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Botulinum toxin is the most powerful toxin ever known. Its huge potential has been used in the last decades to treat some pathologies that attend with acetylcholine’s metabolic disturbances. Botulinum toxin effects are not indefinite in time, so it must be applied several times (usually twice a year), thanks to the changes produced by this toxin the rehabilitation of infantile spasticity are easier (the greatest results are seen on abductor muscles, calves, etc.) and on ocular muscles to treat squint. It is also used in some muscle alterations, pathologies of the autonomic nervous system, painful syndromes. The life quality of children with cerebral palsy is improving thanks to this toxin.
*Address all correspondence to: kampanilla2002@hotmail.com
1. Introduction
At present, botulinum toxin type A is becoming the treatment of choice for a multitude of pathologies related to alterations in the biochemistry of acetylcholine [1, 2].
Since the middle of the twentieth century, many clinical trials of this type have been carried out. Botulinum toxin A is the most widely used in human therapeutic trials; some of these studies are:
Therapeutic trials were conducted by A. Scott [3]. In 1973, this author began to use botulinum toxin type A in the treatment of strabismus, initially in non-human primates and since 1980 in humans. He also described its use in endocrine orbital myopathy and lateral rectus palsy.
Therapeutic trials were conducted by Frueh et al. [4]. They described the use of toxin A in blepharospasm in 1984. In subsequent years toxin injections became the first-line treatment for blepharospasm with very good results (significant improvement in more than 80% of injected patients).
Therapeutic trials were performed by Tsui et al. [5] and Brin et al. [6]. These investigators reported results of therapeutic trials with toxin A injections for torticollis in patients who had not responded to other treatments and were severely affected.
Therapeutic trials conducted by Jankovic [7], Gelb [8], and Greene [9] between 1986 and 1991 have conducted at least five blind, placebo-controlled studies focused on toxin A for cervical dystonia. Afterward, they studied it uses in oro-mandibular, laryngeal, and limb dystonia, confirming its usefulness, particularly in the treatment of closing mandibular dystonia and laryngeal dystonia in adduction.
Botulinum toxin represents the most powerful biological toxin known at present.
This toxin is produced by an anaerobic and Gram-positive bacterium, Clostridium botulinum, of which 8 immunologically distinct types are known, but only types A, B, and E have been linked to human botulism.
Clostridium botulinum is widely distributed by nature (in soils, mud from lakes or ponds, and in vegetation), so the intestinal contents of fish, birds, and mammals can contain this type of micro-organism. Its spores are quite resistant, especially to heat. To avoid this presence in food, canning industries must use sterilization methods.
Various types of Clostridium botulinum are known, each of which produces an immunologically distinct toxin from the others.
These are among the most potent that exist.
One microgram contains 200,000 times the minimum lethal dose for the mice and is approximately the dose lethal for humans.
Types A, B, E, and F are the most common causing human botulism while types C and D cause botulism in poultry and cattle.
Type A is relevant to human pharmacology. It forms a complex with hemagglutinin which can be crystallized.
This is a protein with a molecular weight of 900,000 Daltons. The separation of the hemagglutinin can be carried out without the toxin losing its effectiveness.
It has a neurotoxic fraction made up of protein with a molecular weight of approximately 150,000 Daltons. It is suspected that it is made up of smaller toxic subunits [10].
Botulinum toxin interferes with the conduction of the nerve impulse, once the axonal propagation of the nerve impulse has begun.
The toxin blocks the release of acetylcholine. Therefore, botulinum toxin is an anticholinergic substance which acts as a muscle relaxant and a specific inhibitor of the release of acetylcholine, acting on the presynaptic nerve ending, preventing the action of calcium ions in the exocytosis process necessary for the release of acetylcholine, thus decreasing the plaque potential and causing muscle paralysis [1, 11].
The toxin has two subunits, one of which binds to the membrane receptor responsible for specificity, allowing the entry of the other subunit the one that blocks calcium ions.
In its therapeutic application, due to its form of administration, only neuromuscular transmission interferes at the site of application and the recovery of the nerve impulse takes place gradually as the nerve endings regenerate (Figure 1) [10].
Figure 1.
Principal applications of botulinum toxin in recent decades.
When botulinum toxin is injected into the target tissue, the neurotoxin heavy chain binds to glycoproteins that are specifically found on presynaptic cholinergic nerve receptors. It penetrates the nerve ending of the motor endplate (alpha motor neuron) by endocytosis.
After its internalization, the neurotoxin light chain fragments the SNAP-25 protein, preventing the formation of the SNARE complex (NSF-anchorage protein receptors), which intervenes in the release of acetylcholine by exocytosis.
The blockage of exocytosis becomes definitive on the third day of infiltration and will last until the third month. From the 28th the neuron reacts to the blockage by creating new synaptic buttons (sprouting), restoring the original function. That is, the chemical blockage is irreversible, but the clinical effect is reversible due to the creation of new synaptic buttons [12, 13, 14, 15, 16].
Botulinum toxin diffuses locally through the muscle, preferably longitudinally. This local diffusion is dependent on the dose and the precision of the infiltration.
Hence, it is used in pathologies such as:
Dystonia: Reduced functioning of the neurotransmitter acetylcholine can reduce the excessive functioning of the muscles in different dystonia [17, 18]
Cervical dystonia (torticollis)
Blepharospasm
Apraxia of the eyelid
Oromandibular-facial lingual dystonia
Laryngeal dystonia (spasmodic dysphonia)
Dystonia of the feet, hands
Occupational cramp
Facial dystonia
Meige syndrome
Tics and stuttering
Musician dystonia
Abnormal movements: Botulinum toxin is used to control hyper functional muscular disorders such as [19, 20]
Hemifacial spasm
Tremor (head, voice, limbs)
Myoclonus (palate, spinal)
Dystonic motor tics
Myoclonus
Ophthalmological indications: Very good results have been seen when applying botulinum toxin [10]
Strabismus (esotropia/exotropia): When the botulinum toxin is injected, a transient paralysis occurs, so that when the extraocular muscle is paralyzed, it relaxes and the antagonist contracts, producing a transient overcorrection of the deviation. This causes an imbalance of forces between antagonists
3.2 Applications in disorders of the autonomic nervous system
In disorders of the autonomic nervous system, the reduction of the neurotransmitter acetylcholine reduces the functioning of the autonomic nervous system [10, 12, 14] so that the inhibition of acetylcholine release on the postganglionic endings of the sympathetic and parasympathetic systems justifies its clinical use in these pathologies.
Hyperhidrosis: axillary, palmar, plantar and facial
3.3 Applications in disorders of the afferent nervous systems and pain
The reduction of inflammatory mediators can influence pain syndromes [12, 22, 23, 24], due to possible inhibition of the non-selective peripheral release of pain-mediating neurotransmitters (substance P). This justifies its clinical use in these pathologies
Craniofacial pain
Bruxism
Temporomandibular pain
Trigeminal neuralgia
Tension headache and chronic migraine
Myofascial pain: controversial results
Painful phantom limb syndrome
Peripheral ischemia
Postherpetic neuralgia
Joint pain: An improvement in these pathologies has been observed when treated with intra-articular injections of botulinum toxin
Spasticity consists of “a motor disorder characterized by a speed-dependent increase in the muscle stretch reflex, also called myotatic, with exaggerated pulling on the tendons which is accompanied by hyperreflexia and hypertonia, due to neuronal hyperexcitability being one of the signs of upper motor neuron syndrome, which can be summarized as the abnormal effect of both “tonic and phasic stretch reflexes” [25] (J. Lance, Australian neurologist 1980), which results in an increase in speed-dependent tonic reflexes together with an exaggerated response of tendon (phasic) reflexes in Ref. [25].
This reflex stretching activity can be triggered during voluntary movement when a contraction with shortening of the agonist musculature occurs and is accompanied by a stretching of the antagonist musculature.
4.1 Clinical forms of spasticity
Spasticity presents in characteristic clinical patterns for different neurological etiologies. It should be noted that although the clinical patterns are similar, the response to treatment may vary depending on the etiology.
The most common forms of spasticity are:
4.1.1 Lower limb
Equine foot, equinovarus
Digital claw, hyperextension of the first toe
Thigh adduction
Hip adducts
Knee flexion/knee extension
4.1.2 Upper limb
Shoulder adduction and internal rotation
Elbow flex
Wrist flex
Claw fingers
Thumb included in the palm
The findings on the examination of spasticity:
Razor resistance (spring)
Spasticity is directly proportional to stretching speed
Hyperreflexia with polykinetic response and clonus
Presence of pyramidal release reflexes and/or spinal automatism in antigravity muscles
If we take into account the age of the patient, we can divide spasticity into two large groups:
Infantile spasticity
In childhood, the most common cause of spasticity is infantile cerebral palsy (ICP). An important difference to adult spasticity is that clinical expressiveness in children evolves with growth and causes osteoarticular deformities that interfere with normal development [25].
ICP is classically defined as a persistent movement and posture disorder caused by a non-progressive lesion or defect of the immature brain, before the age of 3–4 years. It has an incidence of 1.5–2.5 per 1000 live births.
However, the current trend is to define ICP by expressing the broad spectrum of its characteristics: ICP is a group of movement and posture disorders that cause activity limitation and is attributed to a non-progressive disorder in fetal development or infant who is frequently accompanied by sensitive, cognition, perception, communication, behavior and/or epilepsy defects.
According to this definition, the classification considers not only the topographic aspect, but also gives special meaning to the severity of the motor impairment, since the functional prognosis will depend not so much on the type of ICP but on the severity.
Motor disorders:
Nature and type (spastic, dyskinetic, ataxic, or mixed)
Motor and its severity according to GMFCS (GROSS MOTOR FUNCTION CLASSIFICATION SYSTEM). Gross motor function is a classification system levels for children with cerebral palsy between the ages of 6 and 12 years. It has five levels [26]:
Level I: Walks without restrictions; limitations in more advanced gross motor skills.
Level II: Walks without assistive devices; limitations in walking outdoors and in the community.
Level III: Walks with assistive mobility devices; limitations in walking outdoors and in the community.
Level IV: Self-mobility with limitations; children are transported or use power mobility outdoors and, in the community,
Level V: Self-mobility is severely limited even with the use of assistive technology [26]
Cause and moment of the disorder.
Location (hemiplegic, diplegic, or tetraplegic). For the diagnosis of ICP, it is essential to ensure that the causing brain alteration is not progressive.
That is, to rule out the other degenerative causes of movement disorders. It is recommended to use the guidelines and diagnostic algorithm of the AAN (American Academy of Neurology).
Spasticity in adults:
The most common causes of spasticity in adults are [25].
Acquired brain damage (ABD) caused by head trauma or cerebrovascular accident (CVA)
Spinal cord injury
The clinical characteristics of spasticity in ABD are:
Gradual development at 6–8 weeks after stroke and 2–8 weeks after head trauma
A dysregulation of motor control appears contraction, relaxation
Pain
Contraction movements
In addition to the muscle tone disorder, different patterns can be presented:
Decortication Pattern: The patient will present shoulder adduction and triple flexion of the upper extremities (elbow, wrist, fingers) and extension of the lower extremities accompanied by equinus.
Decerebration Pattern: There is a pattern in the extension of the four extremities with internal rotation of the upper extremities.
Mixed Pattern: This is a combination of the two previous patterns.
The appearance of these clinical manifestations has a global impact on the patient with ABD, who will present a decrease or loss of balance and gait, a decrease in manual ability, interference in personal hygiene and activities of daily life (ADL), as well as difficulty in communication and swallowing.
When faced with a patient with ABD, we must consider that, as well as having neuromotor deficits, the patient may also have a set of neuropsychological deficits (cognitive and sensory) therefore, the treatment must be considered in a comprehensive way.
4.2 Spinal cord injury
The causes are multiple: trauma, multiple sclerosis, spinal tumors, infections of vascular origin, familial spastic paraparesis, transverse myelitis, amyotrophic lateral sclerosis and neurofibromatosis.
The incidence of spasticity in spinal cord injuries varies from 65–78% per year of evolution, decreasing to 40%.
Spasticity patterns in spinal cord injury are dependent on the level and degree of injury “classification of the American Spinal Injury Association (ASIA)”.
Spasticity in the spinal cord injury is more problematic in incomplete injuries at the cervical level (ASIA grade BCD) and is usually extension spasticity.
Spasticity is not a static phenomenon, it is long-lasting, dynamic, and changing, and there are many factors that influence it, and we must consider it when seeking treatment [27].
Spasticity evolves towards chronicity and is accompanied by static phenomena and alterations in the properties of soft tissues (elasticity, viscosity, plasticity). The alteration of these three properties leads to the establishment of fibrosis of the muscle and of the adjacent structures so that the contracture becomes fixed and retractions and osteoarticular deformities occur, which makes it important to treat as quickly as possible [25, 27].
In the evolution of spasticity, four phases appear, this will determine the treatment.
SPASTICITY PHASE: In this phase, there is an increase in muscle tone which causes it to be defined as the state of increased tension in a muscle when it is passively lengthened by exaggeration of the muscle stretch reflex.
VICIOUS ATTITUDE PHASE: This includes muscle imbalance due to the predominance of spasticity in some muscle groups, the most frequent being the plantar and varicose flexors of the foot, the adductors and hip flexors and the elbow, wrist, and finger flexors in the upper limb.
MUSCLE WITHDRAWAL PHASE: The persistence of these vicious attitudes causes uneven growth between agonist and antagonist muscle groups. This leads to the structuring of this attitude due to the lack of accommodation of the sarcomere, which is unable to achieve normal muscle growth. Understanding by muscle retraction the resistance opposed by the muscle to mobilization when it is not in contraction.
OSTEOARTICULAR DEFORMATION PHASE: When we are dealing with children in the growth phase, all the pressures and traction stimuli of the growth cartilage will be modified consecutively to the previous phases which, according to Delpech’s law, gives rise to osteoarticular deformities (Figure 2).
Figure 2.
Delpech law.
It is important to consider that when spasticity occurs in children, it negatively influences their musculoskeletal development, which usually leads to structured deformities, problems in postural control, and limitations to spontaneous mobility [27].
6.1 Objectives in the treatment of spasticity, presentation, indications, application and botulinum toxin dose in spasticity
A well-coordinated, multidisciplinary team will oversee guiding the spasticity treatment, seeking realistic goals that are agreed upon by the patient and the caregiver.
The objectives should be aimed at improving function, reducing pain, preventing complications, and improving hygiene, that is, improving quality of life. In the child, this allows and favors the longitudinal growth of the muscle, avoiding fixed contractures [25, 26, 27, 28].
6.1.1 Objectives in the treatment of spasticity
The objectives pursued when applying the toxin on the muscle are:
Gradually decrease the potential of the drive plate.
Decrease the state of hyper contraction.
Muscle relaxation.
Facilitate extensibility.
In the case of children, facilitate the longitudinal growth of the muscle.
An improvement in function, after application in the lower limbs there will be an improvement in gait, greater comfort, balance, and a decrease in falls.
If the application is in the upper limbs there will be greater ease to find it to carry out activities of daily life such as hygiene and food preparation.
Prevent long-term complications: dislocations, osteoarticular deformities, mainly of the hip, foot, and wrist.
There are different degrees of recommendation for therapeutic strategies for the treatment of spasticity, but we are going to focus on treatment with botulinum toxin.
Botulinum toxin is the treatment of choice for focal spasticity and as a complement in generalized spasticity because it can be administered in the most affected muscles, regardless of its etiology, and is part of the overall treatment.
In the case of generalized spasticity, it should be associated with treatment with intrathecal baclofen or surgery.
As we already know, botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction which produces transient chemical denervation, as well as the inhibition of nociceptive neurotransmitters, therefore, playing an analgesic role. The result is transient functional denervation that causes paralysis, muscle atrophy, and electromyographic abnormalities. As already advised, the toxin has two subunits, in such a way that one of them binds to the membrane receptor allowing the second subunit to enter the cell where it will exert a toxic effect by inactivating specific enzymes.
This involves an ADP-riboxylation. The reaction of the toxin is believed to inactivate actin in this way.
It is recognized that only a few molecules are needed to inhibit the release of acetylcholine. The muscle weakness caused by this toxin remains restricted to the injected area, there is histological evidence that toxicity is restricted to the extrafusal muscle fibers, while the intrafusal fibers are relatively free of this affectation.
This causes an alteration in the relationship of the alpha and gamma motor neurons and consequently, there is not only a local paralysis but also an effect on the central motor control mechanisms.
Its effect is progressive, starting in 2 or 3 days, until reaching its maximum per month, maintaining its effect for 3–4 months with a variation interval of 2–6 months.
6.1.2 Presentation and application
Regarding its form of presentation, the only type of botulinum toxin commercially available is type A. In the United States, it is marketed by the Californian laboratory Allergan Pharmaceuticals under the trade name “Botox”. It comes in freeze-dried and cold-dried preparations. These are ampoules that must be stored frozen at −5° C so that the toxin is reconstituted at the time of injection with sterile physiological saline (without a preservative). Its potency is expressed in units, in such a way that one unit is equivalent to the amount of toxin capable of killing 50% of a group of female Swiss-Webster mice weighing between 18 and 20 grams (LD50) [21, 26, 27, 28, 29, 30, 31, 32].
In the United States, approximately 0.4 nanograms of protein toxin equal 1 unit (or otherwise expressed 2.5 units are equivalent to 1 nanogram). In the case of European botulinum toxin type A, commercially known as “Dysport”, the potency of the preparation is different since 1 nanogram is equivalent to 40 units. Due to this divergence in potency in commercial botulinum toxin preparations, the use of doses greater than 500 units per session with the European preparation is not uncommon. The lethal dose of American botulinum toxin type A (Botox) injected into young monkeys is approximately 40 units per kilogram of weight, which, when extrapolated, represents about 50 times the average dose injected for the treatment of focal dystonia. The estimated LD50 in humans is 2500–5000 units according to some authors and closer to 5000 according to others. The diluted solution is collected in a tuberculin syringe and the toxin is injected with a 26–30 gauge needle 0.5 inches long in the superficial muscles and a 22 gauge 1.5 inches long in the muscles. Different dilutions can be prepared depending on the site to be injected, such as 2.5–5 units per 0.1 cc for cervical muscles and 1.25–2.5 units per 0.1 cc for blepharospasm or for a hemifacial spasm. The precise time for its action to appear varies between two and 3 days, reaching its maximum effect 5 or 6 days after the injection, its effect lasting a variable period that extends from 2 weeks to 8 months. (Although we have found some studies that indicate that this duration can be extended to 11 months), this is the time necessary for the toxin binding process, integration of the same, and regeneration of the neuromuscular junction. As already advised, the toxin has two subunits, in such a way that one binds to the membrane receptor allowing the entry of the second subunit into the cell where it will exert a toxic effect by inactivating specific enzymes, for which it involves an ADP reaction—riboxylation.
The toxin is believed to inactivate actin in this way. It is thought that only a few molecules are needed to inhibit the release of acetylcholine.
It is injected into large and superficial muscles, infiltrates the muscle belly by means of anatomical landmarks and palpation. Sometimes it is useful to be guided by electromyography, electrostimulation, or ultrasound. It is important to avoid venous spread.
Two toxins type A (Botox and Dysport) are marketed in Spain. Their doses are not interchangeable.
In children, the dose is calculated in international units per muscle and kilogram of weight. It is also a function of the size of the muscle and the degree of spasticity.
It is diluted in sterile 0.9% physiological saline in 1–2 ml.
The lowest effective dose should be used so that (Table 1):
For Botoxr the dose is 1–6 IU/kg/muscle, with a total dose of up to 12–14 IU/kg, not being able to exceed 300–400 IU.
For Dysportr the doses are 3–12 IU/kg/muscle, with a total dose of up to 20–30 IU/kg, not being able to exceed 750–1000 IU.
The maximum dose with Botoxr per injection site is 50 U [21, 26, 27, 28, 29, 30, 31, 32].
6.2 Adverse effects
There are some adverse effects produced by this treatment characterized by the appearance of weakness in injected and non-injected muscles or transient bladder paresis (after treatment of hip adductor spasticity), in a few patients, a generalized syndrome with tetraparesis (botulism type), It occurs after application of botulinum toxin and disappears within a period of about 4 weeks [27].
We can also find local adverse effects, which disappear in a few days, such as:
Injection site pain
Local inflammatory reaction
Appearance of flu-like picture
Diarrhea
Urinary incontinence
Allergic reaction
Fatal systemic adverse effects rarely appear, they have been described in isolated cases and with toxin doses that far exceeded the recommended dose.
6.3 Effectiveness
The main infiltration points in the lower limb are triceps, posterior tibial, anterior tibial, abductor of the big toe, abductors, and psoas [1, 21, 31, 32, 33].
The main application has been used especially in abductor spasticity of the legs, achieving a reduction in spasticity, pain, and improved hygiene and care of the patient. It has also been used in leg extension spasticity (spastic foot drop) by applying it to the soleus, posterior tibial, and calf muscles, observing an improvement in muscle tone, gait, and foot pain with reduction of the Achilles clonus, in hip dysplasia (caused by the psoas) and of special interest because it can become dislocating. Finally, it has also been shown to be useful in spasticity of the upper extremities [1, 21, 31, 32, 33].
It should be noted that in general, the results are better in young people, in whom the joints are more dynamic. Although the use of botulinum toxin is very effective for the correction of retractions, as is the case of the Achilles tendon, it should be taken into account before saying its application is not as effective in the upper limbs as in the lower ones, as can be seen in the graph (Figure 4).
Figure 4.
Effectiveness of botulinum toxin in different limbs.
GARCIN’S SCARVED HAND: Wrist flexion with ulnar deviation, thumb adduction, and pronation. The infiltration points are found in the biceps brachii, brachialis anterior, ulnar anterior, palmar, finger flexors (especially superficial ones).
INCLUSION OF THE THUMB: Adductor pollicis on its posterior aspect because the infiltration on its anterior aspect is very painful due to the presence of many sensory receptors.
CHANDELIER PATTERN: The points of infiltration are in the common flexor of the fingers in the pronator quadratus and round, in the posterior ulnar, long supinator (its flexor component), anterior brachialis, and biceps brachii.
TRIPLE FLEXION: Hip flexion: infiltrate the rectus anterior, sartorius, tensor fascia lata, iliac psoas, pectineum, adductors, gluteus minimus and anterior fibers of the gluteus medius. Knee flexion: hamstrings, tensor fascia lata, calves and popliteus. Plantar flexion (equine): triceps, tibialis posterior, long flexor of the fingers.
Generalized disorders of muscle function (myasthenia gravis).
Take blood thinners.
Inflammation or infection at the injection site.
Administration of high doses of aminoglycoside antibiotics (especially in patients with renal failure).
Pregnancy.
False expectation of cure.
Uncertainty of a therapeutic follow-up.
Regarding the precautions to be taken for the use of these preparations, the following should be indicated:
Caution in patients with respiratory disorders during the treatment of Torticollis due to the risk of aspiration.
During the lactation period, it is not known if it is secreted in significant amounts in breast milk, so as a precaution its use should be avoided in this period [1, 10, 28].
Botulinum toxin offers the advantage that it lacks the systemic side effects of oral drugs such as excessive somnolence or generalized muscle weakness. It allows to offer a local treatment, specifically in the muscle disorder.
Botulinum toxin treatment of spasticity, especially in children, is very effective, always within a global vision. But we cannot forget that it is also a very effective treatment for focal dystonia.
In these cases, its use has been a very effective option, assuming a radical change in the prognosis and in the quality of life of the patients, its use being accepted as routine treatment.
The following table shows a summary of the percentages of efficacy, duration, and complications of the use of this toxin in the different types of focal dystonia:
Gets better
Beginning
Duration
Complications
Laryngeal adductor
96%
1–2 days
10–16 weeks
Voice dysphagia
Blepharospasm
90%
1–3 days
12–15 weeks
Ptosis
Cervical
70%
3–7 days
8–12 weeks
dysphagia
Oromandibular
70%
2–7 days
12–14 weeks
dysphagia
Abductive laryngeal
70%
1–2 days
10–16 weeks
voice dysphagia
Hand in hand
60–80%
3–7 days
12–14 weeks
hand weakness
Nowadays it is also not only used for dystonia and spasticity but for upper obstetric brachial palsy (C5-C6), during the first months of life, where it avoids shoulder limitation, and congenital muscular torticollis (infiltrating the sternocleidomastoid and trapezius).
This toxin is used more and more to treat these pathologies improving the life quality of the patients reducing the adverse effects of alternative treatments used in the past.
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Written By
Francisca del Rosario González Núñez, Francisco Núñez de Castro and Rosa María González Núñez
Submitted: 09 November 2021Reviewed: 26 November 2021Published: 07 February 2022
Open access peer-reviewed chapter
