Botulinum Toxin in Clinical Practice [1st ed. 2021] 3030806707, 9783030806705

Table of contents :
Preface
References
Acknowledgement
Contents
Chapter 1: Introduction
A Brief History of Botulinum Neurotoxins
The Biophysiology of Botulinum Neurotoxins
Botulism
Non-A Botulinum
The Pharmacology of Botulinum Neurotoxins
References
Chapter 2: Anatomical Considerations
Facial Musculature
Frontalis Muscle
Corrugator Muscle
Procerus Muscle
Orbicularis Muscle’
Aging and the Basis of Therapeutic Muscular Relaxation
References
Chapter 3: Basic Concepts of Beauty and Youth
The Importance of the Human Face
Gender Specifics
Skin Pigmentation
History of Awareness of Facial Beauty
Concepts and Analysis of Beauty
References
Chapter 4: Skin
Skin: History
Skin: Structure/Anatomy
Physiology and the Aging Face
Bone
Retaining Structures
Muscles and Supporting Fascia
Subcutaneous Layer
Skin
Epidermis
Dermis
Skin Types
Skin Aging
Genetics
Hormonal
The Sun
Visible Light
Ultraviolet Light
Infrared Light
Gender
Smoking
Ethnicity
Optimisation
Prevention
Retinoids
References
Chapter 5: Clinical Assessment
Consultation: History and Examination
History
Examination
Photography and Consent
Practical Tips
Chapter 6: Administration of Botulinum Neurotoxin
Product Selection, Reconstitution and Storage
Technique and Product Placement
Common Treatment Areas
Glabellar Complex
Top Tips
Forehead
Top Tips
Crow’s Feet
Top Tips
Post-Injection Advice
Safety, Side-Effects and Complications
Systemic
Localised
Lack of Effect/Antigenicity
References
Chapter 7: Medical Uses of Botulinum Neurotoxin
Ophthalmology
Neurology
Gastroenterology
Urology
Dental
Psychiatry
References
Chapter 8: The Patient’s Page
Basic Premises
A Patient Writes
Chapter 9: Education, Training and Regulation
HEE
JCCP and CPSA
References
Glossary
Index

Citation preview

In Clinical Practice

Miles G. Berry

Botulinum Toxin in Clinical Practice

In Clinical Practice

Taking a practical approach to clinical medicine, this series of smaller reference books is designed for the trainee physician, primary care physician, nurse practitioner and other general medical professionals to understand each topic covered. The coverage is comprehensive but concise and is designed to act as a primary reference tool for subjects across the field of medicine. More information about this series at http://www.springer. com/series/13483

Miles G. Berry

Botulinum Toxin in Clinical Practice

Miles G. Berry The London Welbeck Hospital London, UK

ISSN 2199-6652     ISSN 2199-6660 (electronic) In Clinical Practice ISBN 978-3-030-80670-5    ISBN 978-3-030-80671-2 (eBook) https://doi.org/10.1007/978-3-030-80671-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To those no longer with us—Anthony, Jennie & Vivien—who lit and fanned the flame of my academic inquisitiveness. Memories burn bright still. To Wilhelmina for her perseverance, belief and unstinting support in her son. To my darling daughter, AAA, for providing more joy than words will ever be able to convey.

Preface

So why another book about one of the most recognisable names of our times? As a trainer with the UK’s longest established provider of non-surgical aesthetic treatments over the last 5  years, a degree of commonality of the questions and confusions has become apparent amongst the hundreds of delegates I have taught. Less a fault of their own, far more the wider environment, fundamental misconceptions seem deep-­ rooted. A recent article by the Science Editor of one of our broadsheet newspapers also made the same mistake of describing the ‘lumps and bumps’ of Botox! Thus, even relatively well-educated sources fall into the trap of attributing any poor outcome of aesthetic intervention to ‘Botox’. In fact, dermal fillers are the cause of both more frequent and locally destructive adverse outcomes. Whilst dermal fillers ‘fill’ and provide volume, the toxin produced by the bacterium Clostridium botulinum is a highly specific neurological agent that ultimately stops the contraction of muscles. The sought-after clinical consequence in the face, of course, is the relaxation of wrinkles in the skin overlying such muscles. A great deal is now known about its mechanism of action and valuable spin-offs from related research include important biological processes such as neuronal transport, protein–protein interactions and transmembrane transport systems. Neurotoxins in medical and cosmetic scenarios have enjoyed a remarkable life thus far since first appearing in the 1970s, originally as a treatment for squint, and the list of medical uses of botulinum neurotoxin has mushroomed (see Chap. 7). Its cosmetic use arose rather serendipitously from

viii

Preface

the observation of reduced skin wrinkles during treatment for blepharospasm. Its rise has been swift and spectacular with many millions of injections having allowed its safety and optimal indications to be clarified. It now seems to have an indispensable role in modern grooming for many both in and out of the public eye. It has increased so rapidly presumably as a result of minimal pain and widespread beneficial effects, along with the lack of invasiveness, permanent incisions, risk and downtime that accompany surgery. Whilst much has already been written, sources have tended to be either pure research articles in scientific journals or less rigorous, and not infrequently misleading, journalistic copy. The author may have rather more of an interest in science than might be considered healthy (Berry [1]) but was stimulated to write this book as a fusion of the two, often disparate, avenues having initially found this challenging also. It is therefore intended as a source of information, which should be equally relevant to the potential patient seeking a little more understanding of the underlying science, and limitations, of neurotoxin treatment, and the busy healthcare professional seeking to learn anew or refresh knowledge. It is timely, and some might say overdue, as recent focus has turned to the previously unregulated aesthetic medicine sector in the UK following the UK Government’s report (Keogh [2]). Health Education England (HEE) was subsequently charged with establishing some form of education and training system where none had previously existed. Albeit rather intensive, their Level 7 Qualification seeks to outline a globally recognised injector training system and has now been passed on to the JCCP (Joint Council for Cosmetic Practitioners). At the time of writing, it awaits formal incorporation into UK law. Errare humanum est so the facts presented herein are accurate as far as I am aware, but please accept my apologies for errors. I would not be at all offended to receive corrections, omissions and suggestions for future editions at ­info@ milesgberry.com. London, UK

Miles G. Berry

Preface

ix

References 1. Berry MG, Stanek JJ. Botulinum neurotoxin A: a review. J Plast Reconstr Aesthet Surg. 2012;65:1283–91. 2. Keogh. 2013; https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment_data/file/192028/Review_ of_the_Regulation_of_Cosmetic_Interventions.pdf.

Acknowledgement

Progress always involves ‘standing on the shoulders of giants’ and I acknowledge the wisdom, patience and mentorship of numerous valued colleagues, Jan Stanek in particular. Huge thanks also to Lizzie for not only proofreading but being a rare and brilliant spirit of light.

Contents

1 Introduction���������������������������������������������������������������������   1 2 Anatomical Considerations�������������������������������������������  15 3 Basic Concepts of Beauty and Youth���������������������������  29 4 Skin�����������������������������������������������������������������������������������  39 5 Clinical Assessment�������������������������������������������������������  65 6 Administration of Botulinum Neurotoxin�������������������  73 7 Medical Uses of Botulinum Neurotoxin���������������������  95 8 The Patient’s Page ���������������������������������������������������������101 9 Education, Training and Regulation ��������������������������� 105 Glossary����������������������������������������������������������������������������������� 109 Index����������������������������������������������������������������������������������������� 111

Chapter 1 Introduction

A Brief History of Botulinum Neurotoxins As summarised in Table 1.1, the history of Botulinum neurotoxin (BoNT) begins with a German by the name of Justinus Kerner who described it in the early nineteenth century (1817–1822). Perhaps combining his dual professions as poet and physician, he named it ‘sausage’ poison for its tendency to thrive in poorly-prepared meat products, particularly those self-canned. It took quite some time to appreciate the toxin’s sensitivity to heat, it being very heat-labile (Licciardello [1]), and its connection with undercooked meat products. Adequate cooking therefore remains the best defence against food-­ borne botulism. Half a century later Muller borrowed the Latin for sausage—“botulus”—hence the disease becoming known as botulism. The Belgian Emile van Ermengem isolated the bacterium in 1897. Edward Snipe then managed to isolate purified neurotoxin in 1928 and the mechanism of action, as the blocking of neuromuscular transmission, was clarified in 1949 (Burgen [2]). Alan Scott, an ophthalmologist, deserves recognition for his work in the 1970s. Following primate trials he made the rather bold step of the first injection into humans. Recognising the highly-specific paralysing effect he administered BoNT-A © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. G. Berry, Botulinum Toxin in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-030-80671-2_1

1

2

Chapter 1.  Introduction

Table 1.1 Timeline—notable figures in the botulinum neurotoxin story Year Name Milestone 1817– Justinus First description as ‘sausage poison’ 1822 Kerner 1872

Muller

Coined name after the Latin for sausage “botulus”

1895

Van Ermengem

First to isolate the bacterium Clostridium botulinum

1928

Snipe

First to culture and isolate the exotoxin

1949

Burgen

Neuromuscular junction blockade as mechanism of action

1973

Scott

Primate trials

1981

Scott

Strabismus treatment

1985

Scott

Blepharospasm

1989

Clark

Used for symmetry in iatrogenic facial nerve paresis

1992

Carruthers

First prospective study of BoNT for glabellar ‘frown’ lines

1993

Bushara & Park

Inhibition of sweating (autonomic)

into extra-ocular muscles in order to treat squint (Scott [3]). He utilised a fundamental principle; that of the dynamic balance between agonist and antagonist muscles that holds today, of particular importance for the brow as will be seen later. He published further on blepharospasm (Scott [4]), a debilitating condition of involuntary blinking of the eyelids. Bragging rights to the first reported use of BoNT-A for a cosmetic application is subject to something of a ‘bun-fight’. Most authors cite the 1992 landmark contribution of the husband-and-wife Carruthers’ team (Carruthers [5]). Whilst using botulinum neurotoxin to treat blepharospasm the ophthalmologist Jean’s patients noted a reduction in skin wrin-

A Brief History of Botulinum Neurotoxins

3

19 20

17 20

15

11

13

20

20

Year

20

09

07

20

20

05

03

20

01

20

20

19

19

99

8 6 4 2 0 97

Injections per annum (millions)

kling around the eyes. As legend has it, she mentioned this to her husband, dermatologist Alistair, who trialled it on some of his own patients. Given that in excess of 7  million injections were made in the USA alone last year (Fig.  1.1) one wonders if they have ever given idle thought what might have occurred had they patented it! Interestingly, other than a small dip following 2008’s global banking collapse, the graph shows an inexorable increase in prescriptions as shown below although the coronavirus pandemic of 2020 will undoubtedly have a not insignificant effect. A Plastic Surgeon laid retrospective claim to the first use based on symmetrising a contralateral frontal branch paralysis post-facelift originally published in 1989 (Clark [7]). Whilst clever, in truth he did not specifically  highlight the cosmetic association between muscle paralysis and skin wrinkles so credit should probably go to the Carruthers for fully appreciating and taking advantage of botulinum’s ‘penicillin moment’. The first randomised study confirmed both efficacy and safety in 2004 (Ascher [8]) and the rest is, as they say, history. FDA (Food and Drug Administration; United States) approval, for Botox™ Cosmetic, was granted in April 2002, initially limited to the glabellar area. Approval for the use of BoNT-A to treat the crow’s feet area, lateral to the eyes, was

Fig. 1.1  Botulinum toxin A procedures in the USA over the past 22  years (1997–2019) according to the American Society for Aesthetic Plastic Surgeons [6]

4

Chapter 1.  Introduction

granted in September 2013. It is important for all—patients and practitioners alike—to be aware that at the time of writing all other areas are treated in an ‘off-label’ fashion. In 1993 its use was extended beyond the voluntary (somatic) to the involuntary (autonomic) nervous system when it was shown to be useful for hyperhidrosis i.e., excessive sweating (Bushara [9]). Regarding nomenclature, the word Botox, being formed by elision of the initial syllables of Botulinum and toxin, was used as a generic descriptor for years. Simplistically convenient though the word might be, one should be aware Botox® has now been trademarked by Allergan. For completeness, although concerns over overtly malign use have been expressed, botulinum neurotoxin has yet to make the leap from potential to actual biological warfare. One obvious reason is that the incapacitating symptoms (ie., botulism) develop gradually in comparison to nerve agents such as the considerably more immediate sarin. Delivery of the fragile toxin is also an issue as the CIA discovered in their ‘Operation Mongoose’. This plot attempted to assassinate Fidel Castro by impregnating his favoured Cuban cigars with botulinum. Or so rumour has it (Harris [10]).

The Biophysiology of Botulinum Neurotoxins For those with a yen for detail Clostridium botulinum  is an anaerobic, Gram negative, spore-forming bacillus that produces a potent neutral-specific exotoxin. Up to 8 serological types (A, B, Cα, Cβ, D, E, F and G) of botulism have been recognised (Osako; Smith [11, 12]), based on the antigenic specificity of each toxin (Table 1.2). They share functional and structural commonalities in addition to high degrees of similarity at an amino acid sequence level. All act on the same target receptor and produce a flaccid paralysis. Interestingly, although biochemically very similar to tetanus, the latter exerts the diametrically opposite effect with the spastic paralysis of tetanus having earned it the nickname ‘lockjaw’.

The Biophysiology of Botulinum Neurotoxins

5

Table 1.2  Some features of the serological subtypes of BoNTs Serotype Potency Duration A Highest Longest Dysport or Botox 3–6 months B

1/200th of A

Cβ

1/10th of A

6 weeks, less predictable

Neurobloc or Myobloc Rare, in animals

D

Rare, in animals

E

Human

F

4–5 weeks

Human

G

Rare, in animals

H

Most potent—2 ng fatal

Types A, B, E and F are responsible for human botulism. C and D produce most animal cases, typically wild fowl, poultry, cattle, horses and some fish species. Although type G has been isolated from soil in Argentina, there have been no reported outbreaks involving it. The organism and its spores are widely distributed in nature. They occur in both cultivated and forest soils, bottom sediments of streams, lakes, and coastal waters, in the intestinal tracts of fish and mammals and the gills and viscera of crabs and other shellfish. Types A and B are the only forms commercially available and, whilst they have very similar functions, are antigenically dissimilar, which allows those very few who have developed antibodies to one to be able to receive treatment with the other. The formulations, dosing and response are, however, different. Type A is by far the most widespread due to its potency, greater stability and ease of production in culture (Fagien [13]). Botulinum toxin A is a polypeptide comprising two chains: one light (with a 50 kDa molecular weight and enzymatic activity) and the other, heavy (100  kDa), strongly conjoined by

6

Chapter 1.  Introduction

virtue of a disulphide bond. It is this latter that is disrupted upon toxin activation. BoNT-A exists in complex form with the two polypeptide chains of the fragile toxin being surrounded by a coat of proteins that protect it from destruction by the highly acidic environment of gastric juices when ingested into the gastrointestinal tract. After absorption and a rise in pH, however, the protective proteins release the neurotoxin, which produces the well-known clinical features of botulism.

Botulism The very word ‘botulism’ seems enough to strike fear into many so poisonous is Botulinum’s neurotoxin. It is said to be the most acutely toxic substance known to man with a median lethal dose (i.e., that which kills 50%) of 1 ng/kg, that is 1 in 1,000,000,000 g, intravenously (Erbguth [14]) and 3 ng/ kg inhaled (Arnon [15]). Thus 70–210 ng is sufficient to kill a 70 kg adult. Food-borne botulism (as distinct from wound botulism and infant botulism) is a severe food poisoning resulting from ingestion of foods containing preformed neurotoxin. Infant and wound botulism differ with both resulting from infection by spores, rather than preformed toxin, and it is these spores that germinate in anaerobic environments. Whilst the spores are heat-resistant and can survive in inadequately processed foods, the heat-labile toxin is denatured by heating at 80 °C for 10  min or longer. Although uncommon, botulism is of considerable concern because of its high mortality rate if not treated immediately and properly. Most of the 10–30 outbreaks reported annually in the United States are associated with inadequately processed, home-canned foods, but occasionally commercially-produced foods have been involved. Sausages, meat products, canned vegetables and seafood products have been the most frequent vehicles for human botulism. Onset of symptoms in foodborne botulism is usually 18–36  h after ingestion of the food containing the toxin,

The Biophysiology of Botulinum Neurotoxins

7

although cases have varied from 4 h to 8 days. Early signs of intoxication include marked lassitude, weakness and vertigo, usually followed by double vision and progressive difficulty in speaking and swallowing. Difficulty in breathing, weakness of other muscles, abdominal distension, and constipation are also not uncommon symptoms. It is important to appreciate that therapeutic  BoNT-A has a rather different effect when injected into the skin! Biochemically, Botulinum neurotoxin is a complex structure with the chemical formula C6760H10447N1743O2010S32 (Fig. 1.2). The pure neurotransmitter has a molecular weight of 150 kDa, but is provided in two forms according to manufacturer—750  kDa for Dysport and 900  kDa for Botox—in imitation of the situation in vivo. With the potential market so large, and such a wealth of different products within, there has been a move towards the use of generic names, certainly in scientific publications. “Botox” has undoubtedly become the “Hoover” of its generation and is now synonymous, albeit incorrectly, with any number of non-surgical interventions, whether they involve muscular relaxation or not. Unfortunately, the generic terms do not necessarily roll off the tongue as shall be seen … AbobotulinumtoxinA—Dysport® OnabotulinumtoxinA—Botox®; Botox® Cosmetic IncobotulinumtoxinA—Xeomin® (RimabotulinumtoxinB—Myobloc®) Incidentally, not all neurotoxins are created equal and an interesting study sought to allow more accurate and direct comparisons between proprietarily-protected products  as summarised in Table  1.3. For obvious reasons, such direct comparative studies are neither common nor encouraged by parent companies who not infrequently fund the research studies of their own product. With BoNTA acting at the muscular level, the individual’s muscle mass will have a direct bearing on response. It is therefore no surprise that males, with up to 50% more skeletal muscle mass (Janssen [17]), require more neurotoxin for a similar clinical effect.

8

Chapter 1.  Introduction

Fig. 1.2  Not abstract art, but a rather beautiful image of something so deadly: the 3D structure of botulinum toxin A according to Lacy et  al. [16]. [See https://en.wikipedia.org/wiki/Botulinum_toxin#/ media/File:Botulinum_toxin_3BTA.png]

Whilst the above ‘big three’ have dominated the market over the past decades, the sheer size of it has drawn new entrants, including prabotulinumtoxinA (Jeuveau by Evolus, Seoul, South Korea). DaxibotulinumtoxinA (Revance) is currently generating interest for its possible greater duration of action, approaching 6  months, compared to the standard 3–4 months of the others (Carruthers [19]).

The Pharmacology of Botulinum Neurotoxins

9

Table 1.3 Comparison of activities of the three main BoNT-As available in UK (Frevert [18]) Clostridial Specific Molecular protein potency Product weight (kDa) (ng/100 U) (u/ng) Botox®/ 900 0.73 137 Vistabel® Dysport®/ Azzalure®

600 and 300

0.65

154

Xeomin®/ Bocouture®

150

0.44

227

Non-A Botulinum Type B (rimabotulinumtoxin B) is the only non-A subtype commercially available and goes by the name of MyoBloc® in the US and Neurobloc® in the UK and Europe. Its use is primarily in the rare instances where patients have become resistant to type A. Although not considered unduly immunogenic a correlation does exist between dosing schedule and the development of resistance to BoNT-A, aetiopathologically via an antibody-mediated mechanism.

The Pharmacology of Botulinum Neurotoxins BoNT exerts its effect at the neuromuscular junction (NMJ). This important structure translates electrical impulses into a mechanical action by the associated muscle. Muscles are either striated (voluntary, somatic) or smooth (involuntary, autonomic). The former includes those that move the skeleton—e.g., biceps or hamstrings—or produce facial expression, whilst the latter are not under conscious control—e.g., areolar and cardiac muscles. At the end of each nerve is a swelling—the pre-synaptic terminal—filled with tiny packages of pre-formed neurotransmitter (NT). Upon stimulation by the requisite nerve impulse they instantaneously fuse with the membrane and

10

Chapter 1.  Introduction

release the stored NT.  After diffusion across the nerve-­ muscle interspace they bind to specific receptors triggering muscle activity by way of contraction. There are several NTs in the body, one of the most important  being Acetylcholine (ACh), which mediates voluntary and involuntary muscle excitation along with some autonomic secretory functions such as sweating. BoNT interferes with this process through a highly specific mechanism involving a single protein, SNAP-25 (one of 60 or  so transmembrane structures in the SNARE—SNap (Soluble N-ethymaleimide-sensitive factor) Attachment Receptor—complex) that prevents fusion of the ACh-vesicles with the pre-synaptic nerve terminal. Ordinarily, SNAP-25 plays an important role in what has been termed ‘zippering’—Fig. 1.3 (Lagow [20]) and so key is it to the entire process that only 10–15% SNAP-25 cleavage is required for total paralysis (Montecucco [21]).

Fig. 1.3 The descriptively-named ‘zippering’ mechanism that provides an explanation for the fusion of internal vesicles with the cell membrane to permit release of ACh (Lagow [20]) [https://journals. plos.org/plosbiology/article?id=10.1371/journal.pbio.0050072 for Open Access statement]

The Pharmacology of Botulinum Neurotoxins

11

The precise mechanism is fascinating and a wonderful example of the ingenuity of nature. Botulinum neurotoxin is actually two individual elements, one 50 and the other 100 kDa in molecular size, termed ‘light’ and ‘heavy’ for obvious reasons. In vivo the two are joined as a dimer and are protected by surrounding proteins due to the toxin’s inherent fragility. Once in the body, the bond between the two chains is cleaved. The heavy chain is sacrificial, apparently forming a transmembrane channel through which the light chain is ‘chaperoned’ (Koriazova [22]). Once internalised it inhibits the ACh-containing vesicles prohibiting membrane-­ association and thereby release across the NMJ.  This is a chemical denervation and raises the question why, if chemically permanent, the clinical effect wears off over 3 months or thereabouts? It seems the body senses the lack of neuronal feedback and consequently stimulates the production of new axons that sprout from the nerve terminal (AngautPetit [23]). One of BoNTs beneficial pharmacological properties is potency so that very small doses are required for clinical effect. Moreover, it has a very high affinity as demonstrated by the finding of minimal circulating toxin (of the order 10−12–10−14 M) during fulminant botulism (Pirazzini [24]). In a, perhaps brave, clinical experiment BoNT has been shown to be highly neuro-specific, but not neurotoxic in human volunteers (Eleopra [25])! Despite fears of systemic effects, it has a limited local diffusion the range of which depends on volume (Carli [26]) and its effect is reversible with time. Fascinatingly, whilst most toxins kill cells, BoNTs are unusual in their cellular effect: whilst function may be temporarily blocked, the cell remains alive and well (Johnson [27]). Moreover, extensive and long-term clinical experience has yet to demonstrate any particular neurodegenerative sequelae (Naumann [28]).

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Chapter 1.  Introduction

References 1. Licciardello JJ, Nickerson JT, Ribich CA, Goldblith SA. Thermal inactivation of type E botulinum toxin. Appl Microbiol. 1967;15:249–56. 2. Burgen ASV, Dickens F, Zatman LJ.  The action of botulinum toxin on the neuro-muscular junction. J Physiol. 1949;109:10–24. 3. Scott AB.  Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980;87:1044–9. 4. Scott AB, Kennedy RA, Stubbs HA. Botulinum toxin A injection as a treatment for blepharospasm. Arch Opththalmol. 1985;103:347–50. 5. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol. 1992;18:17–21. 6. https://www.plasticsurgery.org/documents/News/Statistics/2019/ plastic-­surgery-­statistics-­full-­report-­2019.pdf. Accessed March 2021. 7. Clark RP, Berris CE.  Botulinum toxin: a treatment for facial asymmetry caused by facial nerve paralysis. Plast Reconst Surg. 1989;84:353–5. 8. Ascher B, Zakine B, Kestemont P, Baspeyras M, Bougara A, Santini J. A multicenter, randomized, double-blind, placebocontrolled study of efficacy and safety of 3 doses of botulinum toxin A in the treatment of glabellar lines. J Am Acad Dermatol. 2004;51:223–33. 9. Bushara KO, Park DM. Botulinum toxin and sweating. J Neurol Neurosurg Psychiatry. 1994;57:1437–8. 10. Harris R, Paxman J. A higher form of killing. London: Chatto & Windus; 1982. 11. Osako M, Keltner JL. Botulinum A toxin (Oculinum) in ophthalmology. Surv Ophthalmol. 1991;36:28–46. 12. Smith TJ, Hill KK, Raphael BH.  Historical and current perspectives on Clostridium botulinum diversity. Res Microbiol. 2015;166:290–302. 13. Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial reshaping. Plast Reconstr Surg. 2003;112:6S–18S. 14. Erbguth FJ.  Historical notes on botulism, Clostridium botulinum, botulinum toxin and the idea of the therapeutic use of the toxin. Mov Disord. 2004;19:S2–6.

References

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15. Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059–70. 16. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol. 1998;5:898–902. 17. Janssen I, Heymsfield SB, Mian Wang Z, Ross R. Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J Appl Physiol. 2000;89:81–8. 18. Frevert J.  Content of botulinum neurotoxin in Botox®/ Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D. 2010;10:67–73. 19. Carruthers JD, Fagien S, Joseph JH, Humphrey SD, Biesman BS, Gallagher CJ, et  al. DaxibotulinumtoxinA for injection for the treatment of glabellar lines: results from each of two Multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). Plast Recon Surg. 2020;145:45–58. 20. Lagow RD, Bao H, Cohen EN, Daniels RW, Zuzek A, Williams WH, et al. Modification of a hydrophobic layer by a point mutation in syntaxin 1A regulates the rate of synaptic vesicle fusion. PLoS Biol. 2007;5:e72. 21. Montecucco C, Schiavo G, Pantano S.  SNARE complexes and neuroexocytosis: how many, how close? Trends Biochem Sci. 2005;30:367–72. 22. Koriazova LK, Montal M.  Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat Struct Biol. 2003;10:13–8. 23. Angaut-Petit D, Molgó J, Comella JX, Faille L, Tabti N. Terminal sprouting in mouse neuromuscular junctions poisoned with botulinum type A toxin: morphological and electrophysiological features. Neuroscience. 1990;37:799–808. 24. Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol Rev. 2017;69:200–35. 25. Eleopra R, Tugnoli V, Rossetto O, Montecucco C, De Grandis D.  Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in human. Neurosci Lett. 1997;224:91–4. 26. Carli L, Montecucco C, Rossetto O. Assay of diffusion of different botulinum neurotoxin type A formulations injected in the mouse leg. Muscle Nerve. 2009;40:374–80.

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Chapter 1.  Introduction

27. Johnson EA, Montecucco C.  Botulism. Handb Clin Neurol. 2008;91:333–68. 28. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981–90.

Chapter 2 Anatomical Considerations

Facial Musculature As can be seen in Fig. 2.1, there is a plethora of facial muscles, hence the importance of having BoNT-A injected by someone who is well versed in human facial anatomy both from a safety perspective and an ability to generate reproducible, high-quality outcomes. It will be helpful to comprehend that wrinkles form perpendicular to the direction of muscle action, thus ‘crow’s feet’ wrinkles, for example, are radial lines extending from the orbit as the result of circular, sphincter-­ like orbicularis oculi action (Fig. 2.5). Another facet often not fully appreciated by the beginner is that facial muscles attach to the skin. We are all familiar with the large muscles that move the body by virtue of being attached to the skeleton. It is less well comprehended that facial muscles must at some point attach to, and thereby, move the skin in order to produce the infinite array of expressivity. One of the most useful things I have found whilst teaching is spending some time marking the surface anatomy as I well recall a degree of bewilderment myself, despite an inherent enthusiasm for human anatomy. The details of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. G. Berry, Botulinum Toxin in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-030-80671-2_2

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Chapter 2.  Anatomical Considerations

Frontalis Corrugator supercilii

Procerus

Orbicularis oculi Levator labii superioris

Naslis

Masseter

Orbicularis oris

Depressor anguli oris Depressor labii

Playsma

Mentalis

Fig. 2.1  Summary of the prime facial muscles involved in expression that consequently find themselves targets for neurotoxin-mediated paralysis [author’s own images throughout Chap. 2]

muscles useful to us in this context rarely seem to have found their way into standard texts so some detail would not go amiss. There are a number of muscles involved, (Figs. 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, and 2.8), and their roles and relative effects must be understood to both achieve satisfactory results and avoid pitfalls. Whilst the primary elevator of the forehead is the frontalis, it has several antagonists that depress the brow. Medially, these comprise the procerus and corrugator supercilii. Orbicularis oculi is an oft-forgotten muscle, but it possesses a lateral brow depressor effect.

Frontalis Muscle

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Fig. 2.2  Frontalis muscle

Frontalis Muscle Frontalis is a thin, quadrilateral-shaped muscle intimately associated with the superficial fascia of the cranium. It may be the only muscle in the body that does not have one of its ends attached to bone (each belly connects to occipitalis via

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Chapter 2.  Anatomical Considerations

Fig. 2.3  Corrugator supercilii muscle

the galea aponeurotica) but is certainly the sole elevator of the eyebrow and therefore key to its shape and position. Origin: from galea aponeurotica Insertion: brow skin (interdigitating with brow depressor muscles) Innervation: temporal branch of facial nerve Action: elevation of the brow, for example with surprise

Frontalis Muscle

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Fig. 2.4  Procerus muscle

Often assumed perfectly symmetrical, recent cadaver study of frontalis has characterised its anatomy in greater detail, particularly the medial variability (Spiegel [1]). Measuring from the orbital rim, mean dehiscence was found to be similar at 3.5 (±1.6) cm and 3.7 (±1.8) cm in males and females respectively. Horizontal angulations, however, differed at 62.4° and 38.2° indicating males may require more

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Chapter 2.  Anatomical Considerations

Fig. 2.5  Orbicularis oculi muscle

lateral injections so as not to inject unnecessarily in central areas lacking muscle. One-third of females had no frontalis dehiscence up to 6 cm from the orbital plane and this correlated with smaller inter-pupillary distances. Moreover, a greater medial proportion of fibrous-to-muscular fibres has been reported so less toxin is usually required medially (Wieder [2]).

Frontalis Muscle

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Fig. 2.6  Orbital portion

Acting vertically as it does frontalis-produced wrinkles are therefore horizontal. Being so expressive a clear u ­ nderstanding of anatomical, gender and individual functionality of the brow is crucial. Crucially, being the only elevator of the eyebrow there is a fine line between total wrinkle effacement and unwanted brow ptosis.

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Chapter 2.  Anatomical Considerations

Fig. 2.7  Preseptal portion

Frontalis Muscle

Fig. 2.8  Pretarsal portion

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Chapter 2.  Anatomical Considerations

Corrugator Muscle A paired, deep muscle of the glabellar complex. It is larger, more rectangular than many expect and is one of the prime contributors to the ‘frown’. Origin: medial superciliary arch Insertion: penetrates frontalis and orbicularis to skin above central eyebrow Innervation: temporal branch of facial nerve Action: depresses brow and draws it medially, e.g., when frowning Corrugator supercilii is the deepest-lying muscle of the glabellar complex and must therefore pass through frontalis and orbicularis oculi to insert into the skin of the forehead some distance above the eyebrow. Although previously assumed to insert around the mid-point, recent cadaver study has delineated the anatomy more precisely (Janis [3]). Origin was found to be between 2.9 and 14 mm from the nasion (the deepest central concavity of the nasal bones) and, with a 43.3  ±  2.9  mm nasion-to-lateral extent the muscles themselves both consistent and symmetrical. Personal experience has also shown it to be larger and more rectangular in shape than many of the original anatomical texts would suggest. With females having a smaller muscle bulk overall it is no surprise that this is reflected in the facial musculature and they are usually more difficult to visualise clinically. A useful tip is to stand further away and look from a different angle to perceive the outline with the patient frowning to activate the muscles.

Procerus Muscle The procerus muscle is a small, thin pyramid-shaped muscle that covers the nasion and upper nasal bones between the eyebrows. It sits superior to the nasalis muscle and works in concert with the other glabellar muscles.

Orbicularis Muscle’

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Origin:

fascia of superior nasal region (bones and upper lateral cartilage) Insertion: merges with frontalis into skin above central eyebrow Innervation: temporal branch of facial nerve Action: depresses medial brow e.g., when frowning. It also assists in flaring of the nostrils Being vertically orientated, procerus is believed to make the greatest contribution to horizontal glabellar lines. Many incorrectly ascribe such lines to the corrugator, but the latter predominantly produce vertical or obliquely orientated ones. Cadaver studies reveal a muscle fairly consistent in its thickness (