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M. V. Goycoolea and M. Castro
Fig. 3.3 Coronal and transaxial CT views showing stula (arrows) and
signs of mastoiditis. (From: Goycoolea MV, Castro M, Galvez M,
Montoya C, Fuentes J, Silva-Pinto V.Otitis media and mastoiditis in
Early Surgical Approaches
The following paragraph was the initial paragraph of my PhD
thesis in the Department of Anatomy (major in histology) at
the University of Minnesota in 1978. It was also my initial
paragraph in our chapter “Complications of Suppurative
Otitis Media” in Michael Paparella’s textbook Otolaryngology
in 1991 [8]. “Man’s efforts to treat and control otitis media
and its complications go far back into history. Ear surgery
proper, or surgery for ear complications may have started as
early as the Neolithic age [36], in which there is evidence that
trephining was performed in skulls.” Since then, we have
studied different skeletal remains and trephinations in Chile
and in Perú, and, to date, we have never found a skull in which
trephination was seemingly performed for relief from suppuration. We found evidence of mastoiditis and even mastoid
stula (as described earlier), but although we looked purposefully we never found evidence of even a mastoidectomy procedure. It was not until 2022 when Sonia Díaz-Navarro and a
team from the University of Valladolid [37] reported the discovery of a skull with evidence of otitis media and mastoiditis
and also with two bilateral perforations, suggestive of mastoidectomy procedures. Moreover, the ndings suggest that
the individual survived both procedures. The skull was found
at the El Pendón site in northern Spain and dates to the fourth
millennium BC.This would be not only the rst mastoidectomy but also the earliest surgical ear intervention in the history of mankind.
temporal bones of prehistoric Chilean populations. A paleopathological
and paleoepidemiological study. Acta Otolaryngol. 2019;139:340–344
[24])
The earliest evidence of trepanation, according to DíazNavarro [38], is documented during the Mesolithic period in
Europe and Northern Africa; however, most cases are dated
to the Late Neolithic and the Bronze Age [38]. Again,
whether trepanation was for relief from suppuration in the
mastoid region or from intracranial conditions is unknown
[39]. Trephining was also practiced in Peru over a long
period of time by various cultural groups from circa 400BC
through the emergence of the Inca Empire, circa 1400AD
[40].
Except for the possibility of trephination as a treatment
for relief from suppuration from either the mastoid or the
brain, and the case of the possible mastoidectomy that has
been described, ancient treatments, up to the early eighteenth
century, were local treatments with different agents, some of
which have been described previously. Although “seemingly
of little use” and limited to local treatment, it is interesting to
note that compounds such as alum (acidic and astringent),
copper (a natural antimicrobial), sea salt (antimicrobial, antifungal), virgin olive oil and wine (strong bactericidal activity
[41]), and frankincense (antimicrobial activity) have all been
demonstrated to have antimicrobial and/or antifungal
activities.
From the Greeks to the Middle Ages, descriptions of otitis
media and local remedies persisted and no signicant modications occurred until the seventeenth century when therapy changes began to establish the basis for signicant
treatment developments in the eighteenth century.
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The Greek physician Claudius Galenus (Pergamon, Asia
Minor, 131AD) recognized the importance of draining an
infected ear [42]. Nevertheless, Jean Riolanus the Younger
[4, 42] published the rst documented recommendation of
mastoidectomy. In 1649, he advocated perforation of the
mastoid process in cases of Eustachian tube obstruction and
when inammatory pulsating pain occupied the back of the
ear [39, 43]. By the eighteenth century, clinical and surgical
treatments began to improve and concepts like Eustachian
tube function and aeration of the middle ear and mastoid
cavities brought about new treatments. Valsalva advocated
evacuating pus from the middle ear by performing “Valsalva’s
experiment” [7]. In 1724, Edmé-Gilles Guyot, a French postmaster, physician, and inventor, described the catheterization
of the Eustachian tube through the mouth and behind the palate [7]. In 1741, Archibald Cleland described catheterization
of the Eustachian tube by way of the nose [39].
As early as 1720, Eli, a French ear surgeon, employed
myringotomy [7]. However, Sir Astley Cooper (1768–1841)
was the rst to propose clear indications for this procedure
and practiced it on a large scale (an opening to permit a free
passage of air to and from the tympanum, perhaps a substitute for the Eustachian tube) [43]. Given that the procedure
was also used for other pathological conditions not related to
drainage of middle ear effusions, and since the opening
tended to heal, the application of myringotomy uctuated in
terms of indications and usage. It was not until 1954 when
Beverly Armstrong developed the pressure equalization (PE)
tube that maintained the myringotomy puncture open.
In 1736, Jean-Louis Petit (1674–1750) adapted the process of trephining the infected mastoid cavity with a chisel
(simple mastoidectomy) [7]. He suggested not only opening
the infected tract but also actively opening the bone in order
to evacuate the pus [42]. Drainage of mastoid infections
through a retroauricular incision were inaugurated by
William Wilde (1815–1876), father of the writer Oscar
Wilde, and Toynbee (1815–1866), “to give an early exit to
imprisoned uid,” and “for a thorough evacuation of the contents of the mastoid,” respectively [39, 42]. By 1873, Herman
Schwartze (1837–1900) established mastoid surgery proper
(as we know it today) for relief from suppuration by drilling
the mastoid cortex and reaching the antrum using chisels,
gouges, and curettes [7, 42].
Ernst Kuster (1838–1930) described radical mastoidectomy in order to promote complete drainage. He removed the
“infected focuses” and posterior wall [39]. Ernst von
Bergmann (1836–1907) went even further and converted the
antrum, attic, middle ear, and external canal into one cavity
[39]. The next step was mastoidectomy with radical surgery
while preserving the middle ear ossicles and tympanic membrane by Janssen (1893), Korner and Scheide (1894), and
Bondy (1910), thus promoting modied mastoidectomy with
preservation of the tense part of the tympanic membrane and
ossicles. German otologists Wullstein and Zollner pioneered
rehabilitation surgery for deafness due to chronic middle ear
and mastoid disease. Wullstein pioneered tympanoplasty to
improve hearing in 1953 [7], but PE tubes were developed by
Beverly Armstrong in 1954 [43].
What followed medically and surgically to the present—
including the revolutionary developments of microscopic
and endoscopic surgery, audiology, imagenology, immunology, vaccines, bacteriology, and virology—is described
throughout both volumes of this book.
An additional important point to mention here is the
improvements in diagnosis that came along in the rst half of
the nineteenth century, such as the inventions of the ear speculum, the ear mirror, and the otoscope. According to Politzer
[5]: “Neuburg deserves the credit for having developed the
rst unslit speculum, though its invention is usually attributed to Ignaz Gruber. Hoffman of Burgsteinfurt deserves
credit for introducing a light source in the form of a centrally
pierced concave mirror. And the otoscope was invented by
Toynbee.” A direct observation made a signicant improvement in diagnostic capabilities.
The greatest and most radical and dramatic change in the
history of treatment of otitis media was the advent of antimicrobials. In 1869, Politzer (published in 1909) [44] stated
that “ the temporal bone has four sides: the outside is bounded
by life, from which there comes the opening of the auditory
canal, one form of our appreciation of what life means; on
the other three sides it is bounded by death” (Lederer [6]).
This statement attests the potential seriousness of otitis
media in the pre-antibiotic era, based on its anatomic location and boundaries with vital structures.
It was the advent of antimicrobials in the mid-twentieth
century, an increasing awareness on the part of physicians
and the public regarding the seriousness of the disease, and
diagnostic methods yielding earlier identication and treatment that immensely reduced the incidence of otitis media’s
lethal complications. Prior to the antibiotic era, intracranial
complications occurred in 2.3% of cases of acute or chronic
otitis media [45] and acute otitis media resulted in mastoiditis in 25–50% of cases [46]. Antibiotics reduced these gures to 0.15% in 1962 [47], to 0.02% in 1985 [48], and
0.04% [49] and that of coalescent mastoiditis to 0.4% in
1959 [50]. However, we must keep in mind that despite this
dramatic decline, the complication rate in acute mastoiditis
still uctuates between 8% and 12% [51, 52].
An example of the dramatic decline in mortality is the
Couville report [53] (from Los Angeles County Hospital in
1955). At this institution, between 1928 and 1933 (in the preantibiotic era), 25 out of every 1000 deaths were due to intracranial complications of otitis media; between 1949 and
1954 (in the antibiotic era), only 25 of every 10,000 deaths
were due to such complications. This represents a 90%
decrease in mortality. Despite this overall decline in the inci-
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M. V. Goycoolea and M. Castro
dence of intracranial complications of otitis media with signicant mortality, complications and/or sequelae of otitis
media in the temporal bone still occur [8] and may have devastating effects both physiologically and psychologically,
resulting in behavioral complications. Unfortunately, severe
complications still exist, and this cannot be emphasized
enough. Although statistical gures have shown a dramatic
decrease in the absolute number of cases, those cases that
still occur represent a signicant medical problem. This is in
part because physicians confronted with such uncommon
cases are obviously less experienced and may underestimate
or misinterpret the symptoms. In many cases, not even the
best treatment available will prevent sequelae. The important
factors in the development of complications include the
infecting agent, the adequacy and timing of treatment, and
the resistance of the infected individual.
In 1986, Samuel etal. [54] reported their experience in
South Africa with 224 otogenic intracranial complications
occurring between 1978 and 1983. Their patient population
comprised of African Blacks with neglected otitis media,
who were reluctant to seek medical attention. Their study
described a prevalent problem at the time in many areas of
the world, which was earlier overlooked. This, in part,
reects the contrast between the incidence and prevalence of
complications in a group of low socioeconomic status (analogous to patients in the pre-antibiotic era) and the results of
the same group when subsequently exposed to modern medicine. Of the 85,000 patients attending the ear, nose, and
throat clinic, Samuel et al. reported that 335 had otogenic
complications, of which 224 presented with intracranial
complications. Meningitis occurred in 83 patients, brain
abscesses in 53, extradural abscesses in 49, and lateral sinus
thrombosis in 39. Of these patients, 74% were children and
young adults (under 15 years of age), which reects conditions of the pre-antibiotic era. The current trend is that of an
increasing number of complications in older individuals with
chronic otitis. With modern-day evaluation and treatment,
the overall mortality of 14% reported by these investigators
compares highly favorably with the more current reports of
European and American groups. Although both prevention
and early diagnosis are crucial, this study, most importantly,
reects the difference that modern-day medicine can make
and is supportive of arguments for the existence of sophisticated facilities.
Going back to our previous considerations about antimicrobials and their dramatic effect on otitis media, even if otitis media continued to have a high incidence and prevalence,
antimicrobials have changed the predominance of mortality
toward morbidity. The success of antibiotics has been such
that they are used on a massive scale to treat all forms of
otitis media, and, since the 1960s [55], different forms of
“prophylactic treatments” have appeared. These consist of
low doses once a day for a prolonged length of time and have
been prescribed for recurrent and serous otitis media [56–
59]. This view coincided with the emergence of “evidence-
based medicine,” which supported these successful results.
The exaggerated use of antimicrobials, in detriment to
other reasonable alternatives, has led some authors to argue
that in many cases it could sufce to remove the effusions
and that low-dose antimicrobials could attenuate and not
eradicate the underlying inammatory process [60]. The fact
that antimicrobials would achieve maintained therapeutic tissue levels was also pointed out [61] as was the importance of
individualizing the patients rather than tting them into rigid
forms of treatment that would not cover all factors of a multifactorial disease such as otitis media [62].
Notwithstanding these considerations, “statistical evidence” indicated that the use of antimicrobials in low or
high doses for prolonged periods was effective. A large part
of the medical community proceeded accordingly, and, literally, millions of children all over the world were treated
with antimicrobials on a massive scale. No too long after
new resistant strains of bacteria began making their appearance, together with studies that suggested that antimicrobial
usefulness was only marginal, statistical evidence shifted to
support such observations, and the same medical community proceeded accordingly and millions of children around
the world with bacterial otitis media were treated without
antibiotics. When new evidence suggested that a middle
point was the solution, there arose the need to dene in
which individuals antimicrobials would work and in which
they would not [62].
Finally, the invention of the ear speculum, the ear mirror,
and the otoscope made a signicant improvement in our
diagnostic capabilities, although they have been far from
ideal. Authors in the United States reported the reexamination of children diagnosed with acute otitis media and found
a 50% diagnostic error [63]. The same situation occurred in
Chile with children over 3months of age referred to the otolaryngologist for otitis media evaluation. Of 522 patients
referred, only in 41.9% of them was the diagnosis of otitis
media conrmed [64]. If we extrapolate these ndings, one
wonders about the validity of statistical studies conducted by
data collectors who do not see patients.
Currently, there is a more holistic approach, as pathogenesis has become relevant, examination skills are improving,
patients are evaluated as individuals and not as numbers, and
bacteriology and virology have made great improvements. A
signicant advance is vaccine development, discussed at
length in this book. Moreover, pronicity factors, immunological status, environmental factors (day-care center conditions etc.) are better dened, and our aims are toward
awareness, timely intervention, and prevention. We believe
that this approach will produce substantial results and
become a new revolutionary change. As far as the future is
concerned, we expect the denition of genetic factors and a
3 Otitis Media andHuman Eorts toDeal withIt Through Time
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27
shift from a preventive to a predictive medical intervention
(before things happen), with treatments based on pathogenesis and drug therapy based on pharmacogenomics.
Summary
Here, the history of otitis media has been briey reviewed.
In ancient times, middle ear disease was seemingly limited
to identication and local treatments of its complications
and approaches used. By the eighteenth century, human
understanding evolved in terms of the concepts of aeration
and the need for drainage either via the Eustachian tube or
myringotomy and, if needed, mastoidectomy. Initially
developed as a method for drilling the bone with the intent
of removing the infection, mastoidectomy was followed by
conservative and reconstructive surgery. The profound
change that occurred with antimicrobials is examined, and
changes from mortality to morbidity are described, with the
understanding that complications still occur. A point is
delivered about the risk of rigid and dogmatic treatments in
multifactorial diseases. Advances in vaccines, a pathogenesis approach, individualization, awareness, and knowledge
of environmental and inherent factors are expected to spark
a new revolution in the comprehension of otitis media.
Finally, as far as the future is concerned, we expect the denition of genetic factors and a shift from a preventive to a
predictive medical intervention (before things happen), with
treatments based on pathogenesis and drug therapy on
pharmacogenomics.
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Development and Anatomy of the
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Human Middle Ear
CharlotteM.Burford , HannahL.Cornwall ,
MatthewR.B.Farr , ClaudiaM.Santoni ,
andMatthewJ.Mason
Introduction
Contained within the temporal bone of the skull, the human
middle ear (Fig.4.1) comprises a system of air-lled cavities, communicating with the nasopharynx via the Eustachian
tube (ET). The tympanic membrane, which separates the
external meatus from the middle ear cavity, is connected to
the malleus, the rst of the three auditory ossicles that cross
the cavity to communicate acoustic vibrations through to the
inner ear. Two small muscles insert on these ossicles, and
several nerves and arteries pass through or near the middle
ear region. The embryology and adult anatomy of this region
is complex and is often covered only briey in textbooks and
undergraduate medical courses. However, a knowledge of
the structural relationships between the middle ear components and how they come to develop is essential for understanding the function of the middle ear and necessary for the
provision of safe surgical care. In this chapter, we shall rst
review middle ear development before providing an overview of adult anatomy.
4
Fig. 4.1 Diagrammatic representation of the human peripheral audi-
tory system (right ear, anterior view). C, cochlea; EAM, external auditory meatus; ET, Eustachian tube; I, incus; IAM, internal auditory
meatus; ICA, internal carotid artery; M, malleus; MAC, mastoid air
cells; S, stapes; TC, tympanic cavity; TM, tympanic membrane
C. M. Burford
East Kent Hospitals University NHS Foundation Trust,
Ashford, Kent, UK
e-mail: charlotte.burford1@nhs.net
H. L. Cornwall
Department of Paediatrics, Ysbyty Gwynedd, Bangor, Wales, UK
M. R. B. Farr
Doncaster Royal Inrmary, Doncaster, S Yorks, UK
C. M. Santoni
School of Clinical Medicine, University of Cambridge,
Cambridge, Cambridgeshire, UK
e-mail: cms208@cantab.ac.uk
M. J. Mason (*)
Department of Physiology, Development & Neuroscience,
University of Cambridge, Cambridge, Cambridgeshire, UK
e-mail: mjm68@cam.ac.uk
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. V. Goycoolea et al. (eds.), Textbook of Otitis Media, https://doi.org/10.1007/978-3-031-40949-3_4
Part 1: Development oftheMiddle Ear
Many of the structures in the head and neck, including the
middle ear, arise from the pharyngeal apparatus of the
embryo (Fig.4.2). The development of the pharyngeal apparatus and its derivatives has been extensively studied in
humans and model organisms [1, 2]. In humans, this apparatus consists of ve pairs of arches (I–IV and VI), which form
on either side of the developing foregut. Although it is sometimes said that arch V appears transiently but then regresses,
it has recently been argued that it does not exist at all in
amniotes and the other arches should be renumbered accordingly [3]. The arches appear between the second and fourth
weeks of gestation [4]. Externally, the pharyngeal arches are
covered with ectoderm, which invaginates to form pharyn-
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Fig. 4.2 Schematic representation of the pharyngeal apparatus in the
early human embryo, demonstrating the contribution of the three germ
cell layers (ectoderm = red; mesoderm = grey; endoderm = green).
A1–6, pharyngeal arches I–VI (there is no arch V); B, developing brain;
C1, pharyngeal cleft I; CS, cervical sinus; P1–4, pharyngeal pouches
I–IV
geal clefts. In humans, there is one distinct cleft (I) between
arches I and II, whereas a cavity called the cervical sinus
represents the combined equivalent of clefts II, III and IV
[1]. Internally, the endodermal lining invaginates to form
pharyngeal pouches. As the clefts and pouches extend
towards one another, they separate the intervening tissue into
individual pharyngeal arches.
The mesodermal core of the pharyngeal arches is surrounded by mesenchyme arising from the neural crest, the
cells of which migrate from the nearby regions on the dorsal
surface of the developing neural tube. The mesodermal core
gives rise to the skeletal muscles, whereas the neural crestderived cells give rise to bony and cartilaginous structures,
including the ossicles. The arches are innervated by particular
cranial nerves, for example V3 to the rst arch and VII to the
second: this has been used to establish muscle origins. The
pharyngeal arches grow at differing rates during embryogenesis, leading to arches I and II becoming larger in volume
than the others. These two arches and their intervening structures will form the components of the external and middle
ears, discussed in more detail in the following sections.
Congenital abnormalities of pharyngeal arch development are well-documented in the literature. They can include
complete stulae arising from the rst or second pharyngeal
cleft and pouch contact, persisting into postnatal life [5].
The Middle Ear Cavity
Using the chick as a model of ear development, studies have
shown that the endodermal cells of the pharyngeal pouches
contain a web of actin bres, just underneath their apical
C. M. Burford et al.
cd
Fig. 4.3 Development of the middle ear cavity. (a) Middle ear ossicles
condensing between the developing external auditory meatus and the
tubotympanic recess. (b) The ‘endodermal model’ in which the epithelium covering the middle ear cavity is entirely endodermal in origin. (c)
The ‘mesenchymal model’ in which the epithelium of the dorsal wall
and the majority of the lateral wall of the middle ear cavity is mesenchymal in origin, whereas the medial and ventral walls are endodermal.
(d) Schematic representation of the ndings of van Waegeningh etal.
[7] in a 25-week fetus, which these authors argue support the ‘endodermal model’. They demonstrated cavitation to the level of the ossicles,
with the loose connective tissue remaining in the attic, and a continuous
epithelium. Both models agree that the tympanic membrane is composed of thin layers of ectoderm, endoderm and mesoderm. EAM,
external auditory meatus; ET, Eustachian tube; MEC, middle ear cavity;
TM, tympanic membrane; TTR, tubotympanic recess. Red=ectoderm;
green = endoderm; grey = mesoderm; blue = auditory ossicles;
orange=middle ear cavity lining that has undergone a mesenchymalto- epithelial transition
plasma membranes, which appear to constrain pouch morphology and direct their expansion [6]. The rst pharyngeal
pouch in humans begins to expand outwards in the fourth
week of gestation [4]. It forms the tubotympanic recess, a
wing-like evagination of the pharynx, which will ultimately
form the middle ear cavity and Eustachian tube (ET;
Figs.4.3a and 4.4). The second pharyngeal pouch may contribute to the posterior part of the recess, at least initially
[8–10]. The recess reaches the middle ear region at around 8
weeks of gestation and reaches the antrum by 29weeks [11].
The middle ear region is originally entirely cellular in the
embryo. As it develops, an epithelium-lined cavity forms,
lled with uid in utero, which contains the auditory ossicles
and the inserting tendons of the two middle ear muscles. This
process by which the mesenchymal cells surrounding the
ossicles and developing muscle tendons are cleared is
referred to as ‘cavitation’. In humans, cavitation begins in
the third month and is normally complete prior to birth [12],
although residual mesenchyme is frequently found in both
children and adults (see later).
How exactly cavitation happens is linked to the origins of
the epithelial lining of the middle ear cavity. There are two
main theories describing the origins of the middle ear cavity
epithelium: the ‘endodermal model’ and the ‘mesenchymal
model’ [13]. The endodermal model, originally proposed by
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Fig. 4.4 Diagrammatic rostral views of ve stages of pharyngeal
development in human embryos, based on WinSurf reconstructions; not
to scale. The pharynges are curved in these embryos: each opens into
the oral and nasal cavities towards the top of the diagram, whileat the
bottom, it tapers into the oesophagus. Derivatives of the rst pharyngeal
arch mesenchyme are colour-coded blue, derivatives of second pharyngeal arch mesenchyme cream. These are shown, where apparent, on
each embryo’s left side only. The rst and second pharyngeal arch mesenchyme is beginning to condense into ossicular precursors in stage C;
just in front of the rst pouch, the two mesenchymal populations cannot
be separated. The developing stapes is hidden behind the rst pouch and
rst-arch derivatives, and hence is not visible in the gures. The original contact between pouch I and the caudodorsal end of pharyngeal
Wittmaack [14], states that the expanding tubotympanic
recess invades the middle ear region and envelopes the developing middle ear structures. In this model, the entire middle
ear cavity is lined with an epithelium which is wholly endodermal in origin (Fig.4.3b). How the endoderm might come
to enwrap the ossicles is unclear, but it might potentially rupture at some point, continue to migrate around the cavity and
later reunite to create a complete lining [13]. The mesenchymal model was rst proposed by Schwarzbart [15] after histological examination of more than 100 human temporal
regions, aged from four fetal months to adulthood. According
cleft I is visible in the stage A embryo but later disappears. The external
auditory meatus develops as a separate invagination from the rostroventral end of cleft I. (Reprinted with the permission of John Wiley & Sons,
Inc. from Burford, C.M. & Mason, M.J. (2016) Early development of
the malleus and incus in humans. Journal of Anatomy 229:857–870.
©2016 Anatomical Society). Key: A1–2 mesenchymal condensations
within pharyngeal arches I–II; C1 pharyngeal cleft I; CS lateral cervical
sinus from which pharyngeal clefts II–IV originate; EAM external auditory meatus; I incus; M malleus; MC Meckel’s cartilage; PW pharyngeal ‘wing’ (precursor of tubotympanic recess); P1–4 pharyngeal
pouches I–IV; RC Reichert’s cartilage; TR tubotympanic recess. Stage
A, 7–9mm crown-rump length (CRL); Stage C, 10–15mm CRL; Stage
E, 14–18mm CRL; Stage F, 20–22mm CRL; Stage G, 24–28mm CRL
to this model, the endoderm of the tubotympanic recess ruptures and the lining of much of the middle ear cavity is
instead formed from the mesenchyme, which migrates and
retracts to the edges of the cavities (Fig.4.3c).
These competing theories were put to the test by
Thompson and Tucker [16]. Immunostaining for E-cadherin
in a mouse model showed that the intact endodermal lining
of the rst pharyngeal pouch on embryonic day 15.5 breaks
down to allow an inux of mesenchyme by day 17.5.
Transgenic mouse lines were used to investigate the origin of
the cells ultimately lining the middle ear cavity: Sox17-
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C. M. Burford et al.
2AicreR26R reporter lines for tissues with endodermal origins and Wnt1creR26R for neural crest-derived cells.
Thompson and Tucker found that the epithelium covering
the dorsal wall of the mouse middle ear cavity, and the majority of the medial wall including the cochlear promontory,
originates from neural crest mesenchyme, whereas that covering the medial side of the tympanic membrane, much of
the ventral wall and the Eustachian tube is endodermal. In
addition, they studied the expression of the epithelial- specic
protein cytokeratin 14 and demonstrated that this protein was
expressed in the neural crest-derived region between postnatal days 14 and 16. This mesenchymal-to-epithelial transition occurred concomitant with the formation of the nal
middle ear cavity. Retraction of mesenchyme consistent with
this model has also been observed in shrew and opossum,
suggesting that it is widespread among mammals [13].
Thompson and Tucker [16] found that the component of
the lining of the mouse middle ear cavity derived from endoderm was ciliated and contained mucus-secreting goblet
cells, whereas the part derived from mesenchyme was a simple, non-ciliated epithelium. In humans, the lining of the
Eustachian tube, anterior tympanic cavity and hypotympanum are ciliated, with goblet cells around the ET region,
whereas the epitympanum, antrum and mastoid are covered
with a squamous epithelium, which normally shows very
few cilia [17–19]. The similar histological pattern between
mice and humans is consistent with a similar dual origin of
the middle ear epithelium in humans.
However, the ‘mesenchymal model’ of the human middle
ear cavity epithelium is not universally supported. van
Waegeningh etal. [7] carefully examined the epithelial lining of the middle ear cavity using immunohistological sections from one 25-week gestation fetus. The process of
cavitation had only just passed the level of the ossicles in
their specimen, as the loose mesenchyme remained around
the attic. Signicantly, the whole cavitated region was covered by an intact epithelium, which, these authors argued,
could represent endoderm, which had expanded to enwrap
the ossicles without rupturing (Fig.4.3d).
Irrespective of whether the epithelium of the human middle ear is derived entirely from endoderm, or from both
endoderm and mesenchyme, the mesenchyme that lls the
middle ear cavity prenatally must somehow be replaced with
uid and, later, air. Based on observations and measurements
made from postnatal human temporal bones, Piza etal. [20,
21] suggest that the mesenchyme recedes as the middle ear
cavity expands, thinning as it does so and thus contributing
to the submucosal lining of the cavity, from which it is not
easily distinguished. Other studies suggest that mesenchymal cells disintegrate. Terminal deoxynucleotidyl transferase
dUTP nick end labelling (TUNEL) assays, which detect
DNA fragmentation, have been used to demonstrate apoptosis of the middle ear mesenchyme, thus contributing to cavi-
tation in rodents, from the 16th embryonic day until after
birth in rats [22] but only on postnatal day 1in mice [23].
Degenerating mesenchymal cells were also observed in
human temporal bones, postnatally [24]. The association
between retained mesenchyme in the middle ear cavity and
otitis media is discussed later.
The Tympanic Membrane andtheExternal
Auditory Meatus (EAM)
The tympanic membrane is made up of three layers (Fig.4.3).
The outermost layer is an invagination of the ectodermal lining of the external auditory meatus, whereas the inner layer
consists of the middle ear cavity lining, which the studies
mentioned above agree would be endodermal in origin at this
location. Fibrous mesenchyme forms a middle layer between
the outer and inner layers. It is often, although mistakenly,
believed that the tympanic membrane forms where the rst
pharyngeal cleft meets the rst pharyngeal pouch. However,
the primitive connection between the rst cleft and the rst
pouch is, in fact, lost [25], and a secondary connection forms
between the true external auditory meatus (EAM) and the
tubotympanic recess [8]. Mouse models of EAM development show the denitive EAM developing in mesenchyme,
which is entirely Hoxa2-negative and therefore seemingly of
rst-arch origin only [26]. The plane of the tympanic membrane is nearly horizontal in the early human fetus, becoming more vertical throughout fetal life and also increasingly
inected at the umbo [27].
It was suggested that the formation of the middle ear cavity and tympanic membrane is coordinated by an ‘epidermoid formation’, identied at the primitive connection where
pouch I meets cleft I [28, 29] and persisting in some specimens postnatally, at the junction between the middle ear and
the ET epithelia, just anterior to the tympanic membrane
[30]. Later molecular studies have focused instead on the
role of the tympanic ring, which undergoes intramembranous ossication to provide a frame for the tympanic membrane and will go on to form part of the temporal bone (see
later). Mouse molecular genetic investigations have strongly
suggested that tympanic ring development is necessary for
the invagination of the external meatus and for the development of the tympanic membrane [31]. For example, mice
decient in expression of Goosecoid (Gsc) fail to develop a
tympanic ring, a tympanic membrane and an EAM and also
have other craniofacial defects [32–34]. Defects, including
bilateral EAM atresia, have been linked to the human syndrome SAMS (a syndrome of short stature, auditory canal
atresia, mandibular hypoplasia and skeletal abnormalities),
which is also caused by Gsc genetic mutations [35].
Experimental evidence in mice suggests that the development of the manubrium of the malleus, which is attached to
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the interior surface of the tympanic membrane, depends on
the normal development of the external meatus [36], and this
appears to be the case in humans too [37]. In one study, 98%
of those with severely defective external ear development
were found to have ossicular dysplasias, and other middle
ear defects were also commonly observed [38].
Eustachian Tube Development
The Eustachian tube (ET), named after the sixteenth century
Italian anatomist Bartolomeo Eustachi (1500–1574) [39], is
also known as the auditory tube or pharyngotympanic tube.
Beginning as an expansion from the rst pharyngeal pouch
around the fourth week of gestation [4], the tube is transformed by epithelial differentiation and the development of
cartilage and muscle from around the ninth week [40]. The
development of the ET is of specic clinical interest due to
its postulated links to pathologies such as otitis media
[41–43].
The cartilage of the ET develops between about the 12th
and 20th weeks of gestation, beginning at the pharyngeal end
and progressing towards the middle ear [40]. The tube
increases in length throughout gestation [40], with the main
period of extension of the cartilaginous part occurring
between weeks 16 and 28 [44]. Mouse models have shown
that most of the ET cartilage is mesodermal in origin, but
there is a small, dorsal component derived from the neural
crest [45]. The bony portion of the Eustachian tube undergoes upward expansion in the late fetal stage, and this continues through childhood, thus contributing to the supratubal
recess [46]. The lumen of the tube begins as round in cross
section, becoming oval, and then, from around the 27th
week, slit-shaped [40], but it is said to remain patent throughout prenatal life [47].
In neonates, the ET has a narrower diameter than in adults,
especially the cartilaginous region [48, 49]. A child’s ET has
a rather uniform cross section along much of its length,
whereas in an adult, it is more gradually tapering from a
large pharyngeal orice towards the narrowest portion,
which is near the tympanic end of the cartilaginous zone
[50]. The tube is also shorter in absolute length in children,
with a relatively shorter bony section, and it is straighter than
that of adults [51]. At 6months’ gestation, the ET is horizontal; by 6 months of age, it forms an angle of around 10° to the
skull base [52]. Although the ET is shorter and more horizontally inclined in children under the ages of around 7,
compared to adults, the fact that older children are more
similar in these respects to adults, and that no difference was
found between children with and without otitis media, suggests that the length and inclination of the tube may not contribute to susceptibility to this disease [53]. Other studies,
however, have suggested that such a link might exist [54].
Muscles oftheEustachian Tube
Derived from the rst pharyngeal arch, the tensor veli palatini (TVP) is rst seen around week 6in the human embryo,
arising with the medial blastema of the muscles of mastication, together with the medial pterygoid and tensor tympani
muscles [55]. All were found to be innervated by the medial
root of the mandibular nerve (V). By week 7, the TVP is differentiated and related to the pterygoid hamulus, and it
becomes continuous with the palatine aponeurosis by week
9. At week 13, there is a connective tissue link between the
TVP and the goniale of the malleus. By birth the TVP has
reached its adult relationship with the ET mesenchyme at
one end, and at the other end with the palatine aponeurosis.
The pterygoid hamulus, around which the TVP tendon
glides, chondries around week 8 [55] and ossies around
week 16 [40]. The TVP remains in mesenchymal and later
tendinous connection with the tensor tympani muscle
throughout its development [56].
The levator veli palatini (LVP) is rst seen around week 8,
just ventromedial to the pharyngeal aperture of the ET; by
week 9, it is found to run along the full length of the ET [57].
Kishimoto etal.found the LVP to receive innervation from
the lesser palatine nerve, a branch of VII. Although innervated via the pharyngeal plexus [58] and classically believed
to derive from pharyngeal arches IV–VI, Kishimoto etal.
[57] suggest that the LVP may actually originate from pharyngeal arch II, based on its anatomical relationship with the
ET and the component of its innervation from the facial
nerve. Both Tbx1
+/−
and Df1/+ mice, used as models of
DiGeorge syndrome in humans, were found to have smaller
LVP muscles than wild-type mice, and this was associated
with an increased incidence of otitis media [59].
Very little is known about the development of the salpingopharyngeus muscle. It is closely associated with the other
longitudinal pharyngeal muscles, representing part of the
palatopharyngeus complex [60, 61]. As such, its innervation
and pharyngeal arch origin are probably similar to those of
the LVP.The salpingopharyngeus muscle was not found to
be present by week 8 of development [62].
Middle Ear Ossicle Development
The three middle ear ossicles, found in all mammals, are the
malleus, incus and stapes. These are the Latin terms for a
hammer, anvil and stirrup, respectively, reecting their
shape.
The pharyngeal arch origins of the ossicles have been
much debated [63, 64]. The currently favoured theory, initially proposed by Reichert [65], states that the malleus and
incus develop from the caudal end of Meckel’s cartilage,
which arises within pharyngeal arch I, whereas the stapes
develops from the cartilage of pharyngeal arch II (Reichert’s
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