Botulinum A exotoxin in cosmetic dermatology

Andrew C. MarkeyDermatological Surgery and Laser Unit, St John's Institute of Dermatology, London, UK

Summary Botulinum A exotoxin, a neurotoxin produced by the bacterium Clostridium botulinum,

is now being used by cosmetically oriented specialists for treatment of a large variety of

movement associated wrinkles on the face and neck. This form of temporary chemical

denervation compliments the cosmetic practitioner's armamentarium alongside

resurfacing and tissue augmentation. Additionally, the use of Botulinum toxin to

block sympathetic innervation of eccrine sweat glands is proving a valuable treatment

of hyperhidrosis of the axillae, palms and soles.

Introduction

Botulinum A exotoxin (BTX-A) is a neurotoxin produced

by the anaerobic bacterium Clostridium botulinum. It has

been described as the most poisonous poison.1 Botulinum

toxin (BTX) is actually present as seven different

serotypes (A-G),2 but it is BTX-A which is available in

two forms for clinical use in the UK 2 BOTOX (Allergan,

High Wycombe, Bucks) or Dysport (Ipsen, Maidenhead,

Berks). Whilst the action of the two forms is similar, the

unit potency is very different: 1 unit of BOTOX is

equivalent to 4 units of Dysport,3 a point of considerable

significance when interpreting studies and treating

patients. For the purposes of clarity, the rest of this

article will deal exclusively with the BOTOX preparation,

users of Dysport should multiply all units described by a

factor of four. The 50% lethal dose (LD50) of BOTOX in a

70 kg human is approximately 2700 units;4 consider-

ably greater than doses used in humans (see later).

BTX-A inhibits the release of acetylcholine from the

presynaptic membrane of the neuromuscular junction of

striated muscle leading to the onset (1±14 days) of

muscle weakness and paralysis.5 Over time (3±4 months)

new neuromuscular junctions are formed and muscle

function slowly returns. Inhibition of acetylcholine release

from sympathetic nerves innervating eccrine sweat glands

likewise produces a profound loss of sweating in the

treated area.6 These two areas of pharmacological

intervention lie behind the recent explosive increase of

the use of BTX-A in cosmetic dermatology for hyperhi-

drosis and for movement-associated wrinkles.

BTX-A was first used in monkeys by Scott in 1973

who demonstrated reversible ocular muscle paralysis

lasting 3 months.7 It was soon reported to be a

successful treatment in humans for strabismus,8 ble-

pharospasm9 and spasmodic torticollis.10 In 1986 Jean

and Alastair Carruthers, a Vancouver based husband

and wife team consisting of an oculoplastic surgeon and

a dermatologist, started to evolve the cosmetic use of

BTX-A for movement-associated wrinkles in the glabella

area; this led to their seminal publication in 1992.11 In

1994, they reported their experience with other move-

ment-associated wrinkles on the face12 and thus the era

of cosmetic BTX-A treatment was born.

Product preparation

BOTOX comes as a dried powder in glass vials

(100 units/vial) which when unconstituted requires

storage in a freezer at 24 8C. The product is recon-

stituted with normal saline for injection (no preserva-

tive) and a variety of amounts of diluent and hence final

concentration of the product have been used, with

2.5 mL of saline/vial giving 4 units BOTOX/0.1 mL ± a

commonly used dilution. Insulin syringes are frequently

used to draw up the diluted product as the small

q 2000 Blackwell Science Ltd X Clinical and Experimental Dermatology, 25, 173±175 173

Clinical dermatology X Review article

Correspondence: Andrew C. Markey, Dermatological Surgery and Laser

Unit, St John's Institute of Dermatology, London SE1 7EH, UK.

Accepted for publication 19 January 2000

amount of residual fluid in these needle hubs increases

dose accuracy and minimizes product wastage. The

product once reconstituted should be stored in the fridge

at 2±8 8C and used promptly as loss of potency over

time does occur, although in practice the author keeps

syringes for up to 1 week without any clinically

apparent loss of effect occurring. Once injected, the

effect on muscle function is usually delayed for several

days (range, 2±7 days). The development of neutraliz-

ing antibodies to BTX-A with loss of clinical effect has

not been reported with the use of less than 100 units/

injection session, an amount often not exceeded in

routine cosmetic treatments.2,13 Should neutralizing

antibodies become a clinical problem, switching to a

different serotype may allow for further therapeutic

benefit.

Movement-associated lines

Many recent publications give specific injection techni-

ques and doses for BTX-A treatment of the face and

should be carefully studied.13,14 In analysing the ageing

face, it is important to understand the proper place for

chemical denervation by BTX-A in facial rejuvenation.

Where lines are formed wholly or significantly by

movement of underlying muscles (corrugator muscle

and glabellar frown lines, frontalis and horizontal

forehead lines) one can expect gratifying results in

appropriately chosen patients. Where there is a mixture

of both actinic- and movement-induced wrinkling

(`crows feet' lines at the lateral canthi), the use of

BTX-A alone may well be sufficient to achieve improve-

ment but additional intervention such as resurfacing

will produce a more complete result. The main

complication of periocular injection is eyelid ptosis

which is probably, in large part, injection-technique

dependant but with the effect of BTX-A spreading for

1.5 cm beyond the point of injection, knowledge of the

underlying anatomy is clearly essential.

Whilst the indications for BTX-A treatment in facial

areas other than the above are increasingly discussed,

the treatment remains, par excellence, a treatment for

the upper third of the face. Off the face proper, BTX-A

treatment to the neck is of great interest,15 offering a

nonsurgical solution to platysmal banding as well as

some effacement of the horizontal neck lines. However,

as with all cosmetic interventions, a detailed analysis of

the ageing face and the understanding of appropriate

usage of tissue augmentation, skin resurfacing and

chemical denervation with BTX-A is necessary to

optimize results. Certainly, the use of BTX-A both before

and after full face laser resurfacing is becoming firmly

established as this combination treatment approach

allows both actinic and dynamic line improvement to be

maximized with longer lasting results being achieved.

Hyperhidrosis

The sympathetic nerves that innervate the eccrine

sweat glands of the body release acetylcholine, which

can be successfully blocked by BTX. Initially reported in

localized gustatory-induced sweating (Frey's syn-

drome)16±19 application of the same principles has led

to the recent use of BTX-A in axillary hyperhidro-

sis6,20,21 and focal palmar hyperhidrosis.22±25 When

compared to the significant morbidity associated with

surgical approaches in intractable cases using upper

thoracic sympathectomy (pneumothorax, Horner's syn-

drome, and compensatory hyperhidrosis),26 the advan-

tages of BTX-A appear to be considerable. Whilst the

need for repeat treatment remains, the clinical reduc-

tion in sweating following BTX-A treatment appears to

be more prolonged than the 4 months commonly seen

with wrinkle treatment ([20] and R.G. Glogau and A. C.

Markey, personal communications). As with wrinkles,

careful attention to detail in the injection technique is

critical to a good response in hyperhidrosis, including

the use of starch±iodine tests in certain cases, particu-

larly the hands. Transient weakness in selected muscle

groups of the hand can occur when treating palmar

hyperhidrosis;22,23 this argues for treating the palms

sequentially, 3 weeks apart, rather than simultaneously.

No such constraint is required in treating the axillae.

Clearly, there are fiscal issues that surround the use of

an established substance in new clinical scenarios.

Compared with the purely financial costs of hospital-

based sympathectomy, a twice-yearly injection of BTX-A

will, over the long-term, prove to be more costly.

However, the relative simplicity of the procedure and

the virtual absence of side-effects or complications of

significance make the case for BTX-A in selected cases of

hyperhidrosis increasingly attractive. Whilst the use of

BTX-A in cosmetic facial rejuvenation will, quite

correctly, remain within the auspices of a cosmetic

dermatological private practice, the same BTX-A pre-

paration is probably in many hospital pharmacies,

already on formulary, ready for dispensing to ophthal-

mology departments. Dermatologists may wish to avail

themselves of this product for use in some of their

distraught patients with hyperhidrosis. Few procedural

interventions offer such gratifying results, with trans-

formational effects on people whose lives have been

plagued by damp handshakes and soaked, rotten

clothing for too many years.

Botulinum A exotoxin in cosmetic dermatology X A. C. Markey

q 2000 Blackwell Science Ltd X Clinical and Experimental Dermatology, 25, 173±175174

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