OnabotulinumtoxinA
AbotulinumtoxinA
IncobotulinumtoxinA
RimabotulinumtoxinB
CBTX-A
Bonta
Commercial name
Botox®, Botox Cosmetic®, Vistabel®, Vistabex®
Dysport®, Reloxin®, Azzalure®
Xeomin®/Bocouture®
Myobloc®, NeuroBloc®
Prosigne®, Lantox®
Neuronox®
Company
Allergan Inc.
Medicis Pharmaceutical Group
Merc Pharmaceuticals
Solstice Neurosciences Inc.
Lanzhou Institute of Biological Products, China
Medy-Tox Inc., South Korea
Type
A
A
A
B
A
A
Strength (BTX-A: product)
1:1
1:2–1:4
1:1
1:50–1:100
FDA approval
Botox ®: cervical dystonia, severe primary axillary hyperhidrosis, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity, strabismus, blepharospasm
Botox Cosmetic ®: glabellar lines (moderate-severe), lateral canthal lines (moderate-severe)
Cervical dystonia, glabellar lines (moderate-severe)
Blepharospasm, cervical dystonia, glabellar lines
Cervical dystonia
None (risk of prion infection)
None
Units/vial
100 or 200
300 or 500
50 or 100
2500; 5000; 10,000
50 or 100
100
Reconstitution
Preservative-free 0.9% NaCl
Preservative-free 0.9% NaCl
Preservative-free 0.9% NaCl
Not necessary
Countries available
Worldwide, including the USA and Canada
>65 countries, including the USA and Canada
The USA since 2011, Germany, other European countries, Mexico, Argentina, Brazil
The USA and some European countries
>10 countries, not in the USA or Canada
South Korea, India, South America, not in the USA or Canada
Botox®/Botox Cosmetic® is the trade name for onabotulinumtoxinA and is approved for over 20 indications in more than 75 countries [20]. It comprises 85% of the worldwide BTX market, and most scientific articles on BTX are about Botox® [20]. This product was initially purified by Shantz and later used clinically by Scott in San Francisco [2].
Dysport®, Reloxin®, and Azzalure® are the trade names for abotulinumtoxinA [21] which was first approved by the FDA in 2009 for the treatment of cervical dystonia and temporary improvement of moderate to severe glabellar lines [22]. Although the same neurotoxin, BTX-A, is used in both Botox® and Dysport®, the difference lies in the purification process. Botox® is purified with repetitive precipitation and redissolution, and Dysport® is purified using a column separation method [20]. Postinjection, Dysport® has been shown to have a greater spreading effect, leading to a more diffuse distribution clinically. Dose ratios between the two toxins have been greatly debated. The literature suggests a dose ratio, in clinical practice, to be approximately 3:1 when compared to Botox® [23].
Xeomin®/Bocouture®, the trade name for incobotulinumtoxinA, is licensed in Germany. In this product, the complexing proteins are stripped from the active toxin. In 2011, Xeomin® was FDA approved in the USA for temporary improvement of moderate to severe glabellar lines in adults. It exhibits a dose ratio with Botox® that is 1:1 [20]. No significant differences in safety and efficacy have been found in studies comparing Botox® and Xeomin®. Xeomin® has been formulated to be free of therapeutically unnecessary complexing proteins, as aforementioned. This is suggested to lead to greater efficacy and reduced risk of antibody formation and sensitization [24] but has yet to be clinically determined. It is also of note that storage of an unopened vial of this product may be stored at room temperature, 20–25 °C (68–77 °F).
Neuronox®, Prosigne®, CBTX-A, and Lantox® are other commercially available BTX-A from other countries but are not FDA approved in the USA [20, 25]. It is worth noting that CNBTX-A is a BTX-A that is not approved or licensed in any country. It should not be confused with CBTX-A or other BTX-A preparations. CNBTX-A has been found to contain much higher levels of neurotoxin than listed on its package insert and could lead to severe health risk if administered to humans [26].
Myobloc® and NeuroBloc® are the trade names associated with rimabotulinumtoxinB. It is the only botulinum toxin type B commercially available in the USA indicated for cervical dystonia and associated neck pain and was the first FDA-approved treatment for cervical dystonia in the USA. Myobloc®/NeuroBloc® has a more rapid onset and greater area of diffusion in clinical use [27]. It is a liquid preparation with a pH of 5.5–6.5, which leads to increased discomfort at the injection site. When compared to Botox®, it is significantly less effective per unit in a rate of 50:1–100:1 [27, 28].
9.2 The Injection Procedure
9.2.1 Reconstitution
OnabotulinumtoxinA (Botox®) is the most studied neurotoxin. From this point forward, the reader should know that we will only discuss treatments using this product. Initially, BTX was thought to be a fragile substance [29], but later studies have dismissed this initial belief and proven the activity of BTX in different preparatory situations. Various other studies have shown that reconstitution of onabotulinumtoxinA (Botox®) with preserved saline, which contains benzyl alcohol, does not affect the neurotoxin’s potency [30, 31]. In 2004 a consensus panel stated that preserved saline is the preferable method for the reconstitution of onabotulinumtoxinA (Botox®) [32]. It is also of note that a second panel reported that the benzyl alcohol component acts as a local anesthetic at low volumes [33]. Other products have also been studied for the reconstitution of BTX, including unpreserved saline [29], lidocaine with epinephrine [34–37], bupivacaine [26], and sterile water [38].
9.2.2 Dilution
The package insert of Botox® recommends dilution of 100 units with varying amounts of saline to achieve a wide range of concentrations. For injection into the vocal folds, accepted doses range from concentrations of 0.625–10 U/0.1 mL. Many physicians believe that the higher the volume of diluted BTX, the greater the chance of diffusion to unwanted sites and the shorter the duration of effect, leading to suboptimal results [39]. Preferably, 0.1 mL of solution is used for injection into a single vocal fold; however, a volume of 0.2 mL is also acceptable. At that volume, there is little to virtually no risk of airway obstruction from vocal fold engorgement. A needle larger than a 21 gauge should be used for reconstitution, dilution, and transfer from vial to injection syringe. This allows for multiple uses of one vial of toxin. Despite the FDA’s recommendation to use Botox® as a single-dose vial, Barrow et al. looked at 743 subjects receiving Botox® using single-dose vials in a multidose fashion with no reported evidence of infection [40]. After the correct dose is sterilely prepared, the appropriate injection needle, which depends on the route of administration, is attached to the syringe.
9.2.3 Storage
FDA-approved product labeling for Botox® recommends intramuscular administration within 4 h of reconstitution [41]. Because a single 100-MU vial may be sufficient to treat more than one patient and administration is limited to a 4-h window, a few issues arise: waste of an expensive product if multiple patients are unable to be treated within this very restricted time limit and inconvenience to patients who are faced with limited or restricted time intervals to receive treatment. Consequently, many physicians have adopted the off-label practice of refrigeration (4 °C) or freezing (−20 °C) of the product in storage. Studies have shown that effectiveness of fresh vs. stored BTX is comparable [29, 42–46]. Storage for up to 30 days is adequate.
9.2.4 Botulinum Toxin Injection Approaches
There are a variety of approaches to delivering botulinum toxin to the larynx, including percutaneous injection with EMG guidance (most traditional), percutaneous injection with laryngoscopic guidance, supraglottic injection with laryngoscopic guidance, and a combined approach using both EMG and laryngoscopic guidance. Distinct advantages and disadvantages exist for the above approaches. The surgeon, equipment availability, patient’s disease characteristics, and preference determine selection of the most advantageous approach. It is important to note that BTX is not FDA approved, and patients should be counseled on its off-label usage, but the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) endorses the use of EMG-guided BTX injection into targeted laryngeal musculature for the primary treatment of laryngeal dystonias [47]. The literature also suggests that EMG-guided BTX injection is the gold standard for spasmodic dystonia (SD)/laryngeal dystonias, and its efficacy of treatment has been supported in double-blind placebo-controlled trials [48, 49].
Percutaneous injection under EMG guidance is the quickest and most precise method of botulinum toxin delivery into the larynx and other areas of the head and neck, including muscles involved in oromandibular dystonias and blepharospasm. This technique does, however, have a learning curve and requires skill, training, and EMG equipment. Given these barriers, some surgeons choose to use an alternate method, which includes a percutaneous or peroral technique under laryngoscopic (visual) guidance or “blind” percutaneous injection. These techniques are less precise and often require a higher dose of BTX than the EMG-guided percutaneous injection technique, and they are suboptimal.
Supraglottic BTX injection for adductor SD (ADSD) with laryngoscopic guidance offers the advantage of a more gradual onset of action, smoothing of vocal “peaks and troughs” associated with true vocal fold injection, less-severe breathy voice, and preservation of singing voice/pitch control in many patients. This approach’s disadvantages include a shorter duration, less-predictable voice results, and a more involved and timely injection procedure. This unreliability most likely occurs from variable anatomy of the supraglottis with variable needle location during the injection. This procedure may be preferred by the professional voice user stricken with ADSD due to the reduced number of days with a soft, breathy, or weaker voice. This same approach can be used for treating the false vocal folds in laryngeal essential tremor (ET).
Treatment of the interarytenoid muscle is accomplished using a combined approach. This muscle is treated by both percutaneous EMG guidance and visualization accomplished via flexible transnasal laryngoscopy.
9.2.5 Equipment
Equipment needed for BTX injection via an EMG-guided percutaneous approach:
EMG machine
Botulinum toxin
Reconstitution solution of choice
Insulated 26 g EMG needle (both 37 mm and 50 mm in length)
Ground and reference electrodes
Tuberculin syringe
Local anesthetic for the skin (1% lidocaine with 1:100,000 epinephrine) (optional)
Additional equipment necessary for percutaneous injection with laryngoscopic guidance and/or peroral supraglottic injection with laryngoscopic guidance:
Flexible laryngoscope (with working channel or EndoSheath® with channeled sheath)
C-Mount camera to attach to flexible laryngoscope (unless using a distal chip flexible laryngoscope)
Video monitor for visualization
Three to 6 mL of 4% plain lidocaine
27 g needle, 37 mm in length (percutaneous injection with laryngoscopic guidance)
Orotracheal injector device for peroral injection approach
Benzocaine topical spray (optional)
Curved Abraham cannula
Fine-gauge injection needle for use with working channel in flexible laryngoscope
9.3 Hyperkinetic Disorders of the Head and Neck and Treatment Techniques
9.3.1 Dystonia
Dystonia is a chronic neurologic disorder of central motor processing within the basal ganglia (extrapyramidal system). Characteristic symptoms of a patient with dystonia include involuntary sustained muscle contractions of agonist and antagonist muscles, which cause twisting and repetitive movements or abnormal postures. Oftentimes, sedatives may mitigate the movements; anxiety will aggravate the movements; and posturing disappears during sleep. Dystonias may be focal, as in spasmodic dysphonia or cervical dystonia; segmental, as in Meige’s syndrome; multifocal when two or more noncontiguous body regions are involved; or generalized and can be secondary to a wide variety of causes or simply idiopathic. Treatment of dystonic conditions of the head and neck commonly involves a multidisciplinary treatment team including the primary care physician, neurologist, and otolaryngologist.
Laryngeal dystonia, also known as spasmodic dystonia (SD), is a focal, task-specific, action-induced spasm of the laryngeal musculature. It is usually classified into adductor (ADSD), abductor (ABSD), and mixed forms via hallmark clinical features. ADSD, the far more common form, is characterized by inappropriate, excessive glottic closure and, as a result, produces strangled breaks in connected speech. ABSD, in contrast, causes inappropriate glottal opening that produces breathy breaks and hypophonia. Classification of SD into ADSD and ABSD is imperative to treatment: ADSD is treated with injection of BTX into the thyroarytenoid/lateral cricoarytenoid (TA/LCA) muscles and/or the interarytenoid (IA) muscle and in ABSD. BTX is injected into the posterior cricoarytenoid (PCA) muscle.
9.3.2 Essential Tremor of the Vocal Tract
Essential tremor of the vocal tract (ETV) is a benign, commonly age-related, and likely inherited voice disorder consisting of involuntary muscle contractions, which can affect the voice to a debilitating extent in some patients [50]. Rhythmic head titubation and shaking of the hands are most commonly seen. These oscillatory movements can also be seen, in varying degrees, along all portions of the respiratory tract (i.e., velum, base of the tongue, pharynx, larynx, vocal folds) and can be graded on laryngoscopy using the Vocal Tremor Scoring System (VTSS) [51]. Although aggravated by anxiety, public speaking, and telephone use and mitigated by alcohol and benzodiazepines, ETV differs from SD with its rhythmic nature and presence across all speaking tasks. Patients with ET are treated with medicinal, systemic agents such as propranolol and primidone; however, in our experience, ETV does not respond as readily as with axial-based tremor disease. BTX treatment has been effective at symptomatic relief for ETV by injecting the false vocal folds, TA/LCA complex, PCA, CT, IA, FVF, strap muscles, etc. [52].
9.3.3 Percutaneous EMG-Guided Botulinum Toxin Injection
- a.
Connecting EMG electrodes: A ground and reference electrode is attached to a patient’s skin near the injection site. The insulated injection needle, which serves as a monopolar sampling electrode during the injection, is attached to an EMG recording device.
- b.
TA/LCA muscle complex localization and injection: The patient is placed in semirecumbent position with the mentum elevated and occiput or the head back. The headpiece of an ENT chair can be positioned to allow neck extension (Fig. 9.1). The patient is asked not to swallow and breathe quietly. With all of the following techniques, the skin is anesthetized with local anesthetic. The author uses a 30 g needle and 3 cc syringe with 1% lidocaine with 1:100,000 epinephrine and sodium bicarbonate. The EMG needle electrode is inserted into the cricothyroid space 2–3 mm off of the midline toward the side to be injected and advanced superiorly and laterally (Fig. 9.2). An off-the-midline entry point is used to attempt to avoid the airway, which is very stimulating to a patient. Entry into the airway produces a characteristic sound in the EMG signal, which should alert the physician to redirect the needle more laterally. Once the needle has been inserted through the cricothyroid membrane, it is maneuvered within the tissues until the tip lies in an area of crisp motor unit potentials. The patient is asked to phonate or perform a Valsalva maneuver, a brisk recruitment and a full interference pattern confirm placement, and the BTX is injected. A characteristic prephonatory burst on EMG is of benefit for optimal injection localization.
- c.
PCA muscle localization and injection: A retrolaryngeal or a translaryngeal approach can be taken to inject the PCA. If using the retrolaryngeal technique, the patient is seated upright, and the physician places his or her thumb at the posterior border of the thyroid cartilage on the side to be injected. Using counterpressure on the opposite side of the thyroid cartilage from the other four fingers, the larynx is gently rotated to expose its posterior aspect. An adequate amount of anesthetic is then used. The needle pierces the skin along the lower half of the posterior border of the thyroid cartilage and is advanced until it stops against the posterolateral surface of the cricoid. The needle is then pulled back slightly, and the patient is asked to sniff for confirmation of placement (Fig. 9.3). When the sniff is initiated and a brisk recruitment is initiated, the BTX is injected. If using the translaryngeal approach, the needle must cross the endolaryngeal mucosa so an intratracheal injection of 4% plain lidocaine is useful to prevent coughing and discomfort. After this, the needle is inserted through the cricothyroid membrane in the midline and directed posteriorly across the glottis lumen and angled toward the side to be injected. Using gentle pressure, it is pushed through the lamina of the cricoid cartilage until the opposite side is reached (this may be difficult in a very calcified cricoid cartilage in an older adult). The first electrical signal encountered on the far side represents the PCA muscle. Confirmation, again, is achieved using a sniff task. Once the physician finds an area with brisk recruitment, the BTX is injected (Fig. 9.4).
- d.
IA muscle localization and injection: The IA muscle is injected using a translaryngeal injection with flexible transnasal laryngoscopic guidance technique. Local anesthesia is applied to the endolarynx. The nasal cavity is anesthetized (50/50 mix of oxymetazoline and 4% lidocaine), and an assistant inserts a flexible laryngoscope, attached to a video monitor through the nasal cavity. After this, the needle is inserted through the cricothyroid membrane in the midline across the glottic lumen and directed straight posterior and slightly cephalad toward the IA muscle, which lies on the inner surface of the cricoid cartilage. The patient is asked to phonate, placement is confirmed with brisk recruitment, and the BTX is injected (Figs. 9.5 and 9.6).
- e.
Supraglottic injection with laryngoscopic guidance: As mentioned earlier, supraglottic BTX injection with laryngoscopic guidance is effective for treatment of ADSD as well as ETV involving the supraglottis. Two different injection approaches can be employed: (1) peroral injection and (2) an approach using a working channel of a flexible laryngoscope (Fig. 9.7). Each of these two approaches is efficacious, and the chosen technique is chosen by the physician. Patients tend to tolerate injection through a working channel of a flexible laryngoscope more than using the peroral route. When using the laryngoscopic technique, the nose is anesthetized (50/50 mix of oxymetazoline and 4% lidocaine) as well as the oropharynx and larynx (nebulized 3 cc of 4% lidocaine). The flexible scope attached to a video monitor is then passed through the nasal cavity. At this point, additional 4% lidocaine can be “dripped” onto the larynx through the channel on the laryngoscope (care should be taken not to give a patient more lidocaine than necessary as toxic doses can be easily reached. Maximum dose of lidocaine should not exceed 4 mg/kg). The patient is bent forward at the waist with the neck extended into a “sniffing” position to maximize laryngeal exposure. An injector needle device is placed through the channel in the scope, and BTX can be injected into the false vocal folds. The plane of injection needs to ideally be into a superficial/submucosal area, forming a characteristic “bleb” (Fig. 9.8). When using the peroral technique with laryngoscopic guidance, the flexible scope is passed through the nasal passage as in the technique above with the same positioning of the patient. After this BTX is drawn up into a 1-mL syringe and secured into a curved injector device (orotracheal injection device, Xomed, Jacksonville, Fl). The needle is advanced into the oropharynx under direct visualization through the laryngoscope (a Hopkins rod-lens telescope, 70° or 90°, can also be used). The patient is instructed to phonate as the needle enters the oral cavity, which elevates the soft palate, clearing a path into the oropharynx. The assistant should position the flexible scope just above the palate until the needle is visualized in the oropharynx. The needle is then advanced to the false vocal folds with the assistant following behind with the laryngoscope. Injection is carried out, again, in the submucosal plane forming a bleb (Fig. 9.9).
- f.
Post procedure care: Patients may be discharged immediately after the injection. Patients receiving TA/LCA injections should be advised that they may have a period of breathiness and dysphagia. Patients receiving topical anesthesia to their larynx should be warned to not drink or eat for 2 h to prevent aspiration.
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