Onabotulinum Toxin A (Botox) in the Treatment of Transfer Dysphagia

Study Overview
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Brief Summary
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Dysphagia in patients with stroke, multiple sclerosis, parkinsonism or dystonia can occur due to relative hypertonia of the cricopharyngeus muscle. In the resting state, muscle is contracted and relaxes only during deglutition. Treatment of dysphagia by injecting botulinum toxin in the cricopharyngeus was described by Schneider et al. in 1994. More than 100 cases have been described after that, however there are no randomized controlled trials. A meta-analysis from Cochrane has also concluded that there is no sufficient evidence to conclude regarding the efficacy and safety of Botulinum toxin injection in cricopharyngeal dysfunction. So this study is necessary to fill this void in knowledge

Detailed Description
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Swallowing is a neurologically coordinated physiologic event that requires sequential and overlapping movements of various craniofacial, pharyngo-esophageal and laryngeal muscles. In the process of swallowing, ingested bolus and oral secretions are shifted from the mouth into the esophagus. Neurological disorders adversely affecting any portion of this coordinated sequence may lead to oropharyngeal or Pharyngo-esophageal dysphagia. During swallowing, the upper esophageal sphincter (UES) transiently relaxes and larynx is subsequently pulled in the antero-cephalad direction by contractions of the suprahyoid muscles; this traction results in active opening of the UES. In the resting state, the function of this sphincter is to keep the upper esophagus closed during inspiration and between swallows. It relaxes only during deglutition in coordination with the other muscles of the tongue, larynx, anterior cervical muscles and allows the ingested bolus to pass into the esophagus from the hypopharynx. In the resting state, this closed UES prevents the reflux of gastric and esophageal contents into the hypopharynx. Dysfunction of the cricopharyngeal relaxation can cause dysphagia and is called cricopharyngeal dysfunction (CPD). It may lead to weight loss, aspiration pneumonia, airway obstruction, need to use nasogastric tube for feeding or change to liquid based diet. Treatment of dysphagia due to CPD by injecting botulinum toxin in the cricopharyngeus described by Schneider et al. in 1994. More than 100 cases have been described after that, however there are no randomized controlled trials. A meta-analysis from Cochrane has also concluded that there is no sufficient evidence to conclude regarding the efficacy and safety of Botulinum toxin injection in cricopharyngeal dysfunction. Problem statement Neurological disorders including stroke, multiple sclerosis, movement disorders including parkinsonism, dystonia etc. can cause dysphagia. In some of these cases there is a relative hyper-tonicity of the cricopharyngeus muscle. There is a relatively newer entity of this form of pure dysphagia due to dystonia which has been described by Samal et al. Increased tone of the cricopharyngeus due to spasticity or dystonia leads to failure of adequate relaxation of the upper esophageal sphincter leading to CPD. When the pharyngeal contraction is adequate, due to pre bolus resistance, the ingested bolus may stay as a residue in the hypopharynx leading to dysphagia or choking sensation or pushed into the upper airway leading to aspiration. In such cases, so far no medical treatment exists which can promote relaxation of the cricopharyngeus and lead to better swallowing function. Two modalities of management have been described in case series and reports, one of is surgical myotomy of the cricopharyngeus and the other is a relatively easy and lesser invasive procedure of injecting botulinum toxin in the horizontal part of the cricopharyngeus muscle. However, since there are no randomized controlled trials, no definite recommendations regarding the efficacy and safety of the procedure can be made. So this RCT is necessary to fill this void in knowledge

Official Title
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Efficacy and Safety of Onabotulinum Toxin A (Botox) Injections in the Upper Esophageal Sphincter for the Treatment of Pharyngo-esophageal Dysphagia Due to Cricopharyngeal Dysfunction- A Randomized Double Blinded Placebo Controlled Trial

Conditions
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Transfer Dysphagia, Oropharyngeal Dysphagia, Cricopharyngeus Muscle Dysfunction, Dysphagia, Late Effect of Stroke

Intervention / Treatment
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* Drug: Botulinum Toxin Type A Injection [Botox]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients attending neurology OPD with swallowing dysfunction due to central nervous system dysfunction At least 14 years of age of all sexes mRS (modified Rankin scale) of ≤3 at time of study enrolment In case of post stroke dysphagia, at least 6 months have passed following stroke Willing to undergo swallowing assessment clinically and with video fluoroscopy, flexible upper GI endoscopy and esophageal manometry before and after the injection Above investigations show impaired cricopharyngeal relaxation, adequate pharyngeal strength and anterocephalad laryngeal movement Ready to provide consent for Botulinum neurotoxin injection. Willing to adhere to protocol and comply with follow up visits No major neurologic or systemic medical condition that reduces life expectancy to less than 1 year based on clinical prediction scores Exclusion Criteria: Diagnosed cases of neuromuscular disorders of the peripheral nervous system and ALS mRS at time of enrolment >3 Patients with expected life expectancy less than 1 year due to primary disease or co morbidity based on clinical prediction scores Known allergy to botulinum neurotoxin or its preservatives/excipients Received botulinum toxin for any indication in the last 12 weeks Those with known antibodies against Botulinum neurotoxin A Those who underwent myotomy of the cricopharyngeus muscle Those who had undergone procedures like denervation of the cervical musculature Dysphagia of other causes not fulfilling inclusion criteria Women of childbearing potential who are not using adequate contraception or who are pregnant and lactating Not willing to provide consent

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botulinum toxin arm<br>100 units of botulinum toxin (Botox, Allergan, CA) diluted in 2.5 mL of normal saline will be injected into the cricopharyngeus muscle under direct endoscopic vision using an esophago-gastro-duodenoscope (GIF 190,Olympus). The procedure will be done under general anesthesia in the endoscopy suite as the position of the endoscope is unstable at cricopharynx and the muscle needs to be relaxed during the procedure. Pre-procedure a Ryle's tube will be placed into the stomach under endoscopic guidance which will be kept a day post procedure. Cricopharyngeus muscle will be identified as the muscle at the upper esophageal sphincter located just behind the laryngeal opening. Botulinum toxin will be injected into the muscle in four aliquots into each quadrant using 23 G needle (160cm). Post procedure patient will be observed for an hour for any untoward adverse event | Drug: Botulinum Toxin Type A Injection [Botox]<br>* 100 units of Botulinum toxin A (Botox, Allergan, CA) under endoscopic guidance will be injected in the cricopharyngeus muscle<br>|
| Placebo Comparator: Placebo arm<br>2.5 mL of Normal saline will be injected into the cricopharyngeus muscle under direct endoscopic vision using an esophago-gastro-duodenoscope (GIF 190,Olympus). The procedure will be done under general anesthesia in the endoscopy suite as the position of the endoscope is unstable at cricopharynx and the muscle needs to be relaxed during the procedure. Pre-procedure a Ryle's tube will be placed into the stomach under endoscopic guidance which will be kept a day post procedure. Cricopharyngeus muscle will be identified as the muscle at the upper esophageal sphincter located just behind the laryngeal opening. Post procedure patient will be observed for an hour for any untoward adverse event | Drug: Botulinum Toxin Type A Injection [Botox]<br>* 100 units of Botulinum toxin A (Botox, Allergan, CA) under endoscopic guidance will be injected in the cricopharyngeus muscle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have moderate to significant improvement in swallowing function on self assessment and clinical swallowing assessment - 3 weeks | To compare the proportion of patients who have moderate to significant improvement in swallowing function on self assessment and clinical swallowing assessment at 3 weeks post injection amongst those who received onabotulinum toxin (Botox, Allergan, Irvine, CA) and those who received placebo. | 3 weeks | 
| Proportion of patients who have moderate to significant improvement in swallowing function on self assessment and clinical swallowing assessment - 3 months | To compare the proportion of patients who have moderate to significant improvement in swallowing function on self assessment and clinical swallowing assessment at 3 months post injection amongst those who received onabotulinum toxin (Botox, Allergan, Irvine, CA) and those who received placebo. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with improvement in swallowing related parameters on video fluoroscopy, flexible endoscopic evaluation of swallowing and esophageal manometry - 3 weeks | To compare the proportion of patients with improvement in swallowing related parameters on video fluoroscopy, flexible endoscopic evaluation of swallowing and esophageal manometry at 3 weeks post injection between Botox group and placebo group | 3 weeks | 
| Proportion of patients with improvement in swallowing related parameters on video fluoroscopy, flexible endoscopic evaluation of swallowing and esophageal manometry - 3 months | To compare the proportion of patients with improvement in swallowing related parameters on video fluoroscopy, flexible endoscopic evaluation of swallowing and esophageal manometry at 3 months post injection between Botox group and placebo group | 3 months | 
| Adverse effects | To compare the proportion of patients with worsening of dysphagia, vocal cord palsy and other adverse effects upto 3 months post injection | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Botulinum toxin, Cricopharyngeal dysfunction