Tiêm Botulinum Toxin Trong Trẻ Hóa Khuôn Mặt (Ấn Bản Thứ 2)

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2015v1.0
ELSEVIER

Botulinum Toxin in Facial
Rejuvenation

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Botulinum Toxin in
Facial Rejuvenation
KATE COLEMAN BSc, PhD, FRCS, FRCOphth
Blackrock Clinic
Dublin, Ireland
S E C O N D E D I T I O N

BOTULINUM TOXIN IN FACIAL REJUVENATION,
SECOND EDITION
ISBN: 978-0-7020-7786-9
Copyright © 2020 by Elsevier, Inc. All rights reserved.
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v
F O R E W O R D , T O T H E
F I R S T E D I T I O N ( 2 0 0 3 )
It is indeed a great pleasure for us to have the opportunity to write the foreword to this important
handbook. Kate Coleman has chronicled and catalogued her extensive observations following the
treatment of her patients with botulinum toxin. These are displayed in an orderly fashion, allow­
ing physicians to readily apply these pearls to the treatment of their patients.
We have used botulinum toxin to treat blepharospasm patients for more than 20 years. Now,
just as botulinum toxin revolutionised the treatment of benign essential blepharospasm, it is
launching noninvasive techniques for facial rejuvenation into another era. Every physician and
surgeon seriously pursuing rejuvenation of the facial structures must include chemodenervation
as a cornerstone of their therapeutic menu. The effects of ablative and nonablative laser therapies
are enhanced with botulinum toxin type A pretreatment. Combination therapy of botulinum
toxin and filling agents yields prolonged effacement of glabellar furrows. The artful application
of botulinum toxin not only reduces facial rhytidosis but also repositions eyebrows, flattens
pretarsal muscle folds and diminishes platysmal bands. Understanding the facial musculature
allows the aesthetic physician to manipulate the balance of counteracting muscles and rejuvenate
the face. This is the dawn of the new age of facial rejuvenations.
Stephen Bosniak, MD, FACS
New York, NY, USA
Marian Cantisano-Zilkha, MD
Rio de Janeiro, Brazil
Co-editors of Operative Techniques in Ophthalmic Plastic and Orbital Surgery.
Authors of Cosmetic Blepharoplasty and Facial Rejuvenation.
National Botox Training Centers—New York, NY, USA, and Great Neck, NY, USA.

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vii
A P P R E C I A T I O N
Thank you to the kind patients who generously donated their photographs and videos, and to the
great team at Elsevier for making it happen, again.
Thank you to my mentors whose principles shaped my surgical and clinical problem solving.
Professor Leo Koornneef and Dr Stephen Bosniak, may you both be resting in peace enjoying
the legacy of new generations of colleagues who now are passing on your teaching.
Little did I think, when I thanked Maria Micheau in the first edition, that she would have
remained a rock for all our patients and team, and for me personally. Everyone needs a rock to
keep their feet on the ground and their eyes in the heavens; thank you Maria.
Special thanks go to my skilled team, in particular, Carmel Finnegan for editing this work and
Karen Murphy for collating the images.
Finally, life is too short not to do something we love. I have been surrounded by my precious
children, Fleur and Tim, and special friends for a very long time. The enrichment they bring to
my life is almost equalled by that amazing feeling one gets when a patient smiles back, with their
confidence renewed and their eye contact back on line. I will continue to campaign, for the rest
of my life, for two passions:
The right to see, the end of needless blindness. In 2018, we now have the technology; support

The right to be seen as who we think we are and how we think we look. Much cosmetic work
is actually rehabilitative and restorative; it should not only be in the demesne of the few who can
afford it.
See better, look better, feel better.
Kate Coleman BSc, PhD, FRCS, FRCOphth
Blackrock Clinic
Dublin, Ireland

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ix
I N T R O D U C T I O N
The first edition of this book was written in 2003, when the world was just awakening to the
possibilities of botulinum toxin. Since then, it has become a billion-dollar industry, and rightly
so. Fifty-five percent of indications for botulinum toxin injections are noncosmetic. It changes
lives and makes them more bearable, particularly in patients following stroke and accidents who
incur severe, unremitting spasm.
In the early days of oculoplastic surgery, we had to excise the orbicularis oculi muscle to allow
a patient with severe blepharospasm to walk, to see. Since the mid-1980s, these patients have
been well corrected with botulinum toxin injections, albeit regularly.
Management of aberrant signalling in the facial muscles of our patients has provided us with
a wealth of information on neuromodulation and facial symmetry. This is the complex side of
predicting the redirection of muscle signalling, once it is interfered with using botulinum toxin.
This new edition brings 30 years of experience to these lessons in the hope of transferring the
intuitive art to a new generation of managers of facial expression.
The goal of our patient treatments is to:
n Reconstruct
n Rehabilitate
n Refresh
n Restore
n Rejuvenate
The art is to always make the patient look like they have not interfered with their face, to look
natural and to look, above all, normal and healthy.
This edition emphasises skills training to free the mind to be intuitive, to grasp the natural
asymmetry most patients have and to move and respond with varying doses accordingly. It again
emphasises the range of solutions which must be considered for a patient without always assuming
that botulinum toxin is the answer. This approach works.
The evidence is here: photos of patients from the first edition, looking as natural and graceful
15 years later.
Never underestimate the gift you give your patients when you give them quiet confidence in
their natural appearance; they look better, but most of all, they feel better. Normal people want
to look normal.
The art of good botulinum treatment is always to make the patient look better, but not necessarily
younger.

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1
C H A P T E R 1
Historical Background
The Clostridium family of bacteria, common to most environments, produces spores that, on
germination, release some of the deadliest toxins known to mankind. Clostridium Perfringens
contaminates wounds and caused the infamous gas gangrene of World War 1; Clostridium
botulinum produces botulinum toxin (BTX)—a powerful neurotoxin.
Clostridium botulinum was first identified in 1897, in Belgium, by Professor Emile van
Ermengenen, who was investigating fatal cases of food poisoning following the consumption of
macerated ham. It was named after the disease it causes, botulism, a lethal form of food poison­
ing originally associated with sausage meat (botulus is Latin for sausage). In the same year, an
antiserum for botulism was made.
There are seven known serotypes of BTX (A, B, C, D, E, F and G). Serotypes A, B and E
cause the classic foodborne disease with a flaccid paralysis of motor and autonomic nerves.
Type B was first discovered in 1910, and the isolation of type A began in the 1920s. During the
Second World War, research continued into this potent neurotoxin as a possible agent (‘agent X’)
for biological warfare. Most of this work was carried out at the chemical warfare laboratories of
Fort Detrick, Maryland, and Porton Down in the United Kingdom. Porton Chemicals was
bought by Ipsen Pharmaceuticals in 1989 and is the source of Dysport.
Dr Alan Scott, an ophthalmologist from the Smith-Kettlewell Eye Research Foundation,
became interested in substances that caused transient muscular paralysis. He acquired BTX type
A from Fort Detrick and performed the first clinical tests on humans in 1978. His results in the
treatment of strabismus (an abnormal contraction of the extraocular eye muscles) were published
in 1982 and led to the extensive use of BTX type A by ophthalmologists in the treatment of
blepharospasm (an abnormal twitching and contraction of the muscles around the eye), hemifa­
cial spasm and cervical dystonia.
By the late 1980s, the author, an oculofacial and ophthalmic surgeon in Ireland, as well as
colleagues in Canada and the United Kingdom, were each exploring different doses and methods
for using BTX. The author worked on patients with facial asymmetry, especially Bell palsy, to
calculate the doses required to ‘balance’ the innervation of the whole face.
Thereafter the story is well known. With good medical training and the correct selection of
patients, BTX can be given easily, safely and repeatedly. There have been relatively few reported
side effects despite ever-increasing demand in increasingly large doses, in particular for large
muscle dystonia and spasm.
Thanks to Dr Scott, many lives have been enhanced and many more made bearable by this
deadliest of poisons and astonishingly precise drug.

2
A working knowledge of the pharmacology of botulinum toxin (BTX) is essential to understand
the contraindications and complications of treatment with it.
Botulinum neurotoxins are metalloprotease polypeptides, comprising a protein molecule
(150 Kd), which can be cleaved enzymatically into a heavy (H) (100 Kd) and a light (L) (50 Kd)
chain (Fig. 2.1). These chains are normally held together by a disulphide bond, which is heat labile.
Disruption of this bond inactivates the neurotoxin. This explains why BTX must be stored at the
correct temperature and reconstituted carefully, preserving the integrity of the two-chained molecule.
Prior to reconstitution, characteristics of Incobotulinum toxin A (Xeomin) reflect the lack of a com­
plexing protein with the neurotoxin, allowing lpng term stability and reduced immunogenicity.
BTX induces paralysis by blocking the release of acetylcholine at the skeletal alpha motor
neurone neuromuscular junction, thereby inhibiting the transmission of nerve impulses across
the synaptic junction to the motor end plate.
USER TIP
Always consider possible central, as well as obvious peripheral, changes to the injected
muscle following treatment (neuromodulation).
Muscular Contraction: Normal Cholinergic
Transmission (Fig. 2.2)
Voluntary muscle contraction is a response to stimulation by action potentials passing along a
nerve to the muscle. Once these action potentials reach a synapse at the neuromuscular junction,
they stimulate an influx of calcium into the cytoplasm of the nerve ending. This increase in
C H A P T E R 2
Botulinum Toxin: Mode
of Action and Serotypes
Imag
e

o
f

F
i
g. 2.1
Fig. 2.1  Diagram of botulinum toxin molecule showing
heavy and light chains. (From Aoki R. The development
of Botox—its history and pharmacology. Pain Digest.
1998;8:337–341. With permission from Springer-Verlag.)
Dr. Kate Coleman, BSc PhD FRCS FRCOphth

2—BOTULINUM TOXIN: MODE OF ACTION AND SEROTYPES
3
Image of Fig. 2.2
Fig. 2.2  Normal cholinergic transmission: (1) A signal passes down the cholinergic nerve, causing calcium to pass through the depolarising presynaptic membrane.
(2) The calcium then triggers the binding of the acetylcholine molecule to a protein membrane complex. (3) The protein membrane complex allows the acetylcholine
to pass into the synaptic cleft. (4) The acetylcholine travels across the synapse to a nicotinic receptor on the muscle, where it stimulates contraction before disin­
tegrating into acetate and choline (5). VAMP, Vesicle-associated membrane protein.

4 
BOTULINUM TOXIN IN FACIAL REJUVENATION
calcium concentration allows acetylcholine to fuse with the membrane, using a protein complex,
before crossing the synapse and fusing with nicotinic receptors on the muscle fibre. The protein
complex consists of three types of protein: vesicle-associated membrane protein (VAMP; synap­
tobrevin), synaptosomal-associated protein (SNAP)-25 and syntaxin.
Mode of Action of Botulinum Toxin (Fig. 2.3)
Acetylcholine depends on a protein complex for its release from the nerve ending into the syn­
apse. BTX, using a specific enzyme in the L-chain, interacts with one component of the protein
complex of the nerve terminal, thereby inhibiting the discharge of the acetylcholine. The protein
attacked is specific to the different serotypes of BTX; for example BTX-A blocks SNAP-25,
whereas BTX-B blocks VAMP. BTX-B acts on a different cytoplasmic protein complex. The
secretion of acetylcholine is disrupted when the L-chain of the BTX-B molecule cleaves a protein
called synaptobrevin, also known as VAMP. Clinical trials have shown BTX-B to be effective for
the treatment of patients with cervical dystonia, including those resistant to BTX-A.
Both the H- and L-chains of the BTX molecule are needed to block the release of acetylcholine.
The H-chain attaches the BTX to the nerve membrane, allowing the L-chain to be transported to
its site of action—the protein complex. The L-chain enzyme then cleaves the protein specific to the
particular neurotoxin. Neuromuscular transmission ceases, and the target muscle atrophies reversibly.
AUTONOMIC ACTION
BTX also blocks autonomic cholinergic receptors. The duration of action is longer than for
skeletal nerve endings, and effects can last for up to 12 months.
CENTRAL ACTION
BTX affects the gamma motor neurone, reducing muscle spindle afferent input to the central
nervous system, and at high doses has been shown to reach the brain. Functional magnetic reso­
nance imaging has shown that glabellar injections of BTX have resulted in functional uncoupling
of brain stem centres with the amygdala. Other studies have confirmed reduction in the size of
areas of basal ganglia in response to high-dose injections for spasticity. These central effects help
to explain how BTX can ameliorate pain and chronic migraine, as well as supporting some stud­
ies suggesting improvement of depression. Studies have demonstrated retrograde and anterograde
axonal transport along the branches of nociceptive neurones following peripheral nerve blockade.
Pain relief has been shown to start prior to paralysis, outlasting the duration of the paralysis, sup­
porting a noncholinergic mechanism. The antinociceptive effect is mediated by blockade of
neuropeptides and inflammatory mediator release. There is evidence of inhibition of plasma
membrane exposure of pain sensors at the peripheral level.
MUSCLE RECOVERY
Cleavage of the protein complex is irreversible, but the changes following BTX include a prolifera­
tion of axonal nerve buds to the target muscle and the regeneration of muscle end plates. New nerves
‘bud’ out across the motor endplates, albeit with irregularly spread cholinergic receptors
Muscle function takes between 24 hours and 5 days to cease; in contrast, recovery takes from
6 weeks with rimabotulinumtoxin B (Neurobloc) and an average of 14 weeks with onabotu­
linumtoxin A (Botox), Incobotulinumtoxin A (Xeomin) and abobotulinumtoxin B (Dysport). In
the author’s experience, duration of effect is dose and location dependent. Some muscles, the
frontalis in particular, remain paralysed in some patients for as long as 5 months, after only one

2—BOTULINUM TOXIN: MODE OF ACTION AND SEROTYPES
5
Image of Fig. 2.
3
Fig. 2.3  Action of botulinum toxin (BTX) at the neuromuscular junction: (1) The heavy chain of the BTX binds to synaptogamin on the presynaptic membrane.
(2) The heavy chain/synaptogamin complex enables the BTX light chain to enter the cell. (3) The light chain attacks the membrane complex and disables it so that
NO ACETYLCHOLINE (AcH) BINDS. (4) BTX-A attacks the SNAP-25 protein of the membrane protein complex, and BTX-B attacks VAMP (synaptobrevin). (5) There
is no release of AcH. SNAP, Synaptosomal-associated protein; VAMP, vesicle-associated membrane protein.

6 
BOTULINUM TOXIN IN FACIAL REJUVENATION
treatment. Prolonged paralysis results in muscle atrophy, which has been shown to last years in
the forehead musculature. There is also a suggestion of long-term reduction in central voluntary
control, ‘breaking the frown habit’, as evidenced by other basal ganglia imaging studies following
BTX-A administration.
The orbicularis oculi muscle requires 3 to 6 months to recover its function, but, even then, the
muscle returns to only 70% to 80% of its original bulk. This explains the fact that even an isolated
treatment can help the ‘crow’s feet’ of patients who are reluctant to engage in a series of treatments.
USER TIP
Choose your dose to modify the desired duration of action.
IMMUNOGENICITY
The development of antibodies to one serotype does not preclude an effective response to another
one. Reports suggest an incidence of 2% rate of antibody formation with serotype A (onabotu­
linumtoxin A, BOTOX) as opposed to 20% to 40% with serotype B (rimabotulinum toxin B,
Myobloc). Research suggests that the production of these antibodies is related to the protein load
of the neurotoxin. This has led to the development of incobotulinumtoxin A, Xeomin/Bocouture,
with its free 150-kD molecule and no haemagglutinin complexing. The original Onabotulinum­
toxin A (Botox) contained 25mg Protein/100units. The more recent Botox preparations have a
reduced protein load of only 5mg/100units in comparison.
Immunogenicity has been linked to the frequency of administration of BTX and to its
concentration. Ideally, therefore, good therapy should be spaced at a minimum of 12-week
intervals and should use the lowest concentration effective for the desired duration of action.
Serotypes
There are seven serotypes of BTX, five of which are effective at the human neuromuscular
junction (BTX-A, B, E, F and G). The different serotypes act by cleaving different proteins at
the presynaptic vesicle.
Four types of BTX are currently licensed and available commercially in Europe and the United
States (Table 2.1); three are BTX serotype A: Botox/Botox Cosmetic (onabotulinumtoxin A),
Dysport/Azzalure (abobotulinumtoxin A) and Xeomin/Bocouture (incobotulinumtoxin A).
Neurobloc/Myobloc is BTX type B. Several types of BTX-A have been emerging in other coun­
tries, some also from the HALL strain of BTX (e.g. Meditox, South Korea).
Concern must be highlighted about unlicensed online availability of poorly regulated toxins
from other countries, including ‘copies’ of Allergan BOTOX with no toxin in the bottles. The
author had experience with a toxin being launched in the Middle East, which caused local
TABLE 2.1  n  Botulinum Toxin Currently Licensed and Available Commercially in Europe
and the United States
BTX-A
BTX-A
BTX-A
BTX-B
Abobotulinumtoxin A
Incabotulinumtoxin A
Onabotulinumtoxin A
Rimabotulinumtoxin B
Dysport
Xeomin
Botox
Neurobloc
Azzalure
Bocouture
Vistabel
Myobloc
BTX, Botulinum toxin.

2—BOTULINUM TOXIN: MODE OF ACTION AND SEROTYPES
7
permanent muscle atrophy and scarring when injected. Other adverse reports include four cases
of botulism in Florida due to toxic levels of BTX in unlicensed vials. The author currently uses
only Dysport/Azzalure, Botox and Xeomin and will refer to these products and their differ­
ences in the rest of this manual.
USER TIP
Botulinum toxin acts by blocking release of acetylcholine from the nerve terminal.
USER TIP
Conditions and/or drugs affecting the nerve/muscle junction could also affect the botulinum
toxin results.

8
C H A P T E R 3
Clinical Indications and Use
The cosmetic indications for botulinum toxin have not changed since the first edition of this book
and are listed in Box 3.1, but the noncosmetic indications now represent 55% of all botulinum
toxin use. In the author’s oculofacial practice, botulinum toxin is an essential first-line treatment
for hemifacial and blepharospasm, post–facial nerve palsy synkinesis, chronic migraine, frontal
‘trigeminal’ headaches and hyperhidrosis. Table 3.1 provides a list of other uses at the time
of press.
Much has been published on the differences between the different products, and the reader is
referred to an excellent 2018 review on the same by Dr. Richard Glogau.
USER TIP
DIFFUSION is influenced by concentration, by product and by the concentration of receptors
on the muscle being injected. More receptors mean less diffusion per volume injected.
BOX 3.1  n  Cosmetic Indications For Botulinum Toxin
Crow’s feet (periocular rhytids)
Vertical (glabellar) frown
Horizontal (frontalis) frown
Wrinkles on nose
Upper lip rhytids
Vermilion border
Angle of mouth
Pebbly chin
Nasolabial folds
Jaw line (platysma)
Venus rings (horizontal neck rhytids)
Turkey neck (vertical platysma bands)
Décolleté
Scar management
Movement Disorders
Internal Organs
Other
Focal dystonias
Detrusor muscle
Hyperhidrosis
Essential tremor
Bladder spasm pain
Chronic migraine
Parkinsonism
Urinary retention
Tension headaches
Spasticity
Hyperactive/overactive
Trigeminal neuralgia
Post-stroke spasticity
Pelvic floor pain
Temporomandibular pain
Traumatic spasticity
Anal fissures
Spinal muscle pain
Multiple sclerosis
Benign prostate hyperplasia
Frey’s syndrome
Eye movement disorders
Sialorrhoea
TABLE 3.1  n  Noncosmetic Indications for Botulinum Toxin

3—CLINICAL INDICATIONS AND USE
9
Concentrations
Botulinum toxin is the most potent toxin known to man­
kind. It functions at very low concentrations and so can be
assessed accurately only in terms of lethal dose unit per
Swiss-Webster mouse. (Research is ongoing in to cell-based
potency assay.) Different serotype A brands are shown in
Table 3.2. One mouse unit (mu) is the median intraperitoneal
dose required to kill 50% (LD50) of a batch of 18- to 20-g
female Swiss-Webster mice over 3 to 4 days.
The types of mice used by different producers differ and
so the units discussed are NOT interchangeable. One vial of
onabotulinumtoxin A (BOTOX, Fig. 3.1) contains 100 mu,
while one vial of abobotulinumtoxin A (Dysport, Fig. 3.2)
contains 500 ‘Speywood’ mu. One vial of Xeomin (Fig. 3.3)
contains 100 mu, similar to the BOTOX units assay. This
variability of assay, coupled with the absence of a definitive
human assay, means that the doses used have to be based
Onabotulinumtoxin A
Abobotulinumtoxin A
Incobotulinumtoxin A
BOTOX/visabel
Dysport/Azzalure
Xeomin/Bocouture
900-kDa complex
,900 kDa
150 kDa
Vacuum-dried powder
Freeze-dried powder
Freeze-dried powder
2–8°
2–8°
Room temperature
HSA 500 mg
NaCl (900 mg/vial
HSA 125 mg
Lactose (2.5 mg/vial)
HSA 1000 mg
Sucrose (4.7 mg/vial)
BOTOX: 100-U or 200-U vial
Vistabel: 50 U
Dysport: 300 U or 500 U
Azzalure: 125 U
Xeomin: 100 U or 200 U
Bocouture: 50 U
5 ng/100 U
4.35 ng/500 U
0.44 ng/100 U
TABLE 3.2  n  Botulinum Toxin Serotype Type A
Fig. 3.1  Bottle of BOTOX.
Fig. 3.2  Bottle of Dysport.
Fig. 3.3  Bottle of Xeomin.

10 
BOTULINUM TOXIN IN FACIAL REJUVENATION
on clinical experience. The three different products have different licences for use for different
countries. Each has a cosmetic use licence for a smaller vial of the same product: BOTOX (Vis­
tabel 50 U), Dysport (Azzalure 125 U) and Xeomin (Bocouture 50 U). (The author uses only
botulinum toxin type A serotypes and refers only to these in this book.)
Clinical efficacy is directly related to the degree of dilution of the toxin, the muscle targeted,
and the volume injected. Botulinum toxin adheres to the muscle receptor, and the diffusion will
be greater for fewer receptors than for more per site.
In a cosmetic practice, different outcomes require different combinations of onset, duration
and diffusion of effect. The art is to learn how to use the combinations of the available products
to ‘mould’ the tone of the area being treated.
USER TIP
A beginner should use one botulinumtoxin A to start, at one dilution, for all treatments and
learn to change the volume and site of injection to get predictable results.
Onset of Effect
A consensus of clinical experience suggests onset may be as early as day 2 and usually before day
6 with all three products.
Early onset of effect is desirable for certain ‘special occasions’ but usually most wanted when
correcting an unpredicted facial muscle movement. This will be discussed in Chapters 6 to 10,
but for example, if a patient experiences an alarming brow ‘peak’, a top-up to the offending
muscle, with effect as soon as possible, is strongly desired. The author chooses abobotulinumtoxin
A (Azzalure), which often becomes active, depending on the patient, on day 2.
In general, treatments are planned with the patient, knowing that the effect will take up to 5 days
to appear and then the following 7 to 10 days to ‘balance out’. This works for all three products.
Diffusion and Duration
Dilutions and resulting unit per volume are shown in Tables 3.3 and 3.4.
BOTOX and Xeomin behave with similar unit-per-vial potency. The potency of one 100 U
vial of BOTOX is not the same as that of one 500 U vial of Dysport. Several studies suggest that
3 to 5 units of Dysport/Azzalure equate with 1 unit of BOTOX.
Both incabotulinumtoxin A (Xeomin) and onabotulinumtoxin A (BOTOX) have similar
durations of action, their effects wearing off after 12 to 14 weeks. Clinical trials have compared
diffusion properties, a theory being that a small protein complex could diffuse further, but results
suggest equal diffusion ‘per equivalent dosage’. The studies referred to used a ratio of 1:4 ona­
botulinumtoxin A (BOTOX) to abobotulinumtoxin A (Azzalure/Dysport).
BOTOX/Xeomin Units Per 0.1 mL
BOTOX/Xeomin 100 IU Add
BOTOX/Xeomin 50 IU Add
10 units
1 mL
0.5 mL
4 units
2.5 mL
1.25 mL
3.3 units
3 mL
1.5 mL
3.5 units
3.5 mL
1.75 mL
4 units
4 mL
2 mL
TABLE 3.3  n  Concentration of BOTOX/Xeomin per Dilution With Preservative-Free Normal Saline

3—CLINICAL INDICATIONS AND USE
11
The author often uses a stronger equivalent dose ratio of 1:3.5. Azzalure appears to diffuse
to more muscle fibres per site of injection than BOTOX and appears to last longer at these
equivalent concentrations. The author modifies the dilution if a shorter duration of action is re­
quired, as will be seen in Chapters 6 to 10.
The protein content of the botulinumtoxin A complex is sometimes cited as a reason for
choosing between the products. Incobotulinumtoxin A, Xeomin, has no haemagglutinin protein
complexed with its 150-kDa botulinumtoxin A molecule and so is unlikely to have the same
antigenic properties as other preparations. This may be relevant in large doses, for example with
cervical dystonia, but does not seem relevant to date with rejuvenation doses.
The protein content of BOTOX has changed since it was introduced to Europe in 1989. The
original batch, from Dr. Scott’s company Oculinum, of 150 g of pure crystallised toxin, was pre­
pared by Dr. Schantz in 1979. BOTOX is a vacuum-dried form of purified botulinumtoxin A,
produced by cultures of the Hall strain of Clostridium botulinus. It is isolated as a crystalline pro­
tein complex from the culture solution by a series of acid preparations and then redissolved in a
solution containing saline and albumin. It is then filtered using a sterile technique before vacuum
drying. This author’s experience with onabotulinumtoxin A (BOTOX) from 1989 to 1997 was
with the original Schantz preparation. In 1997, a new batch was prepared by Allergan with dif­
ferent labelling. This batch, in current use, contains 20% less protein than the original one and so
is less likely to stimulate an albumin-related allergic response. The author has seen no cases of
immunogenicity to onabotulinumtoxin A (BOTOX) since 1997.
n Onabotulinumtoxin A (BOTOX) is produced by a precipitation technique and freeze-dried to a
powder.
n Incabotulinumtoxin A (Xeomin) is a freeze-dried powder.
n Abobotulinumtoxin A (Azzalure/Dysport) is produced by column-based purification and freeze-
dried to a powder.
n Rimabotulinumtoxin B (Myobloc) is a high-molecular-weight botulinumtoxin B that is not
lyophilised but a buffered intact protein complex in liquid form, at a pH of 5.5.
Economics
An experienced practitioner with a busy botulinumtoxin A practice may choose among the three
on economic grounds only—all are currently available at the same price in Ireland. Studies in
management of dystonia have shown that Azzalure/Dysport, followed by Xeomin, followed by
BOTOX were the most economical in Europe.
An inexperienced practitioner, with few patients and an irregular demand for botulinumtoxin
A, may initially prefer the smaller vials of Azzalure, Vistabel and Bocouture.
It is not recommended to store botulinumtoxin A for more than 24 hours following recon­
stitution, but several studies support the author’s long-term experience of at least 2-weeks effi­
cacy when stored at correct temperatures without undue mechanical friction. Furthermore,
Dysport/Azzalure Units Per 0.1 mL
Dysport 500 Units Add
Azzalure 125 Units Add
50
1 mL
0.25 mL
20
2.5 mL
0.625 mL
16.66
3 mL
0.75 mL
14.3
3.5 mL
0.875 mL
12.5
4 mL
1 mL
TABLE 3.4  n  Concentration of Dysport/Azzalure With Preservative-Free Normal Saline

12 
BOTULINUM TOXIN IN FACIAL REJUVENATION
colleagues report successful use of frozen reconstituted onabotulinumtoxin A (BOTOX) after
6 months.
CLINICAL USE GUIDELINES
Here are examples of how, in the author’s clinic, the choice between products is generally made:
Diffusion (Fig. 3.4)
n For a small diffusion zone, one may use a concentrated solution, e.g. 1 mL NaCl added
to 500 U abobotulinumtoxin A (Dysport) and inject 0.02 mL (i.e. 10 units); or a use
a smaller volume of a more dilute solution, which will diffuse more deeply but have a
shorter duration of action or the third option, which the author favours, is to use a con­
centrated solution of BOTOX or Xeomin (onabotulinumtoxin A), e.g., 0.025 mLs of
1 mL added to 100 units.
n For a large diffusion zone, use 3.5 mL/NaCl to 500 U abobotulinumtoxin A (Dysport) or
0.9 mL/NaCl to 125 U Azzalure and inject 0.1 mL. This will create a possible diffusion
circle diameter of 3 cm.
USER TIP
DURATION may be reduced by increasing the dilution, or by placing more superficially on the
muscle complex, or both.
Fig. 3.4  Drawing to demonstrate diffusion circles of three different sizes when injecting three different
volumes of abobotulinumtoxin A.
Image of Fig.3.
4

3—CLINICAL INDICATIONS AND USE
13
Duration
A short duration of action is ideal for new patients with unpredictable facial asymmetry, and
those who are happier to know that if they are unhappy with the results of their treatment, that
the effect will wear off after only 6 weeks, as opposed to over 12 weeks with the higher con­
centrations. They may be offered a ‘top-up’ then. It is also possible to get even shorter durations
of action with further dilution of the dose. It is worth noting that inadequate storage of botu­
linumtoxin A (e.g. at an incorrect temperature), or excessive dilution, also shortens the duration
of effect. Duration may be inadvertently reduced by agitating the bottle of botulinum toxin once
it has been re-constituted.
For a longer duration, greater than 12 weeks, in a suitable site, increase the concentration of
abobotulinumtoxin A (Azzalure) by adding less than 1 mL NaCl to the 125 U vial. NOTE that
in our experience, the diffusion circle will be smaller for onabotulinumtoxin A and incobotu­
linumtoxin A, than for abobotulinumtoxin A, for the same volume of the same concentration.
The author has used Azzalure (abobotulinumtoxin A) since 1988 and BOTOX (onabotu­
linumtoxin A) since 1989, the choice depending on the site of injection. More recently, Xeomin
(incobotulinumtoxin A) has become available and is also used as an alternative wherever BOTOX
may be chosen. However, Neurobloc (rimabotulinumtoxin B) has a high protein load and ‘stings’,
and the author has stopped using it for oculoplastic choices.
USER TIP
Think in volume/millilitre solution and not units/botulinum toxin A when injecting a patient.
This allows good control and safety because one eye should always watch the volume scale
gauge while injecting.

14
Patient Preparation and Injection
Skills
C H A P T E R 4
USER TIP
NEVER handle botulinum toxin without surgical gloves.
Presentation
Botulinumtoxin A (BTX-A) vials have changed in
size and shape over time. Specific instructions are
readily available on the product websites and in the
product insert packaging. Research is ongoing on the
new liquid form of BTX-A, as well as topically ap­
plied preparations, but the three BTX-A products
used by the author, onabotulinumtoxin A (onaBTX-
A), incobotulinumtoxin A (incoBTX-A) and abobo­
tulinumtoxin B (aboBTX-B), are presented as freeze-
dried powder in a glass vial. The vials frequently look
empty to the inexperienced eye because the powder
tends to rest in their bottom angle (Fig. 4.1). The
vials vary in size, depending on brand and quantity of
units, and this will influence the capacity for filling
with normal saline for more dilute preparations.
There are strict guidelines for storage of botulinum
toxin to prevent denaturation and maintain maximum
efficacy. OnaBTX-A and aboBTX-A should be
stored, before reconstitution, either frozen at 25°C or in a refrigerator at 2°C to 8°C until reconsti­
tuted. IncoBTX-A may be stored at room temperature, up to 25°C, until reconstituted. Once
reconstituted, they all must be stored at 2°C to 8°C (refrigeration temperature). A thermos flask or
a vaccination transporter may be used to maintain the solution at 2°C to 8°C if a refrigerator is not
available in the clinic.
Reconstitution
It is recommended that all products are reconstituted with preservative-free normal saline, which
is what the author routinely uses. Several studies have shown successful reconstitution with
preserved normal saline, with reports of 48% more comfort when compared with preservative-
free saline. Some studies have included 0.5% xylocaine to improve comfort.
The rubber seal on the vial should be wiped with an alcohol swab before using a 5-mL syringe
to inject the desired volume of normal preservative-free saline. A green 25-gauge needle is
Fig. 4.1  ​Photograph of BOTOX vial showing
powder at base prior to reconstitution.

4—PATIENT PREPARATION AND INJECTION SKILLS
15
inserted carefully through the centre of the bung, but care must be taken with BOTOX bungs,
which can freeze solid. The needle can easily enter at an angle, releasing pieces of rubber into the
solution.
USER TIP
Never agitate botulinum toxin solution when reconstituting it. It will not work!
The product is vacuum-sealed. If no pull on
the plunger is felt, then the vial must be dis­
carded. Air can be injected into the vial to avoid
too rapid a reconstitution, and a thumb can be
placed under the plunger of the syringe to control
the rate of release of saline onto the powder
(Fig. 4.2). The saline must not gush in and agitate
the solution mechanically. This will denature it by
disrupting the delicate disulphide bonds. Studies
have confirmed that it will still be effective but
with a curtailed duration of effect. Rotating the
vial during injection, and gently swirling the solu­
tion, will capture any powder trapped in the ‘lid’
part of the vials, especially with incoBTX-A
(Xeomin/Bocouture).
Injection
We recommend using no bigger than 1 mL tuberculin or insulin syringes. These are essential
for the dose to be gauged accurately during injection. The doses recommended in this book are
given in units of volume. The finest mark on a 1-mL syringe is 0.01: we often recommend using
0.025 mL and 0.01 mL (more later). Beginners may prefer a 0.05-mL syringe. Constant practice
with 0.5-mL insulin syringes and then 1-mL syringes (Fig. 4.3) will develop the sense of touch
to repeatedly administer small ‘droplets’ if necessary. The author prefers to use a 1-mL syringe
and often more than one 30-gauge needle to keep the needle sharp while minimising stimula­
tion of the nociceptors on the skin surface.
USER TIP
Always watch the gauge of the syringe while injecting to be certain of the volume you are
injecting.
Transport
BTX-A can be transported after reconstitution if the solution is not agitated. Ideally it should
be reconstituted after the journey; agitation denatures the toxin and greatly reduces its duration
of action
Fig. 4.2  ​Controlled reconstitution.
Fig. 4.3  ​One-millilitre syringe.

16 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Aspiration
Always use gloves for self-protection. The solution should be aspirated freshly for each patient,
although some doctors recommend preaspiration of BTX-A in several 1-mL syringes, and then
storing them in the refrigerator. Manufacturers recommend a single vial per patient, which must
be used within 4 hours of reconstitution.
Botulinum toxin is potent and very expensive, so each drop must be used to its maximum
effect. Even an injection as small as 0.01 mL is effective in certain sites.
Take care to remove the 25-gauge needle from the bottle after aspiration, particularly
with Dysport, where the combination of a small vial and a viscous solution encourages seepages
from the needle.
Once aspiration is complete, attach a 30-gauge needle to the hub of the syringe. Take
care that the batches of needles and syringes fit well together, and beware of attachments
so loose that the toxin dribbles from the hub during injection. This is wasteful and may
be hazardous if the leaked fluid contacts the patient’s face (ingestion of botulinum toxin
droplets has been suspected of causing mild gastroenteritis). Clear the air bubble from the
syringe using minimal agitation. This requires more care with Dysport/Azzalure because of
its greater viscosity.
USER TIP
Wipe away any spilled botulinum toxin with a hypochlorite solution
Skill must be acquired to confidently be able to administer the lowest number of BTX units
at the highest concentration (i.e. a very small volume of solution) repeatedly and accurately. It is
easy to administer a dilute solution of the same units at a larger volume.
Injection Technique
Good injection technique is critical for such a powerful agent because it takes a trained light
touch to inject a tiny dose. Very few chemicals continue to be effective at such high dilutions.
There is a real art to being able to manipulate the combination of extremely low with normal
and high doses in the one treatment. The injections for rejuvenation are being administered to
a continuum of facial muscle fibres. To be confident of offering aesthetically optimal treatment,
the user must be skilled with injection technique. Once a single muscle tone is altered with a
primary BTX-A injection, there is an immediate adaptation by both surrounding muscles, as
well as remote ‘paired’ and contralateral muscles. Very small doses are excellent at controlling the
secondary BTX-A effect. The user must be adept at injecting intradermally, subcutaneously,
intramuscularly, giving small and large doses and, most of all, observing and avoiding arteries,
veins and nerves.
The injector must know how to gauge the journey of the needle through the skin and muscle
at different sites on the face and neck. This is a sense of touch which can be acquired only with
practice.
Skill Development
Practise:
1. Entering the skin to create the least amount of pain
2. Entering the skin and muscle to the correct depth
3. Delivering the expected ‘circle of diffusion’ of toxin per volume injected.

4—PATIENT PREPARATION AND INJECTION SKILLS
17
PAIN
Topical anaesthesia makes little difference to the pain of intramuscular injections, unless highly
concentrated (e.g. LMX) or in place long enough to penetrate. SLOW insertion of the needle
makes a big difference to the perception of pain. The goal is to enter the skin without causing it
to ‘dip’ and stimulate the pain receptors on either side (Fig. 4.4). It helps to enter at a 90 degree
angle to the surface because that is the smallest surface area stimulated. With practice, it is actu­
ally possible to ‘get lucky’, to enter in between the pain receptors with the patient feeling nothing.
PRACTISE CIRCLES OF DIFFUSION
Fill a 1-mL syringe with coloured water (the author uses fluorescein) and attach a 30-gauge needle.
Use a wad of thick absorbent paper (e.g. four sheets of thickest kitchen roll).
Use coins or a compass to draw circles ranging from 0.5 cm to 2 cm (some paper comes
preprinted with suitable shapes).
Practise placing the 30-gauge needle tip just under the first ply of the absorbent paper and repeat­
edly filling the exact circles with coloured fluid.
To do this, the injector must inject the exact centre of the circle, injecting an identical volume
repeatedly to fill a specific circle size (Fig. 4.5).
Imag
e of Fig. 4
.4
Fig. 4.4  ​Pin cushion effect of fast entry of needle in to skin.

18 
BOTULINUM TOXIN IN FACIAL REJUVENATION
CIRCLES OF VOLUME
Once practised, focus on carefully watching the syringe mark while injecting precise volumes of
coloured water in to a wad of blank absorbent paper.
Practise 0.1-mL circles
Practise 0.05-mL circles
Practise 0.025-mL circles
Practise 0.01-mL ‘drops’ circles
Patient Skills
The injection practice should now have developed an instinctive sense of ‘volume 5 circle
size’.
The dosages in this book are taught as ‘volumes’.
With practice, the injector can look at a muscle, decide on the ‘size of circle’ of BTX-A needed
and choose the volume to provide that dose for the specific muscle.
It will become intuitive, second nature, to inject varying amounts, with an eye on the volume
scale, to the various muscles to ‘shape’ the result.
The volumes will be suggested in Chapters 8 to 10.
NEXT STEPS: HOW TO INJECT A PATIENT
From now on, examine every patient to calculate where to place which sized circles. The injection
will go in to a dot drawn at the centre of each circle.
As the face is examined, try to visualise the ‘circles’ of coloured water overlapping the
muscles to be relaxed. Decide if a circle size is too close to relaxing the wrong part of a muscle,
and move the circle centre, for example, to a higher place for a higher injection site. Visualise
the different coloured circles fitting over the muscles to be relaxed, and then make sure that
there is no unnecessary overlap with areas to be avoided or adequate overlap with areas to be
treated (Fig. 4.6).
Focus on acquiring a ‘feeling’ of volume equilibrating with ‘effect on the muscle’. This is akin
to a sense of injecting circles of paint under the skin. Injecting a bigger volume will give a sense
of reaching and relaxing a bigger surface area. This ‘feeling’ is an actual physical sensation of more
or less pressure on the syringe as one injects larger or smaller volumes.
Fig. 4.5  ​Creating diffusion circles of different sizes.

4—PATIENT PREPARATION AND INJECTION SKILLS
19
Image of
Fig. 4.6
Fig. 4.6  ​Visualise adjacent diffusion circles over the treatment zones.
Avoid initially focussing on delivering ‘units’, as with many guides, because the delivery of
units will not parallel the area of muscle treated visually with pressure on the syringe. It means
that the injector does not have to constantly remember the number of units per dilution, just
observe different volume marks on the syringe. An excellent result can be achieved by using
different volumes of the same concentration (e.g. dilute a 100-U vial of onaBTX A [BOTOX]
with 1 mL) for all initial treatments until confidence has developed.
‘STARTER’ PATIENTS
Start with a fixed concentration of BTX-A, and select only patients for whom this is appropriate.
It is very helpful to get practice giving 0.05-mL volume to patients who are having `Grid’
treatments of the same volume. For example:
n Neck treatments for thin subdermal injections
n Hyperhidrosis treatments for deeper intradermal ‘blebs’ of 0.05 mL
n Chronic migraine treatments for deep intrascalp 0.05-mL injections.
It is also good to start on patients having treatment for bilateral blepharospasm, taking great
care to develop a sense of difference between the needle entering the thicker orbital orbicularis
muscle versus the paper-thin lower pretarsal orbicularis and, lastly, the very thin upper preseptal
orbicularis under the medial brow. This is where diffusion to the upper levator muscle is most
likely to happen, yet the area must often be treated to reduce disabling spasm. Raise the skin here
with the needle tip and administer 0.0125 mL subcutaneously.
Beginners should not induce PTOSIS by avoiding the following cosmetic low-volume treat­
ments (,0.05 mL) until skilled:
n Any glabellar treatments to patients with low heavy eyebrows, because these require a high
concentration of BTX in a low volume to prevent excursion to the anterior levator muscle
complex and ptosis.

20 
BOTULINUM TOXIN IN FACIAL REJUVENATION
n Any attempt at ‘brow lifts’ which require small volumes to the brow depressors lateral to the
lateral orbital rim and inferior to the supero medial orbital rims.
Once comfortable with the sense of volume and distribution (circle size), in particular admin­
istering 0.0125 and 0.025 mL volumes, then it is safe to prepare more concentrated solutions of
BTX and address more difficult areas with impunity.
USER TIP
Larger volume will cause larger diffusion.
Higher concentration will cause less diffusion.
Patient Preparation
An inexperienced worker should mark the injection sites with a washable skin marker or pale
sharp brow pencil, having first wiped the sites with an alcohol swab. It is important to sterilise
the skin at the injection site because many patients wear a make-up foundation. Local granulo­
mas or erythematous nodules can develop at injection sites (Fig. 4.7), but the author has never
seen areas of infection or cellulitis related to an injection. Some practitioners suggest that alcohol
denatures the toxin. If this were so, then every injection site swabbed with alcohol during a treat­
ment session should have a similar effect on the toxin at the time of injection. However, the au­
thor has seen no difference in the effect of BTX-A when given simultaneously to sites which have
been swabbed (forehead) and have not (eye zone in patients who find alcohol too irritating and
are simply swabbed with saline).
Botulinum toxin can be injected intramuscularly, subcutaneously and as a ‘bleb’ beneath
the epidermis. However, most doses in this book are based on intramuscular injections and
have been derived from experience with blepharospasm. Subcutaneous injections are highly
effective but need more injection sites to allow for maximum absorption. Subepithelial ‘blebs’
are invaluable for smoothing out the superficial attachments of skin to the underlying muscle
whilst continuing to maintain resting muscle tone. These are usually given in a higher dilution
to allow greater diffusion between the surface of the muscle and the skin. The patient is ad­
vised that such treatments last for only 6 weeks as opposed to the full 12 weeks expected from
intramuscular injections. Pretarsal orbicularis injections are usually given intramuscularly be­
cause the skin here is only 0.5 mm thick. Intramuscular placement stings less and produces
less local erythema. However, it carries a slight risk of causing intramuscular bruising. In our
clinic, we use intradermal injections for hyperhidrosis, some dermatitis and some migraine
(scalp) treatments.
Fig. 4.7  ​Granuloma on the forehead from botulinum
toxin injection.

4—PATIENT PREPARATION AND INJECTION SKILLS
21
Fig. 4.8  ​Injecting at 1 cm over superior
orbital area.
Dosage
Each vial comes with recommended doses from the manufacturers of the product for
treatment to the glabellar complex and the crow’s feet area. A review of the literature
provides information on the dosage preferences of a variety of practitioners. The author
has validated the doses suggested in this book over the course of more than 30 years of
treatments given since she herself, then a junior Ophthalmologist, started developing the
cosmetic doses and uses in 1988. With experience, the reader should get a feeling for the
required dose for each patient—and may well modify these doses accordingly. The following
guidelines based on the author’s experience may be useful:
Aim to use the smallest volume of the lowest concentration necessary to provide paralysis of
the target muscle for at least 12 weeks.
Decide in advance how far you want the injection to diffuse (visualising the ‘coloured circles
from practice’).
Remember that, on average, 4 units in 0.1 mL of BOTOX will diffuse 1 cm; 14.3 units of
Dysport in 0.1 mL will diffuse 3 cm; 14.3 units of Dysport in 0.05 mL will diffuse less
(approximately 1.5 cm), as will 2 units of BOTOX in 0.05 mL.
Select the injection site so that treatment will not extend beyond the desired diffusion zone, for
example 0.1 mL of BOTOX injected 1 cm above the superior orbital rim (not brow) to treat
the glabellar muscle. This avoids diffusion towards the levator muscle (Fig. 4.8). Likewise,
inject 0.05 mL of Azzalure 1 cm from the lateral canthus (outer corner of the eyelid) to
avoid diffusion medially.
Base your choice of dosage on the recommendations given in Chapters 7, 8 and 9. Most of
your patients will receive the same dose for the same rhytids; but one aim of this book is to
leave the reader with confidence in how to treat the unpredictable minority too.
USER TIP
Concentration of botulinum toxin:
Too weak 5 short duration of action
Too strong 5 risk of increased side effects
Choose larger diffusion circles for the following sites:
n Treatment of frontalis
n Extended treatment of crow’s feet (inferolaterally over zygomatic arch)

22 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Choose smaller diffusion circles for the following sites:
n Lateral canthus
n Pre tarsal orbicularis
n Close to superior orbital rim
USER TIP
Increased volume dilution per unit botulinum toxin means increased diffusion.
USER TIP
Rough estimate: Add 3.5 mL to 500 units Dysport and expect:
14.3 units Dysport in 0.1 mL gives a 3-cm diffusion circle.
7 units Dysport in 0.05 mL gives a 1.5-cm diffusion circle.
3.5 units Dysport in 0.02 mL gives a 0.5-cm diffusion circle.
Patient Treatment
FRONTALIS ZONE
Ask the patient to frown while assessing the bulk of muscle contraction, then relax the patient
and inject at the point noted. When injecting the forehead, gently tip the periosteum (sensitive)
with the needle, withdraw slightly, and inject while watching the syringe gradations. With expe­
rience, one soon becomes familiar with the sensation of muscle bulk, and the periosteum is rarely
touched. Take care to point the needle away from danger.
It is sometimes useful to hold the muscle site between two fingers, especially in the glabellar
area (Fig. 4.9).
CROW’S FEET
Ask the patients to smile, note the centre point of movement, then ask them to relax. Mark the
centres of expected circles of diffusion, then inject the centre (Fig. 4.10). Take care not to point
the needle towards the orbital septum when injecting the lateral canthus.
Fig. 4.9  ​Holding the muscle between the two fingers when injecting the glabella.

4—PATIENT PREPARATION AND INJECTION SKILLS
23
Fig. 4.10  ​Circles of diffusion in crow’s feet treatment zone.
Post Injection
The patient should be asked to press on the site with a tissue immediately after the injection—
even while other sites are being treated. This minimises bruising. Any bruising that occurs should
be treated immediately with an ice pack from the freezer. Camouflage cream or make-up is then
applied before the patient goes home.
Some experts recommend the avoidance of flying or lying down after treatment. This is
supposed to reduce untoward diffusion and, hence, side effects such as ptosis. However, the author
has had only one case of ptosis in more than 30 years of treatments and has seen no evidence
to confirm this theory.
Time
An average botulinum appointment lasts a maximum of 10 minutes. This excludes the first coun­
selling visit (often 90 minutes) but includes reading and signing the consent form, the injections
and settling the account. A nurse practitioner may prepare the patient and provide information
on other aspects of rhytid prevention and management, thus reducing the time spent with the
practitioner.
USER TIP
Imagine that every time the needle pierces the skin, it is like pressing a soft pin cushion, so
that the pins in it bend down towards each other. Now visualise the pins as pain receptors,
which signal pain only if they move. Aim to enter with NO movement.
USER TIP
Avoid the supraorbital nerve, vein and artery complex when injecting the glabellar area. Study
the anatomy and, if in doubt, feel for the supraorbital notch under the medial aspect of the
brow.

24 
BOTULINUM TOXIN IN FACIAL REJUVENATION
USER TIP
Spread the lateral orbital skin between two fingers to observe the orbital veins clearly and take
care to inject around these.
USER TIP
Steady the injecting hand by resting the little finger on the face while spreading the skin with
the other hand. Look carefully for and avoid superficial veins (Fig. 4.11).
Fig. 4.11  ​Steady the injecting hand, and avoid sudden movement by the patient towards the needle.

25
C H A P T E R 5
Patient Selection: The Art
of Understanding Neuromodulation
and Symmetry
One of the most difficult things to do for a beginner with botulinum toxin (BTX) is to anticipate
how the other muscles on the face will react if injections are given to a muscle. It is easy to see
what happens when the treated muscle is paralysed but less easy to anticipate where the signal to
‘that’ muscle will now divert to.
It is also tempting to assume that a right and left muscle will require the same dose for the
same amount of paralysis, but because of natural asymmetry, this does not always happen.
The art lies in learning how to predict where the signals will go after treatment and how to
anticipate and prevent unwanted action of other muscles on the face.
It is important to have a deep understanding of this signalling to muscles of the face before
interfering with the muscle tone of a patient’s face and neck. Examples of muscle signal pairs are
shown in Table 5.1.
Muscle Action
Paired Muscle Action
Corrugator
Depressor anguli oris (sad)
Frontalis muscle
Mentalis (horror)
Frontalis muscle
Depressor anguli oris
Frontalis muscle
Orbicularis oculi
Frontalis muscle
Zygomaticus
Orbicularis oculi
Zygomaticus (smile)
TABLE 5.1  n  Paired Muscles of Expression
USER TIP
Never assume that both sides of the face receive equal innervation.
Principles of Balancing the Face
n Think of BTX as blocking the innervation of a specific area of muscle, as opposed to blocking
the whole muscle.
n Always try to guess where the innervation will go to instead, once you have blocked it, and
anticipate extra movement elsewhere which might need treatment.
n Always remember the long-term effects you are creating via central control of innervation
and feedback; this how you ‘train’ the muscles.

26 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Resting Tone
The muscles of the face tend to mirror each other.
Many wrongly forget that the muscles have a resting tone when not contracting and assume
that the muscles are relaxed when the patient is not actively contracting them. A good way to
demonstrate what the patient will look like after resting tone is turned off is to examine their
eyebrows. When the brows are gently massaged downwards, with the patient’s eyes shut, they
often descend to a lower resting position. This is without resting tone. This is where they would
‘live’ if all their frontalis received BTX.
The basic nerve signal to a muscle of facial expression is usually from a tonically active neuron
that is a cholinergic neuron that fires at 0.5 to 3 impulses per second during the entire duration of
the stimulus. This allows the muscle to have a resting tone and to provide a baseline support to the
facial structures in between voluntary facial movements. For example, the frontalis muscle of the
forehead, innervated by the zygomaticofacial branch of the facial nerve VII, usually has a resting
tone (Fig. 5.1A). The patient may raise the eyebrows on command by contracting the frontalis
muscle (see Fig. 5.1B), but it is usually possible to ‘relax’ the resting tone and to bring the brows to
a lower level than their normal resting tone (see Fig. 5.1C). This latter position imitates and thus
demonstrates the unwanted result of too much BTX across the forehead in an unsuitable patient.
Voluntary and Involuntary Movement
Right and left muscle pairs tend to contract simultaneously. They may also be accompanied
by relaxation of their antagonist muscles. Each muscle of the pair may have a different bulk in
response to the size of the underlying bony framework
Image of Fig.5.1
Image of Fig.5.1
Image of Fig.5.1
Fig. 5.1  Patient with (A) resting forehead tone, (B) raising eyebrows and (C) forced relaxation, demonstrating
unwanted effect of too much botulinum toxin.

5—PATIENT SELECTION: THE ART OF UNDERSTANDING NEUROMODULATION
27
When a facial muscle is turned on to contract, its opposing antagonist muscle is turned off
to relax. The levator muscle cannot open the eyelid unless the orbicularis muscle stops closing it,
and vice versa.
A voluntary signal to the face (e.g. ‘SMILE’) can cause contraction of the right and left lateral
orbicularis oculi (giving crow’s feet), as well as elevation of the outer corners of the mouth (orbi­
cularis oris), but ALSO relaxation of the opposing brow elevators (frontalis fibres) and mouth
depressors (depressor anguli oris and depressor labii inferioris).
The concept of bilateral signalling to muscles on opposite sides of the face was first expressed
by Ewald Hering in the 19th century when he espoused his theory of binocular vision. Hering’s
law is often referred to when describing how the extraocular muscles of the eyes work. For
example, a gaze to the right side requires contraction of the right lateral rectus to pull the eye to
the right and relaxation of the right medial rectus, whilst contracting the left medial rectus to pull
the left eye in the same direction at the same time as the right, and relaxing the left lateral rectus.
This reflex is so strong that an ophthalmic surgeon may correct an inward turning left eye, due
to an overactive medial rectus, by operating to strengthen the opposing muscle on the other eye,
the right lateral rectus.
The facial muscles are supplied by nerves which have
their roots in the midbrain complex. Information on muscle
tone is relayed through the midbrain and back to both sides
of the face (Fig. 5.2).
Research into facial dystonias has confirmed supranu­
clear motor control of the paired muscle groups. This con­
trol is necessary for functions such as blinking, postural
maintenance and extraocular muscle movements. Imaging
modalities have shown that central control is relayed through
the posterior commissure, rostral brainstem and the basal
ganglia of the brain. The frontal cortex and cerebellum are
also involved in neuromodulation. The size of the grey
matter volume in the left parietal lobe had been observed
to decrease in parallel to BTX treatment of spasticity. For
example, variations in the contralateral blink reflex have
been observed with ipsilateral facial nerve lesions.
It is believed that facial expression is produced by the
branching pattern of the common–stem last order presynap­
tic input fibres innervating motor neurones supplying
different muscles. Multiunit surface/electromyography re­
cordings have demonstrated ‘coding’ of pairs. Voluntary
command through the motor cortex can control expression
and cocontraction through the facial nucleus subnuclei.
In the author’s experience, patients who can ‘wriggle their
ears’ have a very active galea aponeurotica–frontalis action.
BTX to the frontalis redirects extra innervation to the scalp,
and now, brow elevation creates a ‘crumple’ in the upper third
of the forehead (see Chapter 8). However, the author has
found that patients often have great difficulty wiggling their
ears when their corrugators are manually ‘blocked’ to stop
them pushing their eyebrows together! It appears that the
glabellar complex is linked to the galea aponeurotica ear wrig­
gling. This, of course, is what happens when a dog points its
ears and draws its brows together when alerted (Fig. 5.3).
Image of Fig.5.2
Fig. 5.2  Diagram demonstrating pas­
sage of signal from the muscle spin­
dles through the brain and then to
both sides of the face allowing simul­
taneous neuromodulation of bilateral
muscle tone.

28 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Botulinum Toxin as a Powerful Neuromodulator
BTX will stop the release of Acetylcholine at a muscle, but in the author’s experience, it never
acts in isolation. There is almost always a perceptible change in the neighbouring innervated
muscles and the paired muscles. There is also a central response, altering the impetus to signal
the muscle with time.
In the early days of BTX, at the time of printing of the first edition of this book, it was not
uncommon to see patients in the United States who had simply received the US Food and Drug
Administration (FDA)-approved ‘glabellar treatment’, as printed on the BOTOX box leaflet,
without any modulation of the rest of the forehead complex, because that had remained ‘off label’.
The bilateral sharp arched ‘BOTOX brows’ are currently seen only with inexperience when the
injector does not take care to ‘neutralise’ the frontalis fibres, which will receive extra innervation,
relayed through the central brain, in response to the unopposed action of the lateral frontalis fibres.
The beginner is taught to look at a patient’s face to get an understanding of where the impor­
tant muscle complexes causing the dynamic rhytids are and how they work in each patient before
treatment (Fig. 5.4).
Looking carefully at the patient’s features will develop the art of SEEING. Several art colleges
run courses on this for medical students (e.g. ), and recent research has
confirmed that art teaching is a powerful way to stimulate the powers of observation for ophthal­
mologists. The GOAL, as will be explained, is to be able to predict the treatment necessary to
result in a satisfying resting tone, not necessarily a flaccid muscle complex. This is dealt with in
more detail in Chapters 8 to 10.
Seeing Skills
Take photographs of your patient at the start of your consultation.
1. Examine bony contours of the face and socket for symmetry and note differences. In Fig. 5.5,
note the differences in the socket dimensions, in the width of the face from the nose and Image of Fig.5.3
Fig. 5.3  Drawing demonstrating paired expression between glabella and scalp in an alert dog, contracting
the glabella (eyebrows drawn together) and the scalp muscles simultaneously (ears raised).

5—PATIENT SELECTION: THE ART OF UNDERSTANDING NEUROMODULATION
29
in the height of the forehead from brow to scalp. Differences between right and left mea­
surements reflect different muscle bulk and different levels of innervation.
2. Manually examine the paired muscles of expression. Try to simulate the effect of BTX
on particular muscle groups by depressing them manually while asking the patient to,
for example, raise eyebrows. This will accentuate the diversion of signalling and indicate
the best placement of injections to avoid peaking, etc. (Fig. 5.6).
3. Predict how a specific injection site will divert signalling to other muscles.
Image
o
f

F
i
g
.
5
.
4
Fig. 5.4  Drawing of active muscle complexes on a face.

30 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Image of Fig.5.5
Fig. 5.5  Photograph of asymmetric features on a face.
Fig. 5.6  Manually depressing the glabella while asking the patient to raise eyebrows.
4. Observe the anatomy of the patient’s skull. Note in particular the frontal bossing of the
forehead, note the line of the orbital rims, note the angle of the nasolacrimal fossa and note
the lower lid to mouth distances.
5. Observe the difference in bulk between the same muscles on the opposite sides of the face.
Allow for this when calculating the dose.

5—PATIENT SELECTION: THE ART OF UNDERSTANDING NEUROMODULATION
31
Discuss with your patients that they are different on each side, that BTX will have a different
effect on each side and that you are going to modify your treatment to balance out the muscles.
Remind them that you may need to see them for a touch up after the ‘balancing’ has happened.
Let them know that you are training their facial muscles to soften where wrinkles form, while
using other muscles to continue to maintain natural facial expression.
Control of Botulinum Toxin-A Placement
BTX-A can be injected to affect muscle position and tone depending on the patient’s needs, as
established by a practised visual examination as previously.
The degree of muscle contraction can be modified by injecting the BTX in four ways
(Fig. 5.7):
1. Paralysis
Placed intramuscularly.
2. Superficial paralysis with underlying active resting tone:
the BTX-A is placed on the surface of the muscle.
Image of
Fig.5.
7
Fig. 5.7  Drawing showing the levels of possible botulinum toxin placement through the skin.

32 
BOTULINUM TOXIN IN FACIAL REJUVENATION
3. BTX-A to the opposite muscle: for example, BTX-A to the brow depressors, allowing the
frontalis to lift the brow unopposed (a BTX brow lift)
4. Placed in low doses over wider areas to ‘neutralise’ inadvertent signal from a treated muscle,
with time allowing the resting tone to be maintained by the deeper layers
Placement can also be intradermal, affecting the sebaceous and sweat gland function, and
probably the pain mediators.
Specific treatment choices will be discussed in Chapters 8 to 10.
USER TIP
It is prudent to invite new patients to return for observation at week 2–3, because at this point,
it is possible to ‘top-up’ any unexpected overactivity of opposing muscles (e.g. causing brow
‘peaking’).

33
C H A P T E R 6
The Art of Patient Selection
and Short- and Long-Term
Management
Some patients have a clear idea of their requirements and a good aesthetic sense. Others trust
their doctors to advise them on ‘what looks good’. They may come for treatment only because
they were told to do so by their friends or their parents. If so, they may resent a treatment to
which they are not fully committed.
The golden rule here is that if patients are not going to derive any perceivable pleasure from
botulinum toxin, then their expenditure will not be properly rewarded. Their trust in their physi­
cian will be reduced, almost as if they had been ‘sold’ a dress in a shop that they did not really
want—such shops are rarely revisited. It is important not to be influenced by such patients’ de­
mands. If the wrong decision is made by the physician and treatment is refused, then at least no
harm is done. The botulinum treatment cannot be ‘undone’ 1 week later if the patient is unhappy
with the outcome (even though the physician had already described the implications of treatment
clearly). Above all, remember that no one NEEDS botulinum toxin for rejuvenation.
Patients frequently misunderstand the role of botulinum toxin and make an appointment to
have it because they heard it advertised and want to ‘lift’ their face. It is a good idea to politely
educate the patient as to how botulinum toxin actually works, and once they understand its effect
on a muscle, inform them too about how wrinkles form.
How to Identify Suitable Patients
Listen to their presenting complaint and then, while still looking at the patient, decide quickly
whether it can be treated with botulinum toxin or not.
Continue the consultation while carefully assessing the patient’s psychological suitability (more
later).
If, on first impression, the patient seems suitable, spend time providing verbal and written infor­
mation about the treatment (this can be done by a trained nurse).
Always examine patients closely—as described in the following chapters—and discuss the likely
outcome of botulinum toxin injections with them.
Be sure that your patients understand what has been said fully before they sign the consent
form.
Selection Process
The decision must be made, prior to treatment, as to whether botulinum toxin can eliminate
rhytids, reduce them and prevent further rhytids or whether another type of treatment is neces­
sary. Consider whether patients are likely to look unusual after treatment (e.g. with peaked brows
or tired appearance with heavy brows). Would they be better to avoid treatment altogether, to
have gradual treatment over a few weeks or to have a different treatment?

34 
BOTULINUM TOXIN IN FACIAL REJUVENATION
The patient should have given an accurate age and history of smoking (Table 6.1) (although
some do not!), and a full medical history reveals no obvious contraindications such as myasthenia
gravis, pregnancy, etc. (see Chapter 7).
All new patients must be assessed physically and mentally. Written information about botuli­
num toxin should be provided at the time of consultation, and patients should have time to digest
this before an opportunity is provided to ask the physician any relevant questions.
Initial Physical Assessment: Age and Skin Condition
With experience, it is possible to decide at a glance whether or not botulinum toxin will help a
patient and what changes to the face may be expected as a result of the treatment (see Chapter 5 on
neuromodulation). For example, a 29-year-old nonsmoker with crow’s feet that wrinkle only when
she is smiling will do very well (Fig. 6.1). Botulinum toxin will rid her of wrinkles completely. On
the other hand, her sporty friend of the same age, who had not used adequate sun protection, may
have wrinkles at rest with an early reduction in lower lid skin tone. Time must be spent explaining
to her that she may possibly be disappointed with botulinum toxin—the injections might help to
stop the clock and avoid new rhytids, but without alternative treatments (including sun protection,
laser resurfacing, stopping smoking) she will continue to have her wrinkles.
Fig. 6.1  Young nonsmoker with dynamic wrinkles only.
Consider the following:
Look for:
General skin condition
Sun damage, pigment spots, poor tone.
Age
Cardiovascular status, skin perfusion, overall tone and skeletal structure.
Brow position
Examine lash/brow distance.
How does it change with expression?
Are the forehead wrinkles the result of ‘holding’ brows?
Crow’s feet
At rest or in motion?
Do they extend down towards the perioral lines when smiling?
Hooding
Is there a fold of skin at the corner of the eye that disappears when the
patient lifts the brow?
TABLE 6.1  n  Signs to Be Observed Quickly Before a Full Consultation Takes Place

6—THE ART OF PATIENT SELECTION AND SHORT- AND LONG-TERM MANAGEMENT
35
Expected botulinum toxin treatment outcomes may be addressed for short- and long-term
management groups. Some patients just want a treatment for a special occasion; many patients
resist the idea of long-term repeated injections. Other patients want a long-term maintenance
plan in keeping with their personal health and self-care agendas.
SHORT TERM MANAGEMENT
Short-term treatment can be ideal for a special occasion and for many patients is their only af­
fordable option. One treatment can quickly eliminate dynamic lines and soften the underlying
static lines, but the effect almost always lasts only 12 weeks, particularly if the treated muscle is
very strong. Suitability depends on age.
Crow’s feet always return! It appears that the innate drive to smile, particularly as a muscle
paired with perioral smile muscles for expression, is deeply embedded in our primal drive.
Patients may be reassured with photographs that regular botulinum toxin injections are not
necessary to eliminate static rhytids and that these may be eliminated with CO2 laser at any time.
Short-term botulinum toxin (e.g. one treatment lasting 12 weeks) is often indicated following
CO2 resurfacing to maintain a flat muscle as the skin recovers and builds up its collagen (Fig 6.2A
and B, crow’s feet pre- and post-CO2 laser resurfacing).
Younger patients (,35 years old) do very well with ‘one off’ treatments. They respond quickly, and
their underlying skin tone usually protects them from untoward thinning or sagging (Fig. 6.3A and B).
Image of Fig. 6.2
Image of Fig. 6.2
Fig. 6.2  Patient before (A) and after (B) botulinum toxin and CO2 laser resurfacing for static wrinkles.
Image of Fig. 6.3
Image of Fig. 6.3
Fig. 6.3  (A) Crow’s feet before treatment and (B) after treatment.

36 
BOTULINUM TOXIN IN FACIAL REJUVENATION
They can usually receive stronger concentrations of botulinum toxin to the full body of their muscles
with maximum duration of effect.
Patients who present for the first treatment for their facial rhytids over the age of 45 years old
tend to have limited knowledge of active skin care and ultraviolet light protection. Their rhytids
are both dynamic and static. They often have premature brow sagging with blepharochalasis and
ageing of their eyelid skin (Fig. 6.4).
These patients are strong neuromodulators of their muscle signalling. Any asymmetrical age­
ing, in keeping with any underlying basic asymmetry, is easy to spot. A careful examination will
anticipate how they would look, should they select botulinum toxin treatment.
Older patients with sun-damaged loose skin, with reduced ‘lift’, are at a higher risk of the
following undesirable outcomes to botulinum toxin injections:
n Dropping their brow resting tone, creating undesirable heavier brows and eyelid bags (Fig. 6.5).
n Developing vertical sagging of their lateral orbicularis, dropping their Sub orbicularis oculi fat
(SOOF) suspension and therefore increasing and deepening their nasolabial folds (Fig 6.6).
n Reducing their lateral orbital rim volume, creating a ‘thin’ look, sometimes revealing vertical
veins on the rim (Fig. 6.7A and B).
n Getting strong scalp overaction, ‘crumpling’ the superior third of their forehead when their
frontalis is treated (Fig. 6.8A–C).
Such patients can do very well but could be advised to avoid having their first botulinum toxin
treatment within 2 weeks of a major event, when the botulinum toxin would be fully effective. In
the author’s clinic, they are informed if it is obvious that they should have blepharoplasty first.
Some can be successfully treated with a lower volume of botulinum toxin layered at the subcuta­
neous level, with a review for a top up at 3 weeks. It is often wise to recommend filler to the
glabella for a short-term fix (although it does last 9 to 12 months), rather than risk making the
patient look worse with undesired loss of muscle tone. It is easier to ‘train’ the muscles gradually
Fig. 6.4  Sun-damaged skin.
Fig. 6.5  Low, heavy brows.

6—THE ART OF PATIENT SELECTION AND SHORT- AND LONG-TERM MANAGEMENT
37
Image of Fig.
6.6
Fig. 6.6  Drawing of the lateral orbicularis rhytids before (A) and after treatment (B), showing sagging of the
sub orbicularis oculi fat (SOOF) after treatment, with deepening of the nasolabial folds.
with smaller volumes of subcutaneous botulinum toxin whilst keeping resting tone at the deeper
layers of the support muscles.
LONG-TERM MANAGEMENT
A natural youthful look, the goal of the author’s treatments, is one with plenty of facial expression,
with a radiant complexion and with youthful natural facial volume balanced with the patient’s own
asymmetry. The patient must, above all, not look like he or she has been having any treatments.

38 
BOTULINUM TOXIN IN FACIAL REJUVENATION
Image of Fig. 6.8
Image of Fig. 6.8
Image of Fig. 6.8
Fig. 6.8  (A) At rest before botulinum toxin, (B) moving forehead and scalp before botulinum toxin and
(C) after botulinum toxin with movement.
Image of Fig. 6.7
Image of Fig. 6.7
Fig. 6.7  (A) Before and (B) after botulinum toxin treatment: note thinning of lateral orbital rim.
Figs 6.9A, B and 6.10A, B demonstrate this in patients who featured in the first edition of this
book in 2003 and now, in 2018, look almost the same.
USER TIP
The essence of good long-term management is to predict, anticipate and avoid untoward results!
Patients having long-term botulinum toxin maintenance should be told that botulinum toxin
will eventually reduce muscle bulk and therefore facial volume. Advise them that they will have
difference doses in different locations depending on their appearance at their first follow-up visit.
These patients may come at various ages to ‘start taking care’ of their skin, etc.
In the author’s experience, patients who started at a younger age frequently look better after
15 years of botulinum toxin treatments (Fig. 6.11A and B) compared with patients the same age
who attend for the first time.