**4. Local and systemic physiopathological conditions associated to oropharyngeal dysphagia**

A plethora of endogenous and exogenous etiologic factors might disrupt the physiology and anatomical integrity of oral cavity and oropharynx components and, therefore, have an negative affect on salivation, chewing, and swallowing mechanisms. The occurrence of disturbances in these mechanisms play pivotal roles in the occurrence of oropharyngeal dysphagia [1, 5] (Figure 7).

#### **4.1. Age**

**Factors Main characteristics**

food and turn it in small particles;

size of about 3mm).

breakage of food particles;

the food particles for swallowing;

influenced by food characteristics;

consistency;

movements.

⋅ Depends on how well the tongue and cheeks manipulate the food while the teeth crushe the

⋅ Individuals with a high masticatory performance will, on average, swallow finer food particles (median particle size of about 1mm) than subjects with a less high performance (median particle

⋅ Depends of factors such as percent water content, fat percentage, taste, texture, volume, and

⋅ Consistency of food can make the jaw decelerate and accelerate as a result of resistance and

⋅ These characteristics also affect masticatory force, jaw muscle activity, and mandibular jaw

⋅ During chewing cycles, the food particles are reduced in size and consistency. Together, the saliva, due to the presence of water and mucin glycoprotein, facilitates chewing by moistening

⋅ The number of chewing cycles needed to prepare the food for swallowing is importantly

⋅ The number of chewing cycles needed to prepare food before swallowing is rather constant

⋅ Saliva might modify food properties, which may lead to changes in chewing force, mandibular jaw movements, number of chewing cycles to prepare the food for swallowing, and, perhaps,

within an individual for certain foods but varies among different individuals.

⋅ Responsible for mixing of food particles into a bolus that can be swallowed; ⋅ Salivary flow rate is weakly correlated to variation in the swallowing threshold, i.e., individuals with a relatively high salivary flow rate do not necessarily swallow the food after

The process of swallowing includes the voluntary effort to ingest food and an involuntary effort of bolus preparation and transport. During early stages of swallowing, the bolus, which represents food particles bound together under viscous forces determined by components of saliva, is transported from the oral cavity and pharynx to the esophagus [14, 15, 53-55].

Briefly, swallowing mechanisms might be summarized as follows: in the oral cavity, where the initial preparation of swallowing occurs, the food is chewed, moistened, and coalesced. During chewing, the food particles are continuously moved towards the occlusal surface of the teeth through the actions of the tongue and masticatory muscles. A premature spillage of the bolus into the pharynx is avoided by the approach of the soft palate to the tongue that creates a glossopalatal seal, while various movements of the mandible are important for the adequate grinding of the bolus. When the bolus is ready for swallowing, the tongue forms a

fewer chewing cycles compared to a subject with less saliva;

the visual and sound perception of the food.

**Table 3.** Factors related to chewing and mains characteristics.

Performance of food manipulation and trituration

20 Seminars in Dysphagia

Characteristics of the food

Number of chewing cycles until swallowing of food

Salivary flow

**3.3. Swallowing**

The aging process is currently viewed as the result of an accumulation of insults to orofacial structures and function. Dental caries on root surfaces uncovered by gingival tissue, perio‐ dontal disease, tooth loss, oral cancer, infectious diseases (such as oral candidosis), traumatic

**Figure 7.** Schematic representation of the main etiological factors associated with dysfunction in salivation, chewing, and swallowing mechanisms, with promotion of oropharyngeal dysphagia.

lesions (hyperplastic and ulcerations caused by removable prosthodontic appliances), vesiculobullous autoimmune diseases (such as pemphigus vulgaris and cicatricial pemphi‐ goid), and others remain as a constant threat to the maintenance of oral health in older individuals. Although many of these diseases might be promptly prevented, diagnosed and treated, a majority of older persons have encountered significant oral and pharyngeal prob‐ lems that can ultimately have a profound impact on the quality of their lives. Many of these changes are directly connected to problems with genetic and epigenetic susceptibilities, socioeconomic inequalities, health behavior, access to oral health services, and systemic diseases and their treatment rather than the simple passage of time [5, 7, 58-62].

Dysfunctions related to salivary supply may negatively influence the masticatory and swallowing process by making them impossible for individuals to prepare food into a bolus before swallowing adequately. It has been frequently reported that salivation mechanisms seem to be affected with the advancing age. Indeed, mouth dryness (xerostomia) promoted by hyposalivation in older individuals is the most common complaint among the elderly. However, it has been demonstrated that in healthy older individuals there is not a significant alteration in volume and composition of saliva compared to a younger adult. Therefore, hyposalivation in older persons seems to be more associated with age-related diseases, masticatory disturbances, and use of certain therapeutic drugs [36, 63, 64].

Masticatory motor performance function is frequently affected in older individuals, especially those with poor subjective (self-perception of oral health) and normative (decay, periodontal disease, tooth loss) conditions of oral health. Older individuals exhibit a reduced bite which, in turn, determines a higher number of cycles needed to chew a standard piece of food, with increased particle size reduction and longer chewing sequence duration. Due to this, elderly frequently avoid highly textured foods, which are one of the important masticatory muscle activators, and might reduce the salivary flow. Other factors reported to affect masticatory performance in elderly persons include loss and restoration of posterior teeth, number of residual teeth, occlusal force, stimulated salivary flow rate, and oral motor function, which seem to accelerate masticatory dysfunction with ageing. However, it has become increasingly evident that masticatory performance need not decline with age if natural dentition is maintained. Therefore, if tooth loss and hyposalivation are not considered as characteristics of physiological ageing, ageing by itself may not be a risk factor for masticatory dysfunction. With increasing age, maintaining an adequate number of healthy natural teeth is the best guarantee to maintain adequate masticatory ability. Although the loss of teeth may be compensated for by dentures, and the dentures contribute to breaking down of food, it has been noted that prosthetic treatments seem to be unsuccessful for approaching the efficiency of a complete natural dentition, and so, of the masticatory mechanism [49, 65, 66].

Regarding swallowing, older healthy persons do not seem to experience major changes in this mechanism. However, the participation of certain risk factors, such as use of depressor central nervous system drugs or neurological diseases, might increase risk for dysphagia in aged persons. During mastication and swallowing, tongue activity creates a pressure that facilitates the manipulation of food particles and transport of the bolus. Older individuals exhibit a lower isometric swallowing (palate-tongue) pressure compared to younger persons. However, the influence of swallowing changes attributable to age appear to be important only for deglutition of certain types of food with different physical characteristics (consistency, texture). Generally, age does not seem to influence swallowing pressure. Moreover, healthy elderly individual exhibit a higher oral transit time with a prolonged oropharyngeal phase, upper esophageal sphincter relaxation, reduced pharyngolaryngeal sensory discrimination, and a higher threshold to trigger the pharyngeal phase of swallowing [55, 67].

lesions (hyperplastic and ulcerations caused by removable prosthodontic appliances), vesiculobullous autoimmune diseases (such as pemphigus vulgaris and cicatricial pemphi‐ goid), and others remain as a constant threat to the maintenance of oral health in older individuals. Although many of these diseases might be promptly prevented, diagnosed and treated, a majority of older persons have encountered significant oral and pharyngeal prob‐ lems that can ultimately have a profound impact on the quality of their lives. Many of these changes are directly connected to problems with genetic and epigenetic susceptibilities, socioeconomic inequalities, health behavior, access to oral health services, and systemic diseases

**Figure 7.** Schematic representation of the main etiological factors associated with dysfunction in salivation, chewing,

Dysfunctions related to salivary supply may negatively influence the masticatory and swallowing process by making them impossible for individuals to prepare food into a bolus before swallowing adequately. It has been frequently reported that salivation mechanisms seem to be affected with the advancing age. Indeed, mouth dryness (xerostomia) promoted by hyposalivation in older individuals is the most common complaint among the elderly. However, it has been demonstrated that in healthy older individuals there is not a significant

and their treatment rather than the simple passage of time [5, 7, 58-62].

and swallowing mechanisms, with promotion of oropharyngeal dysphagia.

22 Seminars in Dysphagia

A high occurrence of dysphagia in elderly persons has been documented although it is frequently neglected by health professionals and patients themselves. Clinical signs of dysphagia are not specific in geriatric patients and the clinical manifestation of swallowing disorder in these individuals may fluctuate over time, and therefore needs repeated clinical evaluation. In that population, the occurrence of dysphagia has been associated with malnu‐ trition and/or dehydration while compromised safety increases the risk of aspiration pneu‐ monia. With regards to oral health, elderly persons with oropharyngeal dysphagia frequently present with high prevalence of dental caries, periodontal diseases, and edentulism. Moreover, the occurrence of dysphagia in older persons has significant social and psychological conse‐ quences. Other health problems such as modifications of respiration or coughing at mealtime, reduction or refusal of food intake, changes in types of meal texture, recurrent pulmonary infections and unexplained bouts of fever or unintentional weight loss correlate with dyspha‐ gia in older individuals [7, 61, 68].

In this way, many of the pathological conditions that affect salivation, chewing, and swallow‐ ing therefore can cause dysphagia in an older population, but are not an inevitable consequence of advancing age of individuals. Early recognition and appropriate management of dysphagia in elderly patients is pivotal.

### **4.2. Congenital and traumatic anatomic abnormalities**

A series of primary congenital anatomic abnormalities (such as laryngeal, palate and lip clefts, tracheoesophageal fistula, and jaw micrognathia) and traumatic injuries (such as fibrosis of the upper aerodigestive tract mucosa for physical and chemical etiologic factors, and postoperatory insults after surgical procedures) can affect the oral cavity and oropharynx and have been associated with immobility of organs/structures or respiratory difficulty during feeding. These congenital disturbances manifest early in childhood, occurring independently or in combination with other anatomic abnormalities, associated or not with syndromes. Traumatic anatomic abnormalities are typically caused by direct injury. All these types of abnormalities can lead to significant oropharyngeal dysphagia [69, 70].

### **4.3. Medication**

Drugs that directly or indirectly affect the mechanisms of protection of normal oropharyng‐ eal mucosa (antibiotics, cytotoxics/immunossupressors), production of saliva (anxiolytics, anticholinergics/antireflux, anticonvulsants, antidepressants, antihypertensives, antipsychot‐ ics, antihistamines/decongestants, diuretics, and opiates), and chewing (botulinum toxin type A) and swallowing (antipsychotics, antihypertensives, local anesthetic agents) mechanisms may potentiate the development of dysphagia. The dimensions and impact of these side effects vary depending on the response of the individual patient and the duration of medication use [71-73].

#### **4.4. Neurological disorders**

Chewing and swallowing are complex motor tasks characterized by a coordinated and synchronized activation of an afferent system (cortical and subcortical areas and oropharyng‐ eal afferents), the brain stem swallowing center (interneuronal network organizer) and the efferent system (motoneurons). Some cerebrovascular diseases that affect the motor control of the cranio-cervical region may interfere with the appropriate performance of chewing and swallowing mechanisms, which can explain the occurrence of dysphagia. To date, dysphagia is found in about 50% of individuals with dementia and cerebrovascular accident (stroke), 30% with deconditioning, and 90% with Parkinson disease [74].

Dementia is a condition in which there is progressive deterioration in cognition that affects day to day function of patients. All types of neurodegenerative or vascular dementia (vascular, multi-infarct, Lewy body dementia, Alzheimer's disease, and Parkinson's disease), may affect cortical regions involved in chewing and swallowing. Development of deglutition disorders differs with the type of dementia, but most frequently they occur during late stages. The most drastic complication in patients with dementia is the aspiration pneumonia [75]. Alzheimer's disease (AD) represents the most frequent form of dementia. In AD, brain areas underlying swallowing function show early compromise, probably before clinical dysphagia diagnosis. In these patients there occurs a delayed oral transit time due to deficits in the sensory aspects of swallowing. The common reported symptoms in these patients would be pocketing of food in the mouth, difficulties with mastication, coughing or choking with food or fluid, and the need for reminders to swallow food. In Parkinson disease (PD), drooling, persistent food residues, slow transit and repeated tongue movements can be observed during the oral phase. Delayed triggering of the pharyngeal swallow, prolonged opening of the upper esophageal sphincter and vallecular stasis are also reported. In less frequent extrapyramidal disorders (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, and multiple system atrophy), deglutition may be severely impaired even at early stages of the disease [76, 77].

Stroke is a devastating group of neurological diseases responsible for high rates of disabilities and death worldwide. Patients with stroke frequently exhibit a need for artificial feeding and higher length of hospital stay. Swallowing aspiration is reported in up to 50% of patients with stroke, with the major complication being pneumonia, a likely consequence of bacteriainfected secretions or ingested food repeatedly transgressing into the airway. Stroke patients have a worse outcome in terms of mortality and length of hospital stay when dysphagia is present [74, 78].

#### **4.5. Neurodegenerative disorders of the motor system**

quences. Other health problems such as modifications of respiration or coughing at mealtime, reduction or refusal of food intake, changes in types of meal texture, recurrent pulmonary infections and unexplained bouts of fever or unintentional weight loss correlate with dyspha‐

In this way, many of the pathological conditions that affect salivation, chewing, and swallow‐ ing therefore can cause dysphagia in an older population, but are not an inevitable consequence of advancing age of individuals. Early recognition and appropriate management of dysphagia

A series of primary congenital anatomic abnormalities (such as laryngeal, palate and lip clefts, tracheoesophageal fistula, and jaw micrognathia) and traumatic injuries (such as fibrosis of the upper aerodigestive tract mucosa for physical and chemical etiologic factors, and postoperatory insults after surgical procedures) can affect the oral cavity and oropharynx and have been associated with immobility of organs/structures or respiratory difficulty during feeding. These congenital disturbances manifest early in childhood, occurring independently or in combination with other anatomic abnormalities, associated or not with syndromes. Traumatic anatomic abnormalities are typically caused by direct injury. All these types of abnormalities

Drugs that directly or indirectly affect the mechanisms of protection of normal oropharyng‐ eal mucosa (antibiotics, cytotoxics/immunossupressors), production of saliva (anxiolytics, anticholinergics/antireflux, anticonvulsants, antidepressants, antihypertensives, antipsychot‐ ics, antihistamines/decongestants, diuretics, and opiates), and chewing (botulinum toxin type A) and swallowing (antipsychotics, antihypertensives, local anesthetic agents) mechanisms may potentiate the development of dysphagia. The dimensions and impact of these side effects vary depending on the response of the individual patient and the duration

Chewing and swallowing are complex motor tasks characterized by a coordinated and synchronized activation of an afferent system (cortical and subcortical areas and oropharyng‐ eal afferents), the brain stem swallowing center (interneuronal network organizer) and the efferent system (motoneurons). Some cerebrovascular diseases that affect the motor control of the cranio-cervical region may interfere with the appropriate performance of chewing and swallowing mechanisms, which can explain the occurrence of dysphagia. To date, dysphagia is found in about 50% of individuals with dementia and cerebrovascular accident (stroke), 30%

Dementia is a condition in which there is progressive deterioration in cognition that affects day to day function of patients. All types of neurodegenerative or vascular dementia (vascular,

gia in older individuals [7, 61, 68].

24 Seminars in Dysphagia

in elderly patients is pivotal.

**4.3. Medication**

of medication use [71-73].

**4.4. Neurological disorders**

**4.2. Congenital and traumatic anatomic abnormalities**

can lead to significant oropharyngeal dysphagia [69, 70].

with deconditioning, and 90% with Parkinson disease [74].

Muscles need a patent motor innervation to maintain their functionality and trophism. In diseases characterized with progressive degeneration of motor neurons (both higher, cortical, and the brain stem and spinal cord), denervation atrophy occurs with consequent muscle wasting, progressive difficulty in performing movements, and loss of muscle strength. Many neurodegenerative disorders that affect the motor system exhibit a genetic etiology. However, it has been evidenced that immune system disturbances also contribute for development of that group of diseases [79]. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes muscle spasticity and rapidly progressive muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons, which is often asymmetric at least in the early stages. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement. With respect to neuromuscular function occurring in the upper aerodigestive tract, ALS patients usually present with difficulty in speaking, swallowing, and breathing. Up to 30% of patients with ALS present with muscle bulbar (jaw, face, tongue, soft palate, pharynx, and larynx) symp‐ toms, such as dysphagia and dysarthria (poor articulation of phonemes due to neurological injury of the motor component of the motor-speech system) at the onset of the disease, while almost all patients develop such symptoms at later stages of the disease. These patients often lose weight in part because of dysphagia, but also because there is denervation of limb muscles and significant reduction of appendicular muscle mass. Aspiration pneumonia and respiratory difficulties are severe complications of ALS. Bulbospinal muscular atrophy or Kennedy's disease is an X-linked chronic motor neuron disease that also promotes progressive degener‐ ation of bulbar motor neurons. Other chronic motor neuron disorders such as spinal muscular atrophy sometimes affect the muscles of swallowing [80, 81].

#### **4.6. Other muscle disorders**

Dystonia represents an involuntary sustained (tonic) or spasmodic (rapid or clonic) muscle contraction that can occur in various regions of the body producing twisting, repetitive, and patterned movements, or abnormal postures. Its etiology is complex and includes genetic predisposition, peripheral or central nervous system injuries, drug induced or metabolic disturbances, paraneoplastic syndromes, and neurodegenerative or cerebrovascular diseases. Oromandibular dystonia (OD) manifests as focal disturbances on perioral movements performed by masticatory, lower facial, and tongue muscles which may result in trismus, bruxism, involuntary jaw opening or closure, involuntary tongue movement, dysphonia, difficulty with chewing, and dysphagia. OD can manifest alone or in association with other motor control disturbances, such as Meige's syndrome and Brueghel's síndrome [80, 82].

Muscular dystrophies are a group of muscle diseases that have in common a progressive weakening in the musculoskeletal system, defects in muscle proteins, and the death of muscle cells and tissue. Although it has been suggested that this could be caused by environmental factors, the muscular dystrophies are caused by a mutation of the dystrophin gene. Among the muscular dystrophies, oculopharyngeal muscular dystrophy (OMD), myotonic dystrophy (Steinert's disease), and advanced stages of Duchenne muscular dystrophia (DMD) are most commonly associated with dysphagia. Frequently, all phases of swallowing (oral, pharyngeal, and esophageal) are impaired in these disorders. As a consequence, these patients have a delayed onset of swallowing and slowed bolus transit times. Moreover, in these dystrophic diseases, dysphagia occurs as a consequence of a progressive weakness of the tongue, palatal, and pharyngeal muscles. In the onset of OMD, dysphagia is mainly pharyngeal, but the lingual and oral phases are also affected. In DMD, the occurrence of macroglossia complicates the oral phase of swallowing [75, 83, 84].

The primary inflammatory myopathies are polymyositis (generalized and chronic inflamma‐ tory myopathy), dermatomyositis (microangiopathy that affects skin and muscle), and inclusion body myositis (progressive acquired myopathy of late stage and slow progression). They all have in common infiltration of chronic inflammatory cells within muscle tissue and tissue destruction. It has been hypothesized that the presence of specific autoantigen(s) in the muscle tissue initiates the disease, though this has not yet been identified in each disease. These diseases can promote the progressive weakening of the oropharyngeal musculature. Conse‐ quently, dysphagia occurs in about in 60% of patients with primary inflammatory myopathies. Swallowing disorders may be severe in these patients, and complicate significantly any respiratory dysfunction they may have (aspiration, interstitial lung disease, respiratory muscle deficiency). In inclusion body myositis the inflammatory process can promote a prominent cricopharyngeus and inferior constrictor muscles [85, 86].

Myositis ossificans (MO) is a disease that is characterized by non-neoplastic, heterotopic bone formation within a muscle. MO is divided broadly into progressive and traumatic forms. The progressive form of MO is an autosomal dominant disease in which multiple heterotopic ossifications develop in the systemic muscle, fascia, tendons, and ligaments, sometimes within families. Traumatic MO is a disease in which muscles are ossified presumably following acute trauma, burns, surgical manipulation, or repeated injury. When affecting the masticatory muscles, MO exhibits higher frequency of involvement in the masseter, followed by the medial pterygoid, lateral pterygoid, and temporal muscle. In these cases, MO might cause swelling, trismus, pain, and dysphagia [87, 88].

In certain mitochondrial myopathies (Kearns-Sayre disease, chronic progressive external ophthalmoplegia, and mitochondrial myopathy, peripheral neuropathy, gastrointestinal disease, and encephalopathy syndrome), patients present with dysphagia owing to the weakness of the pharyngeal constrictor muscles that, in turn, impairs swallowing mechanisms. Peripheral neuropathy seldom involves the pharyngeal muscles, given the short length of the pharyngeal nerve fibers. However, disorders that are independent of fiber nerve length (Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy) tend to affect the bulbar muscles. In these cases, dysphagia usually involves the pharyngeal phase, but oral manipulation mainly for solid food is also compromised [89, 90].

### **4.7. Autoimmune diseases**

lose weight in part because of dysphagia, but also because there is denervation of limb muscles and significant reduction of appendicular muscle mass. Aspiration pneumonia and respiratory difficulties are severe complications of ALS. Bulbospinal muscular atrophy or Kennedy's disease is an X-linked chronic motor neuron disease that also promotes progressive degener‐ ation of bulbar motor neurons. Other chronic motor neuron disorders such as spinal muscular

Dystonia represents an involuntary sustained (tonic) or spasmodic (rapid or clonic) muscle contraction that can occur in various regions of the body producing twisting, repetitive, and patterned movements, or abnormal postures. Its etiology is complex and includes genetic predisposition, peripheral or central nervous system injuries, drug induced or metabolic disturbances, paraneoplastic syndromes, and neurodegenerative or cerebrovascular diseases. Oromandibular dystonia (OD) manifests as focal disturbances on perioral movements performed by masticatory, lower facial, and tongue muscles which may result in trismus, bruxism, involuntary jaw opening or closure, involuntary tongue movement, dysphonia, difficulty with chewing, and dysphagia. OD can manifest alone or in association with other motor control disturbances, such as Meige's syndrome and Brueghel's síndrome [80, 82].

Muscular dystrophies are a group of muscle diseases that have in common a progressive weakening in the musculoskeletal system, defects in muscle proteins, and the death of muscle cells and tissue. Although it has been suggested that this could be caused by environmental factors, the muscular dystrophies are caused by a mutation of the dystrophin gene. Among the muscular dystrophies, oculopharyngeal muscular dystrophy (OMD), myotonic dystrophy (Steinert's disease), and advanced stages of Duchenne muscular dystrophia (DMD) are most commonly associated with dysphagia. Frequently, all phases of swallowing (oral, pharyngeal, and esophageal) are impaired in these disorders. As a consequence, these patients have a delayed onset of swallowing and slowed bolus transit times. Moreover, in these dystrophic diseases, dysphagia occurs as a consequence of a progressive weakness of the tongue, palatal, and pharyngeal muscles. In the onset of OMD, dysphagia is mainly pharyngeal, but the lingual and oral phases are also affected. In DMD, the occurrence of macroglossia complicates the oral

The primary inflammatory myopathies are polymyositis (generalized and chronic inflamma‐ tory myopathy), dermatomyositis (microangiopathy that affects skin and muscle), and inclusion body myositis (progressive acquired myopathy of late stage and slow progression). They all have in common infiltration of chronic inflammatory cells within muscle tissue and tissue destruction. It has been hypothesized that the presence of specific autoantigen(s) in the muscle tissue initiates the disease, though this has not yet been identified in each disease. These diseases can promote the progressive weakening of the oropharyngeal musculature. Conse‐ quently, dysphagia occurs in about in 60% of patients with primary inflammatory myopathies. Swallowing disorders may be severe in these patients, and complicate significantly any respiratory dysfunction they may have (aspiration, interstitial lung disease, respiratory muscle

atrophy sometimes affect the muscles of swallowing [80, 81].

**4.6. Other muscle disorders**

26 Seminars in Dysphagia

phase of swallowing [75, 83, 84].

The autoimmune diseases represent a broad spectrum of diseases that occur when the immune system turns against components of the body itself, attacking as if it were a foreign molecule. The autoimmune human diseases comprise more than 50 distinct diseases in which oral manifestations are encountered with high frequency, sometimes as the first clinical signs or symptoms of the autoimmune disease [91].

Sjögren's syndrome (SS) is a human chronic autoimmune disorder of the exocrine glands, with a population prevalence of about 0.5% and most commonly found in postmenopausal females. SS may clinically manifest as primary (primary SS, exocrinopathy form) or in the context of underlying connective tissue disease (secondary SS). Secondary SS exhibits connective tissue disorders that can affect the skin, ears, nose and throat, joints, lungs, heart, kidneys, liver, and the neurologic (peripheral and central), haematological, and lymphoproliferative systems [92]. The etiology of SS remains unknown but probably it is multifactorial. Exogenous and endog‐ enous factors (virus infections, stress, and hormonal factors) are thought to trigger chronic inflammation in individuals with a genetic predisposition to the disorder. The initial steps in pathogenesis of SS probably involve disturbances in endothelial, acinar, stromal, and dendritic cells, with consequent upregulation of adhesive proteins that appear to drive the migration and retention of lymphocytes into the gland. The progressive accumulation of lymphocytes is associated with subsequent activation of cytotoxic cells and release of metalloproteinases that are responsible for the tissue destruction [93]. Lesions that affect lacrimal and salivary glands characterize both primary and secondary clinical forms of SS. In the oral cavity, the hallmark of SS is the lymphocytic infiltration of the salivary glands, particularly in the periductal areas, promoting a progressive destruction of the glandular tissues. The development of SS in the salivary gland results in dysfunction in glandular secretion with consequent hyposalivation (xerostomia). SS patients with hyposalivation exhibit loss of the lubricating, buffering, and antimicrobial capacities of saliva with an increased incidence of oral/dental infection, mucosal friability, objective and subjective findings of dryness, irritation, burning sensation, higher difficulty for dry and water bolus swallows, and significantly prolonged pharyngeal transit times as compared to controls. Another important factor that might increase the perception of dysphagia in SS patients is the occurrence of gastrotracheal reflux. Since saliva has high pH that normally neutralizes acid refluxed from the stomach, SS patients can be predisposed not only to gastro-oesophageal reflux but also to reflux into the trachea, which can mimic upper respiratory-tract infection [94, 95].

Major bullous conditions that involve the oral cavity (such as pemphigus vulgaris, cicatricial pemphigoid, bullous pemphigoid, and oral lichen planus) and idiopathic chronic inflamma‐ tory conditions (recurrent aphtous ulcers, Behçet's disease, Crohn's disease, ulcerative colitis, chronic graft-versus-host-disease) clinically manifest as painful and bleeding chronic ulcers in the oral mucosa. These ulcerative alterations may promote adverse affects on taste and smell sensation and impair mastication and swallowing by disrupting the integrity of oral mucosa without specifically affecting the anatomical structures directly related to salivary function and swallowing mechanisms [91].

Myasthenia gravis is an autoimmune disease in which self-antibodies are produced against nicotinic acetylcholine receptors on the neuromuscular junctions that connect the nervous system to the muscular system. This results in modification of the synaptic cleft and destruction of the postsynaptic neuromuscular membrane. In this way, myasthenia gravis is also consid‐ ered a disorder of the neuromuscular junction [96]. Patients with this disease frequently exhibit fatigable muscle weakness that is clinically the hallmark of this disease. The clinical severity ranges from mild, purely ocular forms to severe generalized weakness and respiratory failure. Progressive destruction of neuromuscular junctions in muscles involved in masticatory swallowing mechanisms leads to disordered oral, masticatory, and pharyngeal phases, with consequent dysphagia. Clinically, due to progressive muscle weakness promoted by the disease, patients present with problems with manipulation and transport of food, whereas others have difficulties restricted to the pharyngeal phase. Some patients have greater problems with chewing food or moving it in their mouth, whereas others have difficulties restricted to the pharyngeal phase. About one third of myasthenia gravis patients with dysphagia aspirate food particles [97, 98].

#### **4.8. Cysts and primary neoplasms in the head and neck**

The initial dysphagia associated with hyperplastic and neoplastic lesions located on the upper aerodigestive tract mucosa is attributed to the combination of disrupted normal anatomy secondary to exophytic or infiltrative nature of the tumor growth, along with any muscle, vascular, and nerve involvements, soft tissue tethering, or tumor induced pain. In this way, the presence and development of hyperplastic lesions, large cysts and benign or malignant tumors might potentially promote disturbances in salivation (adenomas, adenocarcinomas, and carcinomas of the major salivary glands), chewing (large cysts, or benign or malignant tumors that occur in the jaws or in soft tissues of the oral cavity and oropharynx, such as dentigerous cysts, ameloblastomas, and infiltrative carcinomas), as well as swallowing mechanisms. Dysphagia also can occur in these patients as a consequence of therapeutics [70].

#### **4.9. Treatment of the upper aerodigestive tract cancer**

of SS is the lymphocytic infiltration of the salivary glands, particularly in the periductal areas, promoting a progressive destruction of the glandular tissues. The development of SS in the salivary gland results in dysfunction in glandular secretion with consequent hyposalivation (xerostomia). SS patients with hyposalivation exhibit loss of the lubricating, buffering, and antimicrobial capacities of saliva with an increased incidence of oral/dental infection, mucosal friability, objective and subjective findings of dryness, irritation, burning sensation, higher difficulty for dry and water bolus swallows, and significantly prolonged pharyngeal transit times as compared to controls. Another important factor that might increase the perception of dysphagia in SS patients is the occurrence of gastrotracheal reflux. Since saliva has high pH that normally neutralizes acid refluxed from the stomach, SS patients can be predisposed not only to gastro-oesophageal reflux but also to reflux into the trachea, which can mimic upper

Major bullous conditions that involve the oral cavity (such as pemphigus vulgaris, cicatricial pemphigoid, bullous pemphigoid, and oral lichen planus) and idiopathic chronic inflamma‐ tory conditions (recurrent aphtous ulcers, Behçet's disease, Crohn's disease, ulcerative colitis, chronic graft-versus-host-disease) clinically manifest as painful and bleeding chronic ulcers in the oral mucosa. These ulcerative alterations may promote adverse affects on taste and smell sensation and impair mastication and swallowing by disrupting the integrity of oral mucosa without specifically affecting the anatomical structures directly related to salivary function

Myasthenia gravis is an autoimmune disease in which self-antibodies are produced against nicotinic acetylcholine receptors on the neuromuscular junctions that connect the nervous system to the muscular system. This results in modification of the synaptic cleft and destruction of the postsynaptic neuromuscular membrane. In this way, myasthenia gravis is also consid‐ ered a disorder of the neuromuscular junction [96]. Patients with this disease frequently exhibit fatigable muscle weakness that is clinically the hallmark of this disease. The clinical severity ranges from mild, purely ocular forms to severe generalized weakness and respiratory failure. Progressive destruction of neuromuscular junctions in muscles involved in masticatory swallowing mechanisms leads to disordered oral, masticatory, and pharyngeal phases, with consequent dysphagia. Clinically, due to progressive muscle weakness promoted by the disease, patients present with problems with manipulation and transport of food, whereas others have difficulties restricted to the pharyngeal phase. Some patients have greater problems with chewing food or moving it in their mouth, whereas others have difficulties restricted to the pharyngeal phase. About one third of myasthenia gravis patients with

The initial dysphagia associated with hyperplastic and neoplastic lesions located on the upper aerodigestive tract mucosa is attributed to the combination of disrupted normal anatomy secondary to exophytic or infiltrative nature of the tumor growth, along with any muscle, vascular, and nerve involvements, soft tissue tethering, or tumor induced pain. In this way, the presence and development of hyperplastic lesions, large cysts and benign or malignant

respiratory-tract infection [94, 95].

28 Seminars in Dysphagia

and swallowing mechanisms [91].

dysphagia aspirate food particles [97, 98].

**4.8. Cysts and primary neoplasms in the head and neck**

Upper aerodigestive tract cancer (UADTC), also known as head and neck cancer, represents a broad term, which encompasses a group of human malignancies that arise in the epithelial lining of the upper aerodigestive tract mucosa. Approximately 90% of UADC are diagnosed as squamous cell carcinoma and it represents the sixth most common type of human cancer, and is responsible for high morbidity and mortality rates worldwide every year. A plethora of socio-demographical, economic, and cultural factors associated with a background of genetic and epigenetic molecular disturbances are pivotal to progression of UADTC [99-102].

All UADTC patients will undergo surgery, chemotherapy, radiotherapy, or a combination of any of these three therapeutic modalities. The choice of modality is dependent on patient and tumor variables (presence of physical disabilities of patients, clinical stage, primary site, type, and resectability of tumor). Patients presenting with early-stage malignancy can be managed by curative surgery or radiotherapy. Frequently, patients diagnosed with a late stage tumor might be treated with complete surgical excision followed by post-operative radiotherapy or with concomitant chemoradiotherapy. The uses of organ-sparing treatments have been recommended in recent years; however, they have not necessarily translated into functional preservation of head and neck tissues. Dysphagia is recognized as a potentially devastating UADC post-treatment complication, occurring in up to 50% of UADTC survivors. The most significant consequences of dysphagia in UADTC patients are alteration of the sense of taste (dysgeusia), xerostomia, malnutrition, dehydration, weight loss, reduced functional abilities, fear of eating and drinking socially, anxiety, depression, reduced quality of life, and food aspiration [103].

During reconstruction or surgical procedures for treatment of tumors located in the head and neck (enucleation of primary tumor, tracheostomy, endoscopic laser surgery on the larynx, partial/supraglottic/supracricoid/total laryngectomy, hypopharyngeal surgery and skull base surgeries), notably for malignant tumors in late stages, the structure and function of specific cranial nerves (CN V, VII, IX, X, XII) or other specific anatomic structures related to salivation, chewing, and swallowing mechanisms are often affected and, therefore, patients might present with site-specific patterns of dysphagia. Surgical resection can have devastating effects on swallowing. When surgical resection extends beyond the tongue to laryngeal or pharyngeal structures the patients may never be functional oral eaters and always have dysphagia [104, 105].

Radiation therapy disrupts cell division in healthy tissue as well as in tumors and also affects the normal structure and function of upper aerodigestive tract tissues, including the oral and pharyngeal mucosa, salivary glands and bones. Frequent and distressing acute and chronic side-effects might occur in UADTC patients during and after radiotherapy. Acute side-effects of radiotherapy are mucositis, xerostomia, dysphagia, hoarseness, erythema and desquama‐ tion of the skin (dermatitis). Other late complications that frequently are observed in radio‐ therapy post-treatment are dental decay, trismus, hypogeusia, subcutaneous fibrosis, thyroid dysfunction, esophageal stenosis, hoarseness, damage to the middle or inner ear, and osteor‐ adionecrosis (infection in a hypovascularized tissue with consequent tissue destruction). These post-radiotherapy sequelae are dependent on radiation field, radiation dose, use of antixerostomic medication, and post-radiotherapy time. In xerostomic patients, irreversible damage can occur to the salivary glands, resulting in dramatic hyposalivation and increases in oral and systemic infections. Moreover, oral mucositis induced by radiation therapy frequently occurs, leading to painful oral ulcerations and local and systemic infection. In patients treated with high dose radiation, swallowing can be affected several years after treatment due to a series of complications such as fixation of the hyolaryngeal complex, reduced range of tongue motion, reduced glottic closure, and cricopharyngeal relaxation, resulting in the potential for aspiration. Irradiated patients have longer oral transit times, increased pharyngeal residue, and reduced cricopharyngeal opening times [106].

Concurrent chemoradiation was introduced to improve prognosis of UADTC patients by increase the tumor cell killing with chemotherapy, which also acts as a radiosensitizer. However, although inoperable tumors showed a better prognosis, the toxicity of the two modalities combined resulted in more significant side-effects. Various side-effects like nausea, vomiting, mucositis induced by chemotherapy, dysphagia, neutropenia, and generalized weakness might occur. The anti-metabolites such as methotrexate and 5-fluorouracil are the cytotoxic agents most commonly associated with oropharyngeal and esophageal dysphagia. Chemotherapeutic agents can impact the ability of UADTC patients to swallow. Severe dysfunction of the base of the tongue, larynx and pharyngeal muscles are observed after chemoradiation, leading to stasis of the bolus, vallecular residue, dysmotility of the epiglottis, and food aspiration [106-108].
