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Laryngeal Botulinum Toxin Injection

Editor: Sungjin A. Song Updated: 4/17/2023 4:41:44 PM

Introduction

Botulinum toxin is a neurotoxin produced from Clostridium botulinum, an anaerobic, gram-positive bacteria.[1] Injection of botulinum toxin into a muscle temporarily denervates the targeted muscle. It also reduces secretory function when injected into a gland. Although botulinum toxin has traditionally been utilized in facial cosmetics/aesthetics to address rhytids, it is also a useful tool in addressing laryngeal pathology. Before introducing botulinum toxin, laryngeal dystonia was historically treated with psychotherapy and speech therapy, both of which were significantly limited in their effectiveness for this disorder.[2]

The use of botulinum toxin has been described in the management of both adductor and abductor laryngeal dystonia/spasmodic dysphonia (SD), vocal tremor, vocal process granuloma, and cricopharyngeal muscle dysfunction. By selectively denervating targeted laryngeal musculature, the surgeon can strategically address these pathologies. 

The vast majority (65%) of SD patients are female, with an average age of onset of 45 years. The prevalence of SD is 1 per 100,000.[3] In adductor spasmodic dysphonia (ADSD), the thyroarytenoid (TA) muscle is targeted for chemodenervation. Botulinum toxin chemodenervation, initiated in the 1980s by Blitzer and colleagues, is now considered the gold standard for the treatment of ADSD.[2]

Anatomy and Physiology

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Anatomy and Physiology

Botulinum toxin exerts its paralytic effect via the blockade of acetylcholine release at the presynaptic motor nerve terminal. Specifically, the light chain of the botulinum toxin binds to a protein called SNARE. The cleavage of SNARE prevents the export mechanism of acetylcholine vesicles at the presynaptic nerve terminal. In this manner, acetylcholine is unavailable to affect the postsynaptic motor endplate, and nerve transduction is halted.[4] Selective intramuscular injection of botulinum toxin can address laryngeal pathology by selective chemodenervation.  

The intrinsic muscles of the larynx are important in respiration and phonation, whereas the extrinsic muscles of the larynx assist in swallowing. Intrinsic muscles include the posterior cricoarytenoid, paired thyroarytenoid (vocalis), cricothyroid, paired lateral cricoarytenoid, and the interarytenoid (grouped transverse and oblique arytenoid) muscles. All of the intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve (RLN), a branch of the vagus nerve, except for the cricothyroid. The cricothyroid is the only intrinsic muscle of the larynx that is not innervated by the RLN; rather, it is innervated by the extrinsic branch of the superior laryngeal nerve (SLN),  which is also a branch of the vagus nerve. The cricothyroid functions to pivot the thyroid cartilage forward and lengthen the vocal cords, increasing the pitch of the voice. 

Laryngeal dystonia, also known as spasmodic dysphonia (SD), results from intrinsic laryngeal muscle spasms. Spasms can result in untimely closure or opening of the glottic inlet. Adductor spasmodic dysphonia leads to the former, leading to a sensation of strangled speech or untimely breaks in speech. Abductor spasmodic dysphonia leads to the latter symptom and can cause a breathy voice or hypophonia.[1]

In abductor spasmodic dysphonia (ABSD), spasms of the posterior cricoarytenoid muscle (PCA) cause breathy voice quality and voice breaks. The PCA is the only muscle of the larynx that functions to abduct and is, therefore, the target of chemical denervation with botulinum toxin in this disorder.[2] The PCA externally rotates the arytenoid cartilages in addition to its abductor function.  

In adductor spasmodic dysphonia (ADSD), the focal laryngeal dystonia is caused by spasms of the laryngeal adductors. Frequently implicated and addressed therapeutically are the thyroarytenoid (TA) and lateral cricoarytenoid (LCA) muscles. The LCA is the primary adductor and also assists in internal rotation. Hyper-adduction (phonation against a closed glottis) in this disorder can improve with alcohol intake and worsen with stress. Singing, whispering, and talking in an accent can also be associated with improved voice quality. Mixed spasmodic dysphonia contains components of both ADSD and ABSD, and therefore may include spasms of both laryngeal adductor and abductor muscles and can be difficult to treat. 

"Tremor," as a perceptual voice abnormality, suggests either organic vocal tremor due to pathology involving the extrapyramidal system, laryngeal dystonia/spasmodic dysphonia, or psychogenic tremor. Laryngeal tremor can occur concomitantly with SD, or it can occur in isolation. Both can be successfully treated with botulinum toxin injections.[5]

The vocal process is the area where the vocal ligament attaches to the anterior surface of arytenoid cartilages. A vocal process granuloma is a non-cancerous lesion, which typically occurs along the medial surface of the arytenoid towers or medial surface of the arytenoid cartilages. Risk factors for the development of vocal process granuloma are gastroesophageal reflux, poor vocal hygiene, and a history of intubation. It is not a true granuloma but rather a reactive process that results in intact stratified squamous epithelium overlying fibrosis or granulation tissue. Vocal process granuloma has no malignant potential, but it does have a propensity for recurrence.[6] Symptoms include excessive urge to clear the throat, cough, globus, and change in vocal quality. Conservative measures such as voice therapy, antireflux medication, steroids, and antibiotics have all been described for treatment. Treatment failures may undergo surgical excision under general or local anesthesia. Botulinum toxin has also become a useful tool in treating this process when administered into the interarytenoid (IA) and/or thyroarytenoid (TA) muscles. 

The cricopharyngeus (CP) muscle, which makes up a part of the upper esophageal sphincter (UES), normally relaxes during swallowing. It is a ring-shaped muscle that has fibers oriented horizontally and obliquely. When the CP relaxes, anterior-superior displacement of the hyolaryngeal complex decreases the pressure needed to open the UES, allowing the bolus to pass into the cervical esophagus. When the CP does not relax properly, patients can have dysphagia. A cricopharyngeal "bar" can be seen on a videofluoroscopic swallow study (VFSS), which narrows the pharyngoesophageal segment (PES). Selective chemodenervation of the CP in this condition has been reported in the literature.[7]

Indications

There are no specific diagnostic tests that are used as the gold standard for spasmodic dysphonia. Typically, it is recognized by its characteristic history, endoscopic and physical exam findings, and auditory-perceptual findings such as voice breaks and breathiness. Additionally, these findings characteristically vanish during emotional vocalizations, such as laughter and crying. On exam, ADSD can be elicited with words that begin with vowels, counting from 80-89, and with classic phrases such as "we eat eggs every day." ABSD is most noticeable following voiceless consonants, classic sentences such as "the puppy bit the tape," and by counting from 60 to 69.

Voice therapy is sometimes trialed prior to botulinum toxin therapy. However, once the disease is recognized, botulinum toxin therapy can be both diagnostic and therapeutic. Select patients who have had alternative surgical procedures for SD, such as selective laryngeal adductor denervation and reinnervation (SLAD-R), may also require botulinum toxin to manage recurrent symptoms after the procedure.[2]

Botulinum toxin is indicated in spasmodic dysphonia with and without vocal tremor, isolated vocal tremor, vocal process granuloma, and cricopharyngeal muscle dysfunction. 

Contraindications

Neuromuscular disorders and allergies to botulinum toxin constituents are the only described contraindications to botulinum toxin injections.[8]

Equipment

A variable set of instruments may be used in office-based laryngeal botulinum toxin injection, depending on the pathology and the preferred route of access. For most laryngeal movement disorders, botulinum toxin type A is the preferred type. 

High definition flexible video endoscope with or without an operating channel (at least 2.2 mm in diameter is preferred) or EMG equipment. The provider will also need 5% lidocaine/0.02% naphazoline nitrate solution, 50 mg/ml lidocaine solution, a 23G 4 mm long flexible needle, as well as the injection device or 27G needle for transcutaneous injections.[9]

Personnel

An operating surgeon, a surgical assistant (nurse, surgeon, technician), a speech-language pathologist, and a neurologist.

Preparation

Topical anesthesia and decongestion of the nasal cavity (for direct visualization techniques) with a solution containing 5% lidocaine/0.02% naphazoline nitrate, as well as laryngeal anesthesia (for both direct and percutaneous techniques) with a solution of 7 ml of 50 mg/ml lidocaine, increases the likelihood of patient tolerability of the procedure.[9]

Topical anesthesia with 2 ml of 4% lidocaine through the cricothyroid membrane or trachea (for transcutaneous techniques).

Technique or Treatment

Three office-based techniques described for accessing the laryngeal musculature are direct visualization, laryngoscopy guided percutaneous injection, and EMG-guided percutaneous injection. 

In the former, after topical anesthesia is applied to the nasal cavity, the provider inserts the flexible video endoscope transnasally and advances past the nasopharynx and pharynx until there is a clear view of the glottis, just above the vocal folds. Lidocaine solution is instilled via the operating channel onto the vocal folds drop by drop, while the patient maintains the /i/ phonation ("eee"). Next, the flexible needle is advanced through the channel and advanced just past the tip of the endoscope while still within its protective plastic sheath. At this point, the assistant will advance the needle while the operating surgeon stabilizes the endoscope's position and the needle trajectory. Under direct visualization, 0.2 ml of botulinum toxin are injected into the area of interest. Intralaryngeal leakage can be avoided by assuring slight swelling and blanching of the mucosa at the site of interest after injection. To minimize the risk of reflux at the injection site, the needle is left in place for 15 seconds before the withdrawal.[9] 

In adductor dysphonia, the TA-LCA muscle complex is injected with equal components bilaterally. In abductor SD, the PCA muscle is injected one side at a time and usually spaced out to avoid airway compromise. In vocal process granuloma, the interarytenoid and/or thyroarytenoid muscles are injected. 

An EMG-guided percutaneous injection is an indirect way to gain access in the treatment of laryngeal movement disorders without direct visualization. For ADSD, an EMG needle is passed through the cricothyroid membrane transcutaneously, 2-3 mm from the midline of the side to be addressed. The needle is advanced superolaterally and maneuvered until the classic crisp motor unit potentials are read on EMG. If the needle is passed into the airway, a "buzz" on the EMG will notify the operating surgeon, and the needle should be withdrawn slightly. When the needle is positioned within the TA muscle, the patient is asked to phonate to help confirm placement, and the EMG should show brisk recruitment.

For ABSD, the needle is inserted transcutaneously along the lower half of the thyroid cartilage's posterior border. The needle is then advanced and should stop when it reaches the posterior surface of the posterior cricoid lamina. To confirm placement, the patient is asked to sniff. If brisk recruitment occurs, then placement is confirmed, and botulinum toxin is injected into the PCA muscle. 

Laryngoscopy guided percutaneous injection is a direct way to visualize the larynx while navigating a needle transcutaneously. Topical anesthesia with 2 ml of 4% lidocaine is applied through the cricothyroid membrane and into the airway, and the nasal cavity is topicalized with lidocaine. Next, a video flexible nasolaryngoscope is passed through the nose and advanced past the nasopharynx and held in a position slightly above the vocal cords by the assistant. A 27-gauge needle attached to a 1 ml syringe filled with botulinum toxin is advanced through the cricothyroid membrane at the midline of the neck. The video endoscope is used to visualize the needle as it enters the airway subglottically directly. For ADSD, the needle is angled posterolaterally, and the posterior one-third of both of the vocal folds are injected.

In cases of laryngeal tremor with or without concurrent SD, treatment consists of unilateral or bilateral TA-LCA botulinum toxin injection using one of the above methods.[5] If there is a significant vertical component to the tremor, botulinum toxin may be injected into the strap muscles.

In the treatment of vocal process granuloma, patients are first seated upright and nares topicalized with oxymetazoline and lidocaine. A transtracheal injection of lidocaine is also performed to anesthetize the airway. A video flexible laryngoscope is passed through the nasal cavity and positioned above the glottis. A botulinum toxin-filled syringe attached to a 25 gauge, the 1.5-inch needle is passed just above the thyroid notch and should enter the larynx at the petiole of the epiglottis. It is then advanced into the interarytenoid region under direct visualization, and botulinum toxin is injected.[10]

In treating cricopharyngeal muscle dysfunction, doses of 80 to 120 units of botulinum toxin have been described. Multiple methods have been described for injecting the CP muscle. Under general anesthesia, rigid endoscopy can be performed to visualize the CP, and EMG is used to confirm the precise location.  Alternatively, EMG-guided injection under videofluoroscopic control, EMG-guided percutaneous injection, and CT-guided injection have all been described.[7]

Complications

Complications of the treatment of spasmodic dysphonia with botulinum toxin injections include dysphagia, excessive breathiness, and aspiration of fluids.[11] Other disadvantages include the need for repeat procedures and a lack of a uniform dose-response relationship between patients.[2]

Clinical Significance

Among patients with laryngeal dystonia, botulinum toxin injections decrease the mean Voice Handicap Index (VHI) score by 9.6%.[1] Improvement in symptoms after successful injection of target muscles helps to confirm the diagnosis of ADSD and ABSD, as well as other laryngeal pathologies. Once the diagnosis is ascertained, the patient can explore options for definitive treatment, which may include intermittent botulinum toxin injections vs. definite procedures. 

Patients with vocal process granuloma treated with botulinum toxin to the thyroarytenoid have had success rates between 77% to 100%; however, there is a high prevalence of breathiness after injection. Interarytenoid (IA) injections alone have shown promising results, with comparable efficacy to thyroarytenoid injections and a lower prevalence of breathiness. Fink et al. reported complete regression in 55 percent of patients. Hamden et al. report that only 50% of their 8 patients reported breathiness after IA injection.[12]

In treating cricopharyngeal muscle dysfunction, botulinum toxin to the CP muscle is both diagnostic and therapeutic. In a study by Schneider et al., 5 of 7 patients with mild to severe dysphagia were effectively treated with botulinum toxin, with a clinically significant reduction in dysphagia.[7]

Enhancing Healthcare Team Outcomes

Voice disorders are a significant issue in the general population, with a prevalence of 16.9% in a Stockholm public health cohort. Prevalence increases in female and elderly populations, among individuals who are in high-stress positions and those who use their voice significantly as part of their profession.[13]Interprofessional communication is paramount in the management of patients with laryngeal disorders. Primary care clinicians may act as the first line of detection for voice disorders, and effective referral and communication will allow the patient to find the appropriate multidisciplinary voice team.

Speech-language pathologists (SLPs) and otolaryngologists/laryngologists play an important role in making a diagnosis, educating patients about their diagnosis, and providing management options. SLPs may serve as the first line of treatment for patients in whom conservative measures, such as speech therapy and vocal hygiene, are indicated. As the patient progresses through their care, shared decision making, and revisiting progress goals will direct the future of care. Once a decision is made to employ invasive treatments such as laryngeal botulinum toxin, the laryngologist must work closely with an assistant to provide high-quality care. The assistant, typically a trained nurse, may steady and advance the flexible video laryngoscope while the surgeon maneuvers the botulinum toxin needle. With EMG-guided injections, the assistant is typically a neurologist, trained to read the EMG monitor and advise the otolaryngologist on how they should maneuver. 

Laryngeal botulinum toxin is unique in that the procedure can be both diagnostic and therapeutic. They should effectively communicate this to the patient. It is important to relay that, although temporary, laryngeal botulinum toxin can help guide future decision making. The patient and provider may agree on repeat botulinum toxin injections vs. more definitive treatment with a shared decision-making process. Considerations for continued care may include patient tolerability of the procedure and the likelihood of tolerating repeat injections every 6 to 12 months. The time to recurrence of symptoms is another factor to consider.

References


[1]

Awan KH. The therapeutic usage of botulinum toxin (Botox) in non-cosmetic head and neck conditions - An evidence based review. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2017 Jan:25(1):18-24. doi: 10.1016/j.jsps.2016.04.024. Epub 2016 Apr 30     [PubMed PMID: 28223858]


[2]

Chhetri DK, Berke GS. Treatment of adductor spasmodic dysphonia with selective laryngeal adductor denervation and reinnervation surgery. Otolaryngologic clinics of North America. 2006 Feb:39(1):101-9     [PubMed PMID: 16469658]


[3]

Hintze JM, Ludlow CL, Bansberg SF, Adler CH, Lott DG. Spasmodic Dysphonia: A Review. Part 1: Pathogenic Factors. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2017 Oct:157(4):551-557. doi: 10.1177/0194599817728521. Epub 2017 Aug 29     [PubMed PMID: 28850801]


[4]

Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arquivos de neuro-psiquiatria. 2005 Mar:63(1):180-5     [PubMed PMID: 15830090]


[5]

Patel PN, Kabagambe EK, Starkweather JC, Keller M, Gamsarian V, Lee J, Kulkarni V, Garrett CG, Francis DO. Outcomes of Onabotulinum Toxin A Treatment for Adductor Spasmodic Dysphonia and Laryngeal Tremor. JAMA otolaryngology-- head & neck surgery. 2018 Apr 1:144(4):293-299. doi: 10.1001/jamaoto.2017.3088. Epub     [PubMed PMID: 29423509]


[6]

Devaney KO, Rinaldo A, Ferlito A. Vocal process granuloma of the larynx-recognition, differential diagnosis and treatment. Oral oncology. 2005 Aug:41(7):666-9     [PubMed PMID: 16023983]


[7]

Haapaniemi JJ, Laurikainen EA, Pulkkinen J, Marttila RJ. Botulinum toxin in the treatment of cricopharyngeal dysphagia. Dysphagia. 2001 Summer:16(3):171-5     [PubMed PMID: 11453562]


[8]

Small R. Botulinum toxin injection for facial wrinkles. American family physician. 2014 Aug 1:90(3):168-75     [PubMed PMID: 25077722]


[9]

Kaderbay A,Righini CA,Castellanos PF,Atallah I, Office-based endoscopic botulinum toxin injection in laryngeal movement disorders. European annals of otorhinolaryngology, head and neck diseases. 2018 Jun;     [PubMed PMID: 29661610]


[10]

Fink DS, Achkar J, Franco RA, Song PC. Interarytenoid botulinum toxin injection for recalcitrant vocal process granuloma. The Laryngoscope. 2013 Dec:123(12):3084-7. doi: 10.1002/lary.23915. Epub 2013 Sep 20     [PubMed PMID: 24115127]

Level 2 (mid-level) evidence

[11]

Yershov D, Partridge R. Life Threatening Delayed Complication of Botulinum Toxin Injection for Treatment of Spasmodic Dysphonia. Prague medical report. 2020:121(2):114-117. doi: 10.14712/23362936.2020.10. Epub     [PubMed PMID: 32553095]


[12]

Hamdan AL, Khalifee E, Jaffal H, Ghanem A. Interarytenoid botulinum toxin A injection for the treatment of vocal process granuloma. The Journal of laryngology and otology. 2019 Dec:133(12):1041-1045. doi: 10.1017/S0022215119002159. Epub 2019 Nov 12     [PubMed PMID: 31711548]


[13]

Lyberg-Åhlander V, Rydell R, Fredlund P, Magnusson C, Wilén S. Prevalence of Voice Disorders in the General Population, Based on the Stockholm Public Health Cohort. Journal of voice : official journal of the Voice Foundation. 2019 Nov:33(6):900-905. doi: 10.1016/j.jvoice.2018.07.007. Epub 2018 Aug 17     [PubMed PMID: 30126692]