CHAPTER 5

PATHOPHYSIOLOGY

Dysfunction of the tubal system plays an important role in the pathogenesis of middle-ear disease; however, other factors are involved because the pathogenesis and etiology are multifactorial and include genetic, infectious, immunologic, allergic, environmental, and social factors (as discussed in Chapter 1, “Introduction and Overview,” see Figure 1–7). A functionally and structurally immature ET and an immature immune system are probably the most important factors related to the increased incidence of otitis media in infants and young children. Human infants are born about 12 months too early compared with our immediate mammalian ancestors.¹ A genetic predisposition is also critical in many infants and children.^2,3 When they are exposed to upper respiratory tract infections, otitis media is a common complication.

As demonstrated in intranasal viral challenge studies in adults in our department (described in detail in Chapter 6, “Pathogenesis”), the pathogenesis of otitis media has the following sequence of events in adults and children^4,5: the patient has an upper respiratory tract viral infection resulting in congestion of the respiratory mucosa of the nose, nasopharynx, and ET. Congestion (edema) of the mucosa in the tube obstructs the narrowest portion, the isthmus. This obstruction causes negative middle-ear pressure followed by a middle-ear effusion, but the susceptibility to develop this sequence of events is related to the individual’s underlying ET function; those whose tubes are dysfunctional are more likely to develop middle-ear underpressures and effusion than those whose function is basically normal.^4,6 The mucosal secretions of the middle ear have no way out and accumulate there; clearance is impaired. If the effusion is relatively asymptomatic (without the signs and symptoms of acute infection), it is termed otitis media with effusion. However, during an upper respiratory infection, the viruses causing the primary infection and the potentially pathogenic bacteria that colonize the nasopharynx can be refluxed, aspirated, or insufflated into the middle ear through the ET and cause an acute otitis media. Because the middle ear has negative pressure, aspiration of nasopharyngeal organisms into the middle ear is most likely. Also, the inflammation can progress distally in the mucosa of the tube and into the middle ear. Acute otitis media is characterized by the signs and symptoms of acute infection: fever and otalgia.⁴ Patients with recurrent episodes of acute otitis media and recurrent and chronic otitis media with effusion, preexisting pathophysiology of the ET appears to be one of the most important factors, especially in infants and children.

My colleagues and I initially described some of the concepts related to the pathologic mechanisms of the ET many years ago but have refined these pathophysiologic factors over the past 40 years.^7,8 The pathophysiology of the tubal system can be summarized as follows: the tube will not open; the tube is too closed, too floppy, too open, too short, or too stiff; or at either end of the ET, the system is either too closed or too open, or there is abnormal pressure at either end. (Figure 5–1).⁹ More precisely, the pathophysiology can be classified into

       •    impairment of pressure regulation

       •    loss of protective function

       •    impairment of clearance

Figure 5–2 depicts some of the types of ET dysfunction, which are described in detail in subsequent sections. Table 5–1 provides the classification of the pathophysiology (or dysfunction) of the tubal system.

TABLE 5–1.  Classification of Pathophysiology (Dysfunction) of the ET System

Impairment of Pressure Regulation

The pressure regulation function of the ET for the middle-ear–mastoid cells can be impaired by

       •    Anatomic obstruction of the ET system—the system is too closed

       •    Failure of the opening mechanism of the ET—the tube does not open

       •    As described subsequently, the tube constricts during swallowing as opposed to dilating and opening

Anatomic Obstruction

The tube can be anatomically (mechanically) obstructed in the cartilaginous or osseous portions of the tube or at either end of the system, regardless of the status of the structure and function of the ET itself (obstruction of the middle ear or nasopharynx).

Obstruction of the ET

When an anatomic obstruction involves the tube, it can be

       •    Intraluminal (intramural)

       •    Periluminal (mural)

       •    Peritubal (extramural)—the tube is too closed

Obstruction of the lumen or within the periluminal tissues (intrinsic obstruction) can be due to inflammation secondary to infection (viral, bacterial)^6,10,11 or allergy.¹² Congenital or acquired stenosis of the tube has also been diagnosed in adults but is a rare finding in children.¹³ Peritubal (extramural) obstruction of the cartilaginous portion of the tube (extrinsic obstruction) can be the result of compression caused by a tumor^14–16 or an adenoid mass.^17–21 Figure 5–3 shows a computed tomographic scan in which congenital cholesteatomas in the base of the skull anatomically (extrinsically, extramurally) obstructed the ET, which caused long-standing chronic otitis media with effusion.

Obstruction at Either End of the System

At either end of the tubal system, anatomic obstruction may be present even when the tube itself functions normally. Obstruction at the middle-ear end of the tube (i.e., the system at the distal end of the ET is too closed) may be due to acute or chronic inflammation of the mucosal lining and may also be associated with polyps or a cholesteatoma. A congenital cholesteatoma—not secondary to tubal dysfunction—can obstruct the middle-ear end (osseous portion) of the tube in the face of a normally functioning cartilaginous portion. Likewise, at the proximal end of the system—in the nasopharynx—the tubal orifice can be anatomically obstructed even when the ET itself is patent and functions normally. This can be due to a variety of etiologies, including adenoids, a foreign body (e.g., packing), or a tumor; the nasopharynx is too closed.

Failure of the Opening Mechanism (Functional Obstruction)

One of the most common types of ET dysfunction is when the lumen of the cartilaginous portion of the tube fails to open during swallowing activity (i.e., the tube will not open). This may be due to

       •    Persistent collapse of the ET due to increased tubal compliance (e.g., lack of stiffness or the tube is too floppy)

       •    An inefficient active opening mechanism

       •    Both defects coexist

This has also been termed functional obstruction; the tube is not anatomically obstructed but is functionally obstructed. This was first described in infants with unrepaired palatal clefts who had had chronic otitis media with effusion (see Dysfunction Related to Cleft Palate).²² Failure of the opening mechanism of the tube is common in infants and younger children without a cleft palate or a history of middle-ear disease but is more common in children with middle-ear disease.^23–28 We demonstrated that inactivation of the tensor, by either transection or expunging the belly through the palate²⁹ or injecting botulinum toxin into the muscle, will inactivate the opening mechanism and result in middle-ear underpressures and effusion. Even though tumor usually anatomically obstructs the tube, as described previously, tumor that inactivates the tensor veli palatini muscle can also cause functional tubal obstruction owing to failure of the active opening mechanism (see Chapter 7, “Pathology”).³⁰

Floppy ET Cartilage

The tube’s failure to open can be caused by persistent collapse of the tubal cartilage because there is less cartilage in infants than in older children and adults. Cartilage cell density changes with advancing age can affect the stiffness of the tubal cartilage in the infant and young child.^31,32 If the tubal cartilage lacks stiffness (or the tube is too floppy), the lumen may not open when the tensor veli palatini muscle contracts. Also, the density of elastin in the cartilage is less in the infant, and Ostmann’s fat pad is less in volume in the infant than in the adult (see Chapter 3, “Anatomy”).^33,34 Figure 5–4 graphically depicts the theory that if the ET cartilage is floppy in children, it will collapse into the lumen when the tensor veli palatini contracts. But, to date, experimental confirmation of this hypothesis is lacking. Low and colleagues studied patients who had nasopharyngeal carcinoma with the aid of magnetic resonance imaging to determine if the cartilage of the tube was eroded and concluded that in some patients, tubal compliance was altered by extension of the tumor into the cartilage.³⁵

Inefficient Tensor Veli Palatini

Also, failure of the ET’s opening mechanism may be due to an inefficient tensor veli palatini muscle, which is related to the effect of age on the craniofacial base. The angle of a child’s tube is different from that of the adult. In the adult, the tube is approximately 45 degrees related to the horizontal plane. In infants, this inclination is only 10 degrees.³⁶ Some think that this difference in the angle is related to possible clearance problems in children, but this hypothesis has not been confirmed. What is more likely is that this difference in angulation affects the function of the active opening mechanism (tensor veli palatini muscle contraction). Swarts and Rood found that the angular relationship between the tensor veli palatini muscle and the cartilage varies in the infant but is relatively stable in the adult (see Chapter 3).³⁷ Dinc and colleagues (2015) found the tube be more horizontal and shorter (though significance was lacking) which could be related to the etiology in the development of chronic suppurative otitis media.³⁸ Also, the tensor veli palatini muscle can be inactivated, by tumor or surgery, in the palate or skull base, resulting in functional obstruction.^39,40

Abnormal Pressures at Either End of the System

Another pathogenic mechanism whereby the ET can be functionally obstructed is when sudden high negative pressure develops at either end of the tubal system. This is graphically demonstrated by the flask model (see Chapter 4, “Physiology,” Figure 4–11). One of the major differences between a flask with a rigid neck and a biologic tube, such as the ET, is that the cartilaginous portion of the human tube is compliant. The effect of applied negative pressure in a flask with a compliant neck is shown in Figure 5–5. Flow of fluid—shown as a liquid for graphic purposes—through the neck does not occur until negative pressure is slowly applied to the bottom of the flask. When the negative pressure within the middle-ear pressure is gradual, such as occurs during a viral upper respiratory tract infection, equilibration of a slowly developing middle-ear underpressure can be accomplished during swallowing; however, if the negative pressure is applied suddenly, temporary locking of the compliant neck prevents the liquid (air) from flowing. This is called the locking phenomenon of the tube (active muscle dilation by swallowing is impaired).⁴¹ Therefore, the speed with which the negative pressure is applied and the compliance in the cartilaginous portion of the tube are critical factors in whether the tubal lumen becomes severely functionally obstructed. This phenomenon can occur during unphysiologic activities when there are rapid alterations in atmospheric pressure, such as descent in an airplane, during diving in water (especially scuba), or during hyperbaric treatment in a pressure chamber (see Swimming, Diving, and Air Flight). Also, locking of the ET can occur during testing of the pressure-regulating function of the tube (see Chapter 8, “Diagnosis and Tests of Function”). Humans did not evolve with the capability of opening the tube following sudden application of negative pressure when engaging in these unphysiologic activities.

Abnormal negative pressures at the nasopharyngeal end of the ET might also prevent physiologic opening of the tube, such as during habitual thumb sucking with the nose obstructed,⁴² sucking on a pacifier (Figure 5–6), or closed-nose swallowing, which I have termed the Toynbee phenomenon (see Toynbee Phenomenon). It has been suggested by some investigators that habitual sniffing can cause abnormal nasopharyngeal negative pressures that can adversely affect the tube and even cause middle-ear disease. They postulated abnormal tubal patency and poor active opening function as possible predisposing factors.⁴³ Also, middle-ear underpressures have been recorded in infants during bottle feeding, with conventional nonventilated bottles, which was presumably due to high negative nasopharyngeal pressures generated during the feeding.⁴⁴

As shown in Figure 5–7, a floppy tube would not only be more susceptible to collapsing (or sucking in) owing to negative pressure than a tube that is stiff, but a highly compliant (floppy) tube would also be more likely to distend than a stiff tube. This latter mechanism may be related to crying in the infant because the tube is floppy in babies. It is a common to (hear) infants crying during descent in an airplane, which is most likely a compensatory mechanism to insufflate air into the middle ear. Probably all infants have some degree of dysfunction of active muscular opening of the tube, especially when attempting to equilibrate negative middle-ear pressure in an airplane during descent (see Swimming, Diving, and Air Flight). It is not uncommon to examine the tympanic membrane of an infant who is crying and, on pneumatic otoscopy, visualize a bulging (with gas) tympanic membrane. This observation has been documented by tympanometry; the positive middle-ear pressure can last for an abnormal amount of time because infants have difficulty equalizing positive, as well as negative, middle-ear pressures. In contrast to infants with an intact palate, infants with an unrepaired cleft palate are less likely to be able to insufflate nasopharyngeal air into the middle ear because the palate is open (i.e., the system is too open) at the proximal end of the tube. Thus, infants with a cleft palate are most likely unable to insufflate air into the middle ear as a compensatory mechanism in the face of poor ET function. In the studies of tubal function in infants with an unrepaired cleft palate, using fluoroscopy and radiopaque dye instilled into the nose, no dye was visualized entering the pharyngeal end of ET, even when the nose was pinched off. By contrast, infants with a normal palate had insufflation of the contrast media into the tube, and in some infants, dye was forced into the middle ear when the nose was pinched off (see Dysfunction Related to Cleft Palate and Chapter 8). Abnormal pressures at either end can also be related to loss of the protective function, as described subsequently.

Constriction of the Eustachian Tube during Swallowing

Our group reported a very significant finding after testing the function of the tube in older children, adolescents, and adults who had otitis media when compared with normal individuals: the ET constricted during swallowing.⁴⁵ Table 5–2 summarizes the outcome of this study and our other investigations in humans showing that constriction of the tube occurs in individuals with otitis media and not normal (control) subjects without middle-ear disease.^46–51 Figure 5–8 compares normal tubal dilation on swallowing with abnormal tubal constriction.

TABLE 5–2.  ET Function Test Results Related to Tubal Constriction in Humans

Adapted from Bluestone CD.⁴⁵

AOM = acute otitis media; CP = cleft palate; ND = not done; OME = otitis media with effusion.

In our laboratory, experiments in the monkey model of ET dysfunction and otitis media showed similar findings in some models but not others. In the monkey models, tubal dysfunction when the tensor veli palatini muscle was severed was characterized by paradoxical constriction of the tube during swallowing activity as opposed to dilation; however, animals that had botulinum injected into the tensor muscle also developed the sequence of events that led to the accumulation of a middle-ear effusion, but they did not exhibit constriction. Table 5–3 summarizes the outcomes of experiments in the monkey.^{29,46,47,52–58}

The underlying cause of constriction of the ET during swallowing is uncertain at present but may be related to abnormalities in the muscles of the tube (levator palatini, tensor veli palatini, or tubal cartilage support). These findings are a current research direction in the laboratory. It is hoped that possible interventions can be developed to prevent this abnormal function and possibly prevent otitis media (see Chapter 11, “Future Directions”).

Loss of Protective Function

The system is also too open at the pharyngeal end when there is an open cleft palate; not only is the proximal end of the tube exposed to the oropharyngeal contents during swallowing, but nasopharyngeal pressures are altered (see Dysfunction Related to Cleft Palate). Each of these pathophysiologic characteristics is described in detail subsequently.

Abnormally Patent ET

The lumen of the ET can be abnormally open, and in the extreme, it is open even at rest. This is called an abnormally patent, or patulous, tube; it is too open. Lesser degrees of abnormal patency result in a semipatulous tube that is closed at rest but with a lumen that has low resistance to the flow of gas or liquids compared with the normal tube.⁵⁹ Increased patency of the tube may be due to abnormal tubal geometry or to a decrease in the peritubal pressure that can occur after weight loss or as a result of periluminal factors.⁶⁰

TABLE 5–3.  Outcomes Following Surgical and Nonsurgical Procedures on the Paratubal Muscles of the ET Related to Tubal Constriction in Monkeys

Adapted from Bluestone CD.⁴⁵

The flask model is illustrative of the loss of the protective function of the ET when the tubal lumen is too open. As shown in Chapter 4 (see Figure 4–11), liquid flow increases as the radius of the narrow neck of the flask increases, to the fourth power. As shown in Figure 5–9, when compared with a flask with a narrow neck, reflux of liquid into the body of the flask occurs if the neck is excessively wide. This is analogous to an abnormally patent human tube in which there is free flow of air and nasopharyngeal secretions from the nasopharynx into the middle ear. The result is reflux otitis media. Another important difference between the flask model and the ET is that the narrowest portion of the human tube, the isthmus, aids in prevention of liquid flow into the middle ear, assuming that the isthmus portion is not floppy. Also as described later, liquid (nasopharyngeal secretions) will more likely be aspirated or insufflated into the middle ear if the lumen of the tube is abnormally wide.

The tube may be abnormally patent even when the caliber of the lumen appears to be normal when collapsed at rest. It can also be functionally hyperpatent, making it less protective of the middle ear. Because the cartilaginous portion of the ET is distensible (compliant), fluid (gas or liquid) can be forced into the middle ear by abnormally high positive nasopharyngeal pressure, which can occur during nose blowing, with the Valsalva maneuver, or during closed-nose swallowing (the Toynbee phenomenon) (see Toynbee Phenomenon). The ability to insufflate the middle ear during these activities depends on the amount of positive pressure developed in the nasopharynx and the degree of compliance (lack of stiffness) of the tube. Because the tube has been found to be highly compliant (the tube is too floppy) in infants and young children, this increase in distensibility of the tube may result in abnormal patency, especially when there is high nasopharyngeal pressure, possibly during crying (see Figure 5–9). A highly distensible tube can easily permit nasopharyngeal secretions to be insufflated into the middle ear, as radiographic studies in infants with middle-ear disease have demonstrated.^22,23 Figure 5–10 shows a radiograph obtained in a child who had recurrent acute otitis media, in which radiopaque contrast material was insufflated into the middle ear during swallowing while the nose was pinched closed. High intranasal and nasopharyngeal positive pressure forced the dye into the highly compliant (floppy) ET and into the middle ear. This abnormal finding did not occur in children without otitis media, especially older children.

The flask model is used to illustrate this phenomenon when the neck of the flask is rigid; liquid is insufflated into the bulbous portion of the flask when positive pressure is applied at the mouth of the flask (Figure 5–11). But if the narrow portion of the flask’s neck is compliant, making it more consistent with the human tube, applying positive pressure at the mouth of a flask will distend the neck and enhance fluid—gas and liquid—flow into the vessel. Thus, less positive pressure is needed to insufflate liquid into the vessel if the neck is floppy. In humans, insufflating nasopharyngeal secretions into the middle ear occurs more readily if the ET is abnormally distensible (has increased compliance or is floppy).

Patulous Eustachian Tube

The patulous tube has been found to be too stiff in teenagers and adults when compared with normal individuals whose tubal compliance was assumed to be normal.⁶¹ This has recently been shown to be associated with chronic middle-ear inflammation.⁶² A patulous ET is too open and usually permits gas to flow readily from the nasopharynx into the middle ear, effectively regulating middle-ear pressure⁶³; however, unwanted secretions from the nasopharynx can more readily gain access (reflux or be insufflated) to the middle ear when the tube is abnormally patent. Figure 5–12 is a comparison between the normally functioning tube and one that is patulous.

Certain special populations have been found to have an ET that is too open, including Native Americans and patients who have Down syndrome and middle-ear disease.^51,64 Chronic suppurative otitis media is a common disease in certain special populations around the world, including Australian Aborigines, North American Inuits, and Native Americans.⁶⁵ Also, a patulous ET has been found in patients following bariatric surgery, complicating gastric bypass and after acute weight loss.^66–68 Failure of the ET’s passive closing mechanism (the tube is too open) has been postulated to be related to sniff-induced middle-ear disease (see Other Causes of Eustachian Tube Dysfunction).⁶⁹

Short Tube

The ET that is too short may lose its protective function, such as in all infants and young children and in certain special populations.

Infants and Young Children

Because one of the most important structural differences of the tube between infants and young children and older children and adults is the length of the tube, this developmental difference can contribute to the high incidence of otitis media in infants and young children. The tube is shorter in children below age 7 years (the tube is too short) (see Chapter 3, Table 3–2).³¹ The effect of a short ET is graphically illustrated in Figure 5–13. A flask with a short neck would not be as protective as a flask with a long neck. Accordingly, the tube that is too short is more likely to reflux secretions from the nasopharynx into the middle ear than a tube that is longer. As the length of the tube (neck) shortens, flow increases proportionally. Because infants have a shorter ET than adults, reflux is more likely in the baby. (An analogy can be made to the length of the urethra: women of all ages have more urinary tract infections than men because the urethra is shorter in the female.) A tube that is too short can be included in the classification of being too open because secretions from the nasopharynx can more easily enter the middle ear than when a tube is of normal length.

From our laboratory using a pressure chamber, 6-year-old children with a history of middle-ear disease had abnormal ET function when compared to children without otitis media.⁷⁰

Special Populations

Certain special populations may also have shorter tubes than other groups. Infants and young children with a cleft palate have tubes that are statistically shorter than age-matched controls below age 6 years (see Chapter 7, Table 7–1). The tube is also shorter in children with Down syndrome.³¹ The shorter the tube, the more likely it is that secretions can reflux into the middle ear in these children. This may be one explanation for the frequent occurrence of troublesome otorrhea in infants and young children, especially those with a cleft palate and Down syndrome when the tympanic membrane is not intact (i.e., there is a perforation or a tympanostomy tube is in place). Cranial anatomy may also play a role in the length of the ET. Todd has postulated from studies in cadavers that the longer the cranial base, the longer the tube, resulting in less middle-ear disease.⁷¹

Abnormal Gas Pressures at Either End of the System

A loss of the tube’s protective function can also occur when abnormal pressures develop at either end of the ET system.

Middle Ear–Mastoid Gas-Cell System

At the distal end of the system, high negative middle-ear pressure, secondary to obstruction of the tube that is anatomic (common during a viral upper respiratory tract infection), due to a failure of active opening (functional obstruction), or both may develop and result in aspiration of nasopharyngeal secretions into the middle ear. Figure 5–14 shows how aspiration can occur in the flask model when negative pressure is within the bulbous portion of the flask. In the study that involved an adult volunteer who had an intranasal inoculation of a respiratory virus, the sequence of events from nasal congestion, tubal dysfunction with middle-ear negative pressure, and then development of an acute otitis media occurred extremely rapidly after the onset of the viral upper respiratory tract infection. The rapid progression of these findings infers aspiration of the viral and bacterial pathogens; both were isolated by tympanocentesis.⁴ A chinchilla model of this process has been established (W. J. Doyle, unpublished data, 1989). Although not related to loss of the ET’s protective function, transudation of fluid into the middle ear and mastoid can also occur when high negative pressure is present, which can result in otitis media with effusion, that is, the hydrops ex vacuo theory (see Chapter 6).^11,72

Nasopharynx

A loss of the tube’s protective function can also occur when high positive nasopharyngeal pressures develop at the proximal end of the ET system. This abnormally high pressure—from blowing the nose, crying in the infant (see Chapter 4, Figure 4–7), or when nasal or nasopharyngeal obstruction is present—can cause nasopharyngeal secretions to be insufflated into the middle ear (see Figure 5–10). An animal model has been developed in which high positive nasopharyngeal pressure produced by Politzer’s technique can insufflate nasopharyngeal liquids into the middle ear (W. J. Doyle, unpublished data, 1990). Rapid alterations in ambient pressures, which can occur during swimming, diving, airplane flying, and hyperbaric pressure treatments, can also result in aspiration or insufflation of nasopharyngeal secretions (see Swimming, Diving, and Air Flight).

TOYNBEE PHENOMENON   The assessment of middle-ear pressures when swallowing while the nose is pinched off is a test of ET function called the Toynbee test.⁷³ Although a rather crude test of tubal function, the results can be helpful, and even more informative, than the Valsalva maneuver or Politizer’s tests. When performing the Toynbee test, the middle-ear pressures developed are either positive, negative, or both (see Chapter 8). But closed-nose swallowing can also occur when there is obstruction in the nose or nasopharynx. Swallowing when the nasal cavities, nasopharynx, or both are obstructed (owing to inflammation or enlarged adenoids) results in an initial positive nasopharyngeal gas pressure followed by a negative pressure phase (Figure 5–15). These pressures are produced in the meso- and hypopharynx during swallowing activity and are reflected in the nasopharynx during closed-nose swallowing. When the tube is pliant, positive nasopharyngeal pressure might insufflate infected secretions into the middle ear, especially when the middle ear has high negative pressure. With negative nasopharyngeal pressure, a pliant tube could be prevented from opening and could be further obstructed functionally. I originally suggested that the effect of swallowing when the nose or nasopharynx is obstructed could be related to ET dysfunction or middle-ear disease and coined the termed Toynbee phenomenon.²⁴ Other investigators have subsequently confirmed that this phenomenon exists.^74–76 Nasal packing has also been identified as being associated with the Toynbee phenomenon.⁷⁷ A recent article (2015) reported that cannulated silicone intranasal splints do not affect ET function.⁷⁸

Further evidence of the Toynbee phenomenon was provided by an experiment in our laboratory in which the ferret animal model of complete nasal obstruction resulted in persistent high positive middle-ear pressure (Figure 5–16), most likely secondary to insufflation of nasopharyngeal gas into the middle ear during swallowing activity.⁷⁹

Related posts:

Future Directions Epidemiology Pathogenesis Role in Certain Complications and Sequelae of Middle-Ear Disease Physiology Anatomy

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