Dysphagia current reality and scope of the problem

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REVIEWS Dysphagia: current reality and scope of the problem Pere Clavé and Reza Shaker Abstract | Dysphagia is a symptom of swallowing dysfunction that occurs between the mouth and the stomach. Although oropharyngeal dysphagia is a highly prevalent condition (occurring in up to 50% of elderly people and 50% of patients with neurological conditions) and is associated with aspiration, severe nutritional and respiratory complications and even death, most patients are not diagnosed and do not receive any treatment. By contrast, oesophageal dysphagia is less prevalent and less severe, but with better recognized symptoms caused by diseases affecting the enteric nervous system and/or oesophageal muscular layers. Recognition of the clinical relevance and complications of oesophageal and oropharyngeal dysphagia is growing among health-care professionals in many fields. In addition, the emergence of new methods to screen and assess swallow function at both the oropharynx and oesophagus, and marked advances in understanding the pathophysiology of these conditions, is paving the way for a new era of intensive research and active therapeutic strategies for affected patients. Indeed, a unified field of deglutology is developing, with new professional profiles to cover the needs of all patients with dysphagia in a nonfragmented way. Clavé, P. & Shaker, R. Nat. Rev. Gastroenterol. Hepatol. advance online publication 7 April 2015; doi:10.1038/nrgastro.2015.49

Introduction

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital de Mataró, Universitat Autònoma de Barcelona, Carretera de Cirera s/n. 08304, Mataró, Spain (P.C.). MCW Dysphagia Research Institute, Division of Gastroenterology and Hepatology, and Clinical and Translational Science Institute of Southeast Wisconsin, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA (R.S.). Correspondence to: P.C. [email protected]

Dysphagia derives from the Greek terms dys meaning ‘disordered’ or ‘ill’, and phago meaning ‘eat’ or ‘swallow’. Swallowing is defined as ‘the function of clearing food and drink through the oral cavity, pharynx and oesopha‑ gus into the stomach at an appropriate rate and speed’ by the International Classification of Functioning, Disability and Health (ICF, code b5105) promoted by the WHO.1 Dysphagia is classified under ‘digestive symptoms and signs’ in the International Classification of Diseases (ICD‑10, code R13), also promoted by the WHO.2 However, the term is often used, not fully appro‑ priately, to mean a disorder or disease. Patients affected can be unaware of their swallow dysfunction. From an anatomical standpoint, dysphagia can result from oropharyngeal and/or oesophageal causes; from a pathophysiological perspective, dysphagia can be caused by organic or structural diseases (either benign or malig‑ nant) or diseases causing impaired physiology (mainly motility and/or perception disorders). Oropharyngeal, head, neck and oesophageal structural causes (such as tumours, webs, pouches and rings) of dysphagia are reviewed elsewhere.3–5 This Review focuses on advances in understanding dysphagia caused by diseases that impair oropharyngeal and/or oesophageal physiology. Competing interests P.C. has received educational grants and performed clinical trials with the support of the following companies: DJO; Fresenius Kabi; Image and Physiology; Nestlé Health Science; Nutricia Advanced Medical Nutrition; and Phagenesis. These competing interests do not specifically affect the contents of this Review. R.S. declares no competing interests.

Oropharyngeal dysphagia is a symptom of a swallow dysfunction that provokes difficulty or inability to form or move the alimentary bolus safely from the mouth to the oesophagus.6 It can include oropharyngeal aspiration (the entry of secretions, food, or drink from the oro‑ pharynx into the trachea or the lungs) and choking (the subsequent mechanical obstruction of pulmonary air flow).6 Oropharyngeal dysphagia should be differenti‑ ated from globus pharyngis, a specific somatoform dis‑ order consisting of the continuous feeling of having a ‘lump in the throat’, phlegm, or some sort of obstruction when there is none.2 Despite the severity of oropharyn‑ geal dysphagia, the standard of care for the majority of these patients is very poor as most are not diagnosed or treated.7,8 By contrast, the prevalence, symptom severity, complications and associated mortality are much lower for oesophageal dysphagia and—although its pathophysi‑ ology also needs further research—it is better recognized and clinically managed.9 This Review provides an overview of advances in the pathophysiology, prevalence and potential complications of both oropharyngeal dysphagia and oesophageal dys‑ phagia, particularly in association with impaired physiol‑ ogy. These are exciting times with increasing awareness of the phenotypes of patients at risk of these disorders, and progressive recognition of the clinical relevance and complications of these conditions by health-care pro‑ viders from many fields. In addition, the emergence of new methods to screen and assess swallow function at both the oropharynx and oesophagus, and the marked advances in understanding the pathophysiology of these

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REVIEWS Key points ■■ Dysphagia is a symptom defined by the difficulty to form or move the alimentary bolus safely from the mouth to the stomach ■■ Oropharyngeal dysphagia is a highly prevalent condition in three main at-risk populations: elderly people, patients with neurological or neurodegenerative diseases, and patients with head and/or neck diseases ■■ Oropharyngeal dysphagia is associated with reduced pharyngolaryngeal sensitivity, damage of cortical areas or the swallowing centre in the central nervous system, and/or impaired efferent neural or muscular drive ■■ Oropharyngeal dysphagia is a serious condition as it impairs quality of life and causes nutritional and respiratory complications associated with poor prognosis and high mortality rates ■■ Oesophageal dysphagia is usually caused by primary or secondary oesophageal motility disorders that affect the enteric nervous system or the oesophageal muscular layers ■■ Advances in research and technology are paving the way for intensive research and active therapeutic strategies for affected patients, and a transdisciplinary field of deglutology

conditions, is paving the way for a new era with new pro‑ fessional domains in deglutology. Therapeutic strategies for affected patients are evolving from compensation to the restoration of impaired swallow function.

Normal swallowing

Normal swallowing is a complex and well-coordinated process that requires the appropriate interaction between several areas of the central nervous system (CNS), sensory and motor cranial nerves, and peripheral receptors of pressure, temperature, chemical stimuli and water.10 It also requires the anatomical integrity of the oropharynx and larynx and the preserved neuromuscular function of up to 30 pairs of cervical striated muscles including the upper oesophageal sphincter (UES) and close coordination with the respiratory system. Our knowledge of the pathophysi‑ ology of swallowing dysfunction has greatly improved with better understanding of the four phases of normal swallow (oral preparatory, oral propulsive, pharyngeal and oesophageal), the mechanisms of swallow control in the CNS and the peripheral sensory and motor components of the oropharyngeal swallow response (OSR).11,12 The oral preparatory phase is under voluntary control and it is different for fluids and solids. Fluid boluses are placed in the anterior part of the mouth by sealing the soft palate down against the tongue. If this glosso‑ palatal seal fails, the bolus falls into the pharynx before the OSR is triggered and while the airway is still open; in this case fluid might be aspirated.13 For solids, food is masticated and the bolus is formed by action of the lips, the tongue and the jaws. Mastication involves cyclic jaw movements and synchronizes with the transport of food by the tongue and cheeks to the molars (Stage I).14 Chewed food is mixed with saliva and transported (Stage II) through the fauces and collected in the oropharynx or vallecula where the bolus is formed prior to swallowing.15 The masticatory function is severely impaired in elderly patients owing to tooth loss, increased number of (weak) chewing cycles and decreased saliva production.16 The oral propulsive phase involves transfer of the bolus from the mouth through the pharynx to the oesophagus

and is mainly caused by the squeezing action of the tongue against the palate, providing driving forces to propel swal‑ lowed material across the UES with minimal resistance.17 Pharyngeal contraction mainly facilitates pharyngeal clearance.17 Bolus propulsion forces are strongly reduced in patients with neuromuscular diseases and elderly patients with malnutrition and sa­rcopenia, and causes post-swallow oropharyngeal residue.13,18,19 The pharyngeal phase of swallow is an automatic, involuntary sequence of neuromuscular events that begins as the bolus crosses the pillars of the fauces propelled by the propulsive tongue thrust. The bio­ mechanical elements of the OSR consist of the tem‑ poral arrangement of oropharyngeal structures from a respiratory to a digestive pathway, the transfer of the bolus from the mouth to the oesophagus—including bolus propulsion and UES opening—and the recovery of the respiratory pathway.20 Configuration of the oral cavity and pharynx during swallow response is defined by opening or closing events occurring at the glosso­ palatal junction, velopharyngeal junction, laryngeal ves‑ tibule and UES. Healthy individuals have a short swallow response, fast laryngeal vestibule closure and fast UES opening.18 By contrast, prolonged intervals to laryngeal vestibule closing and UES opening owing to delay in the early phase of oropharyngeal reconfiguration from a respiratory to a digestive pathway are key abnormali‑ ties of swallow response, leading to unsafe deglutition and aspiration in patients with neurological diseases and elderly people.13,18 Time to laryngeal vestibule closing is the time interval during which the potential for penetra‑ tion or aspiration occurs, and a delay in UES opening increases the bolus volume held in the hypopharynx, thereby increasing the potential for bolus overflow into the laryngeal vestibule. Reduced afferent input from oropharyngeal sensory areas, central or peripheral deaf‑ ferentation, and damage of cortical or brainstem swal‑ lowing areas might explain the serious delay in OSR observed in patients with neurological disorders and elderly people.13,18,21,22 The OSR is triggered by the swallowing centre, an interneuronal network located in the brainstem (medulla oblongata) that receives both central inputs from the cortex and peripheral sensory inputs from the pharynx and larynx 10 (Figure 1). The cortical and subcortical areas allow volitional swallowing and serve mainly to trigger deglutition and control the swallow motor response. Specifically, the areas implicated in the swallowing process are the caudolateral sensori-motor cortex, the premotor, orbitofrontal and temporopolar cortex, the insula, the cer‑ ebellum and the amygdala.23 These areas are represented bilaterally but asymmetrically in the two hemispheres, independently of handedness.23

Oropharyngeal dysphagia Pathophysiology Improvements in our knowledge of the physiology of swallowing have paralleled that of the pathophysiology. Oropharyngeal dysphagia after stroke is the consequence of damage at the ‘dominant’ pharyngeal cortex, direct

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REVIEWS damage to the central pattern generator, or damage to the somatic motor nuclei in the brainstem;24,25 swallow function recovery after a stroke has been associated with increased pharyngeal motor representation (neuroplasti‑ city) in the contralesional hemisphere.25,26 The peripheral sensory inputs allow involuntary onset of the swallow response and modulate volitional swallowing.10 They are mainly transmitted through the maxillary branch of the trigeminal nerve (V cranial nerve), the pharyngeal branch of the glossopharyngeal nerve (IX cranial nerve) and two branches of the vagus nerve (X cranial nerve), the pharyngeal branch and the superior laryngeal nerve.10 Impaired pharyngolaryngeal sensitivity to physi‑ cal or chemical stimuli is now a well-known component of swallow dysfunction and enhances the risk of aspi‑ ration in elderly people and patients with neurological disease.21,22,27 Thus, sensory stimulation using agonists for TRP receptors (TRPV1, TRPA1, TRPM8), or intrap‑ haryngeal or transcutaneous electrical stimulation has become an important emerging therapeutic strategy for patients with dysphagia.28–32 Also in the pharyngeal phase, reduced opening might be due to an intrinsic, restrictive sphincter disorder reduc‑ ing sphincter compliance, as in patients with cricopharyn‑ geal bar and/or Zenker diverticulum.33,34 Alternatively, reduced opening in patients with neurological diseases or in older people might be a manifestation of impaired supra-hyoid traction and/or weak bolus propulsion in which the forces exerted by the advancing swallowed bolus are insufficient to fully open the sphincter.35 Impaired neural UES relaxation observed in spastic neurological diseases such as Parkinson disease or brain injury is char‑ acterized by weak bolus propulsion and reduced or even absent neuromuscular UES relaxation.36,37 The swallow response is also closely coordinated with breathing and the airway mechanisms that prevent aspiration and elicit cough. The neural control centres responsible for breathing, coughing and swallowing are closely located in the brainstem and are also well con‑ nected with the primary sensory cortex, which modu‑ lates the coordination of breathing and swallowing and the elicitation of cough.38 Swallow causes a physiologic apnoea, and the predominant respiratory pattern in healthy adults is expiration before and after the swallow.39 By contrast, patients with neurological diseases, chronic obstructive pulmonary disease or advanced age present with an increased frequency of swallowing occur‑ ring during the inspiratory cycle, increasing the risk of ­swallow-related aspiration.40 Cough is an airway defensive reflex aimed at removing mucus and foreign materials from the respiratory tract. Mechanical or chemical stimuli can elicit the cough reflex by stimulation of receptors and C fibres in the larynx and tracheobronchial tree.41 The IX, X and V nerves transmit the sensory input to the brainstem. The efferent compo‑ nent of cough reflex is mediated by the phrenic, intercostal and other spinal nerves to the respiratory muscles.38 Elderly people or patients with neurological disease present with reduced cough sensitivity to several stimuli, leading to a high prevalence of silent aspirations or aspirations without

Peripheral stimuli of the oropharynx, larynx and oesophagus Sensory neurons (V, VII, IX, X)

Brainstem swallowing centre

Motor nuclei

Motor neurons

Cortical and subcortical structures

Dorsal swallowing group

Ventral swallowing group

Oropharyngeal Trigeminal, facial, ambiguus, hypoglosssal, C1–C2

Oesophagus Dorsal motor nucleus

V, VII, IX, XI, XII, ansa cervicalis

X

Oropharyngeal swallow response

Primary peristalsis

Nature Reviews | Gastroenterology & Hepatology Figure 1 | Scheme of the multidimensional neuronal network of the central nervous system controlling the oropharyngeal swallow response (OSR) and primary peristalsis. The OSR is triggered by the swallowing centre, an interneuronal network located in the brainstem (medulla oblongata) that receives both central inputs from the cortex and peripheral sensory inputs from the pharynx and larynx. The central mechanism mediating peristalsis in the striated cervical oesophagus depends on sequential activation of vagal motor neurons in the nucleus ambiguous, and primary peristalsis in the smooth part involves the activation of the dorsal motor nucleus of the vagus.

an appropriate cough response, strongly enhancing the risk of aspiration pneumonia.41,42

Prevalence The three main populations at risk of oropharyngeal dys‑ phagia are elderly people, patients with neurological or neurodegenerative diseases, and patients with head and/ or neck diseases (Table 1).43,44 Oropharyngeal dysphagia is a highly prevalent clinical condition, with a similar prevalence to that of diabetes mellitus among adults in the general population.45 Elderly people Oropharyngeal dysphagia affects up to 30–40% of the population ≥65 years old.46 An estimated >16 million US, 30 million European and 10 million Japanese elderly citi‑ zens have oropharyngeal dysphagia.47 The aging process causes changes in anatomy as well as in neural and mus‑ cular mechanisms, resulting in a loss of functional reserve that can affect the swallowing process.18,48,49 In healthy older people, these changes in swallowing function are defined as presbyphagia and do not necessarily indicate a pathological condition.49 However, when these changes in swallow physiology occur in frail, co-morbid and polymedicated elderly patients, the risk of oropharyngeal dysphagia increases.50 Antipsychotic, antidepressant and

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REVIEWS Table 1 | Prevalence of oropharyngeal dysphagia in several target populations and phenotypes of patients Target Population

Evaluation Method

Prevalence (%)

References

Screening (questionnaires)

11.4–33.7

Holland et al. (2011)119 Roy et al. (2007)50 Bloem et al. (1990)120 Kawashima et al. (2004)121 Yang et al. (2013)122

Clinical exploration (V-VST)

23

Serra-Prat (2011)52

Hospitalized in an acute geriatric unit

Not specified/Clinical exploration (water swallow test or V-VST)

29.4–47.0

Lee et al. (1999)123 Cabré et al. (2014)124

Hospitalized with communityacquired pneumonia

Clinical exploration (water swallow test or V-VST)

55.0–91.7

Cabré et al. (2010)125 Almirall (2012)68

Hospitalized with communityacquired pneumonia

Instrumental exploration

75

Almirall (2012)68

Institutionalized

Screening (questionnaires)

40

Nogueira & Reis (2013)126

Clinical exploration (water swallow test)

38

Screening and clinical exploration

51

Lin et al. (2002)127

Screening (questionnaires)

37–45

Martino et al. (2005)56

Clinical exploration

51–55

Instrumental exploration

64–78

Clinical exploration

25–45

Instrumental exploration

40–81

Reported by patients

35

Elderly Independently-living older people

Stroke: acute phase

Stroke: chronic phase

Martino et al. (2005)56

Neurodegenerative disease Parkinson disease

Kalf et al. (2012)128

Instrumental exploration

82

Alzheimer disease

Instrumental exploration

57–84

Langmore et al. (2007)129 Horner et al. (1994)130

Dementia

Reported by caregivers

19–30

Langmore et al. (2007)129 Ikeda et al. (2002)131

Instrumental exploration

57–84

Suh et al. (2009)132 Langmore et al. (2007)129 Horner et al. (1994)130

Screening (questionnaires)

24

De Pauw et al. (2002)133

Instrumental exploration

34.3

Calcagno et al. (2002)134

Clinical and Instrumental exploration

47–86

Chen & Garrett (2005)135 Ruoppolo et al. (2013)136

Clinical exploration

50.6

García-Peris 200761

Instrumental exploration

38.5

Caudell et al. (2009)137

Zenker diverticulum

Instrumental exploration

86

Valenza V et al. (2003)138

Osteophytes

Screening

17–28

Utsinger et al. (1976)139 Resnick et al. (1976)140

Multiple Sclerosis

Amyotrophic lateral sclerosis Structural Head and neck cancer

Abbreviation: V‑VST, volume-viscosity swallowing test.

sedative drugs are strongly associated with oropharyn‑ geal dysphagia in elderly people.51 The prevalence of oro‑ pharyngeal dysphagia among independently-living older persons is 16.6% in the 70–79 year age group and 33% in the >80 year age group.52 The prevalence of oropharyn‑ geal dysphagia is higher in elderly patients with neuro‑ degenerative diseases (80% in patients with Alzheimer disease and 60% in patients with Parkinson disease) and is related to age, frailty and muscular, endocrine or psy‑ chiatric diseases.46 Furthermore, the prevalence of oro‑ pharyngeal dysphagia among older hospitalized patients

is very high. Up to 47.4% of frail older patients hospital‑ ized for acute illness have oropharyngeal dysphagia.51,53,54 Oropharyngeal dysphagia affects >50% of older people living in nursing homes, up to 29% of whom are tube fed, mainly because of severe aspirations.55 Patients with neurological diseases Patients with neurological diseases are also at high risk of oropharyngeal dysphagia. 64–78% of patients who have had a stroke have oropharyngral dyspha‑ gia during the acute phase, and 40–81% have dysphagia

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REVIEWS Elderly patient with neurological disease Patient with head or neck disease Oropharyngeal bacterial colonization

Xerostomia Oropharyngeal dysphagia Slow neural response

Muscular weakness

Impaired safety of swallow Impaired airway protection

Impaired efficacy of swallow Impaired bolus propulsion

Dehydration

Hypovolemia Alteration in: ■ Renal function ■ Cardiovascular ■ Level of awareness

Malnutrition

Adipose dysfunction

Chronic inflammation Insulin resistance

Sarcopenia

Aspiration Silent aspirations (Impaired cough reflex)

Immune dysfunction

Aspiration Pneumonia

Re-admissions

Frailty syndrome Functional impairement, disability, pressure ulcers, immunosuppression, intercurrent infections, comorbidity

Institutionalization

Impared muscular or respiratory function

Respiratory infections

Mortality

Figure 2 | Pathophysiology of nutritional and respiratory complications associated oropharyngeal dysphagia.&Dehydration, Naturewith Reviews | Gastroenterology Hepatology malnutrition, respiratory infections and aspiration pneumonia are the most common complications in patients with oropharyngeal dysphagia and lead to frailty and an increase in readmissions and mortality. Permission obtained from ACT Publishing Group Liminted © Ortega, O. et al. J. Gastroenterol. Hepatol. Res. 3, 1049–1054 (2014), which is licensed under a Creative Commons Attribution 3.0 Unported Licence. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/3.0/legalcode.

during the chronic phase.56 Oropharyngeal dyspha‑ gia is more prevalent in brainstem stroke, followed by bilateral and then unilateral stroke.56 The prevalence of dysphagia in patients with stroke also varies depend‑ ing on the diagnostic method used: 51–55% if clinical testing is used for diagnosis and up to 78% when using an instrumental method.56 Up to 70% of patients with severe acute traumatic brain injury have oropharyngeal dysphagia and 50% of patients with chronic traumatic brain injury.57 Oropharyngeal dysphagia is present in 52–82% of patients with advanced Parkinson disease,6,58 30–40% of patients with multiple sclerosis, and 80–100% of patients with an advanced stage of amyotrophic lateral sclerosis, advanced stage dementia or oculopharyngeal muscular dystrophy.59 Patients with head and/or neck diseases Oropharyngeal dysphagia associated with head and neck neoplasms is caused by altered anatomy, mass effect and the consequences of treatments. Nowadays, most patients are treated with radio-chemotherapy and up to 44% of these patients subsequently develop oropharyn‑ geal dysphagia.60 Some 10–15% of patients are treated with surgery, half of whom subsequently have dyspha‑ gia.60,61 Organ preservation after radio-chemotherapy

does not always translate into function preservation owing to inflammation in the acute phase and fibrosis in the late stage. The highest rates of nonfunctional pharynx and larynx, oropharyngeal dysphagia and aspiration are found among patients treated with both surgery and radio-chemotherapy.60 Other head and neck conditions associated with dys‑ phagia are trauma to the throat or larynx, post-tracheal intubation, use of tracheostomy tubes, cervical osteo‑ phytes and cervical surgery. Congenital malformations, Zenker diverticulum and cricopharyngeal bars also cause oropharyngeal dysphagia.43,62 Oropharyngeal dysphagia at birth and during the first months of life is rare and is generally associated with neurodevelopmental delay.62

Complications Oropharyngeal dysphagia causes severe complications, which can lead to morbidity and mortality; these com‑ plications include malnutrition and/or dehydration,51 and choking and tracheobronchial aspiration, which can result in respiratory infections and aspiration pneumo‑ nia3,42 (Figure 2). The effect of oropharyngeal dysphagia on the health of elderly people is as high as that of other chronic conditions such as metabolic and cardiovascular diseases or some types of cancer.63

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REVIEWS Malnutrition and impaired quality of life Independent of age and functional capacity, oropharyn‑ geal dysphagia is associated with an increased risk of malnutrition and low overall quality of life (QOL).52 It is a risk factor for malnutrition, lower respiratory tract infections and community-acquired pneumonia in elderly persons.42,45,63 Oropharyngeal dysphagia has a detrimental impact on QOL; for example, up to 41% of patients feel anxiety or panic during mealtimes and 36% avoid eating with others because of oropharyngeal dys‑ phagia.46 Among elderly hospitalized patients, the preva‑ lence of malnutrition and weakness, prolonged length of stay, impaired functional capacity, morbidity and 1‑year mortality were all markedly increased in patients with oropharyngeal dysphagia. Up to 66% of older patients with oropharyngeal dysphagia are malnourished with severe depletion of muscular protein and intracellular water (that is, subclinical dehydration).63 Studies in frail elderly patients have found that oropharyngeal dysphagia is an independent risk factor for malnutrition, with 1‑year mortality of 65.8% for patients with both conditions.51 Impaired efficacy of deglutition causes malnutrition and/or dehydration in up to 25% of patients who have had a stroke.18 Studies have also found that malnutri‑ tion and sarcopenia are associated with oropharyngeal dysphagia in elderly people.51,64 Sarcopenic dysphagia is a new concept that describes oropharyngeal dysphagia caused by sarcopenia of generalized skeletal muscles and swallowing muscles, and which requires a combination of both rehabilitation and nutritional treatment.65,66 Aspiration pneumonia Aspiration pneumonia is defined as pneumonia occurring in a patient with signs of overt aspiration or in patients with oropharyngeal dysphagia who are strongly suspected of aspirating.63,67,68 Up to 20% of patients with stroke suffer from early aspiration pneumonia and it is one of the major causes of mortality during the first year after discharge.18 Poor oral health with oropharyngeal bacterial coloniza‑ tion, malnutrition with consequent impaired immune system, and aspiration are the three elements increasing the risk of aspiration pneumonia among elderly patients and those with neurological disease. 67,69 Aspiration pneumonia is the main cause of death in patients with Parkinson disease, amyotrophic lateral sclerosis and several types of dementia.68 A 10-year review found that the number of hospitalized older patients diagnosed with aspiration pneumonia had increased 93.5% whereas other types of pneumonia had decreased.70 Among nursing home residents with oropharyngeal dysphagia, aspira‑ tion pneumonia occurs in 43–50% during the first year of living in the nursing home, with a mortality of up to 45%.55 Thus, oropharyngeal dysphagia fulfils most criteria to be recognized as a major neurologic and geriatric syn‑ drome and represents a specific target for therapeutic interventions in these patients.63,71

Oesophageal dysphagia

Patients with oesophageal dysphagia present with the symptoms of food slowing down, temporary or complete

sticking, regurgitation and weight loss. Compared with oropharyngeal dysphagia, respiratory symptoms and complications are rare and are usually only seen in advanced untreated cases. Patients who have an inflam‑ matory process might have associated odynophagia (pain with swallowing). Most patients report food ‘hanging up’ or ‘sticking’ behind the sternum, and lumps of food being caught in the epigastrium. Patients are able to localize the site correctly in only 70% of cases, with 10% local‑ izing the symptoms proximally in the oesophagus, supra­ sternal notch or the throat, which might be confused with orophayngeal dysphagia.72

Normal oesophageal physiology The main mechanisms of neurological control of human oesophageal motility differ in the striated part of the oesophagus and in the smooth muscle oesopha‑ gus. Oesophageal peristalsis in the cervical oesophagus results from the sequential activation of motor units in the swallowing centre and is mediated by vagal fibres that make direct contact on striated muscle through the motor end plate. The main excitatory neurotransmitter at this level is acetylcholine acting on nicotinic cholin‑ ergic receptors.73 In the smooth muscle part, swallowinduced oesophageal peristalsis (primary peristalsis) and lower oesophageal sphincter (LES) relaxation is con‑ trolled by intrinsic mechanisms in the muscular layers and the enteric nervous system (ENS). The ENS—also called the second brain—is organized in two major ganglionated structures: the myenteric plexus, which resides between circular and longitudi‑ nal muscle layers; and Meissner’s plexus, which resides between the muscularis mucosa and circular muscle.74 Here, vagal fibres synapse with ENS neurons, which in turn innervate the circular and longitudinal muscles and enable control of the peristaltic contraction at the distal smooth muscle of the oesophageal body and LES relaxation. Advances in this area found specific myen‑ teric mechanisms of control of LES relaxation and oesophageal body peristalsis.75,76 The main neurotrans‑ mitter mediating up to 75% of human LES relaxation in in vitro studies is nitric oxide, with a minor role for purines (through P2Y1 receptors) and vasoactive intes‑ tinal peptide75,77 (Figure 3). In addition, circular strips from the oesophageal body respond to stimulation of enteric motor neurons with an ‘on’ contraction at the beginning of the stimulus and an ‘off ’ contraction after a latency period. Stimulation of inhibitory neurons releas‑ ing nitric oxide modulates timing of ‘on’ and ‘off ’ con‑ tractions and controls the velocity of oesophageal body peristalsis.75 Amplitude of these contractions is mainly mediated by acetylcholine (Ach) released from excitatory enteric motor neurons75 and tachykinins acting on NK2 receptors.78 Therefore, primary peristaltic contractions in the oesophageal body are always preceded by deglutitive inhibition caused by stimulation of inhibitory neurons. Alterations in these intrinsic mechanisms controlling LES and oesophageal body physiology contribute to the pathophysiology of GERD and oesophageal motility disorders such as achalasia. Further research in selective

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REVIEWS Inhibitory enteric motor neuron

Excitatory enteric motor neuron

Myenteric plexus

nAChR

NO

ATP/ADP

P2Y1R

SK

GC

VIP

?

ACh

SP/NKA

mA3ChR NK2R

P2XR

Circular smooth muscle cell LES relaxation

LES contraction

Figure 3 | Schematic representation of theReviews two main parallel pathways&ofHepatology excitatory Nature | Gastroenterology and inhibitory neurotransmission of the enteric nervous system in the human LES. The main neurotransmitter mediating 75% of LES relaxation in human in vitro studies is NO through the GC signalling pathway.74,75,82 Studies exploring the neurotransmitters involved in the non-nitrergic relaxation of the LES also found a minor role for purines (acting through P2Y1R) responsible for 15% of this relaxation and VIP for 10%.75 LES contraction following stimulation of motor neurons is mainly mediated by ACh acting on mA3ChR.118 Substance P and NKA acting on tachykinin NK2R,78 and P2X agonists induce a sustained contraction.78 Abbreviations: ACh, acetycholine; GC, guanylate cyclase; LES, lower oesophageal sphincter; mA3ChR, muscarinic M3 receptors; NK2R, NK2 receptor; NKA, neurokinin A; NO, nitric oxide; P2Y1R, P2Y1 receptors; SK, substance K; SP, substance P; VIP, vasoactive intestinal peptide. Permission obtained from Lecea B, Thesis, Universitat Autònoma de Barcelona (2013)74 and John Wiley and Sons © Farre, D & Sifrim, D. Brit. J. Pharmacol. 153, 858–869 (2008).118

mechanisms of stimulation of inhibitory and excitatory motor neurons in the human oesophagus is needed to develop new pharmacologic strategies to improve LES relaxation and oesophageal body peristalsis.79,80

Pathophysiology Oesophageal dysphagia is usually recognized by physi‑ cians and many patients undergo imaging techniques, mostly oesophagoscopy, to assess the mechanical and inflammatory causes described in Box 1. Oesophageal dysphagia might also arise from abnormalities in the oesophageal body and the LES, including primary or sec‑ ondary motility disorders.81 However, our knowledge of the relationship between abnormal motor function and oesophageal dysphagia symptoms is limited, as is our understanding of the intrinsic mechanisms and neuro‑ transmitters involved in the control of oesophageal peri‑ stalsis and LES relaxation.75,76,82 Research into these two aspects will be critical to understand the pathophysio­ logy of symptoms of oesophageal dysphagia and develop effective pharmacologic treatments for patients. Studies in animal models in the 1990s described the characteristics of neural pathways including vagal and sympathetic spinal oesophageal afferents and the response of oesophageal mechanosensitive nociceptors

to distension.83–86 These nociceptors might be stimu‑ lated by motor abnormalities, inflammation, sensitiza‑ tion or structural abnormalities affecting bolus flow or oesophageal compliance. Oesophageal dysphagia can be the consequence of hypermotility or hypomotility of the muscles of the oesophagus, decreased oesopha‑ geal or oesophagogastric junction relaxation or disten‑ sibility.87 However, most studies have failed to correlate oesophageal symptoms and oesophageal dysphagia to any pattern of abnormal motor function defined by highresolution manometry during various swallow protocols; thus minimal data support a direct relationship between abnormal motor function and oesophageal dysphagia symptoms.88 Advances in oesophageal impedance enable the recording of patterns of bolus transport without the need for simultaneous radiology, and can demonstrate the relationship between the pressure pattern seen during high resolution manometry and the movement of the bolus and the pressures within it, which might help in understanding oesophageal dysphagia symptoms.89,90 A new conceptual framework of pressure-flow analysis integrating peristalsis and bolus propulsion forces, intraoesophageal pressurization, resistance to flow and bolus residue is under discussion to explain the pathophysiology of symptoms associated with oesophageal dysphagia.89,90

Prevalence Oesophageal dysphagia can occur as a result of intrinsic and extrinsic mechanical causes, primary or secondary neuromuscular disorders or inflammatory processes affecting the LES and/or the oesophageal body (Box 1). Mechanical causes Mechanical disorders and inflammatory causes of oesophageal dysphagia present with difficulty swallowing solid food, which might progress to difficulty swallow‑ ing fluids, whereas oesophageal neuromuscular disorders present with difficulty swallowing both solid and liquid. Mechanical disorders can be due to benign or malignant causes.3 By far the most common benign mechanical cause of oesophageal dysphagia is peptic stricture from GERD. Peptic stricture is reported in 10% of patients with GERD,91 but the prevalence has decreased markedly since the introduction of PPIs.92 Dysphagia was reported in 37% of nearly 12,000 patients in a clinical trial for medical therapy of GERD. In 83% of patients, dysphagic symptoms were resolved after 4 weeks of acid suppressive therapy.93 Ineffective oesophageal peristalsis and bolus transit abnormalities increase with the severity of GERD (from nonerosive reflux disease to esophagitis) and with the presence of hiatal hernia, and might c­ontribute to oesophageal dysphagia in these patients.94,95 Neuromuscular causes Achalasia is the best characterised neuromuscular phenotype of oesophageal dysphagia. The aetiology of achalasia is mostly unknown and has been associated with several genetic variations and immunological dis‑ orders that might cause the generation of antibodies to enteric neurons.96–98 The cause of initial injury in these

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REVIEWS Box 1 | Aetiology of oesophageal dysphagia Mechanical causes ■■ Intrinsic causes: oesophageal rings and webs (Schatzki ring, Plummer–Vinson, or the Patterson–Kelly syndrome [iron deficiency aneamia and oesophageal web]); peptic stricture from gastro-oesophageal reflux or scleroderma; carcinoma (squamous cell cancer and adenocarcinoma); others (diverticulae and benign tumours); post-surgery (laryngeal, oesophageal, gastric cancers, fundoplication) ■■ Extrinsic causes: mediastinal mass (lymph nodes, thyromegaly, lung cancer); vascular compression (enlarged left atrium, aberrant right subclavian artery, or right-sided aorta); cervical spine osteophytes (spurs) Neuromuscular causes ■■ Achalasia ■■ Scleroderma ■■ Nutcracker oesophagus ■■ Diffuse oesophageal spasm ■■ Ineffective oesophageal motility disorder ■■ Hypertensive lower oesophageal sphincter ■■ Others: Chagas disease, paraneoplastic syndrome Inflammatory causes ■■ Eosinophilic oesophagitis ■■ Radiation oesophagitis ■■ Caustic injury ■■ Pill oesophagitis ■■ Infectious oesophagitis: candidiasis, herpes simplex, cytomegalovirus, or HIV-associated oesophagitis Adapted with permission obtained from Elsevier Ltd. © from Lawal, A. & Shaker, R. Phys. Med. Rehabil. Clin. N. Am. 19, 729–745 (2008).

idiopathic cases is thought to be viral in nature. For example, herpes zoster or the measles virus induces a neurodegenerative process that mainly affects inhibi‑ tory but also excitatory enteric motor neurons in the oesophageal myenteric plexus and causes loss of peri‑ staltic function in the oesophageal body and impaired LES relaxation. 99 However, other benign and malig‑ nant conditions can present as achalasia (secondary or pseudo achalasia) (Box 2). The incidence of achalasia ranges from 1.1 to 4 new cases per 100,000 population per year, with a prevalence of 10 cases per 100,000 in Western countries. Incidence increases with age and peaks between 25 and 60 years. Familial clusters have been described.100 Advances in high resolution manometry have improved our understanding of oesophageal motility disorders, which in turn has resulted in new metrics to assess the extent of LES relaxation and the velocity and amplitude of oesophageal peristalsis. New classifi‑ cations of oesophageal dysmotility disorders, including achalasia, have also been developed.101,102 This classifi‑ cation has been defined as the Chicago Classification and has been periodically revised by the International GI Motility and Function Working Group.81 Impaired LES relaxation and absent peristalsis in the oesophageal body are found in all types of achalasia; type I achalasia is characterized by low intra-oesophageal pressure as a consequence of oesophageal dilation; type II is defined as achalasia with compression and is characterized by

pan-oesophageal pressurization >30 mmHg, minimal oesophageal dilation and good response to dilation or surgical treatment;101 and type III achalasia (also known as achalasia with distal spasm or ‘vigorous achalasia’) is associated with high amplitude simultaneous contrac‑ tions, functional obstruction of the distal oesophagus and poor response to all therapies. According to the Chicago Classification, major oesoph‑ ageal motility disorders such as distal oesophageal spasm and hypercontractile oesophagus can cause oesophageal dysphagia in the context of normal oesophagogastric junction relaxation. Distal oesophageal spasm is defined by premature contractions (reduced latency) and spasm (excessive velocity) affecting a segment or all of the smooth part of the oesophageal body. Hypercontractile oesophagus (also known as hypertensive peristalsis or classic Nutcracker oesophagus) is characterized by normal LES relaxation, normal peristaltic velocity but increased distal contractility of the oesophageal body; an extreme phenotype of this disorder is defined as spastic Nutcracker or Jackhammer oesophagus.102 Other causes Other phenotypes of oesophageal dysphagia include a number of connective tissue diseases. The gastrointes‑ tinal tract is the third most common organ affected by systemic sclerosis (scleroderma) after thickening of the skin and Raynaud phenomenon. Oesophageal symptoms are very common in this disease, occurring in 50–80% of patients, and might precede the skin changes. 103 Oesophageal dysphagia might also be present, along with other oesophageal symptoms such as heartburn and regurgitation, in mixed connective tissue disease.104 Idiopathic inflammatory myopathies including der‑ matomositis, polymyositis and inclusion body myositis can also involve the oesophagus and cause impaired or absence of peristalsis and also oropharyngeal dys‑ phagia.105,106 Oesophageal dysphagia is uncommon in patients with systemic lupus erythematosus and has been reported in 1.5–8.0% of these patients.107 Although some reports have estimated more prevalent oesophageal symptoms in patients with type 1 diabetes than controls, these reports have not been confirmed by others.108 The most common oesophageal motility abnormality in these patients is ineffective peristalsis.108 Both hypo­ thyroidism and hyperthyroidism can affect oesophageal function; secondary achalasia has been reported in hypo­ thyroidism and impaired oesophageal peristalsis has been described in hyperthyroidism.109,110 Oesophageal dysmotility has been reported to persist in individuals with ongoing alcoholism while normalizing in those who abstain from alcohol.111,112 Among the inflammatory processes causing oesophageal dysphagia is eosinophilic oesophagitis, which is frequently seen in children and is now recognized in adults as a cause of solid food dysphagia and food impaction.113 >50% of patients who present with food impaction to the emer‑ gency room have eosinophilic oesophagitis.114 This dis­ order is characterized by the presence of allergic s­ymptoms, such as atopy, and environmental and food allergies.

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REVIEWS Radiation oesophagitis is another inflammatory cause of oesophageal dysphagia, affecting nearly 50% of patients after radiation therapy for thoracic and head and neck cancer.115 However, radiation oesophagitis might present as delayed radiation fibrosis with impaired oesophageal peristalsis and impaction. A number of medications, such as tetracycline, quinine, bisphos‑ phonates, potassium chloride and vitamin C can cause inflammation of the oesophagus resulting in oesophageal dysphagia along with pain. Finally, among the benign causes of oesophageal dys‑ phagia is postoperative dysphagia which is a common complaint after fundoplication for GERD. Transient dys‑ phagia is common in the initial weeks and month after fundoplication, but troublesome long-term dysphagia occurs in as many as 5% of these patients.116

A multidisciplinary approach

Despite marked progress in understanding the physi‑ ology of deglutition and the pathophysiology of swal‑ lowing disorders—fuelled by advances in technology and the advent of more precise recording techniques— patients with dysphagia continue to receive fragmented care and do not benefit from the full spectrum of the diagnostic and therapeutic modalities in an expeditious, efficient and cost-effective manner. One can easily trace the source of this shortcoming to the fact that various aspects of this field have evolved within several medical and surgical disciplines, resulting in individual expertise, knowledge and skills with the outcome of an inconsistent pattern of care for patients with dysphagia. The multidisciplinary nature of the management of dysphagia and the varying ways it affects patient pheno‑ types has resulted in a piecemeal approach that has hin‑ dered research in this area. Experts in dysphagia come from widely different backgrounds: from ENT, speech language pathology, rehabilitation medicine, surgery, gastroenterology, radiology, neurology, gerontology, head and neck diseases and paediatrics. Furthermore, dysphagia is not a medical speciality in its own right and is frequently omitted from medical curriculums. There are a few scientific societies specifically dedi‑ cated to dysphagia and they are characterized by having members with diverse professional profiles. The oldest society is the DRS (Dysphagia Research Society), which was formed in the USA in 1992.117 The JSDR (Japanese Society of Dysphagia Rehabilitation) was formed in 1995; it is the largest society with >10,000 members, 20% of whom are dentists. In 2011, the ESSD (European Society for Swallowing Disorders) was formed based on the former European Study Group of Dysphagia and Globus (EGDG). Joint projects and events with European socie‑ ties that encompass dysphagia within their fields have been undertaken to increase awareness, develop guide‑ lines and consolidate research. The ESSD is also develop‑ ing a multidisciplinary postgraduate university diploma with the aim of offering it in several European countries in the academic year 2016–2017. The efforts of all these societies in promoting a multi­ disciplinary approach to dysphagia, and encouraging

Box 2 | Types of achalasia Idiopathic or primary achalasia Secondary (pseudoachalasia) achalasia ■■ Chagas disease ■■ Carcinoma of the gastric cardia ■■ Paraneoplastic syndrome from malignancy elsewhere ■■ Amyloidosis ■■ Neuropathic chronic intestinal pseudo-obstruction syndrome ■■ Triple‑A syndrome: achalasia, alacrimia, and no response to adrenocorticotrohpic hormone ■■ Neurodegenerative disorder with Lewy inclusion bodies, Parkinson disease and hereditary cerebella ataxia ■■ Anderson–Fabry disease ■■ Von Recklinghausen neurofirbromatosis ■■ Post-vagotomy Adapted with permission obtained from Elsevier Ltd. © from Lawal, A. & Shaker, R. Phys. Med. Rehabil. Clin. N. Am. 19, 729–745 (2008).

research and holding congresses and courses, is pro‑ viding an important opportunity for the convergence of various contributory fields to develop a professional discipline of deglutology. A deglutologist, whose initial and foundational training has derived from diverse disciplines, will be equipped with the combined multi‑ disciplinary knowledge and skills necessary to address deglutition disorders in their entirety, providing all the critical pieces of the puzzle that compromises the health and QOL of patients with dysphagia.

Conclusions

Oropharyngeal dysphagia is a highly prevalent, neglected disorder with poor prognosis and severe complications. The burden of this condition is likely to increase given the demographic aging of the population. However, awareness of oropharyngeal dysphagia is growing and many professional domains are involved in the man‑ agement of these patients. Education about dysphagia should be standardized and made available to healthcare providers. International societies can provide forums to discuss and disseminate the latest research at their conferences. Patients have the right to be diag‑ nosed and receive appropriate treatment for this con‑ dition. Familiarity with methods for clinical screening and assessment of swallow function will lead to more diagnostics. Doctors can improve recognition of the condition by including the ICD code in medical reports. Oropharyngeal dysphagia should be recognized as a major neurologic and geriatric syndrome and institu‑ tions should provide human and material resources to avoid complications. Demographic and health economic studies should also be undertaken to quantify the effect of this disorder. Research in the past few years and advances in tech‑ nology have provided new insights into the pathophysi‑ ology of the disease at the central and peripheral levels. More clinical and basic research is necessary to increase knowledge on the specific pathophysiology and natural history of oropharyngeal dysphagia in each disease. This increased understanding will pave the way for specific and

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REVIEWS evidence-based preventive and therapeutic strategies and new targets for treatments, particularly pharmacological and neurophysiological interventions, moving from com‑ pensation to recovery of swallow function. Management of patients at risk should include systematic screening for oropharyngeal dysphagia, oral health and malnutrition, education on oral hygiene, rheological adaptation for fluids and solid foods, and rehabilitation. In the future, research and new products for patients with oropharyn‑ geal dysphagia will hopefully yield active treatments for impaired swallow response, biological treatments for the oral microbiota, and integrated products and strategies for oropharyngeal dysphagia and malnutrition. Finally, although patients with oesophageal dysphagia are initially better recognized by health-care profession‑ als than those with oropharyngeal dysphagia, the patho‑ physiology of the symptom is not fully understood in many phenotypes of patients; future clinical and basic research is needed to provide specific treatments for oesophageal dysphagia.

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To cover all these needs of patients with dysphagia, two complementary strategies should be established: first, the development of well-coordinated multidiscipli‑ nary teams and dysphagia units in hospitals; and second, the development of a new professional profile, the deglu‑ tologist, to bring together knowledge and skills from different disciplines to understand the whole swallow function, from the brain to the neck and oesophageal muscles, and to fully cover the diagnostic and therapeutic needs of all phenotypes of patients with dysphagia. Review criteria This is not a systematic review. This is a report to help readers understand the current reality, state of the art and scope of the problem of oropharyngeal and oesophageal dysphagia. The article summarizes the position, experience, and interpretation of development in this area of the two authors. Articles have been selected according to their relevance, impact and scientific or educational value according to the criteria of the two authors.

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