need to be assessed carefully for

associated cervical dystonia, which requires injection

of the dystonic muscles.

Current available data do not seem to indicate a

dose response-benefit [8,21,23,24]. There is need for

further randomized, placebo-controlled clinical trials

to identify the optimal dosing regimen and injection

sites for BoNT-A. Some data, however, report greater

efficacy with repeated dosing. In the Ondo et al [31]

trial, patients who received a repeat BoNT-A injection

reported better improvement than patients who re-

ceived only a single BoNT-A injection [31]; these data

are also supported by results from retrospective chart

reviews [26,28]. Until results of large, well-conducted

trials are available, optimal method of BoNT-A deliv-

ery remains unresolved.

Tolerability

The clinical dose of BoNT-A commonly used for

migraine therapy is between 25 and 100 units, which is

30 to 120 times below the toxic limit [17]. Most

published trials have reported minimal to no AEs. In

a placebo-controlled, double-blind trial, Silberstein

et al [8] found that although no serious AEs occurred,

some patients receiving BoNT-A injections experi-

enced transient minor AEs, including blepharoptosis,

diplopia, and injection site weakness. The authors also

found that injection of high doses of BoNT-A

(75 units) resulted in a dose-dependent increase in

the side effect profile of BoNT-A. In an open-label

study, Binder et al [21] also reported only minimal and

transient AEs, including brow ptosis, local injection

discomfort, and ecchymosis at the injection site. Over-

all, clinical studies and retrospective reviews confirm

the tolerable side effect profile of BoNT-A and that

associated AEs are typically mild and transient.

Summary

Clinical data and experience to date have demon-

strated that BoNT-A is an effective and well-tolerated

therapy for the prevention of migraine and other

headache disorders. It has a long duration of action

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175174

that may last over 4months with no systemic or serious

AEs. Several issues remain to be defined, however,

including dosing, location, and number of injections;

optimal dilution of BoNT-A; specific headache types

that respond best to BoNT-A; and long-term efficacy

and safety. Data from ongoing well-designed trials that

include a larger patient population investigating these

issues may confirm a role for BoNT-A as a first-line

agent for migraine prevention.

Neurotoxin therapy is part of a broader headache

management approach. Because the injection tech-

niques for headache are unique and vary depending

on the primary headache disorder being treated and

the location and pattern of pain referral, the use of

BoNT-A for headache is not simply an extension of

its use for cosmesis. The use of BoNT-A in the

overall management of primary headache disorders

should be reserved for medical practitioners who not

only have experience with BoNT-A injections, but

possess the expertise in the diagnosis and manage-

ment of complex headache disorders. Educating

patients and addressing headache triggers and opti-

mizing acute treatment improve the outcome of any

preventive program.

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Dermatol Clin 22 (2004) 177–185

Treatment of hyperhidrosis with botulinum toxin

Richard G. Glogau, MD

Department of Dermatology, University of California at San Francisco, 350 Parnassus Avenue, Suite 400,

San Francisco, CA 94117–3685, USA

Focal idiopathic and episodic eccrine sweating of and notice that suddenly and inexplicably their hands,

the axillae, palms, soles, and face troubles afflicted

individuals with a social curse that can only be

imagined by those whose hands or underarms dampen

only occasionally. Although there is no accurate inci-

dence in the epidemiology literature, it seems that

about half of the patients who have presented to the

author with this condition have at least one first-degree

relative similarly affected. Social stigma, lack of

understanding on the part of medical providers as to

the cause and nature of the problem, and lack of

effective therapy keeps most of these patients from

seeking medical care. A larger social sampling is

needed to measure accurately both the number of

patients per 100,000 population who have the condi-

tion, and the exact nature of the genetic influence.

Gravimetric measurements of palmar sweating

show that patients with hyperhidrosis easily exceed

12 to 30 time’s normal rates of eccrine secretion from

the palmar surface of the hands and fingers, and often

the distal dorsal aspects of the fingers and sides of the

hand and digits. Diagnostic rates are arbitrarily de-

fined. In some patients perspiration may exceed 50 mg

of sweat per minute in the axillae and 30 mg of sweat

per minute on the palms [1–5]. Although many pa-

tients sweat on a more or less continuous basis, even

while asleep, many if not most of the patients report

that they suffer from sudden, inexplicable increases in

sweating. These sweating attacks can be brought on by

emotional stressors, such as public speaking or meet-

ing new social contacts at work or leisure; high

ambient temperature; and ingestion of stimulants like

coffee. But they also report that they can be sitting

relatively calm and cool and without situational stress

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00072-X

E-mail address: drglogau@sfderm.com

underarms, soles, or faces begin to drip.

Many patients have covered this affliction up by

resorting to elaborate behavior rituals, repetitively

wiping their palms on clothes, wearing underarm

absorbent pads, carrying towels and handkerchiefs

at all times, and avoiding the dreaded handshake at all

costs. Traditional therapies, such as topical aluminum

chlorides salts in antiperspirants, anticholinergic

drugs, and glutaraldehyde tinctures, are irritating, rife

with side effects, and generally impractical for pa-

tients with this condition [6–8]. Direct excision of

the affected skin has been proposed for treating

axillary sweating [9,10] but cannot be performed on

the palms. Liposuction curettage has been advocated

for axillary hyperhidrosis [11–16], but is of no value

in palmar sweating.

The standard surgical approach for palmar and

facial sweating has been focused on neurosurgical

techniques with elective thoracic sympathectomies

at the T2-T3 level, performed with endoscopic ap-

proaches and minimal incisions, popular for some

time [17–22]. The procedure provides unpredictable

partial relief for axillary sweating and carries the risk of

some significant postoperative complications, includ-

ing Horner’s syndrome, pneumothorax, and partial or

incomplete response [23–26]. Worse, significant por-

tions of patients treated by sympathectomy develop

some degree of compensatory hyperhidrosis [27–29].

This condition affects the skin from the areolas cau-

dally. The patients, although dry over the entire hand,

arm, shoulder, neck and head, paroxysmally sweat

profusely from mid-chest down. This is a highly

distressing and irreversible condition and no known

algorithm to predict its occurrence preoperatively has

yet been described.When compensatory hyperhidrosis

occurs, the result is that one intolerable sweating

problem is traded for another.

s reserved.

Fig. 2. Minor starch-iodine test of axilla 2 weeks after

treatment with 50 U intradermal BOTOXR at a dilution of

2.5 mL/100 U.

R.G. Glogau / Dermatol Clin 22 (2004) 177–185178

Botulinum toxin for sweating

There has been considerable interest in using

selective, focal chemodenervation with botulinum

neurotoxin to control problems of localized but se-

vere sweating [30–36]. There are two commercially

available forms of the A serotype complex: BOTOXR(Allergan, Irvine, CA) and Dysport (Speywood Phar-

maceuticals, Maidenhead, Berkshire, UK). A third

commercially approved product, a B serotype, was re-

cently approved by the Food and Drug Administration

for cervical dystonia and is marketed in the United

States under the name Myobloc (Elan Pharmaceu-

ticals, South San Francisco, CA) and in Europe as

Neurobloc. The A serotypes have accumulated more

clinical experience in treatment of hyperhidrosis. For

the balance of this article, reference is made to

BOTOXR unless otherwise specifically indicated.

Unlike the case with sympathectomy, the focal

areas treated with BOTOXR are confined to the palms

or axillae or the soles, and the total body surface area

treated is less than 3%. In contrast the surgical section

of the sympathetic chain at the T2-T3 level renders at

least 20% of the body’s surface anhidrotic. Ther-

moregulatory stress then creates the compensatory

sweating, which has not been reported with focal

chemodenervation with BOTOXR.

Documentation of problem

There are two methods used to document the

magnitude and distribution of abnormal palmar sweat-

ing: gravimetric measurement and the Minor starch-

iodine test [37]. Gravimetric testing uses filter paper

that is held in contact with the palm for a fixed period

Fig. 1. Minor starch-iodine test of axilla before treatment

with BOTOXR.

of time and then weighed. This technique is useful

largely as a research tool to document the magnitude of

sweat reduction and identify the therapeutic dose

range. The Minor starch-iodine test is performed by

first wiping the skin with a colored iodine tincture (eg,

an antibacterial iodine solution available in pharma-

cies). The iodine solution must be brown-orange in

color. Decolorized iodine solution does not perform

the colorimetric conversion properly. Several seconds

are given to allow the iodine solution to dry. A small

fan is useful for this purpose. The palm is then lightly

dusted with ordinary baking cornstarch powder, avail-

able in any food store. As the eccrine sweat exits the

skin onto the palmar surface a chemical reaction takes

place between the iodide molecule and the starch

present in the powder producing a colorimetric reac-

tion as the powder turns deep purple in a matter of a

couple of seconds (Figs. 1, 2). The exact location of the

active sweating is then mapped and outlined with a

marking pen before beginning injections.

One should take care to perform the starch-iodine

test before applying any regional nerve blocks or

before application of topical anesthetics like prilocaine

or eutectic mixtures of lidocaine (EMLA) in wide use

today. The vasoconstrictive effect of the topical anes-

thetics and the hyperemic response in the skin seen

after regional wrist blocks both interfere with the

amount of sweating and can give misleading results

in the Minor starch-iodine test.

The author has found it useful to take a digital

photograph of the starch-iodine test for the medical

record and a Polaroid picture to give to patients. They

can easily perform a starch-iodine test themselves in

follow-up and ascertain the fractional response to

therapy (Figs. 3 –5). The photographs also help

Fig. 3. By injecting through the starch-iodine, the small

amount of moisture at each injection site readily demonstrates

the scattered pattern of injections.

Fig. 5. Minor starch-iodine test. Two weeks after treatment of

both palms with BOTOXR. (From Glogau RG. Treating

palmar sweating with neurotoxins. Semin Cutan Med Surg

2001; 20:104; with permission.)

R.G. Glogau / Dermatol Clin 22 (2004) 177–185 179

patients visualize the degree of the problem and their

response to therapy after the BOTOXR injections are

performed. Patients are psychologically traumatized

by hyperhidrosis, and most are exquisitely sensitive to

any persisting sweat after treatment. They are often

reassured by comparing the before and after starch test

pictures (Fig. 6). It reinforces their understanding of

the effect of the drug and the therapy.

Anesthesia

Treating the axillary skin with intradermal injec-

tions of BOTOXR through a 30-gauge hypodermic

needle can be accomplished easily without anesthesia,

although topical anesthetics may be used after marking

Fig. 4. Minor starch-iodine test. Right hand untreated. Left

hand 2 days after treatment with BOTOXR. Notice areas ofdiffusion with anhidrosis developing circumferentially

around injection sites. (From Glogau RG. Treating palmar

sweating with neurotoxins. Semin Cutan Med Surg 2001;

20:103; with permission.)

the area to be treated using the Minor starch-iodine

test. Similarly, forehead or facial sweating can be

treated without anesthetic.

A few stoic patients with palmar or plantar sweat-

ing may opt for simple topical anesthesia, such as ice,

EMLA, ELA-MAX, and so forth, but few can tolerate

the discomfort of 60 to 70 needle sticks per palm or

sole without anesthesia. Most patients require regional

nerve block anesthesia, such as wrist or ankle blocks,

before undergoing palmar injection [38,39]. The oc-

casional patient may require twilight anesthesia [40]

or tourniquet limb anesthesia (Bier block) [41].

For palmar anesthesia 1% to 2% lidocaine plain,

without epinephrine, is placed by superficial, subcu-

taneous injections at the wrist to produce blocks of the

Fig. 6. Minor starch-iodine test. Right hand treated 2 weeks

previously. Left hand untreated. (From Glogau RG. Treating

palmar sweating with neurotoxins. Semin Cutan Med Surg

2001;20:105; with permission.)

R.G. Glogau / Dermatol Clin 22 (2004) 177–185180

median, ulnar, and radial nerves. The median nerve is

blocked by injecting between the palmaris longus

tendon and the flexor carpi radialis tendon at the

proximal flexion crease of the wrist. Injecting between

the ulnar artery and the flexor carpi ulnaris tendon

blocks the ulnar nerve. The superficial radialis is

blocked by injecting in the ‘‘anatomic snuff box’’ on

the dorsal-medial aspect of the base of the thumb.

Once the injections are placed, usually a half-hour

wait ensues to allow for the diffusion of anesthetic into

the nerves to produce sufficient anesthesia. The dis-

advantage of using wrist blocks is that the patient’s

reactive hyperemia that develops increases the tend-

ency to bleed from each small injection site, which

may increase loss of material from the injection site

and decrease the relative effectiveness of each injec-

tion. Warning patients off aspirin before treatment is

probably wise for the same reason.

For plantar anesthesia, adequate anesthesia of the

sole of the foot can be achieved with two injections

[39]. The first is a medial ankle block of the tibial nerve

at the level of the medial malleolus posterior to the

posterior tibial artery, in-between the Achilles tendon

and the medial malleolus. The second injection is a

lateral ankle block of the sural nerve, between the

Achilles tendon and the superior border of the lateral

malleolus with the needle pointed perpendicular to

the skin.

Wrist and ankle blocks are usually performed

without significant trauma if 30-gauge needles are

used and if injection pressure is kept slow and steady.

Occasional reflex neuropathy can be encountered as a

rare complication.

Fig. 7. Minor starch-iodine test. Immediately after placing

injections in the right palm. Note how minimal backflow was

achieved in most, but not all, injection sites. (From Glogau

RG. Treating palmar sweatingwith neurotoxins. Semin Cutan

Med Surg 2001;20:105; with permission.)

Injection syringes

The dosage of drug used and injection method has

not been standardized. There are a variety of dosages

reported in the literature [35,38,42–44]. For all areas

to be treated, the author’s technique is to use a dilution

of 2.5 mL per 100 mouse units, dividing the whole

bottle among five Ultrafine II 50-U insulin syringes

(Becton-Dickinson Franklin Lakes, New Jersey).

Each syringe holds 0.5 mL and has the 30-gauge

needle swaged directly into the chamber of the syringe,

eliminating the dead space that occurs with a needle

hub. This minimizes the waste of expensive botulinum

toxin. The syringes are filled by popping the metal cap

and rubber stopper from the bottle and drawing up the

BOTOXR by aspirating with the needle inside the

bottle. This is done to avoid needlessly dulling the 30-

gauge needle passing through the rubber stopper.

Injection technique

Each syringe then holds 0.5 mL of solution that

is 20 U; it is relatively easy to read the graduations on

the syringe and place either 2 U (0.05 mL) or 4 U

(0.1 mL) in each site. With practice, one can generate

about 10 to 12 injections with each syringe.

To treat the axillae, one bottle of 100 U of

BOTOXR is diluted with 2.5 mL of sterile saline

with preservative and then divided into five 0.5-mL

insulin syringes. Following a spiral pattern, 50 U of

BOTOXR are injected in 0.05mL to 0.01mL (2 to 4U)

amounts intradermally raising tiny wheals spaced ap-

proximately 1.5 to 2.0 cm apart, beginning at the pe-

riphery of the hair-bearing skin and circling into the

center of the axillary vault (see Fig. 3). The skin being

rather thin in this area, care is taken to avoid injecting

the material subcutaneously where it could go beyond

the targeted glands. Keeping the needle bevel up and

more parallel to the skin surface and advancing the

needle 2 mm before injecting helps prevent backflow

of the BOTOXR from the injection tract, which

minimizes any loss of the toxin.

The technique for palmar injections is similar, but

injections must be spaced closer together because of

the smaller zone of radial diffusion produced in palmar

skin (Fig. 7). The needle must enter the palmar skin at

an oblique angle.Mechanical needle flanges have been

advocated, which provide a method for assisting the

depth of the injection [38,45]. But if the needle enters

perpendicular to the skin surface, there is usually a

significant amount of backflow of material that leaks

out of the injection tract. Because the volumes of

R.G. Glogau / Dermatol Clin 22 (2004) 177–185 181

BOTOXR are typically small, this backflow signifi-

cantly impacts the effectiveness of the injections.

In axillary skin each injection is placed to produce

a wheal. The palmar skin is comparatively stiffer,

however, and usually a wheal cannot be raised under

any circumstances. It is desirable, however, to pro-

duce a small zone of visible blanching, indicating that

the material is in the deep dermis. One should take

care with each injection to remove the thumb from

the plunger and allow a second or two for the

pressure to normalize before withdrawing the needle

from the skin or else the fluid flows back out the

injection tract directly.

Injection pattern and dosage

A representative sample of the dosage regimens,

pattern of injection, and indications for the botulinum

toxin are presented in Table 1. Injection of the axilla

usually involves placement of 10 to 20 individual

intradermal injections of BOTOXR about 2.5 cm apart

to cover the area of the axillary vault that stains darkly

with Minor starch-iodine test. These can be per-

formed quickly with minimal discomfort and virtually

no sequelae.

Table 1

Sample of dosage regimens and patterns of injections for treatmen

Author

Dilution

mL/100 U

Dose B

otherwi

Odderson, 2002 [57] 2 50 pe

Heckmann 2002 [73] 4 50 pe

Naumann and Hamm, 2002 [52] 4 50 pe

Salmanpoor and Rahmanian, 2002 [58] ? 125 pe

Naumann and Lowe, 2001 [53] 4 50 (3

De Almeida et al, 2001 [38] 2 5 pe

Heckmann et al, 2001 [48] 5 200 (D

Dulguerov et al, 2000 [72] 2 5 pe

Karamfilov et al, 2000 [50] 1 200 pe

Naver et al, 2000 [54] ? 2 pe

Solomon and Hayman, 2000 [44] 2 2–4

Birch et al, 1999 [70] 4 7.5 p

Laccourreye et al, 1999 [74] 2.5 p

Schnider et al, 1999 [59] 33.3 p

Glogau, 1998 [32] 2 2 pe

Heckmann et al, 1998 [49] 400 (D

Naumann et al, 1998 [42] 3

Odderson, 1998 [56] 100 (B

Shelley et al, 1998 [43] 2

Schnider et al, 1997 [35] 20 U

Bushara et al, 1996 [30] 20–50

Cheshire, 1996 [31] 1 U

Drobik et al, 1995 [71] 0.5 U

Sweating of the upper forehead and anterior crown

can be approached in a similar fashion, by injecting 2 to

4UofBOTOXR every 2 cm along the anterior hair line

from sideburn to sideburn, and an additional shorter

row in the anterior crow about 2 cm behind the anterior

hairline, and another horizontal row in the upper third

of the forehead skin. These are also performed easily

without anesthesia and well tolerated (Figs. 8, 9).

In the author’s technique palmar injections are

placed approximately every 1.5 cm across the palmar

surface. On the fingers the volar pad of each phalanx

receives its individual dose. The fingertips usually

receive two: one in mid pad and another at the very

tip, because this is a very problematic sweating area for

people with hyperhidrosis. The dominant or writing

hand also receives an extra row of injections along the

ulnar side, midway between the palm and dorsal

surface, to provide maximum dryness for writing.

Occasionally extra injections can be placed on the

distal dorsal fingers or in the webs depending on the

patient’s complaints. The goal is to place the injections

in a pattern so that diffusion provides overlapping

coverage for the entire palmar surface. One needs to

minimize the number of injections that arrive subcu-

taneously because this increases the likelihood of

diffusion of drug into the intrinsic muscles of the hand.

t of hyperhidrotic conditions with botulinum toxins

OTOXR unless

se labeled

Distance or total

sites per area treated Diagnosis

r axilla 7–10 sites/axilla Axillary

r axilla 2.5 per site Axillary

r axilla 10 per axilla Axillary

r axilla Dysport 10 per axilla Axillary

–5 per site) 10–15 sites/axilla Axillary

r site 1 cm Palmar

ysport) 10 sites/axilla Axillary

r site 1 Frey’s

r axilla Single dose Axillary

r site 4 cm2 Axillary/palm

per site 1 cm Palmar

er site 6 cm2 Frey’s

er site 1 cm2 Frey’s

er axilla 2–3 cm Axillary

r site 1.5 cm Axillary

ysport) 1 cm Axillary

2 cm Axillary, palm

OTOXR) Axillary

1 cm Palmar

6 sites Palmar

Single dose Axillary

1.5 cm Forearm

1 cm Frey’s

Fig. 8. Minor starch-iodine test on upper forehead showing

broad area of excessive sweating.

R.G. Glogau / Dermatol Clin 22 (2004) 177–185182

The total amount of drug used per hand is dependent

on the surface area of the hand. Patients with large shoe

sizes have correspondingly larger hands and require

more injections and larger total dosage. A man with a

size 13 shoe (US) requires up to 150 U per palm,

whereas a woman with a size 6 shoe (US) requires as

little as 75 U to cover the palm. The average dose in the

author’s patients was about 120 U per palm.

Injection of the soles of the feet follows the same

technique and pattern as the palms. The difficulty

arises from the necessity of treating a much larger sur-

face area, so doses usually exceed those of the palms.

Using the Minor starch-iodine test as a guide, and

relying on ankle blocks for anesthesia, the same satis-

factory outcome can be achieved. Duration of effect

seems to be identical to that achieved in the palms.

Fig. 9. Minor starch-iodine test after treatment with 60 U of

BOTOXR. Note that only the upper portion of the forehead

was treated to avoid inactivation of lower frontalis and

secondary disturbance of normal brow elevation. Treatment

also was extended back into the anterior hairline where some

of the most intense staining was visualized before treatment.

Duration of effect

Reported response times for duration of anhidrosis

in the axillae range from 4 months to 10 months in

numerous studies depending on dosage and technique

[1,30,32,42,46–62]. Similar responses are seen in

treatment of forehead sweating [51,63–65].

There is a broader range of responses to palmar

treatment, varying from about 3 months to 12 months

[34,35,42–44,48,54,66]. The average in the author’s

hands is about 6 months. Interestingly, the effect does

not seem as long as it is with axillary hyperhidrosis.

Speculative reasons for this may be the problem with

backflow, the smaller diffusion distance in thicker

palmar skin, the higher number of cholinergic nerve

endings in the palmar skin, or a differential recovery

rate between the nerves of the palm and those in the

axillary skin. On average, patients seem to require

treatment about twice a year to maintain reasonable

control of the palmar sweating. Patients are usually

expecting complete anhidrosis as an end point, at least

with their initial treatment. It may take several treat-

ments before they recognize less than total response as

successful. They are generally unfamiliar with normal

palmar moisture, and at least initially are intolerant of

anything but a totally dry hand as ameasure of success.

With time and release from the mental anguish of

unreliable palmar sweating, many do seem to change

their therapeutic end point goals, and are comfortable

with control as opposed to total ablation of palmar

sweating. This changes the treatment intervals and

dosages, but further work on patient acceptance needs

to be undertaken.

There have been no known reports of compensa-

tory hyperhidrosis from the focal use of botulinum

toxin in the palms or axillae. This is an important

theoretical and practical advantage of the botulinum

toxins in the management of hyperhidrosis. The

downside relates to the fact that the botulinum effect

is neither permanent nor inexpensive. Properly in-

formed patients may elect to pursue the surgical

alternative, however, and referral should be made to

neurosurgical or thoracic surgical practices with ex-

pertise in this method.

Scheduling palmar treatments

Almost every patient who undergoes this treatment

develops a transient period of weakness and instability

R.G. Glogau / Dermatol Clin 22 (2004) 177–185 183

of the lumbrical muscles of the hand, which is pre-

dictably spontaneously reversible [2,34,35,43,

44,54,66]. Such tasks as shoving a button through a

tight button hold, holding heavy objects with chop

sticks, or opening a stuck lock with a key, become

problematic about 5 to 7 days after treatment and

remain so for 3 to 5 weeks. Patients can write, type,

and eat without difficulty, but opening up a tight jar lid,

for example, poses problems for a few weeks.

For this reason, if the patient has ready geographic

access to the treating physician, it may be wise to offer

to stagger the treatments apart. Beginning with the

right hand on the first visit, the author often waits a

couple of weeks and then treats the left hand with any

needed touch up injections of the right hand on the

second visit, and schedules a third visit to touch up the

left hand. By doing so, one can stagger the time line of

weakness to make it easier on the patient. Multiple

visits often are logistically impossible, however, and

the author has no objection to treating both palms

simultaneously as long as the patient is aware of the

implications. One successful strategy has been to offer

to treat the hands separately the first time, but depend-

ing on the muscle weakness, let the patient choose to

schedule future treatments together or staggered

according to their own experience.

Future directions

Further work is needed to optimize the dilution and

units per square centimeter. Introduction of a botuli-

num toxin of the B serotype (Myobloc, Neurobloc,

Elan Pharmaceuticals, Dublin, Ireland) may present an

alternative molecule to the A serotypes currently in

use. No data exist on the behavior of this molecule in

the hyperhidrosis model [67,68]. Work on injection

delivery devices has stimulated some investigators and

further enhancements to the delivery system [38,69]

may optimize the treatment for many patients. Further

investigation of the genetic pattern of the disorder may

give clues to possible therapies. Until then the patients

can benefit from truly life-altering therapy with this

amazing molecule.

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Dermatol Clin 22 (2004) 187–195

Noncosmetic uses of botulinum toxin

Craig Zalvan, MDa, Boris Bentsianov, MDb,c, Omar Gonzalez-Yanes, MDd,Andrew Blitzer, MD, DDSe,f,*

aDepartment of Otolaryngology, New York Medical College, 1055 Saw Mill River Road, Ardsley, NY 10502, USAbDepartment of Otolaryngology, State University of New York–Downstate Medical Center,

450 Clarkson Avenue, Brooklyn, NY 11203, USAcDivision of Laryngology, Voice and Swallowing Disorders, State University of New York–Downstate Medical Center,

450 Clarkson Avenue, Brooklyn, NY 11203, USAdDepartment of Otolaryngology, 525 Roosevelt Avenue, Suite 811, Plaza de les Americas, San Juan, 00918-8058 Puerto Rico

eClinical Otolaryngology, Columbia University, New York, NY, USAfNew York Center for Voice and Swallowing Disorders, 425 West 59th Street, New York, NY 10019, USA

Since the introduction of botulinum toxin as a articles with novel ideas for the use of botulinum

therapeutic tool in the 1970s, the number of uses for

this drug has increased exponentially. The mecha-

nism of action of the toxin is to degrade the SNARE

(soluble NSF attachment protein receptor) proteins

blockading the release of acetylcholine into the neu-

romuscular junction. In many body systems, decrease

of contractility, strength, and tension of certain mus-

cle groups results in improved clinical outcomes.

Applications now include cosmetic, gastroentero-

logic, otolaryngologic, genitourinary, neurologic, and

dermatologic use. In fact, in any situation with

inappropriate or exaggerated muscle contraction,

botulinum toxin can be considered as a potential

treatment. The toxin’s effect on SNARE proteins

may also inhibit the release of pain mediators and

block autonomic nervous system effects such as in

hyperhidrosis. Currently, the Food and Drug Admin-

istration (FDA) has licensed botulinum toxin A

(BOTOX) for the treatment of glabelar lines, bleph-

arospasm, strabismus, hemifacial spasm, cervical

dystonia, and spasticity. With the recent addition of

cosmetic applications to the FDA’s approval list, the

use of botulinum toxin has dramatically increased.

Review of the literature now shows hundreds of

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00020-2

* Corresponding author. Clinical Otolaryngology,

Columbia University, New York, NY, USA.

E-mail address: Ab1136@aol.com (A. Blitzer).

toxin. However, the vast majority of these articles are

anecdotal, with few randomized, controlled, and

blind studies (Box 1).

Neurologic disorders

Perhaps the most widely used neurologic applica-

tion of botulinum toxin is in patients with dystonia.

Patients with cervical dystonia (CD) constitute one of

the largest subgroups of this disorder. Characterized by

abnormal movement and posture of the neck, CD is the

most common form of focal dystonia. Also known as

spastic torticollis, it is characterized by turning and

flexion or extension of the neck. Many patients even-

tually suffer from associated muscular hypertropy. The

majority of patients report a moderate to complete

relief of symptoms often lasting 3 to 4 months after

injection [1]. Similarly, botulinum toxin has been use-

ful in treating oromandibular dystonia [2], lingual dys-

tonia [3], hemifacial spasm [4], and blepharospasm [5].

Benign cramp-fasciculation syndrome is an inher-

ited disease that results in continuous, involuntary,

widespread muscle contractions. Treatment is usually

pharmacologic; however, botulinum toxin has recently

been shown to provide substantial relief. In one study,

injection of botulinum toxin into the calf muscles

and small flexor muscles of the foot resulted in a

markedly decreased symptom severity score, de-

s reserved.

Box 1. Noncosmetic therapeutic uses ofbotulinum toxin

Neuromuscular disordersFocal dystoniasBlepharospasmCervical dystoniaOccupational dystonias (writer’s

cramp)Spasmodic dysphoniaOromandibular dystoniaFacial dystoniaLingual dystoniaMeige’s syndromeBenign cramp - fasciculation syndromeEssential tremorHemifacial spasmMental retardation–cerebral palsySpasticityMyokymiaNeurogenic muscle hypertrophyPalatal myoclonusSpinal myoclonusSynkinesis/VII nerve disordersOphthalmological diseasesEssential blepharospasmStrabismusEsotropiaExotropiaDuanne’s eye-retraction syndromeNystagmusTherapeutic ptosis for corneal

protectionOscillopsiaLaryngeal disordersSpasmodic dysphoniaGranulomaPuberophoniaPosterior glottic stenosisRebalancingStutterTracheoesophageal puncture failureEssential voice tremorVocal ticsCricopharyngeusOromandibular disordersBruxismMasseter hypertrophyTemporomandibular disordersGastrointestinal disordersAchalasiaAnal fissure (chronic)

AnismusIntractable hiccupsSevere constipationAnorectal painGastroparesis (pyloric)Benign anal disordersEsophageal diverticulosisSphincter of OddiSalivary disordersCrocodile tearsSialoceleSialorrheaDroolingParotid fistulaFrey’s syndromePtyalismGenitourinary disordersDetrusor-sphincter dyssynergiaOveractive bladderVaginismusUrinary retentionPain SyndromesBack painHeadacheTensionMigraineCervicogenic painMyofascial painOther disordersApraxia of eyelid openingHemifacial spasmSynkinesis secondary to facial nerve

palsyStuttering with glottal blocksHyperhydrosis (axillary, palmar,

gustatory)Body odor/sweatIntrinsic rhinitisSurgical applicationsPerisurgical and postsurgical muscle

immobilization (aspiration)

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195188

creased fasciculations, and minimal weakening of the

muscle groups. Symptomatic relief was achieved for

3 to 4 months [6].

Writer’s cramp is a focal occupational dystonia that

can prevent a person from writing by causing physical

discomfort and difficulty with control of hand move-

ments. Traditional pharmacologic and surgical therapy

has yielded marginal results. Botulinum toxin injec-

tions into the affected muscle groups of the hand and

wrist have provided significant relief [7]. Although

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195 189

this treatment is not effective for all people, significant

improvement inwriting and reduction of pain is seen in

at least two-thirds of those treated [8].

Another use of botulinum toxin has been in the

treatment of spasticity in stroke patients as well as

patients with mental retardation – cerebral palsy.

Plagued by inability to control contractions of various

muscle groups, these patients often have nonfunctional

limbs and fingers. Often these muscular contractions

can result in permanent contractures, pain, and hyper-

trophy. In one study, decreasing spasticity and improv-

ing upper limb function of young children with

cerebral palsy with normal cognition were found after

injection of the affected muscle groups with botulinum

toxin [9]. Another study addressing poststroke spas-

ticity of the wrist and fingers found greater flexibility,

subjective improvement, and no adverse effects of

botulinum toxin injection [10].

Continuous facial myokymia is an involuntary

undulating movement that spreads across the muscles

of the face. It is often seen in patients with intrinsic

brainstem lesions, particularly inmultiple sclerosis.Al-

though usually lasting only a few weeks, in some

patients symptoms can persist. Botulinum toxin was

used in two of these patients with abrupt and prolonged

cessation of their facial movements [11]. Additionally,

orbicularis oris myokymia is a similar disorder that

frequently occurs in young, otherwise healthy indi-

viduals. These patients are troubled by continuous,

rhythmic movements of the orbicularis muscle. Tradi-

tionally treated with surgical myectomy and muscle

relaxants, botulinum toxin has been shown to be very

effective and well tolerated in these individuals [12].

Botulinum toxin has also been used to decrease the

size of hypertrophiedmuscle in patients with spasticity

and complex repetitive discharges. These injections

effectively decreased the size of the hypertrophied

muscle, helping decrease the pain often associated

with the repetitive movements [13].

Palatal myoclonus is characterized by rhythmic

involuntary movements of the soft palate and occa-

sionally other muscles of the upper aerodigestive tract.

When associated with eye movements, it is called

oculopalatal myoclonus, and a clicking sound is com-

monly heard. Injection of botulinum toxin into the

levator veli palatini and tensor veli palatini muscles

has been shown to weaken the soft palate, prevent the

repetitive movements, and stop the clicking noise [14].

In addition, botulinum toxin therapy has been shown

to be useful in patients with spinal cord injuries and

associated spinal myoclonus [15].

Synkinesis occurring after facial nerve paralysis is

a problem that is difficult to manage. Mass facial

movements, exaggerated response, and inappropriate

segmental movement are commonly seen in patients

who develop synkinesis. Botulinum toxin injection

into the abnormally functioning muscles on the side

of facial paralysis has been shown to decrease the

cosmetic disfigurement synkinesis creates. In addi-

tion, better control of oral and ocular motility helps

the patient to be more functional [16]. Occasionally,

botox is given to the uninvolved side to weaken

the normal musculature and make the bilateral move-

ment symmetrical.

Laryngeal applications

Botulinum toxin has been found useful in the

treatment of laryngopharyngeal disorders [17]. Popu-

larized initially in the treatment of spasmodic dys-

phonia, botulinum toxin can effectively treat a number

of disorders related to dysphagia and dysphonia.

Perhaps the most popular use of botulinum toxin in

the larynx has been with the treatment of spasmodic

dysphonia. Spasmodic dysphonia (SD) is a focal

laryngeal dystonia. Spasmodic dysphonia may further

be classified into abductor or adductor types. The

adductor type of SD is more common and manifests

itself during speaking with a ‘‘strained or strangled’’

voice The abductor type of SD manifests itself during

the speaking with voiceless or hypophonic breaks in

phrases such as ‘‘Harry’s hat.’’ Both types can be

highly debilitating, resulting in social, economic, and

personal hardship. The injections can be given percu-

taneously using electromyographic (EMG) guidance

into the thyroarytenoid muscle or the posterior crico-

arytenoid muscle with doses of 0.1 to 10 U per vocal

cord. [18]. Onset of action is usually within 48 hours

and lasts for an average of 4 months. Up to 90% of

adductor SD patients and up to 70% of abductor SD

patients have significant relief of their symptoms.

Another innovative use in the larynx has been in

the prevention and treatment of granuloma formation.

By injection into the thyroarytenoid muscle with

diffusion to the lateral cricoarytenoid muscle, forceful

closure of the glottis is prevented. In one study, six

patients had resolution of their laryngeal granulomas

after injection of botulinum toxin [19]. In another

study, two patients who failed medical therapy with

proton pump inhibitors showed resolution of their

granulomas after injection of botulinum toxin [20].

Puberophonia, or mutational dysphonia, is a failure

of the vocal pitch to lower in males at puberty. This

disorder is primarily treated with vocal therapy. Botu-

linum toxin has been injected into the cricothyroid

muscle of these patients, resulting in normal vocaliza-

tion after failure of voice therapy [21].

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195190

Posterior glottic stenosis is a challenging problem

encountered by the otolaryngologist. Trauma, surgical

manipulation, reflux, and congenital deformity can

result in fusion of the posterior glottic tissue, aryte-

noids, and posterior vocal folds. The result can range

from aphonia to respiratory distress. The traditional

modality of treatment is surgical, including the use of

the CO2 laser. This approach is often met with failure

and recurrence of the stenosis because of repeated

trauma from vocalization, coughing, and other laryn-

geal movements. To overcome this problem, one

group has used botulinum toxin injections into the

interarytenoid and thyroarytenoid muscles after laser

excision of posterior glottic scar tissue. These patients

experienced complete healing of the interarytenoid

area and resolution of their stenosis [22].

Bilateral vocal fold paralysis or paresis with syn-

kinesis can be a devastating disorder, resulting in res-

piratory insufficiency and often tracheotomy. A unique

approach to alleviating airway obstruction in this

patient group has been the use of botulinum toxin

injection into the thyroarytenoid and lateral cricoary-

tenoid muscles. By weakening these vocal cord adduc-

tors, the abductors can now function with less

opposition and effectively increase the caliber of the

airway [23].

Stuttering is a speech disorder with involuntary,

action-induced utterances of short speech segments.

Many of these patients have interrupted speech due to

intermittent glottal block. Speech therapy has been the

gold standard of treatment. However, some patients

often have difficulty attaining normal speech. Botuli-

num toxin injection into the thyroarytenoid muscle has

been shown to be helpful in alleviating the severity of

stuttering by decreasing the duration of glottal block

and increasing fluency of speech. This therapy is

useful in refractory cases or as an adjunct to traditional

speech therapy [24].

Laryngectomy, most often performed for squa-

mous cell carcinoma, leaves a patient aphonic with

little means of oral communication. Tracheoesopha-

geal puncture (TEP) is a technique in which a catheter

is inserted through the tracheastoma into the esopha-

gus. Inspired air is then redirected into the esophagus,

and the patient is able to create sound in the pharynx

that is then used to propagate speech through the oral

cavity. In some patients, hypertonicity of the crico-

pharyngeus muscle or the upper pharyngoesophageal

segments can result in aphonia after the insertion of the

TEP device. Treatment usually consists of surgical

division of these muscle segments or abandoning the

use of the TEP. Botulinum toxin has been shown to be

very useful in weakening these muscle segments to

allow for continued phonation [25,26].

Essential voice tremor generally affects older indi-

viduals. It is often characterized by an activation-

induced tremor with a frequency of 3 to 7 Hz. Voicing

is marked by decreased fluency, voice breaks, and

occasional voice arrests. Tremor is commonly seen in

patients with a variety of neurologic disorders, such as

Parkinson’s disease, dystonia, and cerebellar disor-

ders. Voice therapy has provided some relief but often

with limited success. Recently, botulinum toxin injec-

tions into the thyroarytenoid or sternothyroid muscles

have resulted in modest improvement in voicing.

Identification of tremor is confirmed by EMG and

used to guide the injection into the appropriate mus-

culature. In some cases, extralaryngeal muscular trem-

or can contribute to the vocal tremor [27].

Vocal tics, a common manifestation of Gilles de la

Tourette’s syndrome, can be psychologically and so-

cially devastating. The vocal tics are often accompa-

nied by repetitive tics of the muscles of the head and

neck. Vocal tics can include simple and complex utter-

ances, grunting, loud talking, and coprolalia. Treat-

ment is traditionally a combination of psychotropic

medication and behavioral therapy. Recently a number

of patients have found relief with botulinum toxin

injections into the thyroarytenoid muscle. Although

not completely understood, a decrease in vocal tics,

outbreaks, and grunting has been demonstrated [28].

Cricopharyngeal dysfunction can be a debilitating

and painful disorder resulting in severe dysphagia.

Patients typically have increased tone to the cricopha-

ryngeal muscle with inability to relax the upper esoph-

ageal sphincter during a swallow. These patients can

have severe pain from cricopharyngeal spasm, aspira-

tion secondary to pooling of hypopharyngeal contents,

and malnutrition. Past treatments have included

mechanical dilation and endoscopic as well as trans-

cervical cricopharyngeal myotomy. Recent reports in

the literature indicate that botulinum toxin treatment

of the cricopharyngeal muscle may be efficacious

[29]. The injection of this muscle may be accom-

plished endoscopically or percutaneously under

EMG guidance.

Pain syndromes

Over the past decade, botulinum toxin has been

found to be very useful in reducing a variety of pain

syndromes. The exact mechanism of this action is

unknown; however, the effect appears to be mediated

by both a decrease in muscular tension and a central

modulation of the afferent pathways. There is evidence

that the effect on the SNARE proteins also decreases

the release of pain mediators such as substance P,

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195 191

GCRP, and glutamate. Research to understand this

mechanism is currently underway.

Another common disorder affecting millions of

patients yearly is headache. Reduction in headache

complaints was noted incidentally during a clinical

trial of botulinum toxin injections for cosmetic use.Mi-

graine headaches have traditionally been treated with

pharmacologic means. A recent study demonstrated

that botulinum toxin injections in the glabelar, tempo-

ral, frontal, or suboccipital regions of the head and

neck can provide a moderate to complete reduction of

migraine symptoms in up to 90% of patients treated

[30]. Another study addressed the use of botulinum

toxin for prophylaxis against migraine headaches. The

results of this double-blind, randomized, controlled

study demonstrated that there were significantly fewer

migraine attacks per month, a decreased severity of

migraine pain and discomfort, a decreased usage of

migraine medications, and reduced incidence of asso-

ciated vomiting [31].

Low back pain is a ubiquitous problem affecting

the middle-aged and elderly populations. Discom-

fort, disability, and financial hardships are often the

outcome of this disorder. Recently, botulinum toxin

injected into the paravertebral lumbar area has been

shown to provide up to 73% of patients with a

greater than 50% reduction in their pain and discom-

fort with no adverse affects. These patients enjoyed

decreased disability and improved function in their

daily lives [32].

Botulinum toxin has also been used to treat head-

ache of musculoskeletal origin. These cervicogenic

headaches are usually associatedwith significant strain

and discomfort along the neck, back, and shoulders,

frequently associated with decreased range of motion.

In a randomized, controlled study, botulinum toxin

injections into affected muscle groups demonstrated a

significant reduction in pain and a greater increase in

range of motion than did placebo injection [33].

Ophthalmologic disorders

Strabismus was the first disorder treated by Alan

Scott with BOTOX. Strabismus or misalignment of the

eyes can have the presentation of exotropia or esotro-

pia. Injections of BOTOX into the extraocular muscles

or at the retrobulbar space improved conjugate gaze

and vision [34–37]. Technical considerations such as

inadvertent ptosis, diffusion into surrounding muscles,

and compliance are greater issues in children, limiting

the use of BOTOX in this patient group [38]. Corneal

protection is of paramount importance in the healing

process of patients with corneal epithelial defect.

BOTOX has been reported to promote healing by

causing protective temporary ptosis [39]. Corneal

protection and symptomatic relief in patients with

severe dry eyes have been achieved by injecting the

medial portion of the lower eyelid and reducing lacri-

mal drainage [40].

Essential blepharospasm is a focal dystonia of the

orbicularis oculi muscles. Management algorithms

now incorporate botulinum toxin injections and lim-

ited myectomy as first-line treatment, reserving com-

plete myectomy for BOTOX failures [41]. Even with

a full myectomy, patients who were undergoing

BOTOX before surgery may need to continue injec-

tions after surgery [42,43].

Duane retraction syndrome is a congenital disorder

that affects horizontal or vertical eye movements,

resulting in restriction of the affected eye. Standard

management, when indicated, involves surgery, but

BOTOX can be used to lessen the restrictive changes

of the medial rectus muscle [44]. Nystagmus or invol-

untary, rapid, rhythmic movement of the eye can be

congenital or acquired. Botulinum toxin injections into

the medial or lateral rectus muscles or retrobulbar

space improve visual acuity in patients with acquired

nystagmus [45–48]. Furthermore, patients with oscil-

lopsia [49] and congenital nystagmus [34] also bene-

fited from injections.

Salivary disorders

Hyperlacrimation due to gustatory lacrimation,

best known as ‘‘crocodile tears,’’ is secondary to

aberrant regeneration of seventh nerve fibers. BOTOX

injection into the lacrimal gland has been used suc-

cessfully for this application [50]. Facial hyperhidrosis

due to gustatory sweating or Frey’s syndrome is

secondary to aberrant regenerated parasympathetic

fibers of the auriculotemporal nerve, which inappro-

priately reinnervate sweat glands of the skin. Intrader-

mal BOTOX injection has been used to decrease sweat

production significantly for a period of 6 months to

2 years [51–53]. Botulinum toxin injections directly

into the salivary gland or into the salivary duct can be

used effectively to treat sialoceles [54] or to improve

sialorrhea [55,56]. Postparotidectomy salivary fistulas

can also be controlled with decreased salivary produc-

tion after BOTOX injection [57]

Genitourinary disorders

Urinary retention due to detrusor sphincter dys-

synergia can be seen in patients with spinal cord injury,

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195192

multiple sclerosis, and other voiding dysfunctions.

Transperineal BOTOX injections can improve clinical

symptoms and urethral hypertonia in this population

[58,59]. Patients who are on maximal doses of anti-

cholinergic medication and perform self-catheteriza-

tion receive the greatest benefit from the injections,

which may last up to 9 months [60]. Botulinum toxin

injections of the anterior vaginal wall muscles have

also been used to treat vaginismus, which is a form of

CNS dysfunction noted by inappropriate vaginal,

periannal, and levator ani muscle spasm that prevents

penile penetration during intercourse and can affect

one in 200 women [61].

Oromandibular disorders

Overall botulinum toxin has been reported to

provide relief in f70% of patients with oromandib-

ular dystonias. These hyperfunctional movements of

the mandible can manifest as a jaw-opening dystonia,

in which toxin injection into the anterior digastric and

lateral or external pterygoid muscles may provide

relief [62]. More commonly hyperfunctional move-

ment of the mandible creates the spectrum of symp-

toms associated with jaw-closing dystonias. Bruxism

is a condition in which patients audibly grind their

teeth, wearing down tooth enamel and creating dif-

ficulty with speech, swallowing, and mastication.

This condition can be successfully treated with botu-

linum toxin injection into bilateral masseter, tempo-

ralis, and internal pterygoid muscles [63]. Injection

of the masseter muscle in patients with masseter

muscle hypertrophy has been effective in symptom-

atic improvement and reduction of muscle bulk up to

30% [64].

There has been great excitement with the use of

botulinum toxin to treat the spectrum of temporo-

mandibular disorders (TMD) of the face and jaw.

Early results have demonstrated significant improve-

ment in pain, overall function, mouth opening, and

decreased tenderness [65]. Multicenter, randomized

studies are currently underway to confirm these

promising results in this difficult patient group.

Gastrointestinal disorders

Uses of botulinum toxin outside the head and neck

region are also gaining popularity. Treatment of the

lower esophageal sphincter in patients with achalasia

has shown success rates of 70% [66,67]. Classically,

surgical myotomy has been the treatment of choice in

patients with nonhealing anal fissures. In chronic anal

fissures, injections of toxin into the internal anal

sphincter and below the fissure have been shown to

decrease anal pain, bleeding, and defactory difficulty

without permanent effects on anal incontinence previ-

ously seen with surgery [68,69]. Botulinum toxin has

also shown early success in the treatment of chronic

constipation [70,71], anorectal pain [72], and anismus

[73] through the injection of selected muscle groups

within the perineum.

Botulinum toxin injection into the pylorus in

patients with idiopathic and diabetic gatroparesis has

been shown to improve gastric emptying and associ-

ated postprandial symptoms [74,75]. Endoscopic in-

jection of botulinum toxin into the papilla of vater has

been proven safe and effective in relief of symptoms in

patients with sphincter of Oddi dysfunction. These

early studies also suggest that toxin may have a role in

predicting which patients will derive long-term benefit

from endoscopic sphincterotomy [76,77].

Botulinum toxin may also prove efficacious in the

treatment of esophageal diverticulosis [78] and has

been suggested for use in the debilitating condition of

intractable hiccups.

Miscellaneous disorders

Patients with autonomic disorders such as hyper-

hidrosis have shown excellent results with botulinum

toxin injection. Use of toxin in the axillary region has

demonstrated relatively complete anhidrosis for peri-

ods of 4 to 7 months [79,80]. Toxin has shown similar

success rates in palmer and gustatory hyperhidrosis

[81]. Another promising use for toxin lies in its ability

to block intrinsic rhinitis. Early animal work in this

field has been promising [82,83], and randomized

human trials are in progress to address this common

disorder. Toxin may also have a use in patients with

pathologic body sweating and odor disorders [84].

Botulinum use has also improved facial function in

patients with synkinesis occurring after idiopathic,

traumatic, and iatrogenic facial nerve injury [85].

Summary

In conclusion, botulinum toxin usage over the past

2 to 3 decades has expanded exponentially. Almost

every discipline in medicine has found some thera-

peutic use for this toxin. Botulinum toxin has been

shown to be safe, effective, and relatively easy to

administer with proper training.

C. Zalvan et al / Dermatol Clin 22 (2004) 187–195 193

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Dermatol Clin 22 (2004) 197–205

Complications with the use of botulinum toxin

Arnold W. Klein, MD

Department of Dermatology, David Geffen School of Medicine at UCLA, 435 Roxbury Drive, Suite 204,

Beverly Hills, CA 90210, USA

The treatment of hyperfunctional facial lines with affected neuromuscular junction, causing muscular

botulinum A exotoxin injection is safe, effective, and

without serious side effects. Properly used, the inci-

dence of complications is low and their severity mild.

Millions of individual clinical doses have been de-

livered without major complications. Indeed, cos-

metic use of botulinum A exotoxin has become

routine within dermatology. Initiated during the

1980s, and refined by leaders in dermatologic surgery

during the past decade [1–5], botulinum toxin injec-

tions have become commonplace.

The bacterium Clostridium botulinum has eight

serotypes, which produce seven serologically distinct

exotoxins. With lethal doses approximating 10�9 g/

kg body weight, these neurotoxins represent some

of the most toxic naturally occurring substances [6].

Not all, however, are associated with botulism in

humans. Although the different serotypes are struc-

turally and functionally similar, specific differences

in neuronal acceptor binding sites, intracellular en-

zymatic sites, and species sensitivities suggest that

each serotype is its own unique pharmacologic entity.

Neutralizing antibodies developed against one sero-

type have not been reported to block the biologic

activity of another serotype [7].

Although the intracellular targets of the toxins

are variable, they all ultimately prevent release of

membrane-bound acetylcholine at the neuromuscular

junction of striated muscles and produce chemical

denervation and paralysis of the muscles [8]. This

chemical denervation is effective for both striated

muscle and eccrine glands. This action may not be

complete for 2 weeks and effectively destroys the

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00122-0

E-mail address: awkmd1@aol.com

paralysis. There is an ongoing turnover of neuromus-

cular junctions, however, such that muscular function

begins to return at approximately 3 months and is

usually complete by 6 months.

Botulinum toxins exist as large protein complexes

consisting of the neurotoxin moiety (approximately

150 kd) and one or more nontoxic proteins, which

are stabilized through noncovalent bonds and that

function to protect the toxin molecule [9]. Botulinum

toxin type B serotype associates with the nontoxic

proteins to form a complex with a total molecular

weight of approximately 700 kd, whereas the type A

complex is estimated to be approximately 900 kd

[10]. These large botulinum toxin complexes are

most stable in the pH range of 5 to 7 [11]. At pH

values above 7, the protein subunits dissociate [12].

The mode of measuring strength of this toxin is

paralytic activity in the mouse. One unit is defined as

that amount of the toxin that kills 50% (LD50) of a

standardized mouse model when injected intraperito-

neally. This is affected by many factors: strain of

mouse, housing conditions, and so forth. Theoretically,

specific activity can be reduced by the presence

of contaminating proteins or inactive, aggregated

toxin that may have been carried through in the

purification procedures [13].

The peripheral blockade of neuromuscular activ-

ity causes muscular weakness, which produces the

therapeutic effect. There has been no evidence to

suggest any permanent degeneration or atrophy of

muscles in those patients treated for dystonic or

spastic disorders who have been injected with high-

dose, repetitive injections of botulinum toxin over

an extended period. Muscle biopsies that were taken

from patients after injections of botulinum toxin type

A two to five times those used for aesthetic improve-

s reserved.

A.W. Klein / Dermatol Clin 22 (2004) 197–205198

ment failed to show any long- term evidence of

permanent degeneration or atrophy [14].

Purified toxin complexes have found a niche in

the treatment of clinical disorders involving muscle

hyperactivity. Botox (Allergan, Irvine, CA) is a toxin

type A approved for use in the United States (for

treatment of cervical dystonia, blepharospasm, and

glabellar lines) and Dysport (Speywood Pharmaceuti-

cals, London, United Kingdom) is also botulinum

toxin type A but is not approved in the United States.

Dysport is primarily used in Europe. It should be

noted that all doses in this article are of Botox unless

otherwise stated. A highly concentrated type B toxin

(Myobloc) developed by Athena Neurosciences (Fos-

ter City, CA) and manufactured by Elan Pharmaceuti-

cals (San Francisco, CA) is approved by the Food and

Drug Administration (FDA) for use in the treatment

of cervical dystonia [15].

Conditions caused by muscle spasms

Local injections of botulinum toxin type A (Botox)

directly into excessively contracting muscles have

been successful in treating dystonia, spasticity, and

other conditions characterized by inappropriate mus-

cle spasm [16,17]. Botox is considered a safe therapy

for these inappropriate muscle spasms and is gener-

ally well tolerated, with adverse effects being typi-

cally self-limited [18].

Effects of a localized injection of botulinum toxin

to nearby or adjacent muscles are believed to be a

result of local diffusion of toxin to that muscle

(eg, ptosis following facial injections) [19]. There is

an area of denervation associated with each point

of injection because of toxin spread of about 2.5 to

3 cm. Although there are reversible and, rarely,

irreversible histologic changes in muscles that are

denervated after Botox treatment, there have been no

irreversible clinical effects reported. There have been

few reports of clinically relevant paresis in muscles

distant from the site of injection. Subclinical effects,

however, such as increased jitter and changes in the

single fiber electromyography (EMG), have been

described [20]. The clinical significance and duration

of this effect have yet to be determined [21]. Gener-

alized reactions that have idiosyncratically occurred

include nausea, fatigue, malaise, flulike symptoms,

and rashes at sites distant from the injection. A report

documenting three cases of generalized muscular

weakness associated with the use of botulinum toxin

type A (Dysport) in patients with dystonia reinforces

the concern about the possible spread of botuli-

num toxin– induced effects [22]. There has been a

single reported case of systemic spread of botulinum

toxin A. The patient had one set of injections for

blepharospasm. After the second set, the patient

immediately went into acute myasthenic crisis. This

was a motor end plate problem. Botox should not

be used in any patient with motor neuron disease.

The main complications of treatment of strabis-

mus with botulinum toxin are ptosis and vertical

deviations [23–25]. Rare instances of ciliary ganglion

injury, retrobulbar hemorrhage, and scleral perfora-

tion have been reported [25].

Transient ptosis, tearing, and dry eye are the most

frequently encountered complications with the use

of botulinum toxin in the treatment of blepharo-

spasm, hemifacial spasm, and Meige’s syndrome.

Diplopia and facial weakness are seen more rarely.

Resistance to botulinum toxin

The possibility of antibody production with result-

ing immunoresistance has always been a concern

with the use of Botox [26]. Hypersensitivity reactions

to the injection of the substance do not occur. The

only consequence is that Botox no longer is effective

as a treatment. With the original Allergan batch [27],

it was recommended that not greater than 100 U be

used at treatment sessions that occur at not less than

monthly intervals. Antigenicity of a foreign material,

however, is almost uniformly proportional to protein

load and the vastly decreased amount of protein

present in the currently used batches of Botox may

allow the application of larger doses of the product

per treatment session without fear of immunogenicity.

Indeed, animal studies have supported the decreased

formation of neutralizing antibodies with these new

batches [28]. Prevalence of Botox resistance is less

than 5% [29] and is associated with dose and fre-

quency of treatment sessions but not by duration of

overall treatment regimen [30].

The intramuscular injection of botulinum toxin

type A into affected muscles is used as therapy for

the treatment of cervical dystonia. After repeated use,

however, some patients receiving high doses, as are

often required in cervical dystonia, develop second-

ary resistance to type A therapy, possibly related to

the development of neutralizing antibodies. The inci-

dence of clinical resistance to type A treatment in

cervical dystonia has been estimated to be as high

as 6.5% [31]. Some of these patients have benefited

from different preparations of Botox [32] or from

other types of botulinum toxin [33,34].

Although there have been reports in the literature

of treated patients developing resistance after a

A.W. Klein / Dermatol Clin 22 (2004) 197–205 199

mean cumulative dose of 192 U of Botox [32],

communication with Allergan indicated that only

1% to 2% of treated patients evidenced resistance

(neutralizing antibodies). Furthermore, the company

could not unequivocally say that this was caused by

size or frequency of dose. The factors that predispose

patients to the development of antibodies are un-

known, but experience has shown that the risk is

increased with repetitive dosages above 300 U

[33,34]. It should be noted that most of these data

are based on older batches of Botox that had greater

amounts of protein load than the newer toxin. Dos-

ages for individual sites treated for the purpose of

minimizing hyperfunctional facial lines usually re-

quire no more than 20 to 40 U per site. To further

minimize the dose and increase the accuracy of toxin

placement, an EMG-guided technique can be used.

In regards to frequency of injection sessions,

many authorities using Botox for cosmetic indica-

tions do additional treatment, when indicated,

2 weeks post– initial treatment. With the small doses

(< 100 U) used for almost all cosmetic procedures,

the limitation of injection interval does not seem to

be crucial.

Cosmetic use of botulinum toxin

Facial wrinkles are frequently caused by repeated

muscle contraction. Botulinum A exotoxin can pro-

duce weakness or paralysis of these muscles and

offers a novel approach for the treatment of certain

facial rhytides. Botulinum toxin type A weakens the

overactive underlying muscle contraction, causing a

flattening of the facial skin and an improved cosmetic

appearance [35]. The effect, although temporary, is

extremely popular with patients, has a very low

incidence of side effects, and is a relatively easy

technique to acquire. For these reasons, botulinum

toxin A (Botox) has gained rapid and enthusiastic

acceptance [36,37]. Botulinum toxin injections have

revolutionized the cosmetic approach to rejuvenation

of the aging face.

There have been no long-term adverse effects or

health hazards related to the use of Botox for any

cosmetic indication thus far [38]. Botox treatments

have not been associated with any permanent clinical

effects, although histologically there are reversible

and, rarely, irreversible histologic changes in muscles

that have been injected.

In general, a higher concentration allows for

more accurate placement and greater duration of

effect and fewer side effects. Lower concentrations

encourage the spread of the toxin. One should re-

member that there is an area of denervation associ-

ated with each point of injection because of toxin

spread of about 2.5 to 3 cm. Large dilutions have

also resulted in larger areas of paralysis.

Botulinum toxin works best when delivered into

the muscle belly. By limiting injections to the imme-

diate subcutis, injection-related pain and risk of

bruising is lessened, and effect is maintained. Inject-

ing into the periosteum on the forehead or glabella is

painful. Around the eyes the skin is extremely thin

and injections need not be deep to reach muscle.

Seldom are botulinum injections too superficial be-

cause the toxin easily penetrates muscle and even

fascia. Pre-existing or anatomic redistribution or re-

alignment of underlying musculature can alter the

effects of Botox, and modifications in injection

technique should be made.

Exclusion criteria include pregnancy or active

nursing and pre-existing neuromuscular conditions.

Patients with neuromuscular diseases (myasthenia

gravis, Eaton-Lambert syndrome) are not suitable

candidates for Botox. Women who have inadvertently

been treated with Botox during pregnancy have had

uneventful deliveries, and no teratogenicity has been

attributed to Botox. Nevertheless, Botox is classified

as a pregnancy category C drug.

Sequelae that can occur at any site because of

injection of Botox include pain, edema, erythema,

ecchymosis, headache, and short-term hypesthesia.

Some unwanted effects are idiosyncratic, but sponta-

neously resolving. Upper eyelid swelling after fore-

head injection, lower lid swelling after injection at

this site, bruising at the injection site, mild headache,

and flulike symptoms can persist for several days

to a few weeks after treatment with botulinum toxin

[39]. Ice applied immediately after injection reduces

the pain and the edema and erythema associated with

an intramuscular injection. Ecchymosis can be min-

imized by avoiding aspirin, aspirin-containing prod-

ucts, and nonsteroidal anti-inflammatory agents for

7 days before injection. Although the onset of head-

aches has been initiated with Botox injections, they

are alleviated with standard over-the-counter analge-

sics. It is, however, more common for patients to

report that chronic tension headaches have been

improved following injections of Botox. Pain associ-

ated with injections can be minimized by infusing

slowly with a 30- or 32-gauge needle, by injecting

small volumes of relatively concentrated solutions,

and by reconstituting the toxin in preserved rather

than preservative-free saline (Alam et al, 2002).

New patients should be told of potential undesired

effects, and their low likelihood and essentially

benign nature.

A.W. Klein / Dermatol Clin 22 (2004) 197–205200

There are, admittedly, patients who do not achieve

their desired goal and are able to contract treated

facial musculature. Combining Botox with adjunctive

therapy is often necessary to appropriately address

the aging anatomy. There are also patients who per-

ceive that the Botox was a failure and are dissatisfied.

In one instance, the muscles treated are, in fact, im-

mobilized, but in an attempt to contract their muscles

they recruit adjacent muscles. Although this can

occur anywhere, it is particularly apparent in the

glabellar area. Additionally, some patients do not

recognize the improvement caused by the Botox

and express disappointment as residual nondynamic

rhytides persist. Demonstrating muscle immobility

with a hand-held mirror or before- and after-injection

Polaroid photographs is often necessary to convince

these patients.

All Botox patients are told to stay upright for at

least 4 hours. There is some controversy as to the

necessity of this, but it is a precaution that is used

almost universally. Immediately after injection,

movement of the treated muscles is encouraged so

that the toxin is taken-up by the involved neural

end plates. Patients are to repeat this muscle move-

ment 10 times per hour for the first 90 minutes. After

that the toxin has all been taken-up.

Glabella

The most common complication in treatment of

the glabellar complex is ptosis of the upper eyelid.

Eyelid ptosis is a significant risk if injections are

placed at or under the middle of the eyebrows in the

vicinity of the mid-pupillary line. This is cause by

diffusion of the toxin through the orbital septum,

where it affects the upper eyelid levator muscle. This

can occur as early as 48 hours or as late as 7 to

10 days following injection when the aesthetic effect

is beginning to appear and can persist for 2 to

4 weeks. With proper technique, the ptosis rate is

very close to zero.

Ptosis, should it occur, can be treated with eye-

drops to the affected side. a-Adrenergic agonists

ophthalmic eyedrops apraclonidine 0.5% (Iopidine)

and phenylephrine hydrochloride 2.5% (Neo-

Synephrine) are mydriatic agents. This causes con-

traction of an adrenergic muscle (Muller’s muscle),

which is situated beneath the levator muscle of the

upper eyelid. This treatment causes 1 to 2 mm of

elevation of the eyelid, which is usually sufficient to

make the individual symmetric. The treatment is

symptomatic and 1 to 2 drops three times a day must

be continued until the ptosis resolves [40].

To avoid eyelid ptosis, it is prudent to be con-

servative when treating elderly patients who may

have a reduced or absent orbital septum. Injecting

the Botox accurately and with low volume can also

decrease the risk for ptosis. Increasing the volume

injected increases the spread of the toxin from the

injection site and increases the possibility of affect-

ing unwanted muscles, and decreasing the volume

allows more accurate placement of the toxin. To

avoid ptosis, injections should be 1 cm above the

eyebrow and for more precise intramuscular injec-

tion, EMG guidance can be helpful [35,41].

The site of deposition of the toxin, not the ap-

proach to it, is important. After injection of the pro-

cerus, one should massage this site horizontally

across the upper nasal bridge to massage the toxin

toward the depressor supercilii. Complications have

not followed the massaging of this area. In the

glabellar area, digital pressure at the border of the

supraorbital ridge while injecting the corrugator also

reduces the potential for extravasation of Botox,

avoiding inadvertent weakening of the levator muscle

and resulting eyelid ptosis. It is important that this

injection site be 1 cm above the bony rim because

lower placement of the toxin in this site is the most

likely cause of ptosis.

In Allergan’s multicenter FDA study, ptosis

occurred in 12 (5.4%) of 263 patients, most of whom

were in one center where the injecting physician had

little experience with the technique.

Individuals treated in the glabellar area are more

likely to complain of an inadequate response than

those treated in other areas. The usual cause is

inadequate dosage.

Brow

The most significant complication of treatment

of the frontalis is brow ptosis. Botulinum A exotoxin

should not be injected above the middle brow so as to

avoid brow ptosis. Injection should also be avoided

within 1 cm of the bony superior orbital rim for the

same reason. Botox works best in younger female

patients (20 to 45 years of age). In some older

patients and in some male patients, redundant skin

can be created under the brow (pseudoptosis), so such

patients should be approached with caution. Treat-

ment of the brow depressors may be necessary,

however, after brow ptosis has become manifest.

Lack of expressivity may be caused by injection

of frontalis lateral to the mid-pupillary line. One

should remember that the brow shape can be changed

because of relaxing the major muscle responsible for

A.W. Klein / Dermatol Clin 22 (2004) 197–205 201

elevating the brow. If the patient has a low eyebrow,

treatment of the forehead lines should be avoided,

or limited to that portion of the forehead 4 cm or

more above the brow. The lower 2.5 to 4 cm of the

frontalis muscle moves cephalad to elevate the eye-

brows. Older people use this to raise their eyebrows

to see. One must always cautiously address the lower

frontalis and stay 2 cm above the brow in all

individuals. One should never try to inject the gla-

bella and the entire forehead during the same session.

This invariably produces brow ptosis. The upper half

of the forehead and the frown, however, can be done

at the same time. Not rendering the frontalis muscle

completely immobile and paralyzed but weakened

can achieve the comparable goal of reducing the folds

while maintaining some forehead movement.

In individuals who have significant brow ptosis,

the possible effects of frontalis injection should be

discussed with the individual and injection of the

brow depressors (the glabellar complex) performed.

The brow depressors should also be treated in indi-

viduals with low-set brows or mild brow ptosis.

There is upward diffusion of toxin, which addresses

the lower forehead lines.

Brow elevation is usually achieved during treat-

ment of the glabella or may be necessary to prevent

or correct brow ptosis caused by treatment of hori-

zontal forehead lines (frontalis) and hence unopposed

action of the brow depressors. Chemodenervation

of all the brow depressors, corrugator supercilii,

depressor supercilii, procerus, and orbicularis oculi

(the glabellar complex) with Botox alone (ie, no

surgery) can elevate the brow from 1 to 2 mm [42].

An equally aesthetically unfavorable outcome

is the brow that assumes a quizzical or ‘‘cockeyed’’

appearance [40]. That is, the lateral eyebrows may

arch upward to an excessive extent because of the

unopposed pull of the frontalis. This occurs when the

lateral fibers of the frontalis muscle have not been

appropriately injected. This may be corrected by in-

jecting 3 U about 2 cm above each brow medial to the

temporal fusion line.

Ptosis of the upper eyelid (levator ptosis), al-

though less likely, can also occur. This is secondary

to downward diffusion of the injected material and

often caused by poor technique.

Before injecting the forehead of a patient for the

first time, it may be best to clarify the anatomic

boundaries. The width of the forehead and location

of the temporal fusion line vary from patient to

patient, and botulinum toxin treatment of the fore-

head needs to be individualized. The high-narrow

forehead must be treated differently than the short

and wide forehead.

Crow’s-feet

Reported complications in this area are bruising,

diplopia, ectropion, or a drooping lateral lower eyelid

and an asymmetric smile caused by injection of

zygomaticus major. To avoid these complications,

one should inject at least 1 cm outside the bony orbit

or 1.5 cm lateral to the lateral canthus, and not inject

close to the inferior margin of the zygoma. Just as

it is important not to inject too close to the eye,

injections should not be placed too far below it or too

deep, because the orbicularis oculi are very superfi-

cial muscles. Lip ptosis can occur if botulinum toxin

is delivered below the zygoma and deeply into the

zygomaticus major, an important elevator of the

upper lip and mouth. Paralyzing the zygomaticus

major can cause an appearance similar to a Bell’s

palsy. Resolution is gradual and often slower than

that of toxin-induced eyelid ptosis.

Medial movement of the toxin from the lateral

canthus can result in diplopia caused by lateral rectus

muscle paralysis. Strabismus can also occur. Both

diplopia and strabismus are exceedingly uncommon

side effects. If they manifest, referral to an ophthal-

mologist is imperative for appropriate management.

If a patient has redundant skin, one should be

careful because the skin can fold on the zygomatic

arch, producing an undesirable cosmetic result. Ec-

chymoses have been common in the past when

treating periorbital wrinkles. This can be almost

totally avoided by injecting the Botox in a wheal or

a series of continuous blebs with each injection at

the advancing border of the previous injection to

avoid hitting blood vessels with resultant bruising.

Injection of 2 to 4 U under the eye, especially

when combined with treatment of the crows’ feet, can

increase the aperture of the eye in a cosmetically

pleasing manner. Tissue should be handled gently,

and superficial vessels identified and avoided. Blebs

should be placed immediately under the epidermis

because the periocular muscles are extremely super-

ficial at this site. Injections under the eye must be

approached cautiously and should not be attempted

if the patient exhibits a significant degree of scleral

show pretreatment; if the patient has had signifi-

cant surgery under the eye previously; or if the pa-

tient has a great deal of redundant skin under the eye

as exhibited by a snap test of the lower eyelid (ie, if

the lid does not return to its previous position when

manually pulled down).

Deeper zygomaticus lines often connect to the

lower crow’s feet lines. Treatment of the crow’s feet

can paradoxically worsen the zygomaticus lines be-

cause the redundant cheek skin gravitates downward.

A.W. Klein / Dermatol Clin 22 (2004) 197–205202

If a patient has redundant skin, one should be careful

because the skin can fold on the zygomatic arch,

producing an undesirable cosmetic result.

Nasolabial folds

Some physicians have treated levator labii supe-

rioris alaeque nasi to soften the superomedial part

of the nasolabial fold. They have used relatively low

doses (2 to 3 U of Botox per side) including EMG

localization of the site but report unimpressive re-

sponse. In those individuals who did get softening

of the folds, some showed lengthening of the upper

lip, which of itself is aging. Initially, several nasola-

bial injections were given. Although they reduced the

nasolabial groove, they also diminished the elevation

of the lip for smiling, which was not an acceptable

cosmetic outcome for most patients. This procedure

has mostly been abandoned.

Injecting the lower face and neck

Many of the muscles in the lower central face,

especially those used in facial expression, are also

involved in the functions of the mouth and cheeks.

An asymmetric smile, biting the inside of a flaccid

cheek, or incompetence of the mouth manifest by

drooling and dribbling are possible complications

of the overly enthusiastic use of Botox in the lower

face. Small doses, however, can be used satisfactorily

(eg, into mentalis, nasalis, and levator labii superioris

alaeque nasi). More recently Botox has been used for

depressor anguli oris and upper lip wrinkles.

For the upper lip lines, some injectors are using

small doses of Botox, 1 to 3 U per wrinkle to a total

of two to three wrinkles. They claim surprising

effectiveness in the treatment of this annoying con-

dition. Because of the importance of the competence

of the mouth, however, it is necessary to be extremely

gentle with the Botox, injecting more superficially

rather than deeply. Although techniques vary, it is

imperative to inject small quantities and maintain

symmetric spacing relative to the facial midline.

Failure to adhere to these rules can result in asym-

metry. The mouth may appear lopsided at rest, and

talking and chewing may accentuate this unat-

tractive appearance. Functional deficits may include

inability to sip from a straw, pucker, put on lipstick,

clearly enunciate Ps and Ss, whistle, kiss with pas-

sion, or play a wind or brass instrument. In severe

cases, drooling may be seen.

A common concern is a downturn at the corner of

the mouth producing a dejected appearance. This is

often treated by the use of fillers, such as injectable

collagen. Brandt and Bellman [43] have suggested

that injection of platysma may produce improvement

in this area. Botulinum toxin may also be used to

correct downward curl in the corners of the lip. For

this, injections of 3 U per side are given into the

depressor anguli oris at the jaw edge lateral to the

first fold. Injecting within the obicularis oris causes

unusual lip movement. Some practitioners inject

depressor anguli oris directly to achieve improve-

ment. They maintain that 2 to 3 U of Botox weaken

this muscle and allow the elevators of the corner

of the mouth to act with less opposition. The treat-

ment may be repeated to increase the effect. One must

be extremely cautious using Botox close to the

mouth, however, because of the danger of producing

a flaccid cheek, an incompetent mouth, or an asym-

metric smile.

On the chin, a prominent mentalis muscle can

cause a horizontal crease or a cobblestoned appear-

ance, which may be reduced by a single injection

of 5 to 10 U directly into the point of the chin with

massage. It is important to keep well away from the

mental fold, although this may be softened by the

injection. Injection into the mental fold area easily

can produce an incompetent mouth. Massage after

this injection is important.

Prominent hypertrophic vertical bands and fine

horizontal lines of the neck may develop with the

aging of the underlying platysma muscles. This mus-

cle is large, originating in the upper chest, and inserts

and blends variably with muscles on the mandible,

face, and ultimately the submusculoaponeurotic

system. Botox has been injected into platysma for

some years to alleviate these platysmal bands and

horizontal neck lines. The use of larger doses also to

improve the lower face and perhaps postpone a

surgical rhytidectomy is more controversial. This

technique has not produced any significant compli-

cations but the use of larger doses (75 to 100 U) can

produce weakness of the neck flexors and dysphagia.

In the neck, the platysma muscle bands can be

reduced by a series of Botox injections into the

anterior aspects of the platysma muscle bands. A

total of 21 U of Botox is injected into the offending

platysmal band at four separate sites: 3 U 1 cm below

the mandibular margin and then three injections

of 6 U each spaced 2.5 cm apart along the band.

Usually 2 to 4 bands are injected per treatment

session for a total dose of 42 to 84 U. This technique

has not produced any significant complications, but

the use of larger doses can produce weakness of the

A.W. Klein / Dermatol Clin 22 (2004) 197–205 203

neck flexors and dysphagia. It is advised that no more

than 100 U be injected into these bands in total.

Brandt and Bellman [43] have expanded this

use to treat platysma more widely and with doses

up to 200 U Botox per treatment session. Injection

of large quantities or inadvertent injection or diffu-

sion into the adjacent sternocleidomastoid and

laryngeal muscles can, however, precipitate dyspha-

gia and neck weakness, which is more apparent

when an attempt is made at raising the head from

a supine position. By affecting the strap muscles,

botulinum toxin may cause singers to have diffi-

culty reaching high notes, and doses should be

limited in this case. Severe overtreatment of the

neck can result in patients having trouble holding

their heads erect.

Complications in treating hyperhidrosis

Chronically sweaty palms are uncomfortable and

socially debilitating. Superficial injection of botu-

linum toxin can provide dramatic relief from this

disorder. Injections should be at the level of the

superficial dermis and no deeper. Given the ability

of Botox to diffuse radially in the axillary skin in a

1.5-cm radius, the physician must first identify the

surface area of involvement using the starch-iodine

test. Intercurrent doses of intradermal botulinum

toxin can then be placed spaced at intervals to allow

overlap of the diffusion patterns. This serves to

maximize the paralytic effect on the eccrine units

while minimizing the total dose needed to achieve

dryness. A total dose of 50 U per axilla is normal in

treating axillary hyperhidrosis. In treating palmar

hyperhidrosis, a total dose of 100 U per hand is

common. A degree of weakness in the hands is a

common consequence of this therapy [44]. Because

of the large quantities injected and the proximity of

the small muscles of the hand, undesired outcomes

can also be seen, particularly if the injections are

too deep. Some impairment of fine motor function is

common, and this may occasionally be clinically

significant. Firm gripping with the distal digits and

rotational motions of the whole hand may be difficult.

This weakness is temporary and resolves after a few

weeks. Because of this weakness in grip strength,

however, it is advisable to only treat one hand per

treatment session.

It is also common to have to do touch-ups on

areas of the axillae or palms that are still sweating

after treatment. These touch-ups can be done 2 weeks

after initial treatment.

Treatment of migraine headaches

In a double-blind clinical study of migraine head-

ache treatment conducted by Silberstein et al [45],

there were no reported cases of true eyelid ptosis,

diplopia, facial nerve or expression problems, kera-

topathy, or idiosyncratic or allergic reactions attrib-

utable to Botox treatment. Two subjects reported

transient brow ptosis; other adverse effects were

limited to transient local pain and ecchymosis at the

injection site [45].

In another double-blind clinical study conducted

by Brin et al [46], the 75-U Botox group had a

higher incidence of treatment-related adverse events

than the vehicle group (50% versus 24%, P = .02),

whereas the 25-U Botox and vehicle groups were

similar in adverse event incidence. All adverse

events were transient and included blepharoptosis,

diplopia, and injection site weakness.

Informed consent

In the informed consent, it must be brought to

the patient’s attention that Botox has been approved

by the FDA as a safe and effective therapy since 1989

for use in blepharospasm, strabismus, and hemifa-

cial spasm and since 1992 for glabellar lines. The

National Institutes of Health consensus conference of

1990 also included Botox as safe and effective ther-

apy for the treatment of adductor spasmodic dyspho-

nia, oromandibular dystonia, and cervical dystonia.

The treatment of facial wrinkles other than the gla-

bellar lines is considered an off-label use. Other off-

label uses include the treatment of Meige’s syndrome,

sphincter dysfunction, migraine headaches, hyperhi-

drosis, tremor disorders, and juvenile cerebral palsy

and other spasticity disorders for which patients are

currently receiving benefit from Botox.

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of NeuroBloc (botulinum toxin type B) in type A-

resistant cervical dystonia. Neurology 1999;53:1431.

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toxin therapy, immunologic resistance and problems

with available materials. Neurology 1996;46:26–9.

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anecdotal memoirs. Dermatol Surg 1996;22:757–9.

[36] Blitzer A, Brin MF, et al. Botulinum toxin for the

treatment of hyperfunctional lines of the face. Arch

Otolaryngol Head Neck Surg 1993;119:1018–22.

[37] Carruthers JDA, Carruthers JA. Treatment of glabellar

frown lines with C. botulinum-A exotoxin. J Dermatol

Surg Oncol 1992;18:17–21.

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In: Moore P, editor. Handbook of botulinum toxin treat-

ment. Oxford: Blackwell Science; 1995. p. 16–27.

[39] Alam M, Arndt KA, Dover JS. Severe, intractable

headache following injection with botulinum A exo-

toxin. J Am Acad Dermatol 2002;46(1):62–5.

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Presented at the 25th Annual Clinical and Scientific

Meeting of theASDS. Portland, OR,May 13–17, 1998.

[41] Foster JA, Barnhorst D, Papay F, et al. The use of

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botulinum A toxin to ameliorate facial kinetic frown

lines. Ophthalmology 1996;103:618–22.

[42] Fraenkel AS, Kamer FM. Chemical brow lift. Arch

Otolaryngol Head Neck Surg 1998;124:321–3.

[43] Brandt FS, Bellman B. Cosmetic use of botulinum A

exotoxin for the aging neck. Dermatol Surg 1998;24:

1232–4.

[44] Bushara KO, Jones JW, Park DM, et al. Botulinum

toxin and sweating [abstract].MovDisord 1995;10:391.

[45] Silberstein S, Mathew N, Saper J, et al. Botulinum

toxin type A as a migraine preventive treatment. Head-

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type A (Botox) for migraine: double blind, placebo

controlled, region specific evaluation [poster 1196].

Poster presented at the Headache World 2000. London,

September 3–7, 2000.

Dermatol Clin 22 (2004) 207–211

Myobloc

Timothy Corcoran Flynn, MDa,b,*

aDepartment of Dermatology, University of North Carolina, Chapel Hill, NC 27514, USAbCary Skin Center, PO Box 5129, Cary, NC 27519, USA

Botulinum toxins have been amajor contribution to Themost commonly used botulinum toxins, the type A

the field of cosmetic dermatology. These compounds

improve facial wrinkles in the skin by relaxing over-

active mimetic facial muscles producing a reversible

improvement of the rhytides. Treatment with botuli-

num toxin is a minimally invasive procedure, and is

currently ranked as the number one cosmetic proce-

dure performed in the United States.

All the botulinum toxins are naturally occurring

compounds produced by the bacterium Clostridium

botulinum [1]. There are seven antigenically different

strains of toxin [2]. The human nervous system is

affected by five toxin subtypes: A, B, E, F, and G. All

botulinum toxins are high molecular weight com-

plexes composed of the neurotoxin plus additional

nontoxic proteins.

The toxins affect striated muscle by creating a

chemical denervation that is temporary and reversible

[3]. They act first by binding to specific membrane

receptors on the presynaptic cholinergic neurons. The

toxin is then internalized by endocytosis, and the toxin

acts to prevent the release of acetylcholine from the

inside of the cell. Each of the toxins binds to a specific

binding protein on the cell membrane and has unique

target proteins within the cell [4]. All affect the soluble

N-ethylmaleimide sensitive factor attachment protein

receptor complex. This complex is necessary to allow

the presynaptic motor neuron to release acetylcholine.

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00070-6

Dr. Flynn has served as a consultant to Allergan Incor-

porated and Elan Pharmaceuticals. He has received funding

for research from Elan Pharmaceuticals and unrestricted

grants from Allergan Incorporated. He is a research partici-

pant with Inamed, and holds stock in Allergan Incorporated.

* Cary Skin Center, PO Box 5129, Cary, NC 27519.

E-mail address: flynn@caryskincenter.com

toxins (Botox and Dysport), affect the SNAP-25

protein, whereas the type B toxin (Myobloc) affects

vesicle-associated membrane protein, also known

as ‘‘synaptobrevin.’’ Both type B and type A are anti-

genically distinct.

The product

Myobloc (Elan Pharmaceuticals, SanDiego, CA) is

the commercial formulation of type B botulinum toxin.

Baumann and Black [5] provide a nice review of the

product. Released in the United States in 2000, it has a

Food and Drug Administration approved indication

for the treatment of cervical dystonia. The toxin is a

highly purified liquid formulation prepared by fer-

menting the type B strain of C botulinum. A series of

chromatography and salt precipitations are used to

purify the product [6]. The process does not involve

lyophilization, and it contains very little contaminating

protein or inactive aggregated toxin. This is desirable

because of the theory that extrasuperfluous proteins

could increase the risk for antibody formation.

Myobloc is formulated as slightly acidic liquid with

a pH of 5.6. This ensures that the integrity of the

complex is maintained and that the product is very

stable. At this pH, the complex retains its integrity as

an approximately 700-kd whole complex containing

the active 150-kd toxin. It is interesting to note that

experiments done by Elan have shown that when the

pH was adjusted to a pH of 7.8, complex dissociation

occurred within 12 hours releasing some of the free

toxin [6].

The product may be purchased in multiple-use,

rubber-stopper, aluminum-crimped vials containing

different quantities of product. The sizes are 2500,

s reserved.

T.C. Flynn / Dermatol Clin 22 (2004) 207–211208

5000, and 10,000 U each at a concentration of 5000 U/

mL. Each vial is slightly overfilled [5], so that the

2500-U vial now contains 4100 U (0.82 mL); the

5000-U vial contains 6800 U (1.36 mL); and

the 10,000-U vial contains 12,650 U (2.53 mL).

The long-term stability of Myobloc has been well

documented. The botulinum type B preparation was

stable for more than 30 months when stored at refrig-

erated temperatures and for 9 months when stored at

room temperature. Dilution of the toxin with normal

saline does not result in any loss of total activity [6].

How is Myobloc different than type A toxins?

The use of botulinum toxins in cosmetic dermatol-

ogy should be thought of as a precise surgical place-

ment of a locally acting compound. Botulinum toxins

do diffuse through tissue andmusculature. This has the

beneficial effect of spreading the effect over a certain

radius, and the radius of diffusion must be considered

when selecting injection points. Diffusion can have a

detrimental effect. For example, instances of lid ptosis

are thought to have occurred because of diffusion of

the toxin into the levator palpebrae muscle. Myobloc

has a different diffusion or ‘‘spread’’ than type

A toxins.

In clinical practice, Myobloc is believed to have an

increased radius of diffusion when compared with

Botox. The author’s study [7] compared the direct

effect ofMyobloc versus Botox in the frontalis muscle.

A single blinded paired comparison study injecting

both types of toxin each into one side of the frontalis

muscle was done. A dose of 5 U of Botox was used

compared with 500 U of Myobloc on the contralateral

side in eight volunteers. Intramuscular injections were

placed in the midpupillary line halfway between the

brow and the hairline. Serial controlled photographs of

the patients were taken approximately daily and the

images digitized to map out the area of effect. The area

of effect was calculated and expressed in real centi-

meters squared. In every case the area of diffusion of

Myobloc was greater than that of Botox. These were

clinical data looking at the visible reduction in wrin-

kles and did not involve the use of electromyography.

It is known, however, that the toxins do not affect

all mammals equally. There are some intriguing data

suggesting increased spread of botulinum A over

botulinum B using a monkey hand model [6,8]. In

the studies of Arezzo [8], one muscle in the monkey

hand was injected with either Botox or Myobloc and

muscular activity in other adjacent muscles was

recorded using electromyography. The spread to adja-

cent muscles of botulinum type B could be compared

with botulinum type A. In the monkeys at doses of

both 5 and 25 times the minimal effective electromy-

ography dose, changes in the adjacent musculature

were increased with botulinum type A as compared

with botulinum type B. The differences were statisti-

cally significant. These data suggested that botulinum

type B exhibited a significantly less spread to adjacent

and distant noninjected muscles compared with botu-

linum type A.

The rate of onset of Myobloc is increased over

Botox. The author’s direct comparison study showed

that the rate of onset of Myobloc was slightly faster.

Photographic analysis showed that the rate of onset of

type B toxin preceded type A by approximately 1 day.

Other scientific studies have documented the rate of

onset of Myobloc as just slightly faster than that of

Botox. Matarasso [3] observed this in his study. In

10 patients whose crow’s feet were treated, the average

onset of Myobloc was 2.3 days with average onset of

Botox being 3.7 days. Lowe et al [9] compared

Myobloc with Botox injection in the glabellar com-

plex. The rate of onset of Myobloc was at 2 to 3 days,

whereas the onset for Botox was 3 to 7 days. Sadick

[10] injected the glabella of 39 patients with either

2400 or 3000 U of Myobloc and followed them daily

until onset of action. Most subjects showed improve-

ment within 2 days, and all subjects responded by

day 3.

All experimental findings are consistent with the

clinically observed phenomenon among patients who

use Myobloc that the rate of reduction of wrinkles is

more rapid than with Botox. Certain patients comment

that they like the more complete effect and also

appreciate the quick onset of action.

The duration of effect has not been shown to be

equivalent or longer than that of the type A toxins. It is

important to keep in mind, however, that duration of

effect can be dose dependant. In comparison studies,

Matarasso’s [3] 10 crow’s feet subjects had an average

duration of 6.4 weeks with 750 U of Myobloc, and

12.7 weeks with 15 U of Botox. Baumann et al [11]

studied 20 volunteers in a double-blinded, placebo-

controlled trial using Myobloc. Subjects’ crow’s feet

were injected with 1500 U of Myobloc and photo-

graphed monthly. Investigator assessment of the pho-

tographs showed that theMyobloc began to wear off at

an average of 68 days. Lowe et al [9] in their glabellar

comparison showed a duration of effect of 6 to 8weeks

with the use of 1000 U of Myobloc in the glabellar

complex and duration of 10 to 12 weeks with use of

2000 U. Duration of greater than 16 weeks was seen

when 20 U of Botox was used. Sadick’s [12] publica-

tion using only Myobloc in the glabella showed a

duration of 8 weeks using a total dose of 1800 U. He

T.C. Flynn / Dermatol Clin 22 (2004) 207–211 209

further increased the dose [10] and showed duration of

effect of 9.6 weeks using 2400 U and 10.4 weeks using

3000 U. Sadick’s data show a nice dose versus

duration curve and suggests that higher doses may

produce an increased duration.

The duration of effect has been addressed in animal

studies. In mice, 1 U of Myobloc is equal to 1 U of

Botox. To evaluate duration of effect, mice were

injected with either type A or type B toxin, and digit

abduction score assessed [13]. The duration of effect

was 36 days in mice treated with Botox and 14 days in

mice treated with Myobloc.

Equivalency studies

What is the ratio of equivalency between Myo-

bloc and the other botulinum toxins for use in

cosmesis? It is the opinion of the author that for

wrinkle reduction, the final rate of equivalency is not

yet known. Botulinum toxins affect individual spe-

cies differently. In mice, 1 U of Botox equals 1 U of

Myobloc, but in monkeys there is a ratio of 1:5.

Many cosmetic dermatologists started with a ratio of

1 U of Botox to 50 U of Myobloc. This ratio was

derived from patients suffering from cervical dysto-

nia, in whom doses of 5000 to 10,000 U of Myobloc

were found to be effective [14]. The corresponding

effective dose of Botox was 100 to 300 U [3]. In

practical use for cosmesis, it was quickly found that

this ratio was too low, and many dermatologists

began working with a ratio of 1:100. Many patients

reported that the effect of the product dosed at 1:100

did not last as long as Botox. The data of Sadick

and others suggest that to achieve an equal duration

of effect to that of Botox, a ratio of greater than 1:100

or 1:125 needs to be surpassed. Even if an increased

ratio is used, there are no data to date to show that

Myobloc has an equal or increased duration over that

of Botox.

Other published clinical studies

A study by Ramirez et al [15] documented the

effectiveness in treating facial lines. The glabellar

frown lines, crow’s feet, and forehead wrinkles all

responded to treatment with Myobloc. At the doses

used, the drug significantly improved facial wrinkles

but duration was shorter than expected. All facial

wrinkles had returned to baseline by week 12, and

glabellar lines had returned to baseline by 2 months.

Lowe et al [9] compared doses of 1000 and 2000 U

of Myobloc with 20 U of Botox injected into the

glabellar complex. They observed a more rapid onset

of action with both doses of Myobloc (2 to 3 days) as

comparedwithBotox (3 to 7 days). In duration of effect

of 16 weeks or greater, the duration of the 1000-U dose

was 6 to 8 weeks and the 2000-U dose 10 to 12 weeks.

The study by Baumann et al [11] on crow’s feet

injections using 1500 U of Myobloc has raised inter-

esting questions regarding side effects. In 20Myobloc-

treated subjects, 55% reported flulike symptoms, 45%

reported dry mouth, and 25% reported dry eyes. There

was a peak in influenza activity in the United States

during that time, but this does not account for the dry

mouth or dry eye symptoms.

Using the glabellar frown lines as a model, Flynn,

Carruthers, Carruthers, and Klein have participated in

a phase 1, randomized, double-blind, placebo-con-

trolled, safety and efficacy study sponsored by Elan

Pharmaceuticals. In this study, cohorts of patients

were injected with 250, 500, 1000, 1500, 2500, or

3000 U of Myobloc in the glabellar complex. The

injections were placed in five equally divided doses

in standard sites. An excellent safety profile was

shown with no ptosis or dry mouth reported. Duration

of effect rose proportionately with increasing dose.

All subjects treated with the 3000-U dose of active

drug reported substantial effect at the primary end

point (4 weeks) and persistent efficacy was demon-

strated in some, but not all, of these subjects at

12 weeks. These safety profile and efficacy results

suggest that additional dose groups (eg, 3500 U)

should be studied. The proper dose necessary to give

an equivalent duration obtainable from the type A

toxins needs to be determined.

Alster and Lupton [16] studied the use of botulinum

type B for dynamic glabellar rhytides believed to be

refractory to type A toxin. Their patients were selected

by having shown a less than 50% reduction in con-

traction of the corrugator muscles when injected with

25 U of Botox. Their patients all responded to 2500 U

total glabellar dose with a 78% drop in wrinkle scores

at 1 month. Duration was markedly shorter than

usually seen when 25 U of Botox is injected in the

glabellar complex.

Practical use

Several practical comments regarding the clinical

use of Myobloc are warranted. Because of the pH of

5.6, there is an increased amount of pain noticed with

Myobloc injections compared with Botox, which is

reconstituted to a more physiologic pH. This in-

creased stinging or burning sensation often elicits

T.C. Flynn / Dermatol Clin 22 (2004) 207–211210

comments from patients. All patients have differing

reactions to pain and some have commented that the

increasing pain was a significant ‘‘hurt.’’ Multiple

authors have noted the increased pain with Myobloc

treatment. Baumann [5] has reported that mixing pre-

servative containing normal saline with Myobloc

reduces the pain on injection. The use of topical

anesthetics reduces the pain of the needle stick but

does not completely eliminate the burning sensation

from Myobloc.

Myobloc has a remarkably long half-life when

stored in the refrigerator [6]. This ameliorates the need

for concern about the stability of the product because

no reconstitution is needed and no decrease in effec-

tiveness is seen long-term. Furthermore, the product is

remarkably stable even at room temperature, so should

a vial be left out of the refrigerator overnight, there is

no cause for concern. No decrease in effectiveness

is seen.

The rapid action of Myobloc makes it helpful for

certain situations. Many clinicians have had patients

who present with wrinkles wanting botulinum toxin

and have an important upcoming social event in less

than a week. These patients may be treated with

Myobloc because the patient has a good clinical result

within 3 days.

The effect of Myobloc particularly in the glabella

and the forehead is a very diffuse and uniform effect,

most likely the result of the increased diffusion of

Myobloc over Botox. Baumann [5] has described this

as a ‘‘hard freeze.’’ Although the author favors an

aesthetic result where a significant reduction in mus-

cular effect occurs with some retention of movement

to allow for expression, certain patients desire to have

no muscular movement of the treated areas. These

people often prefer to be treated with Myobloc and

come more often to maintain the ‘‘Myobloc effect.’’

The issue of the side effects of dry mouth and

dysphagia are interesting. These were seen when

Myobloc was used in randomized, double-blind, pla-

cebo-controlled clinical trials for the treatment of

cervical dystonia. It is important to note that doses

ranged from 2500 to 10000 U and that the side effects

increased in higher doses. These side effects were self-

limited and resolved but were reported in up to 16% of

patients [11]. Baumann also noted dry mouth in her

crow’s feet study. The author has not had any patients

report dysphagia or dry mouth when Myobloc has

been used in cosmetic dermatology for treatment of

rhytides or for hyperhidrosis.

The current cost of the product is $185 for the

2500-U vial, $370 for the 5000-U vial, and $740 for

the 10,000-U vial. It may be ordered directly from the

manufacturer. It must be emphasized that the final

doses of Myobloc for cosmesis are not yet fully

known. Many cosmetic dermatologists are now work-

ing at ratios of 1 U of Botox to 125 U of Myobloc. It

is known that duration of effect is dose-dependent,

and the ultimate length of effect depends on the dose

used. Will Myobloc have the same duration of

Botox? Only further use and carefully conducted

studies can tell.

References

[1] Huang W, Foster JA, Rogachefsky AS. Pharmacology

of botulinum toxin. J Am Acad Dermatol 2000;43:

249–59.

[2] Spencer JM. Cosmetic uses of botulinum toxin type B.

Cosmetic Dermatol 2002;15:11–4.

[3] Matarasso SL. Comparison of botulinum types A and B:

a bilateral and double-blind randomized evaluation

in the treatment of canthal rhytides. Dermatol Surg

2003;29:7–13.

[4] Setler P. The biochemistry of botulinum toxin type B.

Neurology 2000;55(suppl 5):22–8.

[5] Baumann L, Black L. Botulinum toxin type B (Myo-

bloc). Dermatol Surg 2003;29:496–500.

[6] Callaway JE, Arezzo JC, Grethlein AJ. Botulinum

toxin type B: an overview of its biochemistry and pre-

clinical pharmacology. Semin Cutan Med Surg 2001;

20:127–36.

[7] Flynn T, Clark R. Botulinum toxin type B (Myobloc)

versus botulinum toxin type A (Botox) frontalis study:

rate of onset and radius of diffusion. Dermatol Surg

2003;29:519–22.

[8] Arezzo JL, Litwals MS, Caputo FA, et al. A compari-

son of the spread of biologic activity of Neurobloc

botulism toxin (type B) and Botox (botulinum toxin

type A) in a monkey model. Mov Disord 2002;15:159.

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Dermatol Clin 22 (2004) 213–219

Dysport

Andrew C. Markey, MD, FRCPa,b,*

aSt. John’s Institute of Dermatology, St. Thomas’ Hospital, London, SE17EH, UKbThe Lister Hospital, Chelsea Bridge Road, London SW1W 8RH, UK

Although the introduction of botulinum toxin A This new formulation named Dysport was produced as

(BTX-A) for medical and cosmetic therapy in the

United States has been well documented [1,2], such

reviews have dealt with the BOTOX product pro-

duced by Allergan Inc., California, USA. In Europe,

however, a different BTX-A product, Dysport, manu-

factured by Ipsen Limited (formerly Speywood Phar-

maceuticals) has been introduced and used over a

similar period of time.

In 1981, Elston working at the National Hospital

for Nervous Diseases, London, pioneered the clinical

use of BTX-A in the UK for patients with blepharo-

spasm and strabismus [3]. Elston sourced the supplies

of toxin from the Centre of Applied Microbiology and

Research (CAMR), Porton Down, which is part of the

government Public Health Laboratory Service in the

UK. The toxin was released by the government to

Elston and other interested clinicians on a clinical trial

basis in a vial containing 50 ng or 2000 mouse U of

BTX-A. Throughout the 1980s, this form of BTX-A

was used for successfully treating focal movement

disorders such as hemifacial spasm, spasmodic torti-

collis, as well as the initial ocular indications [4].

In 1985, Speywood Pharmaceuticals, (now Ipsen

Ltd), formed an agreement with CAMR to commer-

cially market their BTX-A in a new formulation.

CAMR would be responsible for the primary manu-

facture of the BTX-A, and Speywood would carry out

the secondary manufacturing processes of purification

and formulation at its plant in Wrexam, North Wales.

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00022-6

The author has no significant connection with commer-

cial products or companies mentioned in this article.

* The Lister Hospital, Chelsea Bridge Road, London

SW1W 8RH, UK.

E-mail address: markeyoffice@aol.com

a 12.5-ng or 500 BTX-A unit vial (as it is today). In

1989, a formal product license application was sub-

mitted to the regulatory authorities in the UK for the

use of Dysport in treating blepharospasm and hemi-

facial spasm. The product license was granted in 1990,

and Dysport was commercially launched in the UK in

1991. Throughout the 1990s, other licensed indica-

tions for Dysport were approved, including spasmodic

torticollis and pediatric cerebral palsy spasticity. Dys-

port is currently licensed for use in 49 countries

worldwide and for a variety of indications, including

cosmesis in some markets (Brazil and Argentina). The

Inamed Corporation in the USA has recently acquired

the rights to develop, market, and distribute Dysport

for cosmetic indications in the United States, Canada,

and Japan.

Manufacturing

Although both contain BTX-A, Dysport and

BOTOX are subject to their own individual processes

of manufacture and potency assessment: strains of

toxin-producing organisms used in fermentation,

methods of purification, excipients, and formulation.

Such manufacturing and assay differences have a

bearing on potency, diffusion, and antigenicity of

any biologic product, so Dysport and BOTOX should

be regarded as individual BTX-A products with

their own individual characteristics rather than as

generic equivalents.

Dysport is produced via fermentation of the bacte-

rium Clostridium botulinum. The toxin complex is

recovered through a series of steps, including chroma-

tography, precipitation, dialysis, and filtration. The

toxin complex is then dissolved in an aqueous solution

s reserved.

A.C. Markey / Dermatol Clin 22 (2004) 213–219214

of human serum albumin and lactose, after which it is

filtered and freeze-dried. The lactose acts a bulking

agent and allows the product to be seen in the vial as a

small cake of white powder, facilitating reconstitution.

Immunogenicity

An important area for concern in ongoing BTX

therapy is the issue of neutralizing antibody forma-

tion. Factors contributing to antibody formation may

be the quality (purity) and quantity of protein injected

per treatment, the frequency of such injection, the

antigenicity of the injected molecule, the route of

administration (IM, SC), and the genetic predisposi-

tion of the patient to develop antibodies. In the largest

study of its kind [5], looking for neutralizing anti-

bodies in a condition requiring repeat, high-dose

BTX-A injections, 616 patients undergoing long-term

treatment of cervical dystonia using high dose (800+U

per treatment) Dysport, 1.5% to 2.5% of patients

developed neutralizing antibodies to BTX-A but only

after a minimum of six injection sessions spaced

3monthly. Clearly, this is a low rate of treatment fail-

ure due to serum neutralizing antibodies to Dysport,

even in a repeat high dosage setting. Greater frequency

of injections and high mean dose per treatment were a

feature of the antibody-positive group, but neither

total cumulative Dysport dose nor total number of

treatment sessions correlated with a higher risk. Inter-

estingly, some patients who became nonresponders

did not have neutralizing antibodies, and the incidence

of neutralizing antibodies in patients who continued to

respond was not documented. There is evidence that

where formed, neutralizing antibodies to BTX-A

may eventually decrease (over years) when BTX-A

therapy is withdrawn [6] and that some treatment

failures can be overcome by increasing doses of the

BTX-A toxin without further increasing neutralizing

antibodies [7]. There are no prospective antibody

studies with Dysport.

In the Dysport manufacturing specification, the

protein content per 500 U Dysport vial is noted at

12.5 ng, though according to the company this is a

manufacturing upper limit and current batches are

claimed to be significantly lower than this. BOTOX

was reformulated several years ago and now has a

protein content per 100 U BOTOX vial of approxi-

mately 5 ng. Clearly, total protein delivered per treat-

ment will depend on dosage of the particular BTX-A

molecule used and the protein content of the indi-

vidual manufacturing batch. There are no published

antibody studies comparing Dysport with the cur-

rently formulated BOTOX.

Dilution

As with BOTOX (but unlike NeuroBloc/MyoBloc,

which is provided as a solution), Dysport is provided

in a glass vial as an air-dried powder, though unlike

BOTOX, the Dysport powder is clearly visible in the

vial. The air-dried powder allows for various dilutions

of Dysport to meet clinical requirements. As the

Dysport vial does not contain a vacuum, the insertion

of a needle before introducing the diluent via a

second, separate needle will facilitate the introduction

of the saline—this consideration is irrelevant if the

bung is removed before preparation. Dilution is with

normal saline; quoted volumes of diluent recom-

mended in the product package insert are 1.0 to

2.5cc saline per vial, however, this can be varied to

suit requirements. Interestingly, biologic availability

of Dysport has been reported to be enhanced by

supplementing with albumin, lowering its concentra-

tion and increasing injection volume [8,9].

Biologic activity

As described earlier, individual preparations of

BTX-A will have product-specific unit efficacy, and

the units of Dysport and BOTOX are not, therefore,

directly comparable. Using different bioassay tech-

niques and in vivo animal diffusionmodels to establish

unit equivalence, a range of values of 1 U BOTOX to 2

to 4 U Dysport has been described [10–12]. Extra-

polation of these laboratory and animal data to evolve a

fixed conversion ratio between the products for use

clinically assumes a linear relationship with increasing

dosage between the two BTX-A products, which may

not necessarily be the case. However, in clinical

practice, conversion ratios of units of BOTOX to

Dysport of 1:4 [13–15] or increasingly recently of

1:3 [16–20] have been widely reported and discussed,

though there have been reports outside of these com-

monly used ratios ranging from 1:1 [21] to 1:6 [22].

Practitioners are best advised to be cognizant of

publications using their preferred BTX-A product

in specific clinical situations and the documented

doses used.

Clinical results

Noncosmetic usage

Because of the extensive use of Dysport by Euro-

pean neurologists and other nonaesthetic practi-

tioners, much of the early experience relating to

A.C. Markey / Dermatol Clin 22 (2004) 213–219 215

efficacy and safety of the product is contained in

noncosmetic literature.

Striated and smooth muscle disorders

There is an extensive literature documenting the

use of Dysport in the successful treatment of a number

of disorders involving striated and smooth muscle,

including blepharospasm, cervical dystonia, torticol-

lis, and hemifacial spasm [7,16–18,23–35]. Also,

stroke-associated spasticity [36–44], neurologic dis-

ease associated spasticity [45,46], pediatric cerebral

palsy [26,47–50], brachial plexus birth palsy [51,52],

writer’s cramp [53,54], and dystonic clenched fist [55]

have all been reported to have responded with grati-

fying outcomes. Treatment of sphincteric and smooth-

muscle disorders, such as achalasia [56–59], laryngeal

dysphonia [60,61], laryngeal aspiration [62,63] and

detrusor-sphincter dyssynergia [64,65], has been

documented. Positive impact in headache and mi-

graine is likewise well established [66], though not

always with universal success [67]. Throughout these

studies, positive clinical outcomes with a good safety

profile have been routinely observed

Hyperhidrosis

In 1996, as part of a report on sweat reduction after

localized injections of BTX-A, Bushara et al [68]

documented Dysport producing relative anhidrosis at

the site of subcutaneous injection into the skin of the

dorsum of the hand, whereas BOTOX was used

successfully, in the same study, to treat the axillae.

Shortly afterward, Schneider reported a double-blind,

placebo-controlled study in 11 patients using Dysport

(120 U per palm) for treating palmar hyperhidrosis

[69] with an excellent outcome and low incidence of

side effects (mainly minor weakness of selected small

muscles of the hands in three patients). Heckmann et

al then initially reported in the German [70] and

English literature [71] dramatic reductions in sweat

production in patients with primary axillary hyperhi-

drosis after Dysport therapy. The initial, open study

was followed by a multicenter, double-blind, placebo-

controlled, crossover study of 145 patients with pri-

mary axillary hyperhidrosis [72]. Sweat production

was objectively quantified by gravimetry. All patients

had been unresponsive to the usual topical therapies

and had pretreatment sweat output >50 mg per

minute. In the first part of the study, 200 U Dysport

were injected into one axilla, with placebo placed in

the contralateral axilla. Two weeks later, the treatment

codes were broken and the axilla that had previously

received the placebo received a lower 100 U Dysport

treatment. Mean pretreatment sweat production

was 192 mg per minute, and at 2 weeks in the original

200-U Dysport– treated axilla, this was reduced to

24 mg per minute, with the placebo axilla at 144 mg

per minute. In the later axilla, after the 100-U Dysport

injection, sweating was reduced to 32 mg per minute.

At 24 weeks after the 100-U injection (26 weeks after

the 200-U injection), sweating was still reduced from

baseline at 67 mg per minute in the 200-U–treated

axilla and 65 mg per minute in the 100-U–treated

axilla. All these reductions in sweat production were

highly significant statistically and led to an almost

universal (98%) recommendation of the treatment by

the patients in the study.

Meanwhile, Schneider et al who had initially

reported on palmar hyperhidrosis [69] documented

the group’s experience in treating axillary hyperhi-

drosis with Dysport [73] as part of a double-blind,

randomized trial of 13 patients. A 200-U injection of

Dysport in a single axilla was found to produce a

dramatic reduction in sweating as measured by digi-

tized, ninhydrin-stained sheets. In a subsequent open

label study of 61 patients [74] undergoing repeat

intradermal injections of Dysport for more than

3 years with either axillary (400 U total to axillae

pretreatment) or palmar hyperhidrosis (460 U total to

palms per treatment), repeat injections were found to

be as effective as initial injections in reducing sweat

production. Four weeks after initial injections, mean

sweat production had fallen by 71% compared with

baseline (in axillae) and 42% (in palms) with a mean

time interval between treatments of 34 weeks (axil-

lary hyperhidrosis) and 25 weeks (palmar hyperhi-

drosis). Again, nine of the 21 patients treated for

palmar hyperhidrosis complained of minor hand

muscle weakness.

Whatling and Collin recently reported their expe-

rience in treating 16 patients with axillary hyperhi-

drosis using 240 U of Dysport per axillae with a mean

response duration of 9 months [75].

In a case report of prolonged muscle cramps

presumed to be caused by electrolyte imbalance sec-

ondary to axillary hyperhidrosis, Dysport injections

not only resolved the hyperhidrosis, but also gave

long-lasting relief from the muscle cramps [76].

In idiopathic craniofacial hyperhidrosis, Dysport

has been reported to dramatically decrease facial

sweating with only a minor impact on frowning being

noted by patients [77].

To better quantify the effects of BTX-A on reduc-

tion in sweat volumes, a number of methods of

measurement have been used, and most recently the

sudomotor axon reflex test has been described for this

A.C. Markey / Dermatol Clin 22 (2004) 213–219216

purpose [78], although some of the difficulties inher-

ent in the interpretation of sweat reduction studies

have been discussed [79].

Other assorted medical applications

von Lindern et al [80] have described the novel of

use of Dysport injections (500 U) directly into the

parotid gland in situations where a salivary fistula has

arisen due to trauma or a complication from parotid

gland surgery. By interrupting cholinergic salivary

gland innervation, a new noninvasive approach to

salivary gland therapy is possible. Similarly, in gus-

tatory tearing, or hyperlacrimation, Dysport has been

effective in reducing tear output [81].

In thyroid eye disease, patients with eyelid retrac-

tion will often develop overactivity of the accessory

muscles that facilitate eyelid closure, giving rise to a

particular thyroid ‘‘look.’’ In 14 patients, Olver [82]

injected 40 U of Dysport into each corrugator muscle

mass, with or without a similar dose into the procerus

muscle, and produced dramatic softening of the

facies, which lasted 4 to 6 months after each injec-

tion session.

Heckmann et al have recently reported an open

pilot study of Dysport injections in three patients with

lichen simplex in whom all pruritus and visible lesions

cleared with no recurrences over a 4-month period.

They hypothesize an ameliorative effect of the BTX-A

injections on acetylcholine sensitive C-fibers [83].

Certainly, Dysport has been found to have pain-reliev-

ing actions via a number of proposed effects on the

nociceptive pathways [84].

Cosmetic usage

Following on previous reports by the Carruthers

[85,86] who used BOTOX in the treatment of cos-

metically troublesome, movement-associated lines,

Ascher et al [87] in 1995 described their cosmetic

experiences using Dysport in the glabella and crow’s-

feet areas in 19 patients. They introduced the idea of

documenting effectiveness of BTX-A therapy by

using computer analysis of casts of the treated sites.

Patients were followed monthly over a 12-month to

24-month period with significant decreases in wrin-

kling being noted. After each injection, the effects

lasted between 3 and 4 months, with longer periods of

action being noted with repeated injections sessions.

In 1998 Le Louarn [88] used varying concentra-

tions of Dysport and differing injection depths in an

attempt to limit BTX-A diffusion to adjacent muscles,

aiming to reduce the incidence of ptosis and other

unwanted effects on nontarget muscles in aesthetic

treatments, an approach that he later expanded on by

using both Dysport and BOTOX [89]. Lowe reported

his experience [15] using both Dysport and BOTOX

in cosmetic practice and gave treatment guidelines

based on an approximate dose conversion ratio of 1 U

BOTOX: 4 U Dysport. As with BOTOX, Dysport has

also been used in combination with intradermal and

subcutaneous fillers in patients who needed a com-

bination approach to obtain the desired cosmetic

results [90].

A further study [91] of 13 patients undergoing

Dysport treatment for glabellar, crow’s-feet or platys-

mal changes were assessed according to subjective

criteria. Patients received amean dose of 70U (glabella

area, seven injection points), 40 to 60 U (crow’s-feet

area, four to six injection sites), and 80 U (platysma,

eight sites). Most patients were satisfied with their

treatment; median score for treatment efficacy was 2

(where 1 equaled totally satisfied and 5 equaled not at

all satisfied), although four of 11 patients treated in the

glabella reported temporary headache.

Heckmann and Schon-Hupka [92] have used

digital image analysis of pretreatment and post-treat-

ment photographs to quantify the effects of treatment

with Dysport in the glabella and forehead areas. This

approach to quantification has demonstrated a longer

time course in both onset and wearing off of BTX-A

effects than previously reported and has emphasized

the contribution of tissue elasticity (which declines

with age) to smoothening of facial expression lines.

Summary

Since the commercial launch of Dysport in 1991,

after 10 years of clinical studies on its predecessor

formulations, this BTX-A product has shown great

therapeutic promise with a good safety profile and

low incidence of treatment failures. As with all BTX

products, Dysport should not be seen as a generic

equivalent but as a specific product with individual

unit dosing requirements and side effect profiles. Its

role as an important BTX-A molecule looks set to

expand as new indications for botulinum toxin arise,

and as the cosmetic usage of Dysport is approved in

countries outside of South America.

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Dermatol Clin 22 (2004) 221–226

Comparison of botulinum toxins A and B in the treatment

of facial rhytides

Neil S. Sadick, MDa,*, Seth L. Matarasso, MDb

aDepartment of Dermatology, Weill Medical College, Cornell University, 772 Park Avenue, New York, NY 10021, USAbDepartment of Dermatology, University of California School of Medicine, 490 Post Street, Suit 700,

San Francisco, CA 94102, USA

Facial lines and wrinkles are caused bymany varia- of action of botulinum toxin resides in its ability to

bles, including intrinsic aging, photodamage, gravity,

trauma, subcutaneous atrophy, and the activity of

underlying facial muscles. Hyperfunctional facial lines

are the result of the skin pleating when the underlying

muscles contract chronically. These lines can be prob-

lematic to the patient because they can be the earliest

signs of aging and can be misinterpreted as manifes-

tations of negative emotion (ie, anger, anxiety, and

sadness); fatigue; or stress. Historically, treatment has

been aimed at improving the cutaneous defect with soft

tissue augmentation, resurfacing, or facial surgery.

These treatments, however, do not address the under-

lying musculature that causes the lines and can have

prolonged morbidity and high risk potential.

Botulinum toxin injections have become the most

popular aesthetic procedure for both men and women

in the United States [1]. The first reported use of

botulinum toxin for facial rhytides was in 1992 [2].

It was fortuitously observed that there was a loss of

facial wrinkles in patients whose periocular muscles

were injected with botulinum toxin type A for benign

essential blepharospasm. These findings were subse-

quently corroborated by others [3–5]. The mechanism

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/S0733-8635(03)00040-8

At the time this manuscript was developed, Dr. Sadick

and Dr. Matarasso were not consultants for either Elan

Pharmaceuticals or Allergan, Inc. No financial support was

received for any studies involving botulinum toxins A or B.

* Corresponding author.

E-mail address: nssderm@sadickdermatology.com

(N.S. Sadick).

immobilize striated muscles by inhibiting release

of acetylcholine at the neuromuscular junction. In

2002, following substantial evidence from clinical

studies and unparalleled patient acceptance, the Food

and Drug Administration approved Botox for the

temporary treatment of moderate-to-severe glabellar

wrinkles in patients 65 years of age or younger. The

type B serotype of botulinum toxin (Myobloc) has a

similar mechanism of action and was approved by the

Food and Drug Administration in 2000 for the treat-

ment of cervical dystonia [6,7]. Although not currently

approved for cosmetic use, Myobloc has also been

used for off-label purposes with good results.

Pharmacology

Botulinum toxins are produced by the anaerobic

spore-forming bacterium Clostridium botulinum, and

are among the most potent biologic substances found

in nature [8–10]. Seven immunologically distinct

serotypes of botulinum toxin are known to exist, des-

ignated A, B, C, D, E, F, and G. The different serotypes

do not cross-react, and ultimately they have the same

effect at the neuromuscular junction, but subtle dif-

ferences in their molecular weight, biosynthesis, and

site of action may contribute to differences in clini-

cal efficacy.

Botulinum toxins are large protein complexes that

consist of a neurotoxin and other nontoxic proteins that

exert their effect at the neuromuscular junction by

inhibiting release of acetylcholine. The Botox com-

s reserved.

N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221–226222

plex has a total molecular weight of approximately

900 kd, whereas Myobloc is smaller at approximately

700 kd. These toxin complexes are most stable in

slightly acidic conditions (pH 5.7) and dissociate in

alkaline conditions. Within the large complex the

active neurotoxins are synthesized as 150-kd dichain

molecules consisting of a heavy chain (around 100 kd)

and a light chain (around 50 kd) linked by a disulfide

bond [11,12]. The neurotoxicity is a three-step process

that includes neurotoxin binding to specific membrane

receptors on presynaptic cholinergic neurons, toxin-

receptor complex internalization by endocytosis into

nerve terminals, and vesicle lysis with inhibition of

acetylcholine release from inside the cell [13]. The

heavy chain is responsible for irreversible binding of

the toxin to specific acceptors on the neuronal cell

membrane. Each serotype binds to a unique acceptor,

which accounts for a lack of cross-neutralization

among the serotypes.

Following intramuscular injection, botulinum

toxins cause a flaccid muscle paralysis with an onset

of approximately 3 to 7 days. Muscle reanimation re-

covers through terminal sprouting of motor axons and

formation of new motor end plates [14]. The sprouts

grow rapidly, joining to new end plates formed at the

same time along the damaged neuromuscular junction.

After a period of remodeling the new motor end plates

become activated, completely restoring muscle func-

tion. Recovery generally occurs in 3 to 6 months with

reappearance of rhytides, although bulk sprouting and

remodeling may continue for up to 3 years [15].

Reinjection of the muscle is necessary to maintain

clinical effects and produce disuse muscle atrophy.

Immunoresistance

As a protein, botulinum toxin is capable of eliciting

an immune response [16]. Patients can develop neu-

tralizing antibodies that prevent clinical effects. Resist-

ance has been reported in 3% to 5% of patients with

cervical dystonia who were treated with large doses of

botulinum toxin type A (up to 1200 units) [17,18]. In

patients treated for aesthetic purposes that require

significantly lower doses, the risk of developing resist-

ance is low and has not been well-documented.

Because the botulinum toxin serotypes do not cross-

neutralize, patients who become resistant to one sero-

typemay benefit from treatment with another serotype.

The most significant risk factors associated with de-

velopment of antibodies include injection of high

doses of toxin and increased frequency of administra-

tion [17,18].

Formulations

Botox is available in a vacuum-dried vial with

100 units of neurotoxin at a pH of 7 and requires re-

constitution with saline before use. Myobloc is pro-

duced as a ready-to-use liquid formulation with a pH of

5.6 to stabilize the complex. It is available in vials of

2500, 5000, and 10,000 units, each with a concentra-

tion of 5000 units/mL. Each vial is actually overfilled,

containing more type B toxin than is specified on the

label. The toxins are expressed in terms of units, which

refer to biologic activity or potency and not a specific

weight or volume of protein. Specifically, one unit is

defined as the amount of toxin that is lethal in 50% of

female Swiss-Webster mice after intraperitoneal injec-

tion (mouse LD50 bioassay). Because of variations in

the sensitivity of different species to each toxin sero-

type and the potency assay used, however, individu-

alized dose-ranging studies in humans are necessary

for each toxin serotype, and a conversion ratio can be

imprecise [16].

Botox must be stored at or below �5�C before

the toxin is reconstituted with 0.9% saline. It is rec-

ommended that the reconstituted toxin be used as

soon as possible, because loss of potency has been

reported to occur over time [15]. Botox reportedly

tends to be labile, and mechanical disruption and

prolonged storage can inactivate the product. Re-

cently, however, it was found that Botox retains its

efficacy for at least 6 weeks following reconstitution

if stored at 4�C [26]. Myobloc is kept refrigerated at

2�C to 8�C and is stable in this environment for up to

3 years [13]. Clearly, storage and stability are impor-

tant parameters to consider in toxin selection.

Comparison studies

Despite its relatively recent Food and Drug Ad-

ministration approval for cervical dystonia, Myobloc

has been evaluated in several small clinical trials

for aesthetic purposes. In these settings, most studies

have been conducted to establish dosing guidelines.

To date, however, definitive doses for effectively

treating hyperfunctional facial lines have not been

well-established.

Ramirez et al [19] evaluated Myobloc in 24 sub-

jects with facial rhytides. A total of 82% had been

treated previously with Botox, although not within

6 months before the study. Patients received 200 to

400 units of Myobloc per injection site (total dose

400 to 800 units). The three sites injected included the

frontalis, corrugator supercilium, and the orbicularis

N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221–226 223

oculi muscles. Improvement in facial rhytides was

assessed using two different scales: the Wrinkle Im-

provement Scale (0 indicated no improvement and

3 indicated significant improvement) and the Rated

Numeric Kinetic Line Scale. The Rated Numeric

Kinetic Line Scale assessment was found to charac-

terize wrinkle severity more objectively because this

scale encompasses a description of wrinkles both at

rest and maximum frown. A score of 1 reflects no

wrinkles at rest, which become fine lines with facial

animation; a score of 4 denotes deep lines at rest,

which become deep furrows with facial animation.

Subjects were evaluated in repose and animation

before and after injection at weeks 1, 2, 4, 8, and 12.

Photographs were also obtained. All subjects had a

relatively rapid onset of near complete paresis within

72 hours, and in many cases, within 24 hours. Scores

on theWrinkle Improvement Scale and Rated Numeric

Kinetic Line Scale were moderately to significantly

improved by two to three points following Myobloc

treatment. The duration of effect was suboptimal,

however, with a mean of 8 weeks. There were no

adverse events, including dysphagia, dyspepsia, or dry

mouth. This preliminary study showed thatMyobloc is

effective in treating facial lines of the glabella, fore-

head, and crow’s feet areas, but the authors concluded

that doses higher than 400 to 800 units are necessary

for a longer duration of action [19].

Pain on injection, usually described as a slight

stinging sensation, has been reported to occur with

Myobloc injections. In the study by Ramirez et al [19],

the patients were also evaluated for pain associated

with injection using the McGill Pain Scale. The

McGill Pain Scale is a scale ranging from 0 (signifying

no pain) to 5 (signifying excruciating pain). At the time

of treatment, subjects were asked to rate the pain of

Myobloc injections and to compare it to the pain of

Botox injections. On average, Myobloc was found to

be slightly more painful than the memory of Botox

injections (2.3 versus 1.6, respectively). No patient

indicated, however, that the discomfort would prevent

him or her from undergoing a repeat injection with

Myobloc [19]. The slightly higher pain rating with

Myobloc reflects its acidic formulation.

A much smaller open-label study investigated

preliminary doses of Myobloc and also compared the

effects of the drug with those of Botox in the treatment

of glabellar lines [20]. Subjects received 1000 units

(N = 4) or 2000 units (N = 4) ofMyobloc, or 20 units of

Botox (N = 5), divided equally over five sites (one

injection at the procerus muscle and two injections at

each of the inferomedial and superolateral aspects of

the corrugator muscles). Subjects were photographed

before and after injection, and glabellar line severity

was rated as absent, mild, moderate, or severe, both in

a relaxed state and at maximum frowning. Results

showed that both toxins were effective in treating

glabellar frown lines. At the doses used, however,

Myobloc had a more rapid onset of action by 1 to

2 days, but Botox had a longer duration of effect. The

duration of effect of 20 units of Botox was at least

16weeks, whereas it was 8 to 10weekswith 1000 units

of Myobloc and 10 to 12 weeks with 2000 units of

Myobloc. This study suggests that the duration of

Myobloc may be dose-dependent. Because limited

adverse events were reported, the authors concluded

that higher doses of Myobloc should be studied.

Sadick [21,22] conducted two open-label studies

using higher doses of Myobloc for treatment of gla-

bellar wrinkles. Both studies were similar in design.

The first study evaluated 1800 units of Myobloc

(N = 30). The second study used higher doses of Myo-

bloc: 2400 units (N = 16) and 3000 units (N = 18).

Doses were divided equally among six injection sites:

two into the procerus, two into each corrugator super-

cilia, and two into the orbicularis oculi muscle bilat-

erally. Most subjects in all treatment groups had not

been previously treated with Botox. In the first study

(using 1800 units of Myobloc), efficacy was assessed

using photography and a clinical scoring system that

was completed by both subjects and physicians:

0 noted marked frowning ability, 1 denoted partial

frowning ability, and 2 denoted complete inability to

frown because of paralysis. The second study used

photography, the same clinical scoring system, and the

Rated Numeric Kinetic Line Scale to assess efficacy.

Subjects returned to the office daily postinjection until

the effects of Myobloc were observed, then weekly

thereafter. Both studies found Myobloc to be effective

in treating glabellar frown lines based on photography

(Fig. 1), patient satisfaction, and improvement in

assessment scores. Overall, Myobloc was found to

have a very rapid onset of action and a dose-related

duration of response. The mean duration of effect was

8 weeks with 1800 units, 9.6 weeks with 2400 units,

and 10.4 weeks with 3000 units. Lid ptosis was

reported in one patient who received 2400 units and

in one patient who received 3000 units. Headache and

mild pain on injection were also reported. Overall,

Myobloc was considered safe, and there was no

increase in adverse effects with the higher doses.

Matarasso [23] completed a study of 10 women

comparing Myobloc and Botox in the lateral ocular

canthal region [23]. All patients had been without

botulinum toxin treatment in all areas for at least

6 months before undertaking the study. Based on the

neurologic literature with cervical dystonia patients

and the reported lowest conversion ratio of 1 unit of

Fig. 1. Standardized photographs of a patient with glabellar wrinkles (A) at baseline and (B) 12 weeks after Myobloc injections

(total dose 3000 units: 600 units into the procerus, 2400 units into the corrugator supercilii and orbicularis oculi muscles).

N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221–226224

Botox to 50 units of Myobloc, a double-blind trial was

undertaken primarily to evaluate duration of rhytid

reduction [23,24]. Three aliquots of 5 units (total

15 units) of Botox were injected into one set of crow’s

feet, and three aliquots of 250 units of Myobloc

(750 units) were similarly injected into the contralat-

eral canthal rhytides. The injections were blinded to

both the physician and patient. Evaluation was under-

taken at 7, 30, 60, and 90 days, and results were based

on photographic images at rest and maximal muscle

contraction (Fig. 2), and by patient and physician

assessment. On unblinding of the solutions, the side

treated with Myobloc was found to have a quicker

onset of action (mean 2.3 days) and a shorter duration

of action (mean 6.4 weeks). Conversely, the crow’s

feet that were treated with Botox had a mean onset

of action of 3.7 days and an average duration of

12.7 weeks. Other than a slightly higher degree of

discomfort on injection at aMyobloc-treated site, there

were no reported adverse events.

Fig. 2. Preinjection (A) and postinjection (B) of 750 units of My

To date, the highest doses of Myobloc to be used

for aesthetic purposes are 3125 units for glabellar lines

and 3750 units for the frontalis region, as reported in an

open-label study by Spencer et al [25]. Twenty-six

patients received 1875, 2500, or 3125 units of Myo-

bloc into the glabellar defect. Eighteen patients re-

ceived 2250, 3000, or 3750 units of Myobloc into the

frontalis muscle. Results were comparable with other

Myobloc studies for wrinkles: a rapid onset and a dose-

related duration. At these doses, there were no reports

of lid or brow ptosis. Similar to all other reports, Myo-

bloc seemed to yield a very uniform paralysis, which

may reflect the distinct diffusion characteristics of the

type B toxin [12].

The studies of Myobloc for the treatment of both

cervical dystonia and facial wrinkles clearly show that

it is safe, effective, has a very rapid onset of action, and

has a dose-related duration of effect. It is anticipated

that higher doses of Myobloc will produce an even

longer duration of response in the treatment of facial

obloc into the lateral fibers of the orbicularis oculi muscle.

Table 1

Provisional dosing guidelines for botulinum toxin injections for facial rhytides

Botox Myobloc

Site Muscle Adverse reaction Units

No. of

injections Units

No. of

injections

Glabellar

complex

Procerus,

corrugator

supercilia

Lid ptosis, brow

ptosis, headache

20–35 5–6 2000–3000 3

Forehead Frontalis Brow ptosis, lid ptosis,

‘‘quizzical’’ brow

(lateral brow elevation)

20–40 8 1000–2500 3–6

Crow’s feet

(periorbital)

Orbicularis oculi Ecchymosis, diplopia 10–15 per side 3 per side 750–1500 per side 3 per side

N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221–226 225

wrinkles. Effective doses of Botox andMyobloc in the

treatment of different types of facial wrinkles are

speculated on in Table 1; however, these doses are

based only on preliminary studies.

Summary

Facial rhytides of the upper one third of the face

are common aesthetic concerns, and are caused prin-

cipally by overactivity of the underlying facial mus-

culature. Botulinum toxin, which acts by causing

flaccid paralysis of facial mimetic muscles, has be-

come a treatment of choice for the management of

these hyperfunctional facial lines. Two antigenically

distinct serotypes have been developed and are cur-

rently available for commercial use in the United

States. There are major differences between the two

toxins in terms of pharmacology and formulation that

account for clinical differences, and precise intercon-

version is not well-established. Nevertheless, in these

preliminary studies, Myobloc seems to have a faster

onset of action and potentially a more even and

smoother paralysis. The shorter duration of action

of Myobloc seems to be dose-related. It is clear that

both agents safely and effectively reduce dynamic

facial rhytides. Based on individual efficacy, safety,

diffusion pattern, onset, and duration, ultimately, with

further trials and clinical experience, it is conceivable

that each toxin will have its own set of indications.

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