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
Dysphagia derives from the Greek terms dys meaning Oropharyngeal dysphagia is a symptom of a swallow
‘disordered’ or ‘ill’, and phago meaning ‘eat’ or ‘swallow’. dysfunction that provokes difficulty or inability to form
Swallowing is defined as ‘the function of clearing food or move the alimentary bolus safely from the mouth to
and drink through the oral cavity, pharynx and oesopha‑ the oesophagus.6 It can include oropharyngeal aspiration
gus into the stomach at an appropriate rate and speed’ (the entry of secretions, food, or drink from the oro‑
by the International Classification of Functioning, pharynx into the trachea or the lungs) and choking (the
Disability and Health (ICF, code b5105) promoted subsequent mechanical obstruction of pulmonary air
by the WHO.1 Dysphagia is classified under ‘digestive flow).6 Oropharyngeal dysphagia should be differenti‑
symptoms and signs’ in the International Classification ated from globus pharyngis, a specific somatoform dis‑
of Diseases (ICD‑10, code R13), also promoted by the order consisting of the continuous feeling of having a
WHO.2 However, the term is often used, not fully appro‑ ‘lump in the throat’, phlegm, or some sort of obstruction
priately, to mean a disorder or disease. Patients affected when there is none.2 Despite the severity of oropharyn‑
Centro de Investigación can be unaware of their swallow dysfunction. geal dysphagia, the standard of care for the majority of
Biomédica en Red From an anatomical standpoint, dysphagia can result these patients is very poor as most are not diagnosed or
de Enfermedades
Hepáticas y Digestivas
from oropharyngeal and/or oesophageal causes; from a treated.7,8 By contrast, the prevalence, symptom severity,
(CIBERehd), Hospital pathophysiological perspective, dysphagia can be caused complications and associated mortality are much lower
de Mataró, Universitat by organic or structural diseases (either benign or malig‑ for oesophageal dysphagia and—although its pathophysi‑
Autònoma de
Barcelona, Carretera nant) or diseases causing impaired physiology (mainly ology also needs further research—it is better recognized
de Cirera s/n. 08304, motility and/or perception disorders). Oropharyngeal, and clinically managed.9
Mataró, Spain (P.C.).
MCW Dysphagia
head, neck and oesophageal structural causes (such as This Review provides an overview of advances in the
Research Institute, tumours, webs, pouches and rings) of dysphagia are pathophysiology, prevalence and potential complications
Division of reviewed elsewhere.3–5 This Review focuses on advances of both oropharyngeal dysphagia and oesophageal dys‑
Gastroenterology and
Hepatology, and Clinical in understanding dysphagia caused by diseases that phagia, particularly in association with impaired physiol‑
and Translational impair oropharyngeal and/or oesophageal physiology. ogy. These are exciting times with increasing awareness
Science Institute of
Southeast Wisconsin,
of the phenotypes of patients at risk of these disorders,
Medical College of Competing interests and progressive recognition of the clinical relevance and
Wisconsin, 9200 W.
P.C. has received educational grants and performed clinical complications of these conditions by health-care pro‑
Wisconsin Avenue,
Milwaukee, WI 53226,
trials with the support of the following companies: DJO; viders from many fields. In addition, the emergence of
Fresenius Kabi; Image and Physiology; Nestlé Health Science;
USA (R.S.). new methods to screen and assess swallow function at
Nutricia Advanced Medical Nutrition; and Phagenesis. These
Correspondence to: P.C. competing interests do not specifically affect the contents of both the oropharynx and oesophagus, and the marked
[email protected] this Review. R.S. declares no competing interests. advances in understanding the pathophysiology of these

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REVIEWS

Key points and is mainly caused by the squeezing action of the tongue
against the palate, providing driving forces to propel swal‑
■■ Dysphagia is a symptom defined by the difficulty to form or move the alimentary
lowed material across the UES with minimal resistance.17
bolus safely from the mouth to the stomach
■■ Oropharyngeal dysphagia is a highly prevalent condition in three main at-risk
Pharyngeal contraction mainly facilitates pharyngeal
populations: elderly people, patients with neurological or neurodegenerative clearance.17 Bolus propulsion forces are strongly reduced
diseases, and patients with head and/or neck diseases in patients with neuromuscular diseases and elderly
■■ Oropharyngeal dysphagia is associated with reduced pharyngolaryngeal patients with malnutrition and sa­rcopenia, and causes
sensitivity, damage of cortical areas or the swallowing centre in the central post-swallow oropharyngeal residue.13,18,19
nervous system, and/or impaired efferent neural or muscular drive The pharyngeal phase of swallow is an automatic,
■■ Oropharyngeal dysphagia is a serious condition as it impairs quality of life involuntary sequence of neuromuscular events that
and causes nutritional and respiratory complications associated with poor
begins as the bolus crosses the pillars of the fauces
prognosis and high mortality rates
■■ Oesophageal dysphagia is usually caused by primary or secondary oesophageal
propelled by the propulsive tongue thrust. The bio­
motility disorders that affect the enteric nervous system or the oesophageal mechanical elements of the OSR consist of the tem‑
muscular layers poral arrangement of oropharyngeal structures from
■■ Advances in research and technology are paving the way for intensive research a respiratory to a digestive pathway, the transfer of
and active therapeutic strategies for affected patients, and a transdisciplinary the bolus from the mouth to the oesophagus—including
field of deglutology 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
conditions, is paving the way for a new era with new pro‑ by opening or closing events occurring at the glosso­
fessional domains in deglutology. Therapeutic strategies palatal junction, velopharyngeal junction, laryngeal ves‑
for affected patients are evolving from compensation to tibule and UES. Healthy individuals have a short swallow
the restoration of impaired swallow function. response, fast laryngeal vestibule closure and fast UES
opening.18 By contrast, prolonged intervals to laryngeal
Normal swallowing vestibule closing and UES opening owing to delay in
Normal swallowing is a complex and well-coordinated the early phase of oropharyngeal reconfiguration from
process that requires the appropriate interaction between a respiratory to a digestive pathway are key abnormali‑
several areas of the central nervous system (CNS), sensory ties of swallow response, leading to unsafe deglutition
and motor cranial nerves, and peripheral receptors of and aspiration in patients with neurological diseases and
pressure, temperature, chemical stimuli and water.10 It also elderly people.13,18 Time to laryngeal vestibule closing is
requires the anatomical integrity of the oropharynx and the time interval during which the potential for penetra‑
larynx and the preserved neuromuscular function of up tion or aspiration occurs, and a delay in UES opening
to 30 pairs of cervical striated muscles including the upper increases the bolus volume held in the hypopharynx,
oesophageal sphincter (UES) and close coordination with thereby increasing the potential for bolus overflow into
the respiratory system. Our knowledge of the pathophysi‑ the laryngeal vestibule. Reduced afferent input from
ology of swallowing dysfunction has greatly improved oropharyngeal sensory areas, central or peripheral deaf‑
with better understanding of the four phases of normal ferentation, and damage of cortical or brainstem swal‑
swallow (oral preparatory, oral propulsive, pharyngeal and lowing areas might explain the serious delay in OSR
oesophageal), the mechanisms of swallow control in the observed in patients with neurological disorders and
CNS and the peripheral sensory and motor components of elderly people.13,18,21,22
the oropharyngeal swallow response (OSR).11,12 The OSR is triggered by the swallowing centre, an
The oral preparatory phase is under voluntary control interneuronal network located in the brainstem (medulla
and it is different for fluids and solids. Fluid boluses oblongata) that receives both central inputs from the
are placed in the anterior part of the mouth by sealing cortex and peripheral sensory inputs from the pharynx
the soft palate down against the tongue. If this glosso‑ and larynx 10 (Figure 1). The cortical and subcortical areas
palatal seal fails, the bolus falls into the pharynx before allow volitional swallowing and serve mainly to trigger
the OSR is triggered and while the airway is still open; deglutition and control the swallow motor response.
in this case fluid might be aspirated.13 For solids, food Specifically, the areas implicated in the swallowing process
is masticated and the bolus is formed by action of the are the caudolateral sensori-motor cortex, the premotor,
lips, the tongue and the jaws. Mastication involves cyclic orbitofrontal and temporopolar cortex, the insula, the cer‑
jaw movements and synchronizes with the transport of ebellum and the amygdala.23 These areas are represented
food by the tongue and cheeks to the molars (Stage I).14 bilaterally but asymmetrically in the two hemispheres,
Chewed food is mixed with saliva and transported (Stage independently of handedness.23
II) through the fauces and collected in the oropharynx or
vallecula where the bolus is formed prior to swallowing.15 Oropharyngeal dysphagia
The masticatory function is severely impaired in elderly Pathophysiology
patients owing to tooth loss, increased number of (weak) Improvements in our knowledge of the physiology of
chewing cycles and decreased saliva production.16 swallowing have paralleled that of the pathophysiology.
The oral propulsive phase involves transfer of the bolus Oropharyngeal dysphagia after stroke is the consequence
from the mouth through the pharynx to the oesophagus of damage at the ‘dominant’ pharyngeal cortex, direct

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 REVIEWS

damage to the central pattern generator, or damage to Peripheral stimuli of the oropharynx, larynx and oesophagus
the somatic motor nuclei in the brainstem;24,25 swallow
function recovery after a stroke has been associated with Sensory neurons Cortical and
increased pharyngeal motor representation (neuroplasti‑ (V, VII, IX, X) subcortical
structures
city) in the contralesional hemisphere.25,26 The peripheral
sensory inputs allow involuntary onset of the swallow
Dorsal
response and modulate volitional swallowing.10 They swallowing
are mainly transmitted through the maxillary branch of Brainstem
group
the trigeminal nerve (V cranial nerve), the pharyngeal swallowing
centre
branch of the glossopharyngeal nerve (IX cranial nerve) Ventral
and two branches of the vagus nerve (X cranial nerve), swallowing
group
the pharyngeal branch and the superior laryngeal
nerve.10 Impaired pharyngolaryngeal sensitivity to physi‑
cal or chemical stimuli is now a well-known component Oropharyngeal Oesophagus
Motor
of swallow dysfunction and enhances the risk of aspi‑ nuclei Trigeminal, facial, ambiguus, Dorsal motor
hypoglosssal, C1–C2 nucleus
ration in elderly people and patients with neurological
disease.21,22,27 Thus, sensory stimulation using agonists
Motor V, VII, IX, XI, XII,
for TRP receptors (TRPV1, TRPA1, TRPM8), or intrap‑ neurons ansa cervicalis
X
haryngeal or transcutaneous electrical stimulation has
become an important emerging therapeutic strategy for
Oropharyngeal Primary
patients with dysphagia.28–32 swallow response peristalsis
Also in the pharyngeal phase, reduced opening might
Nature Reviews
Figure 1 | Scheme | Gastroenterology
of the multidimensional & Hepatology
neuronal
be due to an intrinsic, restrictive sphincter disorder reduc‑
network of the central nervous system controlling the
ing sphincter compliance, as in patients with cricopharyn‑ oropharyngeal swallow response (OSR) and primary
geal bar and/or Zenker diverticulum.33,34 Alternatively, peristalsis. The OSR is triggered by the swallowing centre,
reduced opening in patients with neurological diseases an interneuronal network located in the brainstem (medulla
or in older people might be a manifestation of impaired oblongata) that receives both central inputs from the cortex
supra-hyoid traction and/or weak bolus propulsion in and peripheral sensory inputs from the pharynx and larynx.
which the forces exerted by the advancing swallowed bolus The central mechanism mediating peristalsis in the striated
are insufficient to fully open the sphincter.35 Impaired cervical oesophagus depends on sequential activation
of vagal motor neurons in the nucleus ambiguous, and
neural UES relaxation observed in spastic neurological
primary peristalsis in the smooth part involves the
diseases such as Parkinson disease or brain injury is char‑ activation of the dorsal motor nucleus of the vagus.
acterized by weak bolus propulsion and reduced or even
absent neuromuscular UES relaxation.36,37
The swallow response is also closely coordinated an appropriate cough response, strongly enhancing the risk
with breathing and the airway mechanisms that prevent of aspiration pneumonia.41,42
aspiration and elicit cough. The neural control centres
responsible for breathing, coughing and swallowing are Prevalence
closely located in the brainstem and are also well con‑ The three main populations at risk of oropharyngeal dys‑
nected with the primary sensory cortex, which modu‑ phagia are elderly people, patients with neurological or
lates the coordination of breathing and swallowing and neurodegenerative diseases, and patients with head and/
the elicitation of cough.38 Swallow causes a physiologic or neck diseases (Table 1).43,44 Oropharyngeal dysphagia
apnoea, and the predominant respiratory pattern in is a highly prevalent clinical condition, with a similar
healthy adults is expiration before and after the swallow.39 prevalence to that of diabetes mellitus among adults in
By contrast, patients with neurological diseases, chronic the general population.45
obstructive pulmonary disease or advanced age present
with an increased frequency of swallowing occur‑ Elderly people
ring during the inspiratory cycle, increasing the risk of Oropharyngeal dysphagia affects up to 30–40% of the
­swallow-related aspiration.40 population ≥65 years old.46 An estimated >16 million US,
Cough is an airway defensive reflex aimed at removing 30 million European and 10 million Japanese elderly citi‑
mucus and foreign materials from the respiratory tract. zens have oropharyngeal dysphagia.47 The aging process
Mechanical or chemical stimuli can elicit the cough reflex causes changes in anatomy as well as in neural and mus‑
by stimulation of receptors and C fibres in the larynx and cular mechanisms, resulting in a loss of functional reserve
tracheobronchial tree.41 The IX, X and V nerves transmit that can affect the swallowing process.18,48,49 In healthy
the sensory input to the brainstem. The efferent compo‑ older people, these changes in swallowing function are
nent of cough reflex is mediated by the phrenic, intercostal defined as presbyphagia and do not necessarily indicate
and other spinal nerves to the respiratory muscles.38 Elderly a pathological condition.49 However, when these changes
people or patients with neurological disease present with in swallow physiology occur in frail, co-morbid and poly-
reduced cough sensitivity to several stimuli, leading to a medicated elderly patients, the risk of oropharyngeal
high prevalence of silent aspirations or aspirations without 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
Elderly
Independently-living older people Screening 11.4–33.7 Holland et al. (2011)119
(questionnaires) 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 Not specified/Clinical exploration 29.4–47.0 Lee et al. (1999)123
geriatric unit (water swallow test or V-VST) Cabré et al. (2014)124
Hospitalized with community- Clinical exploration (water swallow test 55.0–91.7 Cabré et al. (2010)125
acquired pneumonia or V-VST) Almirall (2012)68
Hospitalized with community- Instrumental exploration 75 Almirall (2012)68
acquired pneumonia
Institutionalized Screening (questionnaires) 40 Nogueira & Reis (2013)126
Clinical exploration (water swallow test) 38
Screening and clinical exploration 51 Lin et al. (2002)127
Stroke: acute phase Screening (questionnaires) 37–45 Martino et al. (2005)56

Clinical exploration 51–55

Instrumental exploration 64–78
Stroke: chronic phase Clinical exploration 25–45 Martino et al. (2005)56
Instrumental exploration 40–81
Neurodegenerative disease
Parkinson disease Reported by patients 35 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
Multiple Sclerosis Screening (questionnaires) 24 De Pauw et al. (2002)133
Instrumental exploration 34.3 Calcagno et al. (2002)134
Amyotrophic lateral sclerosis Clinical and Instrumental exploration 47–86 Chen & Garrett (2005)135
Ruoppolo et al. (2013)136
Structural
Head and neck cancer 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
Abbreviation: V‑VST, volume-viscosity swallowing test.

sedative drugs are strongly associated with oropharyn‑ is very high. Up to 47.4% of frail older patients hospital‑
geal dysphagia in elderly people.51 The prevalence of oro‑ ized for acute illness have oropharyngeal dysphagia.51,53,54
pharyngeal dysphagia among independently-living older Oropharyngeal dysphagia affects >50% of older people
persons is 16.6% in the 70–79 year age group and 33% in living in nursing homes, up to 29% of whom are tube fed,
the >80 year age group.52 The prevalence of oropharyn‑ mainly because of severe aspirations.55
geal dysphagia is higher in elderly patients with neuro‑
degenerative diseases (80% in patients with Alzheimer Patients with neurological diseases
disease and 60% in patients with Parkinson disease) and Patients with neurological diseases are also at high
is related to age, frailty and muscular, endocrine or psy‑ risk of oropharyngeal dysphagia. 64–78% of patients
chiatric diseases.46 Furthermore, the prevalence of oro‑ who have had a stroke have oropharyngral dyspha‑
pharyngeal dysphagia among older hospitalized patients gia during the acute phase, and 40–81% have dysphagia

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Elderly patient with neurological disease

Patient with head or neck disease

Xerostomia Oropharyngeal
bacterial colonization
Oropharyngeal
dysphagia

Muscular Slow neural

weakness response

Impaired safety of swallow

Impaired efficacy of swallow Impaired airway protection
Impaired bolus propulsion

Aspiration
Dehydration Malnutrition Silent aspirations Respiratory
(Impaired cough reflex) infections

Hypovolemia Adipose Chronic Sarcopenia Immune Impared Aspiration

Alteration in: dysfunction inflammation dysfunction muscular or Pneumonia
■ Renal function Insulin respiratory
■ Cardiovascular resistance function
■ Level of awareness

Frailty Re-admissions
syndrome

Functional impairement, disability,

Institutionalization pressure ulcers, immunosuppression, Mortality
intercurrent infections, comorbidity

Figure 2 | Pathophysiology of nutritional and respiratory complications associated

Naturewith oropharyngeal
Reviews dysphagia.&Dehydration,
| 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‑ does not always translate into function preservation
gia is more prevalent in brainstem stroke, followed by owing to inflammation in the acute phase and fibrosis in
bilateral and then unilateral stroke.56 The prevalence of the late stage. The highest rates of nonfunctional pharynx
dysphagia in patients with stroke also varies depend‑ and larynx, oropharyngeal dysphagia and aspiration are
ing on the diagnostic method used: 51–55% if clinical found among patients treated with both surgery and
testing is used for diagnosis and up to 78% when using radio-chemotherapy.60
an instrumental method.56 Up to 70% of patients with Other head and neck conditions associated with dys‑
severe acute traumatic brain injury have oropharyngeal phagia are trauma to the throat or larynx, post-tracheal
dysphagia and 50% of patients with chronic traumatic intubation, use of tracheostomy tubes, cervical osteo‑
brain injury.57 Oropharyngeal dysphagia is present in phytes and cervical surgery. Congenital malformations,
52–82% of patients with advanced Parkinson disease,6,58 Zenker diverticulum and cricopharyngeal bars also cause
30–40% of patients with multiple sclerosis, and 80–100% oropharyngeal dysphagia.43,62 Oropharyngeal dysphagia
of patients with an advanced stage of amyotrophic lateral at birth and during the first months of life is rare and is
sclerosis, advanced stage dementia or oculopharyngeal generally associated with neurodevelopmental delay.62
muscular dystrophy.59
Complications
Patients with head and/or neck diseases Oropharyngeal dysphagia causes severe complications,
Oropharyngeal dysphagia associated with head and neck which can lead to morbidity and mortality; these com‑
neoplasms is caused by altered anatomy, mass effect plications include malnutrition and/or dehydration,51
and the consequences of treatments. Nowadays, most and choking and tracheobronchial aspiration, which can
patients are treated with radio-chemotherapy and up to result in respiratory infections and aspiration pneumo‑
44% of these patients subsequently develop oropharyn‑ nia3,42 (Figure 2). The effect of oropharyngeal dysphagia
geal dysphagia.60 Some 10–15% of patients are treated on the health of elderly people is as high as that of other
with surgery, half of whom subsequently have dyspha‑ chronic conditions such as metabolic and cardiovascular
gia.60,61 Organ preservation after radio-chemotherapy diseases or some types of cancer.63

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REVIEWS

Malnutrition and impaired quality of life sticking, regurgitation and weight loss. Compared with
Independent of age and functional capacity, oropharyn‑ oropharyngeal dysphagia, respiratory symptoms and
geal dysphagia is associated with an increased risk of complications are rare and are usually only seen in
malnutrition and low overall quality of life (QOL).52 It advanced untreated cases. Patients who have an inflam‑
is a risk factor for malnutrition, lower respiratory tract matory process might have associated odynophagia (pain
infections and community-acquired pneumonia in with swallowing). Most patients report food ‘hanging up’
elderly persons.42,45,63 Oropharyngeal dysphagia has a or ‘sticking’ behind the sternum, and lumps of food being
detrimental impact on QOL; for example, up to 41% of caught in the epigastrium. Patients are able to localize
patients feel anxiety or panic during mealtimes and 36% the site correctly in only 70% of cases, with 10% local‑
avoid eating with others because of oropharyngeal dys‑ izing the symptoms proximally in the oesophagus, supra­
phagia.46 Among elderly hospitalized patients, the preva‑ sternal notch or the throat, which might be confused
lence of malnutrition and weakness, prolonged length of with orophayngeal dysphagia.72
stay, impaired functional capacity, morbidity and 1‑year
mortality were all markedly increased in patients with Normal oesophageal physiology
oropharyngeal dysphagia. Up to 66% of older patients The main mechanisms of neurological control of
with oropharyngeal dysphagia are malnourished with human oesophageal motility differ in the striated part
severe depletion of muscular protein and intracellular of the oesophagus and in the smooth muscle oesopha‑
water (that is, subclinical dehydration).63 Studies in frail gus. Oesophageal peristalsis in the cervical oesophagus
elderly patients have found that oropharyngeal dysphagia results from the sequential activation of motor units in
is an independent risk factor for malnutrition, with 1‑year the swallowing centre and is mediated by vagal fibres
mortality of 65.8% for patients with both conditions.51 that make direct contact on striated muscle through the
Impaired efficacy of deglutition causes malnutrition motor end plate. The main excitatory neurotransmitter
and/or dehydration in up to 25% of patients who have at this level is acetylcholine acting on nicotinic cholin‑
had a stroke.18 Studies have also found that malnutri‑ ergic receptors.73 In the smooth muscle part, swallow-
tion and sarcopenia are associated with oropharyngeal induced oesophageal peristalsis (primary peristalsis)
dysphagia in elderly people.51,64 Sarcopenic dysphagia is and lower oesophageal sphincter (LES) relaxation is con‑
a new concept that describes oropharyngeal dysphagia trolled by intrinsic mechanisms in the muscular layers
caused by sarcopenia of generalized skeletal muscles and and the enteric nervous system (ENS).
swallowing muscles, and which requires a combination The ENS—also called the second brain—is organized
of both rehabilitation and nutritional treatment.65,66 in two major ganglionated structures: the myenteric
plexus, which resides between circular and longitudi‑
Aspiration pneumonia nal muscle layers; and Meissner’s plexus, which resides
Aspiration pneumonia is defined as pneumonia occurring between the muscularis mucosa and circular muscle.74
in a patient with signs of overt aspiration or in patients Here, vagal fibres synapse with ENS neurons, which in
with oropharyngeal dysphagia who are strongly suspected turn innervate the circular and longitudinal muscles
of aspirating.63,67,68 Up to 20% of patients with stroke suffer and enable control of the peristaltic contraction at the
from early aspiration pneumonia and it is one of the major distal smooth muscle of the oesophageal body and LES
causes of mortality during the first year after discharge.18 relaxation. Advances in this area found specific myen‑
Poor oral health with oropharyngeal bacterial coloniza‑ teric mechanisms of control of LES relaxation and
tion, malnutrition with consequent impaired immune oesophageal body peristalsis.75,76 The main neurotrans‑
system, and aspiration are the three elements increasing mitter mediating up to 75% of human LES relaxation
the risk of aspiration pneumonia among elderly patients in in vitro studies is nitric oxide, with a minor role for
and those with neurological disease. 67,69 Aspiration purines (through P2Y1 receptors) and vasoactive intes‑
pneumonia is the main cause of death in patients with tinal peptide75,77 (Figure 3). In addition, circular strips
Parkinson disease, amyotrophic lateral sclerosis and from the oesophageal body respond to stimulation of
several types of dementia.68 A 10-year review found that enteric motor neurons with an ‘on’ contraction at the
the number of hospitalized older patients diagnosed with beginning of the stimulus and an ‘off ’ contraction after a
aspiration pneumonia had increased 93.5% whereas other latency period. Stimulation of inhibitory neurons releas‑
types of pneumonia had decreased.70 Among nursing ing nitric oxide modulates timing of ‘on’ and ‘off ’ con‑
home residents with oropharyngeal dysphagia, aspira‑ tractions and controls the velocity of oesophageal body
tion pneumonia occurs in 43–50% during the first year of peristalsis.75 Amplitude of these contractions is mainly
living in the nursing home, with a mortality of up to 45%.55 mediated by acetylcholine (Ach) released from excitatory
Thus, oropharyngeal dysphagia fulfils most criteria to enteric motor neurons75 and tachykinins acting on NK2
be recognized as a major neurologic and geriatric syn‑ receptors.78 Therefore, primary peristaltic contractions in
drome and represents a specific target for therapeutic the oesophageal body are always preceded by deglutitive
interventions in these patients.63,71 inhibition caused by stimulation of inhibitory neurons.
Alterations in these intrinsic mechanisms controlling
Oesophageal dysphagia LES and oesophageal body physiology contribute to the
Patients with oesophageal dysphagia present with the pathophysiology of GERD and oesophageal motility
symptoms of food slowing down, temporary or complete disorders such as achalasia. Further research in selective

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 REVIEWS

Inhibitory Excitatory to distension.83–86 These nociceptors might be stimu‑

enteric motor neuron enteric motor neuron
lated by motor abnormalities, inflammation, sensitiza‑
tion or structural abnormalities affecting bolus flow or
Myenteric oesophageal compliance. Oesophageal dysphagia can
nAChR plexus
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 high-
resolution manometry during various swallow protocols;
thus minimal data support a direct relationship between
abnormal motor function and oesophageal dysphagia
NO ATP/ADP VIP ACh SP/NKA
symptoms.88 Advances in oesophageal impedance enable
the recording of patterns of bolus transport without the
need for simultaneous radiology, and can demonstrate
mA3ChR
P2Y1R SK ?
NK2R P2XR
the relationship between the pressure pattern seen during
GC high resolution manometry and the movement of the
Circular smooth muscle cell bolus and the pressures within it, which might help in
LES relaxation LES contraction understanding oesophageal dysphagia symptoms.89,90
Figure 3 | Schematic representation of theReviews
Nature two main parallel pathways&ofHepatology
| Gastroenterology excitatory A new conceptual framework of pressure-flow analysis
and inhibitory neurotransmission of the enteric nervous system in the human LES. integrating peristalsis and bolus propulsion forces, intra-
The main neurotransmitter mediating 75% of LES relaxation in human in vitro oesophageal pressurization, resistance to flow and bolus
studies is NO through the GC signalling pathway.74,75,82 Studies exploring the
residue is under discussion to explain the pathophysiology
neurotransmitters involved in the non-nitrergic relaxation of the LES also found a
of symptoms associated with oesophageal dysphagia.89,90
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 Prevalence
NK2R,78 and P2X agonists induce a sustained contraction.78 Abbreviations: ACh, Oesophageal dysphagia can occur as a result of intrinsic
acetycholine; GC, guanylate cyclase; LES, lower oesophageal sphincter; mA3ChR, and extrinsic mechanical causes, primary or secondary
muscarinic M3 receptors; NK2R, NK2 receptor; NKA, neurokinin A; NO, nitric neuromuscular disorders or inflammatory processes
oxide; P2Y1R, P2Y1 receptors; SK, substance K; SP, substance P; VIP, vasoactive affecting the LES and/or the oesophageal body (Box 1).
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
Mechanical causes
Mechanical disorders and inflammatory causes of
oesophageal dysphagia present with difficulty swallowing
mechanisms of stimulation of inhibitory and excitatory solid food, which might progress to difficulty swallow‑
motor neurons in the human oesophagus is needed to ing fluids, whereas oesophageal neuromuscular disorders
develop new pharmacologic strategies to improve LES present with difficulty swallowing both solid and liquid.
relaxation and oesophageal body peristalsis.79,80 Mechanical disorders can be due to benign or malignant
causes.3 By far the most common benign mechanical
Pathophysiology cause of oesophageal dysphagia is peptic stricture from
Oesophageal dysphagia is usually recognized by physi‑ GERD. Peptic stricture is reported in 10% of patients
cians and many patients undergo imaging techniques, with GERD,91 but the prevalence has decreased markedly
mostly oesophagoscopy, to assess the mechanical and since the introduction of PPIs.92 Dysphagia was reported
inflammatory causes described in Box 1. Oesophageal in 37% of nearly 12,000 patients in a clinical trial for
dysphagia might also arise from abnormalities in the medical therapy of GERD. In 83% of patients, dysphagic
oesophageal body and the LES, including primary or sec‑ symptoms were resolved after 4 weeks of acid suppressive
ondary motility disorders.81 However, our knowledge of therapy.93 Ineffective oesophageal peristalsis and bolus
the relationship between abnormal motor function and transit abnormalities increase with the severity of GERD
oesophageal dysphagia symptoms is limited, as is our (from nonerosive reflux disease to esophagitis) and with
understanding of the intrinsic mechanisms and neuro‑ the presence of hiatal hernia, and might c­ontribute to
transmitters involved in the control of oesophageal peri‑ oesophageal dysphagia in these patients.94,95
stalsis and LES relaxation.75,76,82 Research into these two
aspects will be critical to understand the pathophysio­ Neuromuscular causes
logy of symptoms of oesophageal dysphagia and develop Achalasia is the best characterised neuromuscular
effective pharmacologic treatments for patients. phenotype of oesophageal dysphagia. The aetiology of
Studies in animal models in the 1990s described achalasia is mostly unknown and has been associated
the characteristics of neural pathways including vagal with several genetic variations and immunological dis‑
and sympathetic spinal oesophageal afferents and the orders that might cause the generation of antibodies to
response of oesophageal mechanosensitive nociceptors enteric neurons.96–98 The cause of initial injury in these

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REVIEWS

Box 1 | Aetiology of oesophageal dysphagia pan-oesophageal pressurization >30 mmHg, minimal

oesophageal dilation and good response to dilation or
Mechanical causes
surgical treatment;101 and type III achalasia (also known
■■ Intrinsic causes: oesophageal rings and webs
(Schatzki ring, Plummer–Vinson, or the Patterson–Kelly as achalasia with distal spasm or ‘vigorous achalasia’) is
syndrome [iron deficiency aneamia and oesophageal associated with high amplitude simultaneous contrac‑
web]); peptic stricture from gastro-oesophageal reflux tions, functional obstruction of the distal oesophagus
or scleroderma; carcinoma (squamous cell cancer and poor response to all therapies.
and adenocarcinoma); others (diverticulae and benign According to the Chicago Classification, major oesoph‑
tumours); post-surgery (laryngeal, oesophageal, gastric ageal motility disorders such as distal oesophageal spasm
cancers, fundoplication)
and hypercontractile oesophagus can cause oesophageal
■■ Extrinsic causes: mediastinal mass (lymph nodes,
thyromegaly, lung cancer); vascular compression
dysphagia in the context of normal oesophagogastric
(enlarged left atrium, aberrant right subclavian artery, junction relaxation. Distal oesophageal spasm is defined
or right-sided aorta); cervical spine osteophytes (spurs) by premature contractions (reduced latency) and spasm
Neuromuscular causes (excessive velocity) affecting a segment or all of the
■■ Achalasia smooth part of the oesophageal body. Hypercontractile
■■ Scleroderma oesophagus (also known as hypertensive peristalsis
■■ Nutcracker oesophagus or classic Nutcracker oesophagus) is characterized by
■■ Diffuse oesophageal spasm normal LES relaxation, normal peristaltic velocity but
■■ Ineffective oesophageal motility disorder increased distal contractility of the oesophageal body; an
■■ Hypertensive lower oesophageal sphincter
extreme phenotype of this disorder is defined as spastic
■■ Others: Chagas disease, paraneoplastic syndrome
Nutcracker or Jackhammer oesophagus.102
Inflammatory causes
■■ Eosinophilic oesophagitis
■■ Radiation oesophagitis Other causes
■■ Caustic injury Other phenotypes of oesophageal dysphagia include a
■■ Pill oesophagitis number of connective tissue diseases. The gastrointes‑
■■ Infectious oesophagitis: candidiasis, herpes simplex, tinal tract is the third most common organ affected by
cytomegalovirus, or HIV-associated oesophagitis systemic sclerosis (scleroderma) after thickening of the
Adapted with permission obtained from Elsevier Ltd. © from skin and Raynaud phenomenon. Oesophageal symptoms
Lawal, A. & Shaker, R. Phys. Med. Rehabil. Clin. N. Am. 19, 729–745
(2008). 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
idiopathic cases is thought to be viral in nature. For with other oesophageal symptoms such as heartburn
example, herpes zoster or the measles virus induces a and regurgitation, in mixed connective tissue disease.104
neurodegenerative process that mainly affects inhibi‑ Idiopathic inflammatory myopathies including der‑
tory but also excitatory enteric motor neurons in the matomositis, polymyositis and inclusion body myositis
oesophageal myenteric plexus and causes loss of peri‑ can also involve the oesophagus and cause impaired
staltic function in the oesophageal body and impaired or absence of peristalsis and also oropharyngeal dys‑
LES relaxation. 99 However, other benign and malig‑ phagia.105,106 Oesophageal dysphagia is uncommon in
nant conditions can present as achalasia (secondary or patients with systemic lupus erythematosus and has
pseudo achalasia) (Box 2). The incidence of achalasia been reported in 1.5–8.0% of these patients.107 Although
ranges from 1.1 to 4 new cases per 100,000 population some reports have estimated more prevalent oesophageal
per year, with a prevalence of 10 cases per 100,000 in symptoms in patients with type 1 diabetes than controls,
Western countries. Incidence increases with age and these reports have not been confirmed by others.108 The
peaks between 25 and 60 years. Familial clusters have most common oesophageal motility abnormality in
been described.100 these patients is ineffective peristalsis.108 Both hypo­
Advances in high resolution manometry have thyroidism and hyperthyroidism can affect oesophageal
improved our understanding of oesophageal motility function; secondary achalasia has been reported in hypo­
disorders, which in turn has resulted in new metrics thyroidism and impaired oesophageal peristalsis has
to assess the extent of LES relaxation and the velocity been described in hyperthyroidism.109,110 Oesophageal
and amplitude of oesophageal peristalsis. New classifi‑ dysmotility has been reported to persist in individuals
cations of oesophageal dysmotility disorders, including with ongoing alcoholism while normalizing in those who
achalasia, have also been developed.101,102 This classifi‑ abstain from alcohol.111,112
cation has been defined as the Chicago Classification Among the inflammatory processes causing oesophageal
and has been periodically revised by the International dysphagia is eosinophilic oesophagitis, which is frequently
GI Motility and Function Working Group.81 Impaired seen in children and is now recognized in adults as a cause
LES relaxation and absent peristalsis in the oesophageal of solid food dysphagia and food impaction.113 >50% of
body are found in all types of achalasia; type I achalasia patients who present with food impaction to the emer‑
is characterized by low intra-oesophageal pressure as a gency room have eosinophilic oesophagitis.114 This dis­
consequence of oesophageal dilation; type II is defined order is characterized by the presence of allergic s­ymptoms,
as achalasia with compression and is characterized by such as atopy, and environmental and food allergies.

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Radiation oesophagitis is another inflammatory Box 2 | Types of achalasia

cause of oesophageal dysphagia, affecting nearly 50%
Idiopathic or primary achalasia
of patients after radiation therapy for thoracic and head
Secondary (pseudoachalasia) achalasia
and neck cancer.115 However, radiation oesophagitis ■■ Chagas disease
might present as delayed radiation fibrosis with impaired ■■ Carcinoma of the gastric cardia
oesophageal peristalsis and impaction. A number of ■■ Paraneoplastic syndrome from malignancy elsewhere
medications, such as tetracycline, quinine, bisphos‑ ■■ Amyloidosis
phonates, potassium chloride and vitamin C can cause ■■ Neuropathic chronic intestinal pseudo-obstruction
inflammation of the oesophagus resulting in oesophageal syndrome
■■ Triple‑A syndrome: achalasia, alacrimia, and no
dysphagia along with pain.
response to adrenocorticotrohpic hormone
Finally, among the benign causes of oesophageal dys‑
■■ Neurodegenerative disorder with Lewy inclusion bodies,
phagia is postoperative dysphagia which is a common Parkinson disease and hereditary cerebella ataxia
complaint after fundoplication for GERD. Transient dys‑ ■■ Anderson–Fabry disease
phagia is common in the initial weeks and month after ■■ Von Recklinghausen neurofirbromatosis
fundoplication, but troublesome long-term dysphagia ■■ Post-vagotomy
occurs in as many as 5% of these patients.116 Adapted with permission obtained from Elsevier Ltd. © from
Lawal, A. & Shaker, R. Phys. Med. Rehabil. Clin. N. Am. 19, 729–745
(2008).
A multidisciplinary approach
Despite marked progress in understanding the physi‑
ology of deglutition and the pathophysiology of swal‑ research and holding congresses and courses, is pro‑
lowing disorders—fuelled by advances in technology viding an important opportunity for the convergence
and the advent of more precise recording techniques— of various contributory fields to develop a professional
patients with dysphagia continue to receive fragmented discipline of deglutology. A deglutologist, whose initial
care and do not benefit from the full spectrum of the and foundational training has derived from diverse
diagnostic and therapeutic modalities in an expeditious, disciplines, will be equipped with the combined multi‑
efficient and cost-effective manner. One can easily trace disciplinary knowledge and skills necessary to address
the source of this shortcoming to the fact that various deglutition disorders in their entirety, providing all the
aspects of this field have evolved within several medical critical pieces of the puzzle that compromises the health
and surgical disciplines, resulting in individual expertise, and QOL of patients with dysphagia.
knowledge and skills with the outcome of an inconsistent
pattern of care for patients with dysphagia. Conclusions
The multidisciplinary nature of the management of Oropharyngeal dysphagia is a highly prevalent, neglected
dysphagia and the varying ways it affects patient pheno‑ disorder with poor prognosis and severe complications.
types has resulted in a piecemeal approach that has hin‑ The burden of this condition is likely to increase given
dered research in this area. Experts in dysphagia come the demographic aging of the population. However,
from widely different backgrounds: from ENT, speech awareness of oropharyngeal dysphagia is growing and
language pathology, rehabilitation medicine, surgery, many professional domains are involved in the man‑
gastroenterology, radiology, neurology, gerontology, agement of these patients. Education about dysphagia
head and neck diseases and paediatrics. Furthermore, should be standardized and made available to health-
dysphagia is not a medical speciality in its own right and care providers. International societies can provide
is frequently omitted from medical curriculums. forums to discuss and disseminate the latest research
There are a few scientific societies specifically dedi‑ at their conferences. Patients have the right to be diag‑
cated to dysphagia and they are characterized by having nosed and receive appropriate treatment for this con‑
members with diverse professional profiles. The oldest dition. Familiarity with methods for clinical screening
society is the DRS (Dysphagia Research Society), which and assessment of swallow function will lead to more
was formed in the USA in 1992.117 The JSDR (Japanese diagnostics. Doctors can improve recognition of the
Society of Dysphagia Rehabilitation) was formed in 1995; condition by including the ICD code in medical reports.
it is the largest society with >10,000 members, 20% of Oropharyngeal dysphagia should be recognized as a
whom are dentists. In 2011, the ESSD (European Society major neurologic and geriatric syndrome and institu‑
for Swallowing Disorders) was formed based on the tions should provide human and material resources to
former European Study Group of Dysphagia and Globus avoid complications. Demographic and health economic
(EGDG). Joint projects and events with European socie‑ studies should also be undertaken to quantify the effect
ties that encompass dysphagia within their fields have of this disorder.
been undertaken to increase awareness, develop guide‑ Research in the past few years and advances in tech‑
lines and consolidate research. The ESSD is also develop‑ nology have provided new insights into the pathophysi‑
ing a multidisciplinary postgraduate university diploma ology of the disease at the central and peripheral levels.
with the aim of offering it in several European countries More clinical and basic research is necessary to increase
in the academic year 2016–2017. knowledge on the specific pathophysiology and natural
The efforts of all these societies in promoting a multi­ history of oropharyngeal dysphagia in each disease. This
disciplinary approach to dysphagia, and encouraging increased understanding will pave the way for specific and

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REVIEWS

evidence-based preventive and therapeutic strategies and To cover all these needs of patients with dysphagia,
new targets for treatments, particularly pharmacological two complementary strategies should be established:
and neurophysiological interventions, moving from com‑ first, the development of well-coordinated multidiscipli‑
pensation to recovery of swallow function. Management nary teams and dysphagia units in hospitals; and second,
of patients at risk should include systematic screening for the development of a new professional profile, the deglu‑
oropharyngeal dysphagia, oral health and malnutrition, tologist, to bring together knowledge and skills from
education on oral hygiene, rheological adaptation for different disciplines to understand the whole swallow
fluids and solid foods, and rehabilitation. In the future, function, from the brain to the neck and oesophageal
research and new products for patients with oropharyn‑ muscles, and to fully cover the diagnostic and therapeutic
geal dysphagia will hopefully yield active treatments for needs of all phenotypes of patients with dysphagia.
impaired swallow response, biological treatments for the
oral microbiota, and integrated products and strategies Review criteria
for oropharyngeal dysphagia and malnutrition.
This is not a systematic review. This is a report to help
Finally, although patients with oesophageal dysphagia readers understand the current reality, state of the art and
are initially better recognized by health-care profession‑ scope of the problem of oropharyngeal and oesophageal
als than those with oropharyngeal dysphagia, the patho‑ dysphagia. The article summarizes the position,
physiology of the symptom is not fully understood in experience, and interpretation of development in this area
many phenotypes of patients; future clinical and basic of the two authors. Articles have been selected according
research is needed to provide specific treatments for to their relevance, impact and scientific or educational
value according to the criteria of the two authors.
oesophageal dysphagia.

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