Botulinum neurotoxin for the treatment of movement disorders: Practical considerations

Ajith Cherian; Asish Vijayaraghavan; Divya KP; Syam Krishnan

doi:10.4103/AOMD.AOMD_40_21

REVIEW ARTICLES

Year : 2022 | Volume : 5 | Issue : 1 | Page : 38-48

Botulinum neurotoxin for the treatment of movement disorders: Practical considerations

Ajith Cherian, Asish Vijayaraghavan, Divya KP, Syam Krishnan
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

Date of Submission	24-Aug-2021
Date of Decision	26-Jan-2022
Date of Acceptance	02-Mar-2022
Date of Web Publication	25-Apr-2022

Correspondence Address:
Dr. Divya KP
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Medical College P.O, Trivandrum - 695011, Kerala
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_40_21

Abstract

Botulinum neurotoxin (BoNT), produced by spore-forming anaerobic bacteria, is the most potent biological toxin and is a powerful therapeutic tool for several clinical indications in neurology and beyond. BoNT inhibits the release of acetylcholine from the presynaptic terminals of the neuromuscular junction by interfering with the normal process of vesicle–plasma membrane fusion. The spectrum of indications for the use of BoNT in the treatment of various disorders in neurology, ophthalmology, gastroenterology, urology, autonomic, and dermatology is widening. The major indications for BoNT are in hyperkinetic movement disorders. Because BoNT must be injected locally, neurologists should possess the appropriate expertise to effectively deliver the therapy. Although it is considered to be effective and safe, there are many limitations to its use such as the therapeutic effect wearing off and high cost. Here, we review the indications, techniques of muscle selection, and administration of BoNT for maximum benefit in various movement disorders.

Keywords: Blepharospasm, botulinum incobotulinum, cervical dystonia, hemifacial spasm, movement disorders

How to cite this article:
Cherian A, Vijayaraghavan A, KP D, Krishnan S. Botulinum neurotoxin for the treatment of movement disorders: Practical considerations. Ann Mov Disord 2022;5:38-48

How to cite this URL:
Cherian A, Vijayaraghavan A, KP D, Krishnan S. Botulinum neurotoxin for the treatment of movement disorders: Practical considerations. Ann Mov Disord [serial online] 2022 [cited 2023 May 30];5:38-48. Available from: https://www.aomd.in/text.asp?2022/5/1/38/343842

Ajith Cherian, Asish Vijayaraghavan both authors have contributed equally to the manuscript.

Introduction

Botulinum neurotoxin (BoNT) is produced by spore-forming anaerobic bacteria such as Clostridium botulinum, C. barati, C. butyrricum, C. argentinensis, and other related species.^[1] It is the most potent biological toxin. The 21st century has witnessed the use of BoNT in the treatment of various ailments in neurology, and the major indications of BoNT are in hyperkinetic movement disorders.

Materials and Methods

We searched electronic databases such as PubMed, Medline, JSTOR (journal storage), and EMBASE for articles from January 1995 to June 2021 using the following MeSH terms: “botulinum neurotoxin,” “BoNT,” “onabotulinumtoxinA,” “abobotulinumtoxinA,” “incobotulinumtoxinA,” “RimabotulinumtoxinB,” “LanbotulinumtoxinA,” and “DaxibotulinumtoxinA.” In addition, we combined the above terms with “cervical dystonia,” “blepharospasm,” “hemifacial spasm,” “writer’s cramp,” “oromandibular dystonia,” “task-specific dystonia,” “laryngeal dystonia and voice tremor, ” “tremor,” “camptocormia,” “spasticity,” “sialorrhea,” “tics,” and “restless legs syndrome.” Only articles written in English were included ([Figure 1]).

Figure 1: PRISMA chart showing the methodology of the systematic review

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Types of toxins

While all BoNTs comprise two peptide chains linked through a disulfide bond, there are remarkable differences in the amino acid sequence of the various peptide chains found in each subtype of BoNTs. The entire protein comprises three domains—two in the heavy chain and one in the light chain—and each domain performs a specific function at the molecular level.^[2] The molecular weight of the heavy and light chains are 100 and 50 kDa, respectively.^[3] The C-terminal of the heavy chain is responsible for binding the toxin to the receptor site, while the N-terminal is responsible for “translocation.” The light chain contains the catalytic unit. Based on the serological typing of BoNTs, eight types, from A to H, are described in the literature. The specific neutralizing antisera determine the type. The serotypes and subtypes not only differ structurally but significant differences are also apparent in their toxopharmacological properties.^[4] Types A and B, because of their prolonged mode of action, are approved by the United States Food and Drug Administration for clinical use. They have a substantially different affinity to the motor and the autonomic nervous systems.^[5] OnabotulinumtoxinA (Botox; Allergan, CA, USA), abobotulinumtoxinA (Dysport; Ipsen-Pharma, UK), and incobotulinumtoxinA (Xeomin; Merz Pharma, Germany) are the approved type A (BoNTA) toxins. RimabotulinumtoxinB (Myobloc in the USA) is a type B (BoNTB) preparation. Novel preparations of BoNTA include LanbotulinumtoxinA (Prosigne; Shanghai, China), marketed primarily in Asia, and DaxibotulinumtoxinA, which was evaluated in a phase 3 trial (ASPEN-1) for cervical dystonia.^[6] If focal action with least dispersion in a small muscle is required, onabotulinumtoxinA is the agent of choice, such as in the case of a blepharospasm. In contrast, the toxin of choice for conditions like spasticity where larger muscles are injected would be abobotulinumtoxinA since it tends to diffuse to larger areas. The biological activity of therapeutic BoNT preparations is measured in mouse units (MU), shortened to units (U). One MU is the calculated median lethal intraperitoneal dose (LD50) injected in a 20-g Swiss–Webster mouse (which would kill 50% of a BoNT-administered mouse population).^[7] Therefore, MU or U describes the biological activity. In addition, according to the amount of inactivated botulinum toxin contained, it corresponds to different mass units. Comparable units for various commercial preparations are as follows: 1-U onabotulinumtoxinA = 1-U incobotulinumA = 2.5–3-U abobotulinumtoxinA = 50-U rimabotulinumtoxinB.^[8]

Mechanism of Action of BoNT

BoNT inhibits the release of acetylcholine (ACh) from the presynaptic terminals of the neuromuscular junction by interfering with the normal process of vesicle–plasma membrane fusion ([Figure 2]). This is achieved by the inhibition of synaptic SNARE proteins (soluble N-ethylmaleimide-sensitive factor-activating protein receptor),^[8] which occurs in the following steps ([Figure 2]): 1) The heavy chain of BoNT binds to the surface receptor, and through its interaction with the synaptic vesicle protein (SV-2) and synaptophysin (SYP), it is internalized into the synaptic vesicle. 2) The active proton transporters in the synaptic vesicle pump-in protons produce a low pH mileu within the vesicles, which helps in the import of ACh from the cytoplasm into the vesicle. 3) The BoNT is extruded from the vesicle with the aid of the translocation domain. When the catalytic enzymes act on the toxin protein, the light chains are cleaved from the rest of the toxin, which then inactivates the target SNAP receptor (SNARE) proteins (SNAP25, Syx, and VAMP). 4) BoNTA inhibits the release of ACh by cleaving the SNARE protein SNAP 25, while BoNTB cleaves the vesicle-associated membrane protein (VAMP) II. 5) In addition, BoNT produces plasticity of the central nervous system circuits due to blockade of the sensory afferent gamma units of the muscle spindles. Paralysis usually occurs within a few days and peaks 2 weeks after the injection. Because of the molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return at 3 months, with the restoration of complete function at approximately 6 months.^[9]

Figure 2: Molecular mechanism of botulinum neurotoxin in the synaptic end at the neuromuscular junction (LC-light chain; HC-heavy chain; Ach- acetyl choline; SV2- synaptic vesicle protein; Syx-syntaxin; SYP-synaptophysin; VAMP-vesicle associated membrane protein)

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In addition, BoNT prevents the release of other neurotransmitters, such as substance P, adenosine triphosphate, and calcitonin-gene-related peptide. Furthermore, it negatively regulates the sensory receptors involved in the pain pathways, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), commonly termed as the capsaicin receptor and vanilloid receptor1, and purinergic (P2X3) receptors.^[10] The effects of BoNT on these transmitters and receptors are being explored in managing autonomic and pain syndromes.^[11]

Nonresponsiveness to BoNT

Neutralizing antibodies jeopardize sustained responses to the toxin.^[9] Larger protein content in specific toxin formulations, higher individual and cumulative toxin doses, and narrow intervals between injections and booster doses have been implicated in exalted risk of resistance to BoNT.^[12],[13] The risk of developing neutralizing antibodies varies with regard to immunogenicity with BoNT formulations, varying form 0% for incobotulinumtoxinA to 42.4% for rimabotulinumtoxinB.^[13] Nonresponsiveness with incobotulinumtoxinA is rare because it has a molecule free from antigenic proteins. For onabotulinumtoxinA, the low rate (approximately <1%) is due to the reduction in albumin content from 25 ng, present in the formulations prior to 1997, to only 5 ng in the current ones.^[14]

Guiding principles, indications, and contraindications for BoNT injections

Videography of the patients at baseline and maintaining records of the site and dosage of injection, mentioning responses, and adverse effects is prudent. The intervisit intervals for consecutive injections should maintain a gap of at least 3 months. The major indications for BoNT are in hyperkinetic movement disorders ([Table 1]). The contraindications of BoNT should be considered, especially in conditions with multisystem afflictions ([Table 2]).

Table 1: Indications for botulinum neurotoxin therapy in movement disorders with the level of recommendations of various toxin preparations

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Table 2: Contraindications of botulinum neurotoxin

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Clinical Use in Specific Conditions

Cervical dystonia

Cervical dystonia (CD), the most common adult-onset focal dystonia, has a prevalence of 5/100,000 individuals.^[15] In the Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy study, the mean age of onset of CD was 49 years, and 74% were females.^[16] Major abnormal neck postures observed in CD are head rotation (torticollis, most common), head tilt (laterocollis, next common), head bent forward (anterocollis), and head bent backward (retrocollis). The most common combination in CD is torticollis with laterocollis. Combinations of complex cervical dystonia have recently been classified depending on the head (caput) and neck (collis) movements.^[17] In CD, two levels of movement of head-neck complex can be defined: upper, between the skull and C2 (caput) and lower, between C2 and C7 (collis), with the C2 vertebra being a fixed point. Depending on their insertions, the cervical muscles involved in cervical dystonia can be divided into muscles acting mainly on the head or mainly on the neck. Based on this concept, CD can be classified into 11 fundamental types: anterocollis, antecaput, laterocollis, laterocaput, retrocollis, retrocaput, torticollis, torticaput, anterior sagittal shift, posterior sagittal shift, and lateral shift. It is crucial to identify if the dystonia involves movements at the caput or collis, as the muscles involved in these movements are disparate.

Approximately 70% of the patients with CD have associated neck pain.^[18] Torticollis is sometimes associated with head jerks when the patient attempts to rotate the head opposite to the sustained abnormal rotation. Anticholinergic medications and baclofen often alleviate neck posture and pain, while clonazepam may improve head jerks. The emerging data regarding the efficacy of deep brain stimulation (bilateral GPi) in CD^[19] is encouraging.

BoNT is the first choice of treatment in patients with CD.^[20] The long-term response rate in open and double-blind studies is between 60% and 80%.^[21] In addition, BoNT substantially improves the neck pain associated with CD and maximum benefit is noticed at 6 weeks following the injection.^[22] Neck weakness and dysphagia are the two most common side effects. Dysphagia may be less common in onabotulinumtoxinA therapy (3.4%) than in the other neurotoxins (12.6, 15.6, and 19.6% with incobotulinumtoxinA, rimabotulinumtoxinB, and abobotulinumtoxinA, respectively).^[23] Bilateral injections of the sternocleidomastoid muscle (SCM) and higher doses of BoNT into the anterior neck muscles have been associated with a higher incidence of dysphagia, which is usually mild and disappears after several weeks.

Technique of administration for CD

The initial dose for a patient should be low, and subsequent doses should be adjusted based on individual responses ([Figure 3], [Table 3]). Multiple electromyography (EMG)-guided injections in the neck and shoulder muscles work better than a single injection. It is imperative to limit the total dose injected into the SCM to ≤100 U of onabotulinumtoxinA to reduce occurrence of dysphagia, and ≤50 Units per site should be administered.

Figure 3: Anatomy of the common muscles for botulinum neurotoxin injection in cervical dystonia

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Table 3: Common muscles for botulinum neurotoxin injection in cervical dystonia

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Injections should not be placed very low in the SCM to avoid injecting the tendon and to diminish the risk of dysphagia. Lying down with head up often brings the full muscle into view. For isolated and uncomplicated torticaput in a patient with an average neck size, a starting dose of 60 U (20 U at three sites each) injected into the SCM and 60 U (divided into three areas) into the splenius capitis muscle (for onabotulinumtoxinA and incobotulinumtoxinA) is used (Video 1). Furthermore, if laterocollis is a problem, additional injections into the ipsilateral scalene (middle), levator scapulae, or trapezius may be necessary.

[Additional file 1]

Oromandibular dystonia

Oromandibular dystonia (OMD) is a type of focal dystonia characterized by repetitive, involuntary jaw movements, affecting women more than men, and the age at onset ranges from 50 to 60 years. Dystonic jaw movements can present as intermittent jaw opening, jaw closure, jaw deviation, protrusion, retraction, or a combination. Furthermore, associated lingual movements can often manifest as dystonic rolling, tongue retraction, or protrusion. The etiology includes drug-induced dyskinesias; tardive dyskinesias; and neurodegenerative disorders such as neuroacanthocytosis, neurodegeneration of brain with iron accumulation, and Wilson’s disease. In addition, specific genetically determined dystonias [DYT6 dystonia (THAP 1), Lubag: DYT3 dystonia of the Philippines] demonstrate mandibular dystonia. The symptoms may be disabling, especially when it interferes with activities like swallowing, chewing, feeding, and speaking.^[24–26] OMDs, especially the primary OMDs, may be ameliorated by different proprioceptive sensory inputs (sensory trick), such as touching the lips or chin, chewing gum, or biting on a toothpick. OMD may be associated with blepharospasm (known as Meige syndrome) or CD. Sinclair et al.^[27] showed that among 59 patients with OMD, 47.5% had jaw-closing dystonia, 35.6% had jaw-opening dystonia, and 16.9% had lateral deviation of the jaw. Jaw-opening OMD occurs due to dystonia involving the lateral pterygoids and anterior belly of the digastric and submental muscles. Jaw-closing OMD chiefly occurs due to dystonia of the masseter and temporalis muscles, resulting in bruxism and trismus.

Pharmacological treatment of OMD is ineffective. Deep brain stimulation targeting the globus pallidus on both sides has been shown to be effective in some patients, with favorable results lasting years.^[28] BoNT therapy is the first line of treatment for OMD. Tan and Jankovic reported a mean total duration response of up to 16.4 ± 7.1 weeks in a large prospective open study.^[24] The best response is obtained with jaw-closing OMD.

Technique of administration for OMD

Jaw-opening OMD requires BoNT injection to the lateral pterygoid muscles through an intraoral or external approach, with the aid of electromyography for accurate targeting. The lateral pterygoid muscle can be located in front of the temporomandibular joint, below the zygomatic arch, after asking the patient to open the mouth widely. The injected dose varies from 15 to 30 U of onabotulinumtoxinA per side (mean 20 U), under EMG guidance.

For jaw-closing OMD, the masseter is often the initial muscle targeted, followed by the temporalis and medial pterygoid muscles.^[24] The masseter, is easily palpated by asking the patient to clench their teeth. The needle is inserted 1 cm behind the anterior border and 1 cm cephalad to the caudal border of mandible. It is important to avoid going posterior and cephalad to avoid the parotid gland and parotid duct, respectively. A good starting dose is 50 U of onabotulinumtoxinA.

The medial pterygoid muscle occupies the inner aspect of the ramus of the mandible and EMG guidance is preferred due to its deep location. It can be approached intraorally or from below. In the more common submandibular approach, the needle is inserted approximately 0.5–1 cm anterior to the angle of the mandible along the interior aspect of mandible and angled perpendicularly to it, until it is verified by EMG, with the patient clenching their teeth. Care are should be taken to avoid the facial artery, which lies anteriorly (starting dose of 20 U of onabotulinumtoxinA).

The temporalis muscle is approached perpendicular to its plane and high in the temporal fossa, since the injection is usually painful in the lower part of the muscle, which is mostly tendon. It is advised to administer three to four injections. The recommended dose is 50–100 U of onabotulinumtoxinA.

BoNT for lingual dystonia (rolling and retraction) can be administered by two techniques: a submental approach or a lateral tongue approach. In the first approach, the genioglossus muscle is submentally injected at a two-finger breadth behind the midline of the body of the mandible ([Figure 4]), with a mean dose of approximately 20 U of onabotulinumtoxinA, and it is divided into four sites. For the lateral approach, the tongue is held firmly with a gauze close to the tip and pulled out. Injections are performed using a 27.5-gauge, three-fourth-inch long needle laterally inserted at the tongue’s midpoint. The starting dose is 5 U of onabotulinumtoxinA; however, in case of a large tongue or severe dystonia, it can be increased to 7.5 U per side.

Figure 4: Botulinum neurotoxin injection site for the genioglossus muscle in lingual dystonia via submental approach

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Blepharospasm

Blepharospasm (BSP) is a type of focal cranial dystonia caused by excessive involuntary closure of the eyelids, usually bilateral, although it may briefly be unilateral at onset.^[29] The initial symptoms include unpleasant sensations, eyelid fluttering, or increased blink rate to stimuli, which progresses to chronic involuntary bilateral spasms of the eyes.^[30] The muscle frequently involved in BSP is the orbicularis oculi, a sphincter muscle around the eye that consists of an orbital, preseptal, and pretarsal part. In addition, BSP can affect the levator palpebrae superioris, corrugator, procerus, and frontalis. Both eyes are usually affected. The mean age of onset of BSP in the fifth and sixth decades of life, and women are more commonly affected than men, with a female to male ratio of 2.8:1.^[31],[32] When isolated, it is called essential blepharospasm, and it is called secondary BSP, when related to the brain stem pathology (<10% cases). Differentials of BSP include eyelid opening apraxia (elderly), tics of Tourette’s syndrome, and psychogenic blinking (in young patients). BoNTA is highly effective, providing improvement in 90–95% cases at doses between 25 and 50 U with very few side effects (visual blurring and ptosis).^[33]

Technique of administration for blepharospasm

Injections around the eye are performed using a small 30-gauge needle as the orbicularis oculi is a delicate structure. The starting doses are 2.5 U of onabotulinumtoxinA and incobotulinumtoxinA per site at all sites. Four injections are usually given in the orbital or preseptal portion of the orbicularis oculi muscle; however, the number of injections to the orbicularis oculi can be increased to include the lateral canthus ([Figure 5]). Injections should be avoided in the middle of the upper lid, in order to prevent ptosis. In addition, BoNTs can be injected into the pretarsal portion of the orbicularis oculi for better, sustained optimal response. The dose of BoNTA injected per session (for both eyes together) ranges from 25 to 50 U of onabotulinumtoxinA or from 100 to 150 U of abobotulinumtoxinA. The mean treatment interval is approximately 3–4 months. Furthermore, in patients with severe BSP involving nearby facial muscles, the corrugator, frontalis, and procerus can also be injected.

Figure 5: Botulinum neurotoxin injection sites for blepharospasm

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Hemifacial spasm

Hemifacial spasm (HFS) is characterized by involuntary irregular clonic or tonic movements of the facial muscles innervated by the seventh cranial nerve on one side of the face.^[34] It is often unilateral, due to vascular compression at the facial nerve root exit zone. Facial muscle twitches typically begin in the periocular region and can progress to involve the cheek and perioral muscles. HFS has female preponderance and commonly begins in the fifth decade, and symptoms may fluctuate. Unlike blepharospasm, which is a dystonia, hemifacial spasm is a myoclonus, since the electromyographic discharges that correlate with facial spasms usually have a duration <100 ms.

In contrast to essential BSP, symptoms of HFS often continue during sleep and can cause insomnia. Facial twitching is often exacerbated by emotions and stress. Other HFS etiologies include tumors and space-occupying lesions in the cerebellopontine angle. BoNT treatment is the first line of treatment for HFS. Approximately, 76–94% of patients respond well to BoNT therapy, with satisfactory effects sustained for decades after repeated injections at 3–4-month intervals.^[35],[36]

Technique of administration for Hemifacial spasm

Injection points around the eye for HFS are similar to that for BSP. The muscles injected for the treatment of HFS are the orbicularis oculi, corrugator, frontalis, zygomaticus major, buccinators, and depressor anguli oris^[37] ([Figure 6]). Two points along the lateral orbital rim that produce no side effects are valuable. Since most patients experience spasms in the cheek area, approximately 10 injection points (each with a low dose, subcutaneously administered over a large area below the bony orbital rim) are found to be effective. It is important to orient the needle as far away from the midline as possible to avoid levator paralysis. The side effects are drooping upper lip and/or of the corner of the mouth. The suggested starting doses are 20 U of onabotulinumtoxinA or 40 U of abobotulinumtoxinA. Injection pain can be reduced with local anesthetic creams (containing lidocaine 2.5% and prilocaine 2.5%).

Figure 6: Botulinum neurotoxin injection sites for hemifacial spasm

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Focal hand dystonia and task-specific dystonia

Task specific dystonia (TSD) is the most common cause of focal hand dystonia. Writer’s cramp and musician’s cramp are the most prominent types of TSD. Many other unique TSD have been described.^[38] An interaction of proprioceptive, behavioral, gestural, environmental, genetic, and psychological factors plays a role in its etiology.

Writer’s cramp

Writer’s cramp can be simple or complex. Simple writer’s cramp is when other acts of dexterity, such as buttoning of clothes, are unimpaired. It can be flexion or extension type depending upon the type of abnormal finger movements. Presence of difficulties with tasks other than writing are termed complex writer’s cramp. Writer’s cramp can be divided into various subtypes, depending on the hypothesized muscle group. Most common muscles involved include the flexors and extensors of the fingers and wrists.

Technique of BoNT administration for writer’s cramp

Patients are asked to perform the acts that cause dystonia, such as writing, without trying to compensate for the inability. They are instructed to describe any abnormal pulling that they experience. In addition, it is often helpful to have the patient perform other activities that may elicit the dystonia. Writing with the nondominant hand can evoke dystonia in the dominant, resting hand (mirror dystonia). Mirror dystonia can help identify dystonic muscle activity and distinguish dystonia from compensatory muscle activity.^[39],[40]

Injections should be given under careful EMG guidance to locate the specific muscle(s) of interest, since the muscles are tightly clustered together in the forearm. The recommended mean total onabotulinumtoxinA dose is 24.9 U and abobotulinumtoxinA dose is 82 U for writer’s cramp.^[41] Weakness in the muscle injected is the most frequent side effect.^[42] The Writer’s Cramp Rating Scale and Burke–Fahn–Marsden Scale are used to assess the clinical response after BoNT injection.^[43]

Laryngeal dystonias and voice tremor

Spasmodic dysphonia or laryngeal dystonia (LD) is a focal dystonia characterized by task-specific, action-induced spasm of the vocal cords. The thyroarytenoid muscle hyperactivity leads to overadduction of the vocal cords (adductor dysphonia) during speech and presents with strain strangles, tremulous, harsh, and staccato-like voice with inappropriate pitch and pitch breaks. The less common abductor type that illustrates hyperactivity of posterior cricothyroid muscles manifests with breathy, hypophonic, and whispered speech, due to prolonged abduction of vocal cords. Patients can have mixed LD, with presentations of both.

Technique of administration for LD

Injections can be given by the intraoral or intranasal route through a laryngoscope or percutaneously. Most injectors prefer the percutaneous, external approach. It uses a special EMG needle, which both records and allows injection through its hollow core. For adductor dystonia, which is the common form of LD, the needle is aimed at the thyroarytenoid muscle. The tip of the needle is placed close to the midline at the thyrocricoid membrane (between the thyroid and cricoid cartilage). After gently passing through the membrane, the tip is directed 30° superiorly and 30° laterally until it reaches the muscle. The patient may activate the muscle by saying “ii” or “hiss.” The toxin is then injected into the muscle after hearing typical sounds in the EMG unit. For abductor LD, the injection is given into the posterior thyroid lamina. In adductor LD, starting doses of 0.5–1 U of onabotulinumtoxinA are recommended for bilateral injection. Patients usually experience improvement of symptoms 4–6 months after BoNT injection.

Tremor

Essential Tremor

Essential tremor (ET), the most common movement disorder, is characterized by bilateral postural or kinetic tremor of the hands, with a 4–12 Hz frequency. In addition, it may affect the voice, neck, face, tongue, and legs. Approximately, 30% patients with ET are refractory to medical treatment; therefore, BoNT is considered.^[44] Mittal et al.^[45] reported a randomized, double-blind, placebo-controlled, cross-over study in 33 patients with essential hand tremor with incobotulinumtoxinA injections into 8–14 hand and forearm muscles using a EMG-guided customized approach. Remarkable improvement was observed compared to that with placebo at 4 and 8 weeks.

Technique of administration for ET

The injected muscles for ET include flexors and extensors of the wrists (flexor carpi radialis and ulnaris) ([Figure 7]), with a lower dose to the extensors since they are sensitive to the effects of BoNT, especially the extensor digitorum communis.^[46] The average starting dose is 25–50 U of onabotulinumtoxinA/incobotulinumtoxinA and 75–150 U of abobotulinumtoxinA, equally divided between the flexors of the wrist. Furthermore, patients with severe essential hand tremor may have pronation-supination movement of the forearm. In such instances, an additional injection is given into the biceps brachii muscle to decrease the tremor by weakening the supination. In patients with “negation” or “no-no” head tremor, injections of both splenius capitus muscles with a starting dose of 50 U of onabotulinumtoxinA or incobotulinumtoxinA or 150 U of abobotulinumtoxinA is generally effective in reducing the amplitude of the tremor. Patients with “affirmation” or “yes-yes” head tremors are more challenging to treat; in such cases, the sternocleidomastoid and scalene muscles usually need to be injected.

Figure 7: Anatomy of the muscles commonly injected for essential tremor

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Tremor in Parkinson’s disease

BoNT has been recently gaining acclaim for treatment of tremor in Parkinson’s disease (PD), which is usually resistant to conventional pharmacological therapy. However, the need for higher doses, larger number of muscles requiring injection, and transient hand and finger weakness in a substantial number of patients, even with a customized approach, has been limiting the use of BoNT in PD.^[47]

Identification of the muscles to be injected for the treatment of ET and PD tremor through incobotulinumtoxinA use and a kinematic approach has been emphasized in a recent open-label study that assessed the efficacy of incobotulinumtoxinA in 28 PD and 24 ET patients.^[48] The patients received six sets of injections over 96 weeks. Marked reduction of tremor amplitude was noted in 70% and 76% of PD and ET patients, respectively. However, 14% of PD patients and 8% of ET patients, withdrew from the study due to hand weakness.

Camptocormia

Camptocormia is an abnormal, severe, and involuntary forward flexion of the thoracolumbar spine, which reverses in the recumbent position and becomes obvious during standing and walking.^[49] Weakness of the paraspinal muscles, considered secondary to neurodegenerative diseases, has been observed. BoNT injections into the rectus abdominus and the external abdominal oblique muscles have yielded meaningful improvements, particularly in patients with dystonic camptocormia.^[50]

Spasticity

Disabling spasticity overriding the weakness is observed in some conditions like spastic cerebral palsy, poststroke spasticity, multiple sclerosis, and sometimes hereditary spastic paraparesis; BoNT is useful in such cases. Spasticity can further result in abnormal joint postures, hygiene issues, and pain, in addition to worsening the disability caused by weakness or impaired motor and sensory coordination.^[51],[52] Chemodenervation by intramuscular injection of BoNT can reduce the spastic muscle tone, ameliorate pain, normalize limb posture, prevent contractures, and improve motor function. The muscles involved in spasticity are the flexors in the upper limbs (shoulder adductors, elbow flexors, forearm pronators, and wrist and finger flexors) and the hip adductors, plantar flexors, and invertors of the foot. However, in children with spastic cerebral palsy, early insult leads to an increased tone in the flexors of the hip and knees, in addition to the classic pattern described above. A meta-analysis by Andringa et al.^[52] presented strong evidence that BoNT reduced spasticity, as measured by the Modified Ashworth scores, and improved selfcare. The final functional outcome in patients with poststroke spasticity was dependent on the motor power of the distal muscles. OnabotulinumtoxinA was safe in patients with hereditary spastic paraplegias, and it reduced the adductor tone according to the SPASTOX trial.^[53] BoNT doses for spasticity are much higher than the usual doses for dystonia or other hyperkinetic movement disorders. Higher doses, multiple injection sites, and end-plate targeting are key to effective reduction in spasticity, in addition to physiotherapy and rehabilitation.^[54] Larger, longer, or broader muscles are best injected at two to four sites. When the needle tip is within the target muscle belly, crisp staccato sound of motor unit firing close to the tip is heard and sharp motor units with short rise times are visible on the video monitor.

Sialorrhea

BoNT has shown excellent results in sialorrhea, especially in patients with PD.^[55] However, the dose needs to be carefully adjusted and uptitrated, since side effects such as dry mouth, infection, and dysphagia may occur and cause discomfort.

Tics

Focal or segmental motor tics and phonic tics may be successfully treated with onabotulinumtoxinA injections in the affected muscles.^[56] However, evidence supporting this hypothesis is scarce. Along with improving the motor component of tics, BoNT provides relief from premonitory sensations.

Myoclonus

Few case reports have shown variable success in treating myoclonus associated with various etiologies. A few case series have shown BoNT to be effective in the treatment of palatal myoclonus.^[57] However, there are no large-scale studies to support these results.

Restless legs syndrome

There is limited published data on the use of BoNT in the treatment of restless legs syndrome; however, it may be useful in a selected group of patients with “malignant” restless legs syndrome.^[58] The treatment should be individualized with 100–300 U of onabotulinumtoxinA in the thigh muscles (quadriceps or hamstrings) and/or 50–100 U in muscles of the leg (gastrocnemius or tibialis posterior).^[59],[60]

Conclusions

Indications for BoNT in the treatment of movement disorders have gradually increased over the last century, making it one of the world’s most versatile drugs. Although considered effective and safe, several limitations to its use still remain, such as its therapeutic effect wearing off and high cost. The technical aspects are of utmost importance and play a significant role in the treatment outcomes.

Acknowledgements

None

Author contribution

A. Conception, B. Organization, C. Execution

Manuscript Preparation: A. Writing of the first draft, B. Review and Critique

Ajith Cherian 1A,C, 2B;

Asish Vijayaraghavan 1A-C, 2B;

Divya K P 1A-C, 2B

Syam Krishnan 1C,2B;

Ethical compliance statement

This article does not contain any studies with human participants or animals performed by any of the authors

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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