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24 Essentials of neuromodulation
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2. Dysport (abobotulinumtoxinA) is a prescription drug for injection made
by Galderma. It is an acetylcholine release inhibitor and neuromuscular
blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and
corrugator muscle activity in adult patients less than 65 years of age.
Dysport (2020) (https://www.dysportusa.com/healthcare-professionals
#importantsafetyinformation)
3. Merz Aesthetics makes Xeomin (incobotulinumtoxinA) for injection. It
is used for intramuscular use and is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines with corrugator and procerus muscle activity in adult patients.
Xeomin (2020) (https://www.xeominaesthetic.com/professionals/)
4. Jeuveau (pronounced Juvo) (prabotulinumtoxinA-xvfs) for injection is
made by Evolus and goes by Newtox. Jeuveau is a prescription medicine
injected into muscles and used in adults for a short period (temporary) to
improve moderate to severe frown lines between the eyebrows (glabellar
lines). It is not known if Jeuveau is safe and effective for use in children.
Jeuveau (2020) (https://jeuveau.evolus.com)
Each formulation can vary by the following characteristics:
1. Amount of neuromodulator
2. Units and or concentration of the product
3. Composition
4. Accessory proteins
5. Toxin complex size
6. Molecular weight
7. Biological activity
8. pH
9. Storage
10. Risk of antigenicity
11. Indication for use
12. Geographical distribution
13. Chemical properties
Each FDA approved formulation of BoNT-A has specific indications for
reconstitution, limited indications and are not universal worldwide. Each
neuromodulator is manufactured differently and has unique characteristics,
which makes the products not universally interchangeable. These drug formulations are not interchangeable in preparation nor delivery and or
efficacy. When treating a patient with four units of Botox, it is equivalent
to four units of Xeomin, four units of Jeuveau, and ten units of Dysport
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as long as they are reconstituted according to the branded drugs package
insert. There is a variety of reconstitution options which can change the formula unit by unit.
BoNT-A effect is correlated with the concentration, dose, placement of
the product, amount of spread, and is relative to the depth of the procedure
and the size and health of the target muscle. The products vary mainly in
diffusion and spread; however, efficacy is still being debated. Most literature
reports and demonstrates that Botox is still the leader concerning efficacy
and longevity. The onset of action is also not universally validated and is
mainly dependent on reports by the practitioner and the patient. The
patient’s genetics, target muscle size, and thickness, skin condition regarding
the thickness or amount of laxity all play a role in the satisfaction rate of
BoNT-A. The onset and outcome of treatment are further influenced by
the practitioner’s choice of a particular drug, the reconstitution process,
placement, depth of injection, and dosing.
Given that BoNT-A is a metalloprotease drug, it is necessary to have an
ample supply of zinc at the nerve terminal in order for effect. So, a patient’s
zinc level also plays a role in the effect and duration of treatment. There is
more to the treatment than just learning injection points. The patient’s overall health and function are equally as important as understanding where to
inject and how to inject. Despite increased public demand for the
BoNT-A, the pharmacological understanding of the commercially available
products’ differences is still vastly poorly understood.
Surprisingly enough, despite the overwhelming statistics on consumer
utilization, there is still some debate on the reconstitution of BoNT-A.
The impact of reconstitution has on the denervation process is still debatable.
Although well studied, the makers of BoNT-A may have overstated the fragility of the product initially with the new research that has since come out
after the products received their FDA approval. When the product is reconstituted with normal saline versus 0.9% benzyl alcohol saline, the patient
experiences more discomfort. When the BoNT-A is reconstituted with
the preserved saline with benzyl alcohol, the patients experienced less discomfort, and it was reported that there was less of an incidence of postinjection infection. Many studies have refuted that the preservatives break
down the BoNT-A and that the preserved saline may be a better option.
Most injectors around the globe do reconstitute their BoNT-A with the
preserved saline over the non-preserved saline. Greater detail will be provided later in the text on how to reconstitute each product properly. All
FDA and commercially prepared BoNT-A’s will have a package insert on
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the FDA approved areas for use and adequately reconstituting the product
for injection.
Cosmetic and therapeutic uses of BoNT-A
BoNT-A is used in various medical settings for a host of diseases,
symptoms, and beauty treatments.
Cosmetic uses
Hyper functional facial lines
Brow ptosis
Hyperhidrosis
Facial contouring
Lateral canthal lines
Beautification by way of symmetry
Therapeutic use in ophthalmology
Strabismus
Blepharospasm
Nystagmus
Therapeutic use in neurology
Hemifacial spasm
Facial asymmetry
Oromandibular dystonia
Cervical dystonia
Therapeutic use in otolaryngology
Vocal ties
Stuttering
Spasmodic dysphonia
Oromandibular dystonia
Therapeutic use in pain
Migraine
Tension headaches
Knee
Shoulder
Neuropathic pain
Chronic low back pain
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Therapeutic use in autonomic dysfunction
Freys syndrome
Sialorrhea
Rhinorrhea
Therapeutic use in gastroenterology
Gastroparesis
Delayed gastric emptying
Chronic anal fissure
Achalasia
References
Allergan. (2020). Botox Cosmetic history. https://www.botoxcosmetic.com/what-is-botox-
cosmetic/botox-cosmetic-history. (Accessed March 2020).
Dolly, J. O., & Aoki, K. R. (2006). The structure and mode of action of different botulinum
toxins. European Journal of Neurology, 13(Suppl. 4), 1–9. https://doi.org/10.1111/j.1468-
1331.2006.01648.x. 17112344.
Dysport. (2020). For health care professionals. https://www.dysportusa.com/healthcare-
professionals#importantsafetyinformation. Accessed March 2020.
Jeuveau. (2020). Ready for a modern-made tox?. https://jeuveau.evolus.com (Accessed July
2020).
Xeomin. (2020). A uniquely purified choice for frown lines. https://www.xeominaesthetic.com/
professionals/. (Accessed March 2020).
Further reading
Stone, H. F., Zhu, Z., Thach, T. Q. D., & Ruegg, C. L. (2011). Characterization of diffusion
and duration of action of a new botulinum toxin type A formulation. Toxicon, 58(2),
159–167. Science Direct https://doi.org/10.1016/j.toxicon.2011.05.012. Accessed
May 2020.
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CHAPTER 5
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History of neuromodulators
In the early 1800s, Justinus Kerner and John Muller first describe botulism. It
was referred to as “sausage poison” Then Clostridium botulinum (BoNT) was
later isolated by Emile van Ermengem in 1895. Emile was a bacteriologist
professor in Belgium who discovered the bacteria after a dinner that caused
an outbreak of illness, at which time botulism was identified. Eighty years
before the outbreak, there were the beginning rumblings of chatter about
food born illness. Botulism received its name due to the Latin word for sausage, which is botulus. The name botulus was given because the food that
was suspected of causing the outbreak was pork filled sausage. Fast forward
to 1946, and at the time, the purification process of onabotulinumtoxinA
(Botox) occurred. Dr. Edward J Schantz succeeded in purifying BoNT-A
in crystalline form cultured Clostridium botulinum and isolated the toxin.
In 1950, Dr. Vernon Brooks discovered the toxins’ true potential when
he concluded that it prohibited acetylcholine release and thus impeded
motor nerve innovation in a hyperactive muscle. In 1980 Dr. Alan
B Scott revolutionized the world of ophthalmology with the treatment of
strabismus. It was only 9 years later that onabotulinumtoxinA received its
first FDA approval. The utilization of onabotulinumtoxinA in strabismus
was just one of many FDA approvals; this particular brand would get
FDA approval.
The 1989 FDA approval set the stage for many great things to come with
this unique and extremely deadly toxin. In 1989, onabotulinumtoxinA
received the FDA approval for therapeutic use in Strabismus and Blepharospasm and hemifacial spasm in patients younger than 12 years. That same
year it was rebranded as Botox, which is the drug name consumers recognize. Through expanded research into esthetic uses, Allergan later commenced clinical trials to study the treatment’s safety and efficacy for
moderate to severe frown lines (Allergan, 2020).
Then in 2002, the first treatment was approved for cosmetic use. On
15 April 2002, the FDA approved Botox as a temporary esthetic treatment
for moderate to severe frown lines in adults and requested the product be
marketed as Botox Cosmetic to distinguish esthetic from therapeutic uses.
Essentials of Neuromodulation Copyright © 2021 Elsevier Inc.
https://doi.org/10.1016/B978-0-323-89920-8.00016-3 All rights reserved.
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It is the first treatment of its kind to be approved for esthetic use in three
different areas. Today it is the only product FDA-approved to temporarily
make moderate to severe frown lines, crow’s feet, and forehead lines look
better in adults (Allergan, 2020). The FDA has approved others; however,
Botox is the only one with three cosmetic use indications.
History of onabotulinumtoxinA (Botox),
incobotulinumtoxinA (Xeomin), abobotulinumtoxinA
(Dysport), prabotulinumtoxinA-xvfs (Jeuveau)
1895—Clostridium botulinum (BoNT) was isolated by Emile van
Ermengem.
1946—Purification process of onabotulinumtoxinA (Botox). Dr.
Edward J Schantz succeeded in purifying BoNT-A in crystalline form
cultured Clostridium botulinum and isolated the toxin.
1949—Discovery that botulinum toxin blocks neuromuscular toxin by
Dr. Burgen’s ASV group.
1950—Discovery that botulinum toxin blocks the release of acetylcholine from motor nerve innovation when injected into a hyperactive muscle by Dr. Vernon Brooks.
1980—Strabismus was treated in humans for the first time by Dr. Alan
B. Scott.
1989—FDA approval for use of Strabismus and Blepharospasm and
hemifacial spasm in patients aged younger than 12 years. This was done
under the trade name of Botox.
1990—BoNT-A received US FDA approval for treatment of cervical
dystonia.
2001—United Kingdom approved onabotulinumtoxinA (Botox), synthesized by Allergan, for axillary hyperhidrosis. Canada approved onabotulinumtoxinA (Botox) for axillary hyperhidrosis, focal muscle spasticity,
and cosmetic treatment of wrinkles at the brow line.
2002—US FDA approval of onabotulinumtoxinA (Botox) Cosmetic to
temporarily improve the appearance of moderate to severe frown lines
between the eyebrows (glabellar lines).
2011—US FDA approved incobotulinumtoxinA (Xeomin) for temporary improvement in the appearance of moderate to severe glabellar lines
in adult patients.
2004—FDA approved for Axillary Hyperhidrosis under the trade name
of Botox.
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2009—FDA approved a new botulinum toxin A; abobotulinumtoxinA
under the trade name of Dysport. It had been used in the United
Kingdom since 1994. It was approved for the use of treatment of adults
with cervical dystonia and Glabella region.
2010—US FDA approved onabotulinumtoxinA (Botox) to treat spastic-
ity in the flexor muscles of the elbow, wrist, and fingers in adults with
stroke, traumatic brain injury, or the progression of multiple sclerosis.
US FDA announced the approval of incobotulinumtoxinA
(Xeomin) for the treatment of adults with cervical dystonia, to decrease
the severity of abnormal head position and neck pain in both botulinum
toxin-naı¨ve and previously treated patients and for blepharospasm in
adults previously treated with onabotulinumtoxinA (Botox).
US FDA approved onabotulinumtoxinA (Botox) injection to
prevent headaches in adult patients with chronic migraine.
2011—US FDA approved onabotulinumtoxinA (Botox) injection for
the treatment of urinary incontinence due to detrusor overactivity
associated with a neurologic condition (e.g., spinal cord injury, multiple
sclerosis) in adults who have an inadequate response to or are intolerant
of an anticholinergic medication.
2013—US FDA approved onabotulinumtoxinA (BOTOX) for the
temporary improvement in the appearance of moderate to severe lateral
canthal lines, known as crow’s feet. This is the only FDA-approved drug
treatment option for lateral canthal lines.
2015—US FDA approved abobotulinumtoxinA (Dysport) for the treatment of upper limb spasticity (ULS) in adult patients to decrease the
severity of increased muscle tone in elbow flexors, wrist flexors and
finger flexors. US FDA approved incobotulinumtoxinA (Xeomin) for
the treatment of upper limb spasticity (ULS) in adult patients.
2017—US FDA approved onabotulinumtoxinA (Botox) for the use of
forehead rhytids.
2019—US FDA approved prabotulinumtoxinA-xvfs (Jeuveau) for
injections into facial muscles to improve the appearance of moderate
to severe frown lines between the eyebrows.
Reference
Allergan. (2020). Botox Cosmetic history. https://www.botoxcosmetic.com/what-is-botox-
cosmetic/botox-cosmetic-history. (Accessed March 2020).
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Essentials of neuromodulation
Further reading
Jabbari, B. (2016). History of botulinum toxin treatment in movement disorders. Tremor and
Other Hyperkinetic Movements (New York, NY), 6, 394. https://doi.org/10.7916/
D81836S1.
CHAPTER 6
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Safety of neuromodulators
After seeing how long BoNT-A has been around, it is easy to say it is a wellstudied drug and has a proven safety track record. Further understanding, it
does not cross the blood-brain barrier and works locally at the peripheral
nerve terminal continues to prove its safety in the use of esthetics. However,
there is always the risk with the BoNT-A drug in the untrained provider’s
hands. Nevertheless, in the hands of skilled and trained injectors, BoNT-A’s
are very safe and can bring consumers a lot of joy, control over the aging
process, and confidence. The FDA held a 13.5-year review of adverse events
with the use of Neuromodulators. Throughout this review, it was identified
that there were 36 severe adverse events, six of which were more of a user
error (Cote, Mohan, Polder, Walton, & Braun, 2005). During this time,
there were no deaths related to the use of neuromodulators. The results concluded that 25% of patients would bruise when having their crows feet treated (Cote et al., 2005). 15% of patients will have a headache post-injection
(Cote et al., 2005). Very rarely will someone report the headache as severe
and debilitating. 3–5.4% of patients suffer from lid ptosis from inadvertent
injection into the levator palpebrae. 5% of patients will suffer a lateral tail
droop (Cote et al., 2005).
Little nuisances within the injecting craft can make a world of difference
in the outcomes and comfort during the injections. The use of fixed needles
to the syringe to gain access to the product is contraindicated as the needle
will become blunt very quickly, and then the injections will be more painful
and will also cause more trauma to the patient’s tissue, increasing bruising. As
trained professionals versed in injection techniques, we can anticipate a
bruise and see it as a usual occurrence. The esthetic patient does not see
the bruise as a worthy and necessary risk to the treatment. 99% of the patients
will expect their injector to penetrate the skin 60 times during treatment and
miss every single one of their vessels. Here is an excellent time to remind the
reader to correctly set the treatment expectations, duration, and downtime,
including bruising. Cote et al. (2005); study demonstrated that only
36 patients in 13.5-year review had an adverse event. However, the adverse
Essentials of Neuromodulation Copyright © 2021 Elsevier Inc.
https://doi.org/10.1016/B978-0-323-89920-8.00017-5 All rights reserved.
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