BOTOX THERAPY IN THE LARYNGOPHARYNX

1. BOTOX THERAPY IN THE LARYNGOPHARYNX Sam J. Cunningham, MD, PhD David Teller, MD University of Texas Medical Branch Galveston, Texas October 2004

2. Overview Review of Botox Overview of uses in the laryngopharynx Spasmodic dysphonia Types Anatomy Botox techniques

3. Clostridium botulinum Spore forming obligate anaerobic bacillus Gram + (young cultures) Produces a potent neuroexotoxin Causes the disease botulism

4. Botox Species Divided into 4 groups (I-IV) Produce 7 different botulinum neurotoxin serotypes Group I: A, B, F Group II: B, E, F Group III: C, D Group IV: G

5. Pharmacology 7 neurotoxins, serotypes A-G Antigenically distinct Similar molecular weights (~150 kDa) Dichain molecule (heavy and light)-active molecule 3 functional domains: Binding domain (C terminus of H chain) Translocation domain (N terminus of H chain) Catalytic domain (C terminus of L chain) Zn metalloprotease

6. Pharmacology 3 steps in toxin-mediated paralysis Step1: Binding BTX-A binds irreversibly to motor endplates Step 2: Internalization Internalized by endocytosis Step 3: Inhibition of neurotransmitter release

7. Pharmacology After internalization: Cleaves proteins required for release of Ach vesicles (fusion or docking proteins) SNARE proteins: N-ethylmaleimide-sensitive factor attachment protein receptor Each serotype binds to a specific residue of one of the docking proteins

9. Pharmacology Paralysis is seen 24-48 hours after injection presynaptic vesicles are depleted Recovery Initially new axons sprout – 28 days Return of synaptic function of the initial NMJ – 91 days Muscle function usually present by 3 to 4 months

10. Pharmacology Duration of neurotransmitter inhibition varies among serotypes Based on the cleavage of different SNARE proteins Different SNARE proteins, different duration of action among serotypes: A>C1>B>F>E

11. Pharmacology Potency Determined through in vivo mouse assays 1 U of BTX-A = median intraperitoneal lethal dose (LD50) in female Swiss-Webster mice Estimated human LD50 2500-3500 Units

12. Botox Uses in the Laryngopharynx Stuttering Vocal tics Puberophonia Ventricular dysphonia/Dysphonia plica ventricularis Dysphagia TEP speech failure Prevention of posterior glottic stenosis and recurrent vocal fold granuloma Arytenoid Rebalancing Bilateral vocal fold paralysis SPASMOTIC DYSPHONIA

13. Stuttering Affects children and adults Patients often stigmatized, teased, etc Affects 1% of adult population Involuntary break in vocal fluency Larynx, pharynx, lips, oral cavity Decrease laryngeal contribution by injecting the thyroarytenoid muscles Return of symptoms in 12 weeks

14. Vocal Tics Tourette’s syndrome Repetitive dyskinetic movements of eyes, facial muscles, neck, oral cavity Dyskinetic movements of larynx-leads to grunts, abrupt breaks in fluency, and complex formations like screams, loud talking, repetitive word or vowel sounds, copralalia Botox injections into thyroarytenoid muscles have shown clinical improvements

15. Puberophonia AKA mutational dysphonia Men and adolescent boys Higher fundamental frequency of prepubescent years Speech and behavioral therapy Botox as adjunct into cricothyroid muscles Enables larynx to relax and allow for lowering of pitch

16. Ventricular dysphonia/Dysphonia plica ventricularis Hyperfunctioning of supraglottic larynx Over adduction of false vocal folds Propagation of fundamental frequency from FVC’s Gravelly, wet, hoarse quality voice-prone to vocal fatigue Compensatory response after injury, cysts, sulci allowing air escape Botox injections into the false vocal folds Aryepiglottic muscle

17. Dysphagia Cricopharyngeal dysfunction and dyscoordination Botox into cricopharyngeus Identify patients that would benefit from CPM

18. TEP speech failure Post laryngectomy if no CPM Patients with good TEP speech initially, then fail

19. Vocal fold granuloma and prevention of posterior glottic stenosis Following repair of posterior glottis clefting (interarytenoid) Recurrent granulation/scarring Botox into the thyroarytenoid muscles to decrease the strength of vocal fold closure and allow more lateral position at rest Decreases strength of vocal fold closure to help in treatment of vocal fold granuloma (less local trauma)

20. Arytenoid rebalancing Arytenoid dyslocation following traumatic intubation or blunt trauma to anterior neck. Hoarseness/breathiness after surgery Immobile vocal cord EMG analysis and operative endoscopy Endoscopic manipulation of arytenoid back into native position Botox injected into interarytenoid muscle, ipsilateral thyroarytenoid muscle, and lateral cricothyroid muscle Weakens ipsilateral adductory muscles, allowing ipsilateral abductor to provide traction on the arytenoid allowing a more physiologic position

21. Bilateral vocal cord paralysis Botox injected into the thyroarytenoid and interarytenoid muscles Weakens the adductory muscles, allowing increased patency of the airway at rest and with activity “Rebalance” position of the paralyzed cords to a more abducted position

22. Spasmodic Dysphonia Usual onset in mid 30’s More common in women (63%) Two types: ADductor and ABductor Dx based on careful history and examination of the glottis during a variety of laryngeal tasks

23. Adductor Dysphonia Most common-80% Inappropriate glottal closure Produces harshness, strain, and strangled breaks in connected speech

24. Adductor Spasmodic Dysphonia Most common type Hyperactivity of the thyroarytenoid m. (TA) Inappropriate closing or tightness of the glottis Strained voice

25. Abductor Dysphonia Less common Inappropriate glottal opening Produces hypophonia and breathy breaks

26. Abductor Spasmodic Dysphonia

27. Spasmodic Dysphonia Treatment alternatives to Botox: Surgical denervation: crush, neurolysis Speech therapy (adjunct) ? Psychological therapy American Academy of Otolaryngology-Head and Neck Surgery endorses Botox as primary therapy for this disorder. (Policy Statement: Botulinum Toxin. Reaffirmed March 1, 1999)

28. Injection Strategy Adductor spasmodic dysphonia: EMG-guided transcutaneous injections of the thyroarytenoid muscle, using equal amounts of Botox (1-1.25U initially) Abductor spasmotic dysphonia: EMG-guided transcutaneous injection of one posterior crycoarytenoid muscle with Botox (3.75U initially)

29. Adductor spasmodic dysphonia: Injection Technique Reclined position with neck extended Local anesthesia unnecessary (hinder) Bend needle 30-450 (esp in women) Insert needle through skin just off midline at level of cricothyroid membrane Characteristic ‘buzz’ when in airway Advance superiorly and laterally Patient asked to phonate for EMG confirmation Botox injected

30. Thyroarytenoid injection

31. Injection for Spasmodic Dysphonia Supine with neck extended +/-Local anesthetic for TA injection EMG guidance

32. TA injection with Botox

33. Abductor spasmodic dysphonia: Injection technique: PCA may be reached in two ways: Retrocricoid (lateral) approach transcricoid (anterior) approach

34. Abductor spasmodic dysphonia: Lateral approach Thumb placed on posterior aspect of thyroid cartilage and entire larynx is rotated to expose the posterior aspect Insert needle along the lower half of the posterior edge of the thyroid cartilage, traversing the inferior constrictor, and advance until the cricoid is encountered. Pull needle back slightly and ask the patient to sniff EMG confirmation and Botox injected

35. Abductor spasmodic dysphonia: Lateral approach

36. PCA injection with Botox (lateral approach)

37. Abductor spasmodic dysphonia: Transcricoid approach Insert needle through the cricothyroid membrane in the midline Characteristic ‘buzz’ in lumen Pass through the posterior lamina of the cricoid cartilage to either side of midline Topical lidocaine to prevent coughing (does not hinder) First electrical signal encountered is PCA Placement confirmed by sniffing and Botox injected Better in younger patients (cartilage is not calcified)

38. Abductor spasmodic dysphonia: Transcricoid approach

39. PCA injection with Botox® (transcricoid approach)

40. Conclusions Botulinum toxin therapy is an extremely useful and versatile tool in the laryngologist’s armamentarium. By chemically denervating the various laryngeal muscles, it is possible to effectively diagnose and treat a number of disorders of the laryngopharynx.

41. References: Blitzer, A et al: Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): A 12-year experience in more than 900 patients. Laryngoscope 108:1435-14441, 1998. Hogikyan, ND et al: Longitudinal effects of botulinum toxin injections on voice-related quality of life for patients with adductory spasmodic dysphonia. J Voice 15:576-586, 2001. Benninger MS et al: Outcomes of botulinum toxin treatment for patients with spasmodic dysphonia. Arch Otolaryngology Head and Neck Surgery 127:1083-1085, 2001. Maloney, AP et al: A comparison of the efficacy of unilateral vs bilateral botulinum toxin injection in the treatment of adductor spasmodic dysphonia. J Otolaryngology 23:160-164, 1994 Blitzer, A: Botulinum Toxin Therapy. Operative Techniques in Otolaryngolgy Head and Neck Surgery. 15:2, 2004. Blitzer, A et al: Botulinum toxin: Basic science and clincal uses in otolaryngolgy. Laryngoscope. 111:218-226, 2000. Jankovic, J: Botulinum toxin in the treatment of tics. Therapy with botulinum toxin. New York, Dekker, 1994, pp503-509. Rosen, CA et al: Botox for hyperadduction of the false vocal folds: a case report. J. Voice 13:234-239, 1999. Woodson, GE et al: Botulinum toxin in the treatment of recalcitrant mutational dysphonia. J Voice 8:347-351, 1994.

42. References cont. Nathon, CO et al: Botulinum toxin: Adjunctive treatment for posterior glottic synechiae. Laryngoscope 109:855-857, 1999. Orloff, LA et al: Vocal fold granuloma: Successful treatmetn with botulinu toxin. Otolaryngology-Head and Neck Surgery 121:410-413, 1999. Muller, C: Botox. Oral presentation. UTMB. 2003. Ashan, SF et al: Botulinum toxin injection of the crycopharyngeus muscle for the treatment of dysphagia. Otolaryngology head and neck surgery 122:691-696, 2000. Netter, FH: Human anatomy. Ciba. Rontal E et al: Laryngeal rebalancing for the treatment of arytenoid dislocation. J voice. 12:383-388, 1998.