Description of the condition

The upper oesophageal sphincter (UOS), or pharyngo‐oesophageal segment (POS), is defined physiologically as a high pressure zone forming a barrier between the pharynx and the oesophagus. This obstruction prevents diversion of air into the oesophagus during inspiration. It also protects the airway from any retrograde passage of material refluxed from the oesophagus or stomach (Singh 2005). Three muscles contribute to the formation of the UOS, the cricopharyngeus (CP) muscle; the most inferior muscle fibres of the inferior pharyngeal constrictor muscle; and the most superior portion of the longitudinal oesophageal muscular fibres (Sivarao 2000). First described by Valsalva in 1717, the cricopharyngeus is the main component of the UOS. Arising from the lateral borders of the cricoid lamina, it is a C‐shaped muscle which forms a sling around the wall of the superior aspect of the cervical oesophagus (Sivarao 2000). At rest the sphincter has a slit‐like configuration, with the CP making up the lateral and posterior walls and the cricoid lamina positioned anteriorly. The CP is bordered superiorly by the inferior constrictor muscle and merges inferiorly with the muscular layers of the cervical oesophagus. While the UOS is normally in a tonic state of contraction, it relaxes intermittently to allow trans‐sphincteric flow of fluid or gas during antegrade (for example swallowing) and retrograde (for example emesis or belching) events (Cook 2000).

In order for the swallow to be safe and efficient, the UOS needs to open adequately to allow material to pass from the pharynx into the oesophagus. Adequate UOS opening is critical to safe and efficient swallowing due to the close proximity between the UOS and the airway entrance. Manofluoroscopic studies have demonstrated that UOS opening occurs by a combination of CP relaxation, anterior and superior hyolaryngeal excursion and bolus pressure (Cook 1989). In the initial relaxation phase, there is vagal inhibition of the tonic contraction of the CP muscle, as observed by needle electromyography (EMG) (Ertekin 2002). This precedes UOS opening by 200 msec and lasts 300 to 600 msec. In the second phase, UOS opening occurs via the biomechanics of hyolaryngeal excursion (Cook 1989). The suprahyoid muscles (geniohyoid, mylohyoid, stylohyoid, hyoglossus and the anterior belly of the digastric) contract causing the hyoid bone to be pulled both anteriorly and superiorly. This movement, paired with contraction of the thyrohyoid, an infrahyoid muscle which is the main connection between the hyoid bone and the larynx, pulls the laryngeal complex in a superior and anterior direction. As the UOS is connected to the laryngeal complex via CP muscle attachment to the cricoid cartilage, the anterior portion of the UOS is pulled open. The UOS assumes an oval cross section and is raised 2 to 2.5 cm in an orad direction. In the third distension phase, pressure applied by the weight and volume of the onrushing bolus distends the lumen of the UOS. This distension collapses in the fourth phase as the bolus passes through the sphincter. Finally, in the fifth phase the UOS closes as the cricopharyngeus actively contracts (Cook 1989).

UOS dysfunction during swallowing has been reported in numerous acute and progressive neurological conditions including, but not limited to, brainstem stroke (Bian 2009), motor neuron disease (Higo 2002), Parkinson's disease (Restivo 2002), myasthenia gravis (Colton‐Hudson 2002) and inclusion body myositis (Oh 2008). The prevalence of UOS dysfunction in people with neurological dysphagia (difficulty swallowing) varies in the literature as rates depend on the definitions of UOS used, the heterogeneity in neurological populations studied and the evaluation methods employed. For example, the reported prevalence for UOS dysfunction in people with Parkinson's disease varies from 21% (Ali 1996) to 43% (Higo 2001), and in stroke from 15% (Steinhagen 2009) to 44% (Bian 2009). Diagnosis of UOS dysfunction cannot be made from a clinical swallow examination as the sensitivity and specificity of this examination are extremely poor in predicting UOS dysfunction. Videofluoroscopy, fibreoptic endoscopic evaluation of swallowing (FEES), manometry (Butler 2009) and EMG (Ertekin 2002) are the most commonly employed instrumental evaluations to evaluate UOS function for swallowing. The causes of impaired UOS opening vary across neurological conditions and can result from disordered neurally‐mediated CP muscle relaxation, suboptimal anterior and superior hyolaryngeal excursion, weak bolus propulsion, cricopharyngeal fibrosis or a combination of these factors (Cook 2000). Dysphagia frequently results, characterised by the prevention of material passing safely and efficiently from the pharynx into the oesophagus during swallowing. Solid food can pose particular problems and can lead to choking and multiple swallowing. This typically leads to aspiration (passage of material into the trachea beyond the level of the true vocal cords), post‐swallow and pharyngeal retention of material. Clinical complications include aspiration pneumonia, weight loss, dehydration, malnutrition, the need for tube feeding and increased mortality (Martino 2005; Smithard 1996). Quality of life is also frequently affected (Leow 2010).

Management of impaired UOS opening during swallowing varies across individuals and intervention can be pharmacological, compensatory, rehabilitative or surgical in nature. Frequently it involves a combination of these methods. Compensation includes the use of postural strategies (for example head turn, chin tuck) (McCulloch 2010) and voluntary manoeuvres (for example effortful swallow) (Hiss 2005), which are employed clinically to improve and prolong UOS opening hence minimising aspiration and facilitating bolus clearance during swallowing. Rehabilitation programs designed to target impaired UOS opening during swallowing include jaw exercises (Wada 2012), the Shaker 'head lifting' exercises (Shaker 1997; Shaker 2002) and the Mendelsohn manoeuvre (Kahrilas 1991). The Shaker exercises are isokinetic and isometric head lifting manoeuvres designed to strengthen the suprahyoid muscles (that is the mylohyoid, geniohyoid, stylohyoid and anterior belly of digastric) and infrahyoid muscles (that is the thyrohyoid), which pull open the UOS during swallowing. The Mendelsohn manoeuvre involves purposeful prolongation of the anterio‐superior displacement of the larynx at mid‐swallow. In cases where patients have demonstrated little or no benefit from a trial period of rehabilitation, among other factors, they may be considered for surgical or pharmaceutical interventions to optimise UOS opening. Surgical approaches employed to treat UOS dysfunction comprise cricopharyngeal myotomy (Kelly 2000; Kos 2010) and upper oesophageal dilatation (Hatlebakk 1998; Hu 2010). Pharmacological treatment consists of botulinum toxin injections into the CP muscle to improve UOS opening during swallowing (Alberty 2000; Alfonso 2010; Krause 2008; Moerman 2006).

Description of the intervention

While there are seven different subtypes of botulinum toxin, botulinum toxin A (BTA) is the most commonly used subtype in the treatment of UOS dysfunction. While botulinum toxin B (BTB) is used to treat conditions such as cervical dystonia and drooling, particularly when patients have developed a resistance to BTA (Costa 2005), it is used less widely in clinical practice to treat UOS dysfunction. BTA formulations that are available include Botox® (Allergan Inc) and Dysport® (Ipsen Ltd). These products differ in terms of molecular structure and manufacturing processes, and use different methods for determining biological activity (Heinen 2006). One unit of Botox® is estimated to be comparable to three to four units of Dysport® (Fuster Torres 2007). Schneider 1994 initially described the use of BTA for the treatment of CP dysphagia, resulting in a temporary relaxation of the CP musculature and improved opening of the UOS during swallowing. Seventy per cent of participants had more efficient bolus transport into the oesophagus during swallowing and reduced aspiration events. The intervention usually brings improvement in deglutition but most patients require reinjection in three to five months (Krause 2008). Also, reported side effects include inadvertent injection outside the cricopharyngeus, which may result in temporary paralysis of the laryngeal musculature causing dysphonia and, rarely, aspiration. In cases where there is uncertainty regarding the diagnosis of impaired UOS dysphagia, a positive response to a trial of botulinum toxin treatment can suggest candidacy for cricopharyngeal myotomy (Krause 2008).

Since this initial 1994 study, cricopharyngeal BTA injection has been reported in over 200 patients with dysphagia of varying aetiologies with success rates between 43% and 100% (Alberty 2000; Alfonso 2010; Chiu 2004; Krause 2008). However, studies have recruited heterogeneous diagnostic groups and the candidacy criteria for BTA injections vary considerably across studies. Additionally, BTA brand and dosage (2.5 to 50 units Botox®; 60 to 360 units Dysport®), injection site, technique (rigid endoscopy, flexible endoscopy, transcervical with EMG, transcervical computed tomography (CT)‐guided) and outcome measure evaluations (videofluoroscopy, manometry, EMG), among other factors, have differed across studies. This has led to confusion regarding the usefulness of this technique.

How the intervention might work

Botulinum toxin is a neurotoxin that inhibits presynaptic acetylcholine release and hence chemically denervates the motor endplate. Once injected, botulinum toxin binds rapidly to presynaptic cholinergic nerve terminals, impairing the release of acetylcholine (chemical denervation) at the neuromuscular junction. This results in a temporary dose‐related weakness or reversible palsy of the innervated muscle. Therapeutic effects are usually seen within three days of the injection. Peripheral neuronal sprouting prevents the effects from being permanent. Reports to date suggest that effects last from two to up to 24 months (Kim 2006; Masiero 2006). BTA has been used effectively in the past for the management of a number of hyperkinetic disorders (for example blepharospasm, torticollis, spasmodic dysphonia) with good results and limited side effects (Jankovic 1991). In more recent times, its use has been expanded to treat UOS dysfunction in neurogenic dysphagia (Alberty 2000; Alfonso 2010; Bian 2009; Kim 2006; Parameswaran 2002; Restivo 2002; Zaninnotto 2004). However, several methodological aspects of these studies vary and its usefulness remains unclear.

Why it is important to do this review

Clinicians working with people with dysphagia secondary to UOS dysfunction as a result of acute or progressive neurological disease have difficulty determining the efficacy of botulinum toxin injections to treat dysphagia in individuals with neurogenic dysphagia. The most effective formulation, sites for injection, the optimum dosage, the method of delivery (endoscopic or transcutaneous) and the length of time before the effects wear off are as yet undetermined. There are currently no systematic reviews examining the efficacy of botulinum toxin to treat UOS dysfunction in acute or progressive neurological populations despite it being a topical issue. Given that botulinum toxin is being used clinically to treat UOS dysfunction, supported by a limited evidence base, as well as the adverse events associated with the intervention, a systematic review of the evidence is required in this area. Evidence is required not only from a clinical perspective but also to identify the specific direction for future clinical trials and intervention studies in the area.