TITLE: Botulinum Therapy in the Laryngopharynx
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: October 27, 2004
RESIDENT PHYSICIAN: Sam J. Cunningham, MD, PhD
FACULTY PHYSICIAN: David Teller, MD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"This
material was prepared by resident physicians in partial fulfillment of
educational requirements established for the Postgraduate Training Program of
the UTMB Department of Otolaryngology/Head and Neck Surgery and was not
intended for clinical use in its present form. It was prepared for the purpose
of stimulating group discussion in a conference setting. No warranties, either
express or implied, are made with respect to its accuracy, completeness, or
timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
INTRODUCTION
Clostridium Botulinum is
a spore forming obligate anaerobic bacillus.
It displays Gram + characteristics in young cultures. Clostridium botulinum species produce
potent neuroexotoxins that cause the disease botulism. There exist 4 separate groups of C.
botulinum, I-IV, based on physiologic properties. These four groups produce seven different
serotypes of botulinum toxins. The seven
types are A, B, C, D, E, F and G. Group
I organisms produce types A, B, and F.
Group II organisms produce types B, E, and F. Group III produces types C and D, while group
IV produces type G.
The serotypes are antigenically distinct, but do have
conserved regions of amino acid homology.
The toxins are of similar molecular weight, about 150 kilo
Toxin-mediated paralysis by botulinum toxin is
accomplished in three steps: First, the
toxin binds irreversibly to the presynaptic terminal of the motor end
plate. Next, the toxin is internalized
into the axon by endocytosis, followed by cleavage of SNARE proteins resulting
in the inhibition of neurotransmitter release.
SNARE proteins are a family of proteins that facilitate the docking of
the neurotransmitter vesicle to the presynaptic membrane. The SNARE protein family,
N-ethylmaleimide-sensitive factor attachment protein receptors, consist of
three main members. These include
synaptobrevin, SNAP-25, and syntaxin.
Synaptobrevin is incorporated into the neurotransmitter vesicle
membrane, while syntaxin is incorporated into the post synaptic membrane. SNAP-25 forms a complex with syntaxin. As the vesicle approaches the presynaptic
membrane, this complex binds to the synaptobrevin. Once all three proteins complex together, the
vesicle is ‘docked’ to the axon terminus.
Neurotransmitter is released across the synapse by exocytosis. The SNARE proteins are each degraded by
different serotypes of botulinum toxin.
Synaptobrevin is cleaved by serotypes B, D, E, and G. The SNAP-25 protein is cleaved by serotypes
A, C, and E. Syntaxin is cleaved by
serotype C. Presence of just one of the
toxins is sufficient to prevent vesicle docking, thereby depleting the
neurotransmitter at the synapse. This
results in flaccid paralysis of the corresponding muscle fiber. Paralysis is seen 24-48 hours after injection,
with return of synaptic function of the neuromuscular junction at about 90
days. Return of muscle function is
usually present by 3-4 month. Duration
of neurotransmitter inhibition varies with the various serotypes. Inhibition lasts longest with Type A. Duration of type C is approximately equal to
A, but there is no clinical application for type C thus far. Type B is of moderate duration and types F
and E are of short duration.
Potency of botulinum toxin
is determined by in vivo mouse assays.
One unit of botulinum toxin type A is equivalent to the median
intraparitoneal lethal dose (LD50) in female Swiss Webster mice. The estimated LD50 for humans is 2500-3500
units.
USES OF BOTOX IN THE LARYNGOPHARYNX
Stuttering
Stuttering is an involuntary break in the vocal fluency. It affects both children and adults, with approximately 1% of the adult population affected. These patients are often teased and stigmatized. The larynx, lips, oral cavity and pharynx are all thought to contribute to stuttering. Botox injection into the thyroarytenoid muscles decreases the laryngeal contribution. Symptoms tend to return in 12 weeks.
Vocal Tics
Vocal tics are dyskinetic movements of the larynx that
result in grunts, abrupt breaks in fluency, and complex formations like
screams, loud talking, repetitive words or vowel sounds and coprolalia. Vocal tics are a common finding in Tourette’s
syndrome and are often accompanied by uncontrolled movements of the eyes,
facial muscles, neck and oral cavity.
Botox injection into the thyroarytenoid muscles has shown some clinical
benefit in treatment.
Puberophonia
Puberophonia, also known as mutational dysphonia,
affects men and adolescent boys. The
fundamental frequency reverts to a higher frequency similar to the prepubertal
fundamental frequency. Speech and
behavioral therapy are the mainstay of treatment with botox injection into the
cricothyroid muscles serving as an adjunct to therapy. The injection into the cricothyroid muscles
enables the larynx to relax, thereby lowering the pitch.
Ventricular dysphonia/Dysphonia plica ventricularis
Ventricular dysphonia is caused by hyperfunctioning of
the supraglottic larynx, with an overadduction of the false vocal folds. The fundamental frequency therefore, comes
from the false vocal folds. This results
in a wet, gravely, hoarse quality voice that is prone to vocal fatigue. This is usually a compensatory mechanism
following trauma, cyst, sulci or anything that allows air escape. Treatment consists of botox injection into
the false vocal fold, namely the aryepiglottic muscle.
Dysphagia
Dysphagia may result from
cricopharyngeaus dysfunction or dyskinesis.
Botox injection into the cricopharyngeus results in resolution of the
dysphagia. A trial of botox injection
may identify patients that would benefit from cricopharyngeal myotomy.
Tracheoesophageal speech failure
Botox injection into the cricopharygeus muscle facilitates TEP speech following laryngectomy in patients that did not receive cricopharyngeal myotomy. It has also been affective in patients who have delayed failure in their TEP speech.
Vocal fold granuloma and
prevention of posterior glottic stenosis
Botox injection into the thyroarytenoid muscle
following repair of an interarytenoid cleft prevents recurrent scarring and
granulation by decreasing the strength of the vocal fold closure and allowing
for a more abducted position at rest.
This same decrease in the strength of vocal fold closure results in less
local trauma and is beneficial in preventing and treating vocal fold
granulomas.
Arytenoid rebalancing
Arytenoid dislocation usually follows traumatic intubation. The patient awakens from surgery with a hoarse or breathy voice. Exam reveals an immobile cord. Work up must include EMG evaluation as well as operative endoscopic evaluation. This includes manual repositioning of the arytenoid back to its native position. Botox injection into the interarytenoid, the ipsilateral thyroarytenoid, and the lateral cricothyroid muscles weakens the ipsilateral adductory muscles, allowing for ipsilateral abductory muscles to provide traction, keeping the arytenoid in a more physiologic position.
Bilateral true vocal fold paralysis
Botox injection into the interarytenoid and thyroarytenoid muscles weakens the adductory muscles allowing increased patency of the airway at rest and during activity.
SPASMODIC DYSPHONIAS
Spasmodic dysphonia is a
laryngeal dystonia that results in altered speech. Spasmodic dysphonia usually occurs in the
third decade of life and is slightly more predominant in women (63%). There exist two types of spasmodic dysphonia,
adductor dysphonia and abductor dysphonia. The diagnosis can be made with
careful history and examination of the glottis with various laryngeal tasks.
Adductor Dysphonia
Adductor dysphonia is the more common of the two types of spasmodic dysphonia. It accounts for 80% of all cases and is characterized by inappropriate glottal closure caused by hyperactivity of the thyroarytenoid muscles. This produces strain, harshness and strangled breaks in connected speech.
Treatment of adductor dysphonia with botox is
recognized as the primary treatment for the disorder by the American
Abductor dysphonia
Abductor dysphonia occurs less frequently than adductor dysphonia and is characterized by inappropriate glottal opening. This opening, caused by hyperactivity of the posterior cricoarytenoid muscles, produces hypophonia and breathy breaks in phonation.
Abductor dysphonia is treated with EMG-guided transcutaneous injection of one posterior cricoarytenoid muscle. This unilateral injection is to prevent airway compromise. The initial injection is with 3.75U of botox. This dose may be increased if re-injection is necessary. Upon re-injection, the contralateral pca may be injected. The posterior cricoarytenoid muscle may be reached in one of two approaches, the anterior or transcricoid approach or the lateral or retrocricoid approach.
The lateral approach is performed by placing the thumb on the posterior aspect of the thyroid cartilage and rotating the entire larynx to expose its posterior aspect. The needle is inserted at the inferior aspect of the thyroid cartilage, transversing the cricopharyngeus, and advanced until the cricoid cartilage is encountered. The needle is pulled back slightly and the patient asked to sniff. The needle placement is confirmed by EMG and the botox injected.
The transcricoid approach is performed by inserting the needle in the midline through the cricothyroid membrane and advancing until the posterior lamina of the cricoid is encountered. The needle is passed through the cricoid, just lateral to midline. Topical anesthetic may be beneficial in preventing the patient from coughing and it will not interfere with the EMG recording, as the muscle is beyond the cricoid cartilage. The needle is advanced and the first electrical signal encountered is the posterior cricoarytenoid muscle. Needle placement is confirmed by EMG by asking the patient to sniff and the botox injected. The transcricoid approach works better in children than in adults as their cricoid cartilage is not calcified.
Conclusion
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.
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