The treatment of laryngeal dystonia (spasmodic dysphonia) with botulinum toxin injections

Operative Techniques in Otolaryngology (2012) 23, 96-101

The treatment of laryngeal dystonia (spasmodic dysphonia) with botulinum toxin injections Tanya K. Meyer, MD From the Department of Otorhinolaryngology—Head and Neck Surgery, University of Washington, Seattle, Washington. KEYWORDS Spasmodic dysphonia; Dystonia; Botulinum toxin

Spasmodic dysphonia is a neurologic voice disorder classified as a task-specific focal laryngeal dystonia. Botulinum toxin injection into affected musculature is the gold standard of treatment. The efficacy of this treatment practice has been supported in double-blind placebo-controlled trials. This technique is detailed in this monograph. © 2012 Elsevier Inc. All rights reserved.

Spasmodic dysphonia (SD) is considered a task-specific focal laryngeal dystonia in which a patient experiences excessive laryngeal muscular contractions (dystonic contractions) during speech (the task in question) sparing other laryngeal tasks such as laughing, singing, breathing, or swallowing. The most common form, adductor SD, produces a strained and strangled speaking pattern. Abductor SD is less common and results in a breathy or whispering speaking pattern.1 Although the task specificity for focal laryngeal dystonia has been observed mostly for speech, there is a low incidence of adductor breathing dystonia that may produce inspiratory stridor yet preserve normal voicing.2 Singing dystonias have also been described.3 The etiology of laryngeal dystonia falls into the same categories as forms affecting other areas of the body. Drug-induced glottic dystonic reactions can cause acute upper airway obstruction necessitating intubation.4,5 The gold standard treatment for laryngeal dystonia is electromyography (EMG)-guided botulinum toxin (BTX) injections into the affected musculature. Efficacy of this treatment practice had been supported in double-blind placebo-controlled trials.6,7 Although use of BTX for laryngeal dystonia is not currently Food and Drug Administration

Address reprint requests and correspondence: Tanya K. Meyer, MD, Department of Otorhinolaryngology—Head and Neck Surgery, University of Washington, 1959 NE Pacific Street, Box 356515, Seattle, Washington 98104. E-mail address: [email protected]. 1043-1810/$ -see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.otot.2011.11.006

(FDA) approved, the American Academy of OtolaryngologyHead and Neck Surgery endorses BTX as primary therapy for this disorder8 and also recommends laryngeal EMG (LEMG) to guide the BTX injections9 into the targeted laryngeal musculature.

Diagnosis The diagnosis of SD relies on clinical history, voice analysis, and physical examination, including flexible fiberoptic laryngoscopy. LEMG is used as an adjunct to diagnosis and to guide chemodenervation of affected musculature. SD is a chronic adult-onset disorder, although some children with generalized dystonia may have laryngeal involvement. Some individuals describe a gradual onset with symptoms noted only during periods of stress or increased speaking demands, and others describe a sudden occurrence, which may be related to an illness, trauma, or life event. Almost all individuals remark that symptoms are markedly exacerbated or more acutely perceived when speaking on the telephone. Speech may be better on awakening in the morning or after an alcoholic drink. Although the symptoms can wax and wane, there is almost always some sense of presence of the disorder. Certain words or combinations of words will be more difficult to say depending on the type of SD. Individuals usually report that emotional expression such as laughter, crying, and shouting in addition to singing and falsetto are relatively spared.10 Cough and swallow,

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along with other vegetative laryngeal tasks, are also preserved. Vocal tremor is frequently coexistent and can be present in up to one-third of patients.11 Vocal characteristics vary depending on the type of SD. Patients with adductor SD have a characteristic strained, strangled, effortful speech with vocal breaks and frequency shifts. There is often a reduction in loudness and prosody. These individuals have spasms of the laryngeal adductor musculature (primarily the thyroarytenoid [TA], interarytenoid [IA], and lateral cricoarytenoid [LCA]) causing the vocal folds to oppose too tightly and cutting off airflow and vocalization. These spasms are most prominent with voiced sounds such as vowels, and thus sentences such as “we mow our lawn all year” or counting from 80 to 90 will be difficult. Patients with abductor SD have a breathy, although still effortful, voice quality with aphonic whispered segments. These individuals have spasms of the laryngeal abductor musculature (posterior cricoarytenoid [PCA]) causing the vocal folds to remain open. Abductor breaks are particularly marked when attempting to phonate a vowel after a voiceless consonant such as /p/, /f/, /t/, /s/, /d/, /k/, or /h/. Examples of sentences that these individuals have particular difficulty with are “Harry had a hard head,” “The puppy bit the tape,” or “Taxi.” Patients experiencing spasms in both adductor and abductor groups are occasionally seen. These individuals can be quite challenging, as appropriate treatment may only be determined after treatment of the individual muscle groups singly has failed. Cannito and Johnson12 proposed that abductor and adductor abnormalities exist in all patients, and the final symptoms depend on the net abnormal activity of the laryngeal musculature. Some individuals with SD exhibit compensatory behavior in an effort to overcome their spasms. This is most common in adductor SD in which individuals will exhibit compensatory abduction producing a breathy voice by whispering or incomplete contraction of the vocal folds. Compensatory adduction in abductor dysphonia is rare. These behaviors can create diagnostic confusion with functional voice disorders such as muscle tension dysphonia, in which there is no neurologic defect and which often responds to speech therapy. A trial of BTX injection in conjunction with speech therapy may be needed to clarify the diagnosis. LEMG can confirm abnormal laryngeal muscle spasms in diagnostically ambiguous cases and can guide treatment to the more involved muscle groups. Typically, EMG will demonstrate an abnormally long latency (⬎400 ms) from the initiation of electrical signal to the beginning of sound production. Additionally, a significant increase in muscle activity will occur during vocal breaks within connected speech.13 On flexible fiberoptic laryngeal examination, the patient should exhibit a normal glottic aperture and movement with vegetative laryngeal tasks such as sniffing, coughing, and swallowing. The patient is then asked to perform eliciting speech tasks as described earlier in the text. For adductor

97 SD, the patients will exhibit excessive glottal closure. For abductor SD, the patient will demonstrate the appearance of a delay in closure of the vocal fold or “hanging” of the arytenoid with speech tasks.

Treatments Injection dosing and timing The goal of treatment is to give an injection that will provide just enough weakness to relieve spasm in target muscles for as long as possible without causing unnecessary weakness in neighboring muscles resulting in dysphagia, prolonged breathiness (adductor), or airway compromise (abductor). As a general rule, the maximum biologic effect of BTX A should last approximately 4 months. Thus, a dose is chosen that will cause effect for 3-4 months but without unnecessary initial side effects. If there are side effects, the dose can be decreased, although this may shorten the duration. If there are not excessive side effects but the duration of effect is too short, the dose can be increased. With regard to dilution of BTX, the goal is to inject a volume that is sufficient to accurately inject the desired dose, but is not too large that there will be unwanted diffusion of toxin into adjacent musculature. A volume between 0.1 and 0.3 mL is optimum. A standard 100-U vial of BTX A (Botox, Allergan, Irvine, CA) can be diluted with 4 mL of sterile injectable saline to give 2.5 U/0.1 mL. This concentration can be further diluted to provide the desired dose. The dose range for each patient is unique and is not dependent on mass, gender, or severity of dystonic spasms. Thus, an initial dose is chosen between the patient and the clinician empirically. Because there are 3 main muscle groups that are generally chosen for the treatment of adductor SD (TA, LCA, or IA), the results of a fine-wire LEMG can guide the choice of muscles to be treated.14 The majority of patients will improve with injection of the TA. For adductor SD, the average dose is approximately 1 U bilaterally.15 Thus, the patient can try the average dose, or if they are concerned about unwanted weakness, can start with a lesser dose with the option of a booster injection at 2 weeks if there is not sufficient effect. Based on response to the initial treatment, the dose will be adjusted. If there is too much initial weakness, then the dose can be decreased. If the effect is not sufficient, the dose can be increased. A typical pattern may be onset of weakness 2-3 days after injection, with 5-7 days of mild breathiness and occasional coughing on thin liquids and a resultant plateau of good voicing for 2.5-3 months. Patients are encouraged to seek reinjection as soon as they feel any return of symptoms and not delay until the spasms return to the original severity. Some patients experience prolonged initial weakness and also have a shorter-than-desired duration of effect. In these patients, either more frequent low-dose bilateral injections or staggered unilateral injections can be performed with the goal of maintaining a more constant level of weakness

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rather than experiencing the extremes of profound weakness and recovery of full spasms. Another alternative injection strategy is to inject a higher dose on one side and lower dose on the contralateral side, with alternation of this pattern between injections. Finally, other adductor muscle groups can be additionally injected. Patients with vocal tremor may respond to IA injections, and patients with dystonic tremor may respond to LCA injections.16-18 For abductor SD, the average dose is 3.75 U of BTX to the PCA muscle.15 The favored method is to give the dose unilaterally, with endoscopic assessment of airway patency at a 2-week interval, and then administration of a dose to the contralateral PCA. If there is some movement of the injected cord, a full contralateral dose can be given. If there is no or minimal movement, the contralateral dose can be postponed or a smaller dose chosen. Simultaneous bilateral weakness of the PCA can lead to airway narrowing and stridor, which can be life threatening. Bilateral PCA injections are given by some institutions in patients with an established dosing pattern.19 Even in established patients, there will be fluctuations in disease severity, which will require some titration of dosing. Rarely, patients will develop antibodies to BTX A, and a different serotype can then be used, usually with good effect. Patients may also become recalcitrant to BTX injections (even without development of antibodies), usually after long-standing dystonia or development of generalized dystonia.

Injection technique Although EMG-guided injections are the preferred method of this author, techniques that involve injections

Figure 1 This demonstration shows the patient in the classic Rose position. The clinician is seated at the head of the patient. Because of the close proximity, the clinician may choose to wear eye protection and a mask. The advantage of this position is that the clinician is seated at the exact midline of the patient. This is the author’s preferred position for LEMG. The patients seem to be more uncomfortable in this position, and it is a more cumbersome position for the room layout. (Color version of figure is available online.)

Figure 2 This demonstration shows the patient in a beach chair position. Most patients prefer this position for the therapeutic injections as opposed to lying completely supine. There is more distance between the patient and clinician, and a mask is not strictly necessary. The clinician stands to one side of the patient, and it is more difficult to determine the exact midline of the patient in this position. (Color version of figure is available online.)

guided solely by anatomic landmarks—termed point-touch technique20— have proven efficacy. All percutaneous techniques use similar anatomic landmarks, but the additional verification of correct muscular placement through a confirmatory electrical signal is available with EMG guidance. There are many different methods to access the laryngeal musculature for therapeutic injection; however, in this monograph, the percutaneous technique will be described. Most commonly a 27-gauge insulated 1.5-inch needle is used that also serves as a monopolar electrode for EMG guidance. Ground and reference electrodes are placed over the skin of the neck or face in close proximity to the injection site. Use of local anesthesia is optional, and many patients will not require it. Some clinicians give a small dose of local anesthesia into the skin at the injection site. More commonly, especially for patients with a vigorous cough response, 1-2 mL of 2% plain lidocaine is injected through the cricothyroid ligament into the tracheal airway, and the patient is asked to cough the lidocaine into the glottis. The patient is positioned supine with the neck extended. The clinician can either be positioned midline, at the head of the patient (patient in the Rose position, Figure 1), or along the patient’s side, facing the patient (patient in beachchair position, Figure 2). For abductor SD, the main intrinsic laryngeal muscles injected are the TA, LCA, and the IA (Figures 3 and 4). These muscles can all be accessed through the cricothyroid membrane, and the verification gesture is phonation of \i\. For the TA muscle, it is helpful to bend the needle upward to 30-45°. The needle is inserted through the skin either at or just off midline. The cricothyroid membrane is punctured, and, if the airway is entered, an “airway buzz” will be noted from the EMG signal. The needle tip is then directed superiorly and laterally, advancing towards the ipsilateral

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TA muscle. An insertional potential should be noted and crisp motor unit recruitment on phonation of \i\. The desired dose of BTX is then injected. Some clinicians always enter the airway and then pierce the TA muscle from an intraluminal direction (midline insertion), or other clinicians prefer a submucosal route (slight lateral insertion). To inject the LCA muscle, the cricothyroid membrane is palpated, and the most lateral aspect of the membrane is noted, at the angle between the thyroid and cricoid cartilages. The needle is placed through the cricothyroid membrane in this location and is angled superiorly, and the LCA muscle is more lateral than the TA muscle and is encountered more superficially. The IA muscle is accessed through a midline needle placement. The needle is directed into the tracheal air column and straight posteriorly. The needle is “walked” up the cricoid rostrum until it falls into the IA space and muscle. The needle insertion often gives the patient a mild sharp pinching sensation, and the patient grimace along with an appropriate EMG signal confirms needle placement. In tall males, the needle may need to be inserted full length to span the glottic distance. If there is significant soft tissue anterior to the larynx, the 1.5-inch needle may not be long enough. The PCA muscle can be accessed anteriorly by piercing through the cricoid rostrum or laterally by rotating the

Figure 3 The percutaneous approach for injection of the TA and LCA muscles for adductor SD. For the TA, the needle electrode is inserted at the midline or just lateral to midline, through the cricothyroid membrane. The needle tip is directed in a rostral and lateral direction toward the superior thyroid cornu. The tracheal air column can be entered, or the needle can be directed entirely submucosally. For LCA injections, the needle insertion is at the point indicated by the red arrow, and the needle tip is directed in a rostral direction. Correct placement in either muscle is verified with phonation of /i/ causing electrical activity on the EMG tracing. Image from Sulica L, Blitzer A, Oper Tech Otolaryngol 15:76-80, 2004 © Elsevier, adapted and reprinted by permission. (Color version of figure is available online.)

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Figure 4 Technique for translaryngeal injection of the IA muscle (adductor SD) and the PCA muscle (abductor SD). In this technique, the needle is inserted in the midline and directed posteriorly. For the IA, the needle is walked up the midline of the cricoid rostrum posteriorly until it pierces the IA muscle at the superior edge of the cricoid rostrum. The verification gesture is phonation of /i/ causing electrical activity on the EMG tracing. For the PCA, the needle is directed very slightly laterally, and the cricoid rostrum is pierced to access the muscle on the far side of the cartilage. The verification gesture is the sniff maneuver causing electrical activity on the EMG tracing. Image from Sulica L, Blitzer A, Oper Tech Otolaryngol 15:76-80, 2004 © Elsevier, reprinted by permission.

larynx (Figures 4 and 5). The confirming gesture for this muscle is brisk recruitment with a sniffing maneuver. For the anterior approach, the needle is inserted through the cricothyroid membrane in the midline traversing the glottic space and directed very slightly laterally. Firm pressure is used to pierce through the cricoid rostrum. Often, there will be a cartilage plug within the needle lumen, and firm pressure is used to expel the plug and deliver the toxin dose. Because of this, it is important to only put the desired dose in the delivering syringe and also to ensure the syringe and needle are well secured together so that they do not become disassociated with the increased pressure applied. The lateral approach to the PCA requires a relaxed patient, preferably with a relatively thin neck. The patient must tolerate the clinician applying moderate pressure/force on their larynx to rotate the posterior aspect of the cricoid into a position to allow access. The clinician rotates the larynx by hooking the thumb of the nondominant hand over the edge of the thyroid cartilage on the side to be injected and using counterpressure from the other fingers to rotate the larynx to expose the posterior aspect. The ring finger is placed on the anterior arch of the cricoid cartilage and marks the inferior aspect of the cricoid cartilage. The needle is then inserted below the position of the thumb, traversing the pyriform sinus and inferior constrictor. The needle is

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Operative Techniques in Otolaryngology, Vol 23, No 2, June 2012 Patients rated their average benefit as achieving 70.3% of normal function. Because these patients did not achieve the same degree of voice normalization, 30% received additional systemic agents, including clonazepam, trihexyphenidyl, or baclofen. Side effects were mild exertional wheezing in 2% of patients and mild dysphagia to solids in 6%. Although no cases of resistance because of antibody formation in patients injected solely for laryngeal dystonia have been reported, some patients may respond to one isoform of toxin better than another. Therefore, if subjects do not demonstrate good response with BTX A, a trial of BTX B should be considered.21 The relative toxin potencies are a bit different, with dose ratio being approximately 52:1 (Myobloc units: Botox units), an onset of action in 2 days, benefit lasting 10 weeks, and a more abrupt offset.22

Conclusions Figure 5 This image demonstrates rotation of the larynx to allow injection in the PCA muscle for abductor SD. The thumb of the noninjecting hand is hooked behind the posterior edge of the thyroid lamina to rotate the larynx away and expose the posterior aspect. The needle is inserted at the level of the cricoid ring, transversing the inferior constrictor until it stops against the rostrum of the cricoid cartilage. Correct placement is verified with the sniffing maneuver causing electrical activity on the EMG tracing. Image from Sulica L, Blitzer A, Oper Tech Otolaryngol 15:76-80, 2004 © Elsevier, reprinted by permission.

SD can be a challenging disorder to diagnose and treat because of the high degree of variation in patient presentation, pattern of muscle involvement, and response to treatment. The physician and patient must work together to develop an individualized treatment regimen, taking into consideration toxin dose adjustments, injection interval, and selection of muscles to be treated. Most patients with SD will achieve a satisfactory improvement in voice with BTX injections.

References advanced until it stops against the rostrum of the cricoid cartilage abruptly. The patient is then asked to sniff to confirm proper recruitment pattern. BTX may also be administered transcutaneously with flexible fiberoptic guidance, transorally with a curved injection needle, through the working channel of an endoscope, or by direct laryngoscopy.

Results Excellent results from treatment of adductor SD with BTX have been reported by multiple groups. Blitzer15 describing his series of 1300 patients injected from 1984 to 2007 reports that the average dose was 0.9 U of Botox bilaterally, producing an onset of action in 2.4 days, peak effect in 9 days, and average duration of benefit lasting 15.1 weeks. Patients rated their average benefit as achieving 91.2% of normal function. Side effects were as follows: incidence of mild breathy voice in 25%, transient cough on drinking fluids in 10%, and local pain, bruising, or itch in ⬍1%. In the same series, abductor SD was successfully treated with staggered injections to the PCA muscle in 80% and unilateral injections in 20%. The average dose was 3.75 U to one side and 0.6-2.5 U to the contralateral side 2 weeks later. The onset of action occurred in 4.1 days, peak effect in 10 days, and the average duration lasted 10.5 weeks.

1. Meyer TK, Blitzer AB: Spasmodic Dysphonia, in Stacy MA (ed): Handbook of Dystonia. New York, Informa Healthcare USA Inc, 2007, pp 179-188 2. Grillone GA, Blitzer A, Brin MF, et al: Treatment of adductor laryngeal breathing dystonia with botulinum toxin type A. Laryngoscope 104(1 Pt 1):30-32, 1994 3. Chitkara A, Meyer T, Keidar A, et al: Singer’s dystonia: first report of a variant of spasmodic dysphonia. Ann Otol Rhinol Laryngol 115:8992, 2006 4. Warren J, Thompson P: Drug-induced supraglottic dystonia and spasmodic dysphonia. Mov Disord 13:978-979, 1998 5. Newton-John H: Acute upper airway obstruction due to supraglottic dystonia induced by a neuroleptic. BMJ 297:964-965, 1988 6. Troung DD, Rontal M, Rolnick M, et al: Double-blind controlled study of botulinum toxin in adductor spasmodic dysphonia. Laryngoscope 101(6 Pt 1):630-634, 1991 7. Watts CC, Whurr R, Nye C: Botulinum toxin injections for the treatment of spasmodic dysphonia. Cochrane Database Syst Rev: CD004327, 2004 8. Schwartz SR, Cohen SM, Dailey SH, et al: Clinical practice guideline: hoarseness (dysphonia). Otolaryngol Head Neck Surg 141(suppl 2): S1-S31, 2009 9. Blitzer A, Crumley RL, Dailey SH, et al: Recommendations of the Neurolaryngology Study Group on laryngeal electromyography. Otolaryngol Head Neck Surg 140:782-793, 2009 10. Ludlow CL: Spasmodic dysphonia: a laryngeal control disorder specific to speech. J Neurosci 31:793-797, 2011 11. Schweinfurth JM, Billante M, Courey MS: Risk factors and demographics in patients with spasmodic dysphonia. Laryngoscope 112: 220-223, 2002 12. Cannito MP, Johnson JP: Spastic dysphonia: a continuum disorder. J Commun Disord 14:215-233, 1981

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13. Hillel AD: The study of laryngeal muscle activity in normal human subjects and in patients with laryngeal dystonia using multiple finewire electromyography. Laryngoscope 111(4 Pt 2 suppl 97):1-47, 2001 14. Klotz DA, Maronian NC, Waugh PF, et al: Findings of multiple muscle involvement in a study of 214 patients with laryngeal dystonia using finewire electromyography. Ann Otol Rhinol Laryngol 113:602-612, 2004 15. Blitzer A: Spasmodic dysphonia and botulinum toxin: experience from the largest treatment series. Eur J Neurol 17(suppl 1):28-30, 2010 16. Maronian NC, Waugh PF, Robinson L, et al: Tremor laryngeal dystonia: treatment of the lateral cricoarytenoid muscle. Ann Otol Rhinol Laryngol 113:349-355, 2004 17. Kendall KA, Leonard RJ: Interarytenoid muscle botox injection for treatment of adductor spasmodic dysphonia with vocal tremor. J Voice 25:114-119, 2011

101 18. Hillel AD, Maronian NC, Waugh PF, et al: Treatment of the interarytenoid muscle with botulinum toxin for laryngeal dystonia. Ann Otol Rhinol Laryngol 113:341-348, 2004 19. Stong BC, DelGaudio JM, Hapner ER, et al: Safety of simultaneous bilateral botulinum toxin injections for abductor spasmodic dysphonia. Arch Otolaryngol Head Neck Surg 131:793-795, 2005 20. Morzaria S, Damrose EJ: The point-touch technique for botulinum toxin injection in adductor spasmodic dysphonia: Quality of life assessment. J Laryngol Otol 125:714-718, 2011 21. Adler CH, Bansberg SF, Krein-Jones K, et al: Safety and efficacy of botulinum toxin type B (Myobloc) in adductor spasmodic dysphonia. Mov Disord 19:1075-1079, 2004 22. Blitzer A: Presentated at American Academy of Otolaryngology, 2004