Sordera

Genetic Sensorineural 148
Hearing Loss
Seiji B. Shibata | A. Eliot Shearer | Richard J.H. Smith
Key Points
■ In developed countries, more than 50% of congenital hearing impairments have a genetic origin.
■ Hearing loss can be defined by numerous clinical criteria that include causality, time of onset, age of
onset, clinical presentation, anatomic defect, severity, and frequency of loss.
■ The worldwide rate of profound hearing loss is 4 in every 10,000 infants born.
■ The basic forms of inheritance can be mendelian (single-gene inheritance—autosomal or X-linked),
mitochondrial, or complex (multifactorial inheritance).
■ Nonsyndromic hearing impairment in the absence of other phenotypic manifestations accounts for
70% of hereditary hearing losses.
■ Mutations in GJB2 account for 50% of severe-to-profound autosomal-recessive nonsyndromic
deafness in several world populations.
■ Syndromic hearing impairment refers to deafness that cosegregates with other features and results in
a recognizable constellation of findings known as a syndrome. Sensorineural deafness has been
associated with more than 400 syndromes.
■ The most common syndromic form of hereditary sensorineural hearing loss, Pendred syndrome, is
inherited in an autosomal-recessive fashion; affected individuals also have goiter.
■ After a well-performed patient history, physical examination, and audiologic evaluation, genetic
testing should be the next test ordered in the evaluation of a patient with hearing loss.
■ Prenatal diagnosis of some forms of hereditary hearing loss is technically possible by analysis of
DNA extracted from fetal cells.
■ Cochlear implantation is becoming an increasingly important option for individuals with severe to
profound deafness; in many cases, cochlear implantation can be predicted by genetic testing.
I t was famously put by Terry Savage that “A child will hear his loss has mandated a basic understanding of genetics. This

mother’s voice for the rest of his life.” However, many children chapter provides an introduction to the genetics of hearing
never hear their mother’s voice, and others do not hear it well loss. An overview of hearing loss is followed by discussion of
throughout their lives. In fact, hearing loss is the most common the fundamentals of genetics and a synopsis of syndromic and
human sensory disorder. Congenital hearing impairment nonsyndromic deafness. The final section focuses on the clini-
affects at least 1 child in every 500 born and impacts 360 million cal approach to a child with suspected genetic deafness and
people worldwide.1,2 Hearing impairment commonly involves includes new advances in genetic testing and potential thera-
dysfunction of the inner ear or auditory nerve, a condition pies for genetic hearing loss.
known as a sensorineural hearing loss (SNHL). Individuals with
SNHL are often referred to as deaf (lowercase “d”) by the com-
munity. The term Deafness (capital “D”) is used to describe an BACKGROUND
individual with SNHL who is part of a cultural group based on CLASSIFICATION OF
their use of sign language for communication. Members of this
group tend to be the offspring of Deaf parents and generally HEARING IMPAIRMENT
have congenital SNHL. In contrast, individuals who acquire A hearing loss can be defined by numerous clinical criteria that
SNHL later in childhood or adulthood often do not use sign include causality, time of onset, age of onset, clinical presenta-
language and persist with oral communication. These individu- tion, anatomic defect, severity, and frequency loss (Table
als are usually not part of the Deaf community. 148-1). Etiologically based classifications can be broadly divided
In developed countries, over 50% of congenital hearing into genetic versus nongenetic factors. This distinction is
impairment has a genetic origin.1,2 Late-onset hearing loss can important, because hereditary deafness does not imply con-
also be caused by genetic defects. As understanding of the genital deafness; the latter describes a condition present from
genetics of deafness increases, the role of the otolaryngologist birth regardless of causality, whereas hereditary deafness may
in the diagnosis, interpretation, and management of hearing be present at birth or may develop at any time thereafter.
2285
2286 PART VII | OTOLOGY, NEUROTOLOGY, AND SKULL BASE SURGERY
TABLE 148-1. Hearing Loss Classification and Features DIAGNOSIS OF HEARING IMPAIRMENT

Criteria Classification Comment The primary diagnosis of hearing loss is by auditory testing to
Causality Genetic Hereditary detect loss in hearing acuity. Hearing function is measured in
Environmental Nonhereditary decibels and is considered to be normal if the lowest level
Multifactorial (threshold) at which a sound can be perceived is between 0 and
Time of onset Congenital At birth 20 dB. The value of 0 dB is defined as the intensity at which a
Acquired Develops any time tone burst of a given frequency is perceived 50% of the time
after birth by a young adult. The severity and frequency loss sustained
Age of onset Prelingual Before speech during a hearing impairment are given in Tables 148-1 and
development 148-2. Hearing acuity can be measured quantitatively and objec-
Postlingual After speech tively by numerous physiologic tests that include auditory brain-
development stem response (ABR) measurements, auditory steady-state
Clinical Nonsyndromic Hearing loss only response evaluation, impedance testing (tympanometry), and
presentation symptom otoacoustic emission testing. For all these auditory tests except
Syndromic Hearing loss and other tympanometry, normal middle ear function is required for a
symptoms normal response to be generated.
Anatomic Conductive Dysfunction of outer or ABR testing records the electrophysiologic response of the
defect middle ear auditory nerve (eighth cranial nerve) and brainstem to tone
Sensorineural Dysfunction of inner ear bursts, sound wave “trains” that consist of several cycles of the
Mixed or auditory nerve same frequency, or clicks, unidirectional rectangular voltage
Severity Mild 20 to 40 dB pushes, applied to the outer ear.1,4 The waveform patterns are
Moderate 41 to 55 dB detected by electrodes connected to the skin, with maximal
Moderately severe 56 to 70 dB obtainable values at 94 to 100 dB sound-pressure level, which
Severe 71 to 90 dB refers to the ratio of the pressure of a sound wave to the stan-
Profound >90 dB dard air-pressure level. Otoacoustic emissions are distinct from
Frequency loss Low frequency <500 Hz ABRs in that they are sounds generated only from the cochlea,
Mid frequency 501 to 2000 Hz and they represent the activity of outer hair cells in response to
High frequency >2000 Hz transient or continuous stimulation. The emissions are mea-
Ears affected Unilateral One ear affected sured in the external auditory canal and are usually absent in
Bilateral Both ears affected individuals with hearing loss greater than 40 to 50 dB.1
Symmetric Both ears affected equally The audiometry steady-state response has some similarity to
Asymmetric Both ears not the ABR, but the stimulus is continuous. A continuous tonal
affected equally stimulus generates a higher sound-pressure level than is possi-
Prognosis Stable Severity remains ble with click stimuli, and it allows a better estimation of hearing
unchanged acuity in profoundly deaf individuals.1 Impedance audiometry
Progressive Severity increases is used in conjunction with ABR, otoacoustic emissions, or audi-
over time tory steady-state response testing, because it does not measure
hearing. This technique is used routinely to determine middle
ear pressure, movement of the tympanic membrane and middle
It is well known that heritable and environmental factors ear ossicles, and eustachian tube activity.1
make strong contributions to hearing loss. Three types of ana-
tomic defects are noted—conductive, sensorineural, or a com- EPIDEMIOLOGY OF
bination of both (mixed)—and these defects may arise from
syndromic or nonsyndromic conditions. Generally, when dis-
HEARING IMPAIRMENT
cussing hereditary deafness, a clinically based classification that Hearing loss is a prevalent human sensory defect. The World
reflects the presence or absence of coinherited anomalies— Health Organization has estimated that worldwide, 360 million
that is, syndromic or nonsyndromic deafness—is most useful. people are affected by a significant hearing loss. Other estimates
Syndromic and nonsyndromic conditions can be subclassified of the worldwide rate of profound hearing loss have found that
by inheritance pattern as autosomal dominant, autosomal it affects 4 in every 10,000 infants born.5,6 The rate of SNHL
recessive, X-linked, mitochondrial, or complex. Hearing loss determined in universal newborn screening programs in devel-
can also be distinguished by differences in severity and fre- oped countries, 2 to 4 children per 1000 born, compares favor-
quency loss. Additional features of a hearing loss that are ably with this figure.7,8 The incidence of congenital SNHL in
assessed include whether one or both ears are affected and the developing countries is likely to be much higher,9,10 although
prognosis for the condition (see Table 148-1). more data are required to conclude this. The implications are
Although these classifications assist clinicians in their assess- significant for the communicative, cognitive, scholastic, and
ment of patients and lead to better clinical outcomes, they do social development of children with early-onset hearing loss.
not adequately represent the complex interactions that under-
lie most forms of hearing loss. This limitation is exemplified in TABLE 148-2. Quantification of Hearing Impairment
hearing loss that is attributable to exposure to the ototoxic
aminoglycoside antibiotics. Although at high concentration Impairment Pure Tone Average Residual Hearing
(%) (dB)* (%)
these antibiotics do interfere with the normal function of the
cochlea, individuals with an A1555G mutation in their mito- 100 91 0
chondrial 12S rRNA gene are more susceptible to the ototoxic 80 78 20
effect of these drugs even at normally appropriate dosing 60 65 40
levels.3 In some cases, hearing loss is attributable to genetic and
environmental factors, and this dual causality can make classify- 30 45 70
ing hearing loss less informative. *Pure tone average of 500, 1000, 2000, and 3000 Hz.
148 | GENETIC SENSORINEURAL HEARING LOSS 2287
HISTORIC BACKGROUND OF GENETICS

Mendel is considered the father of modern genetics. His work
formulating the fundamentals of heredity by experimenting on
the garden pea is well known. From this research, he postulated
the principles of segregation and independent assortment, pub-
lishing these concepts in 1865. In the early 1900s, the impact
of these ideas was recognized. Johannsen described the basic
unit of heredity as the gene in 1909, and Avery showed that A
genes are composed of deoxyribonucleic acid (DNA) in 1944.
In 1953, Watson and Crick described the physical structure of
DNA, and 3 years later, the correct number of human chromo-
somes was confirmed to be 46. Sequencing these chromosomes
was the goal of the Human Genome Project, initiated in 1991
and completed with first-pass data in 2001. The impact of this
project on medicine has been tremendous, with the field of
genetic deafness being just one of many areas of medical science
to have flourished. A list of the current known deafness genes B
can be found on the Hereditary Hearing Loss Homepage.11
FUNDAMENTALS OF GENETICS
Each person has 46 chromosomes—22 pairs of autosomes and
one pair of sex chromosomes (XY in males or XX in females).
According to Mendel’s principle of segregation, in sexually
reproducing organisms, each partner contributes only one
member of each chromosome pair to an offspring. This fact C
means that each individual has inherited one copy of each
chromosome from each parent. Carried on these chromosomes
are genes, estimated to number approximately 30,000. Varia-
tions in these genes impart uniqueness to each individual.
These variations, termed alleles, can sometimes be deleterious.
If a mutation changes the normal or wild-type sequence of
a gene expressed in the inner ear, and if the protein translated
from this new allele variant does not function as well as the
normal protein, deafness may result. However, if the remaining D
normal protein (recall that each gene is represented in dupli-
FIGURE 148-1. Inheritance patterns. A, Pedigree illustrating autosomal-
cate) is able to replace or compensate for the defective mutant
dominant inheritance. The inheritance pattern shows vertical transmission of
protein, deafness will manifest only in individuals who carry two the affected phenotype, including father-to-son transmission. No generations
copies of the abnormal gene. This scenario is an example of are skipped. B, Pedigree of autosomal-recessive inheritance. Note the
autosomal-recessive inheritance. However, if the abnormal protein disease phenotype is not usually seen in the parents or other ancestors.
interferes with normal protein function, deafness will manifest Likelihood of affected males to females is equal. (Refer to the Punnett square
in an individual who carries a single abnormal gene. This sce- in Figure 148-2 for estimating risks for recessive inheritance in heterozygous
nario is an example of autosomal-dominant inheritance. parents.) C, Pedigree of X-linked–recessive inheritance. The disease pheno-
In describing these inheritance patterns, we are describing type is present with one disease allele in the male but requires a homozygous
a person’s genotype or genetic makeup. The term homozygosity genotype to be expressed in the female. D, Pedigree illustrating mitochon-
drial inheritance. Note the maternal transmission of the affected phenotype.
means that a person carries two identical alleles of a gene;
There is no paternal transmission.
heterozygosity represents the state in which a person carries two
different variants of a given gene. The observable consequence
that derives from an individual’s genotype is his or her pheno- of inheritance, we recommend more appropriate texts.12,13
type. Individuals who carry identical genetic mutations often Punnett squares are used to show inheritance patterns by dis-
exhibit a spectrum of phenotypic features. For instance, not playing the outcomes of crosses with both parents and allowing
every person with Waardenburg syndrome type 1 has synoph- probability estimates for the offspring (Fig. 148-2).
rys, premature graying of the hair, or heterochromia irides, a
phenomenon called variable expressivity. In some cases, the phe- Autosomal Dominant
notype can be so subtle as to be entirely absent, and the caus- In autosomal-dominant diseases, heterozygotes express the
ative genetic mutation is said to exhibit incomplete penetrance or disease phenotype. The affected parent can pass either a disease
to be nonpenetrant. This occurrence can give the impression that allele or a normal allele to offspring, with the likelihood of each
a disease “skips” generations. event being 0.5, or 50%. This means that 50% of offspring
inherit the normal allele and 50% inherit the disease allele. In
the case of dominant diseases, 50% of offspring express the
PATTERNS OF INHERITANCE disease.
The basic forms of inheritance can be mendelian (single-gene Autosomal-dominant transmission implies several things.
inheritance, autosomal or X-linked), mitochondrial, or complex First, no sexual predilection exists for the disease phenotype;
(chromosomal and multifactorial inheritance). Pedigrees for males and females are equally likely to be affected and to trans-
these inheritance patterns are shown in Figure 148-1. Mende- mit the disease allele to their offspring. Second, unless the
lian and mitochondrial forms of inheritance are discussed in disease gene is nonpenetrant, the disease does not skip genera-
this chapter; for the reader who is interested in complex forms tions. This type of transmission is called vertical transmission.
process is not random, and inactivation of the mutated X chro-
Male heterozygous carrier mosome is usually much higher than is inactivation of the
normal X chromosome. Males have only a single X chromo-
A a some and always express the disease phenotype.
In a pedigree showing X-linked–recessive inheritance, the trait
is seen more frequently in males; there is no father-son trans-
mission; affected fathers transmit the disease allele to all female
Aa offspring, who may have affected males (“skipped generation”);
AA
Female heterozygous carrier
A
and heterozygous females transmit the disease allele to half of
Not affected
Carrier all sons, who manifest the disease, and half of all daughters,
not affected who are heterozygous and phenotypically normal. In X-linked–
dominant inheritance, affected fathers transmit the disease allele
to all daughters who exhibit the disease phenotype with com-
plete penetrance; there is no father-son transmission. Hetero-
zygous females are affected and transmit the trait to half of all
sons and half of all daughters.
Aa
aa
a Mitochondrial Inheritance
Carrier
Affected The “powerhouses” of the human cell, mitochondria are the
not affected
sites of oxidative phosphorylation, the process that leads to the
production of adenosine triphosphate. Mitochondria possess
their own intrinsic DNA, with several copies of the mitochon-
FIGURE 148-2. Punnett squares are used to estimate inheritance probabili- drial genome in each mitochondrion. The mitochondrial
ties for mendelian inheritance patterns. This Punnett square illustrates the genome is a 16,569 base pair circular molecule that encodes
mating of two individuals who are heterozygous carriers of an autosomal- two ribosomal RNAs, 22 transfer RNAs, and 13 polypeptides.14
recessive gene; the genotypes of all potential offspring show a 25% chance The remaining mitochondrial proteins required for oxidative
of having a child with the recessive phenotype (aa), a 50% chance of having phosphorylation are encoded by the nuclear genome.
a child who carries the recessive allele but is not affected (Aa), and a 25% Mitochondrial DNA (mtDNA) is inherited solely through
chance of having a child who does not carry the recessive allele (AA). the maternal lineage, reflecting the presence of large amounts
of mtDNA in the cytoplasm of the egg. Therefore, maternal
transmission of the affected phenotype occurs, but no paternal
transmission takes place (see Fig. 148-1, D). If all of the mtDNA
Third, male-to-male (father-son) transmission is seen. This molecules are abnormal, a condition known as homoplasmy, all
observation in a pedigree rules out mitochondrial or X-linked progeny cells contain abnormal mitochondria. If normal and
inheritance. abnormal mtDNA molecules coexist, a condition known as het-
eroplasmy, a wide range of expression of the mutant phenotype
Autosomal Recessive is seen, which reflects the random distribution of mitochondria
In contrast to autosomal-dominant inheritance, in autosomal- to progeny cells. Because mitochondria lack a DNA repair
recessive inheritance, two mutant copies of a gene are necessary mechanism, mtDNA accumulates mutations at a higher rate
for expression of the disease phenotype. An affected parent than nuclear DNA.
transmits a disease allele to all offspring, but offspring do not
show the disease phenotype unless the other parent carries at
least one mutant copy of the same gene. Most frequently, GENETIC HEARING IMPAIRMENT
however, neither parent is affected, but both carry a single
mutant gene, and by chance, each passes this mutant copy on NONSYNDROMIC HEARING IMPAIRMENT
to the affected offspring. In this scenario, 25% of offspring Genetic hearing loss is common in humans. Nonsyndromic
carry two mutant copies of the gene and express the disease hearing impairment in the absence of other phenotypic mani-
phenotype; 50% of offspring are carriers of a mutant copy, festations accounts for 70% of hereditary hearing loss.15 More
similar to the parents; and 25% of offspring have two wild-type than half of SNHL that occurs in neonates is attributable to
copies of the gene. As with autosomal-dominant diseases, there simple mendelian inherited traits (Fig. 148-3). In most cases,
is no sexual predilection; males and females are equally likely the inheritance pattern is recessive (75% to 80% of cases), and
to be affected, but vertical transmission is rarely seen. Recessive consequently, the parents of affected children generally do not
diseases tend to be generation specific. If the disease is excep- exhibit the phenotype. Congenital nonsyndromic hearing
tionally rare, the likelihood of parental consanguinity, albeit loss is inherited in an autosomal-dominant (~20%), X-linked
distant, is high. (2% to 5%), or mitochondrial (~1%) mode. Nomenclature is
based on the prefix “DFN” to designate nonsyndromic DeaFNess.
X-Linked Inheritance DFN followed by an A implies dominant inheritance, whereas
X-linked inheritance may be either recessive or dominant. In B implies recessive inheritance and X implies X-linked inheri-
recessive X-linked inheritance, females are unlikely to be tance. The integer suffix denotes the order of gene locus dis-
affected, because two mutant copies of the gene are needed for covery. DFNA1 and DFNB1 were the first autosomal-dominant
the disease phenotype to manifest. However, heterozygous and recessive nonsyndromic deafness gene loci to be identified.
females do occasionally exhibit subtle aspects of the disease As is described in the following sections, great progress has
phenotype because of the randomness of X-chromosome inac- been made in the scientific study of genetic nonsyndromic
tivation (the Lyon hypothesis). In females, in each cell, only hearing loss (NSHL) since the discovery of the first deafness
one of the two X chromosomes is active, and when X chromo- gene in 1993. These discoveries have improved our understand-
some inactivation is entirely random, 50% of cells in a hetero- ing of the molecular physiology of hearing and deafness and
zygous female will express the disease-carrying X chromosome. have laid the groundwork for clinical genetic testing for deaf-
Through mechanisms that are not clearly understood, this ness, as described under Diagnosis.
75%-80% Autosomal recessive
70% Nonsyndromic 20% Autosomal dominant
50% Genetic
2%-5% X-linked, <1% mitochodrial
Congenital
hearing loss 30% Syndromic
50% Environmental
FIGURE 148-3. Incidence of different forms of congenital hearing loss.
Autosomal-Recessive Nonsyndromic DFNB1. In 1994, Guilford and coworkers17 mapped the first
Hearing Impairment autosomal-recessive nonsyndromic deafness locus to 13q12-13
Autosomal-recessive nonsyndromic hearing impairment is and called it DFNB1. Three years later, Kelsell and colleagues18
usually prelingual and severe to profound across all frequen- identified the DFNB1 gene as a gap junction gene called GJB2.
cies.16 To date, 95 loci have been mapped, and 41 causative The encoded protein, connexin 26, oligomerizes with five
genes have been cloned (Table 148-3).11 Expression patterns of other connexin proteins to form a connexon; the docking of two
autosomal-recessive nonsyndromic deafness-related genes in connexons in neighboring cells results in a gap junction (see
the cochlea are demonstrated in Figure 148-4. Fig. 148-4, B). These gap junctions are thought to be conduits
TABLE 148-3. Autosomal-Recessive Nonsyndromic Hearing Loss

Locus Name Location Gene Symbol Phenotype*
DFNB1A 13q11q12 GJB2 Prelingual† SNHL that remains stable17,18
DFNB1B 13q12.11 GJB6 Prelingual† SNHL and vestibular dysfunction in some patients166,167
DFNB2 11q13.5 MYO7A Prelingual or postlingual SNHL of an unspecified type168,169
DFNB3 17p11.2 MYO15A Prelingual SNHL that remains stable170,171
DFNB4 7q22.3 SLC26A4 Prelingual or postlingual SNHL that may be stable or progressive; may also be associated
with dilation of vestibular aqueduct104,105,172
DFNB6 3p21.31 TMIE Prelingual SNHL that remains stable173,174
DFNB7/11 9q21.13 TMC1 Prelingual SNHL that remains stable175,176
DFNB8/10 21q22.3 TMPRSS3 Postlingual (DFNB8)‡ or prelingual (DFNB10) SNHL that may be progressive or
stable177,178
DFNB9 2p23.3 OTOF Prelingual SNHL that remains stable179,180
DFNB12 10q21,1 CDH23 Prelingual SNHL that remains stable39,181
DFNB15/72/95 19p13.3 GIPC3 Prelingual SNHL that remains stable182-184
DFNB16 15q15.3 STRC Prelingual SNHL that remains stable and is more pronounced in higher frequencies185
DFNB18 11p15.1 USH1C Prelingual SNHL that remains stable186,187
DFNB21 11q22-q24 TECTA Prelingual severe to profound isolated SNHL41
DFNB22 16p12.2 OTOA Prelingual moderate to severe SNHL188
DFNB23 10q21.1 PCDH15 Prelingual severe to profound SNHL47
DFNB24 11q22.3 RDX Prelingual profound SNHL189
DFNB25 4q13 GRXCR1 Prelingual severe to profound SNHL190
DFNB28 22q13.1 TRIOBP Prelingual severe to profound SNHL191,192
DFNB29 21q22.3 CLDN14 Prelingual profound SNHL193
DFNB30 10p11.1 MYO3A Progressive SNHL that first affects high frequencies and begins in the second decade;
severe in high and middle frequencies, moderate at low frequencies by age 50 years194
DFNB31 9q32-q34 WHRN Prelingual profound SNHL195,196
DFNB35 14q24.3 ESRRB Prelingual profound SNHL197
DFNB36 1p36.31 ESPN Prelingual SNHL of unspecified or unknown type198
DFNB37 6q13 MYO6 Prelingual SNHL of unspecified or unknown type199
DFNB39 7q21.11 HGF Prelingual severe to profound SNHL200
Continued
TABLE 148-3. Autosomal-Recessive Nonsyndromic Hearing Loss—Cont’d

DFNB42 3q13.33 ILDR1 Prelingual mid to high-frequency SNHL201
DFNB49 5q13.2 MARVELD2 Prelingual moderate to profound SNHL202
DFNB53 6p21.32 COL11A2 Postlingual (second decade) midfrequency SNHL203
DFNB59 7q22.1 PJVK Prelingual severe to profound auditory neuropathy204
DFNB61 7q22.1 SLC26A5 Prelingual severe to profound SNHL205
DFNB63 11q13.4 LRTOMT/COMT2 Prelingual profound SNHL206,207
DFNB66/67 6p21.3 LHFPL5 Prelingual profound SNHL208-210
DFNB74 12q14.3 MSRB3 Prelingual profound SNHL211,212
DFNB77 18q21.1 LOXHD1 Prelingual mid to high-frequency progressive SNHL213
DFNB79 9q34.3 TPRN Prelingual severe to profound SNHL214,215
DFNB82 1p13.3 GPSM2 Prelingual stable profound SNHL216
DFNB84 12q21.31 PTPRQ Prelingual severe to profound SNHL217
DFNB91 6p25.2 GJB3/SERPINB6 Postlingual (second decade) progressive moderate to severe SNHL218,219
SNHL, sensorineural hearing loss.
*Most important references are cited.
†Prelingual deafness also includes congenital deafness.
‡The onset of DFNB8 hearing loss is postlingual (10 to 12 years old), whereas the onset of DFNB10 hearing loss is prelingual (congenital). This
phenotypic difference reflects a genotypic difference; the DFNB8-causing mutation is a splice-site mutation. This suggests that inefficient splicing
is associated with a reduced amount of normal protein, which is sufficient to prevent prelingual deafness but insufficient to prevent eventual
hearing loss.
Modified from Van Camp G, Smith RJ: Hereditary Hearing Loss. Available at http://hereditaryhearingloss.org.
through which potassium ions are recycled from the outer hair
cells back through the supporting cells and spiral ligament to
Autosomal-Dominant Nonsyndromic
the stria vascularis.19 The ions are pumped into the endolymph Hearing Impairment
to perpetuate the mechanosensory transduction of hair cells. To date, 64 loci for autosomal-dominant nonsyndromic deafness
Mutations in GJB2 may disrupt this recycling process and may have been mapped, and 27 causative genes have been cloned
prevent normal mechanosensory transduction.18 This role is (Table 148-4).11 Generally, the onset of deafness is postlingual,
consistent with the expression of GJB2 in the stria vascularis, progressive, and milder than recessive forms, and several loci
nonsensory epithelial cells, spiral ligament, and spiral limbus have characteristic audioprofiles.28,29 Several common forms
of the inner ear.18 of dominant hearing impairment have unique or characteristic
Mutations in GJB2 are found in 50% of people with audioprofiles. One of the most common types of autosomal-
severe to profound congenital autosomal-recessive nonsyn- dominant nonsyndromic deafness is high-frequency hearing
dromic deafness in many world populations.20 More than 100 loss as a result of KCNQ4 mutations at the DFNA2 locus.30 Expres-
different deafness-causing mutations are described, and several sion patterns of autosomal-dominant nonsyndromic deafness–
are common in specific ethnic groups.21 For example, the related genes in the cochlea are demonstrated in Figure 148-4.
35delG mutation predominates in populations of European
descent22; this mutation has a carrier frequency in the Midwest- DFNA2 (High-Frequency Hearing Loss). Autosomal-dominant
ern United States of 2.5%.23 For comparison, in the Ashkenazi high-frequency hearing loss can be the consequence of muta-
Jewish population, the most common mutation is the 167delT; tions in a variety of genes that include KCNQ4 (DFNA2), DFNA5
its carrier frequency is approximately 4%.24 In Japanese popula- (DFNA5), COCH (DFNA9), and POU4F3 (DFNA15). Mutations
tions, the 235delC mutation is the most common deafness- in many of these genes cause autosomal-dominant deafness
causing allele variant of GJB2.25 through a dominant-negative mechanism of action.30-32 One
The DFNB1 auditory phenotype is varied, although homo- example is deafness at the DFNA2 locus, which is caused by
zygosity for protein-truncating mutations is generally associated dominant-negative mutations in KCNQ4.30,31 KCNQ4 is orga-
with impaired gap junction activity and moderate to profound nized into 14 exons that encode a protein with six transmem-
deafness.21-26 With missense mutations, the degree of residual brane domains and a P-loop to confer Κ+ ion selectivity to the
hearing can be substantially greater.21 Most frequently, the loss channel pore.31 A voltage sensor in the fourth transmembrane
is symmetric between ears and does not progress over the long domain drives a conformational change that leads to channel
term. Temporal bone anomalies are not part of the DFNB1 opening. KCNQ4 subunits are typically organized into homotet-
phenotype, which obviates the need for routine temporal bone ramers to form functional channels.31
imaging. The G285S allele was the first DFNA2 mutation identified,
Genetic testing is available to diagnose GJB2-related deaf- and a mouse model carrying the orthologous mutation (equiva-
ness and is warranted, because the relative contribution of this lent to the human G285S allele variant) has been generated.33
gene to the total genetic deafness mutation load is high. Muta- The substitution of a serine for a glycine affects the first highly
tion screening facilitates genetic counseling and prediction of conserved glycine in a GYG signature sequence of the P-loop of
the chance of recurrence. It also provides prognostic informa- the channel pore, and it abolishes channel function by prevent-
tion, because several studies have shown that cochlear implant ing correct subunit assembly. Impaired KCNQ4 function in the
recipients with GJB2-related deafness do very well.27 inner ear affects Κ+ ion recycling. Normally, mechanosensory
FIGURE 148-4. Schematic illustration of cochlear duct cross-section includes an enlarged representation of two important cochlear structures (A and B)
and shows the cochlear expression pattern of genes related to deafness. A, Inset illustrates the stereocilia tip link, mechanotransduction channel, and interac-
tion between anchoring proteins Harmonin-b, MYO1C, CDH23, and PCDH15. B, The gap junction and its constituents. Three-dimensional view of a connexon
hexamer composed of six connexin monomers; each connexin encoded by GJB2 is also known as a connexin 26 molecule, one of which is highlighted. Gap
junctions are composed of two connexons in adjacent cells. Small molecules can pass through the gap junction pore from one cytoplasm to another without
having to cross two cell membranes. 1, Inner hair cells: ACTG1, CDH23, CLDN14, GJA1, GIPC3, ILDR1, KCNQ4, LOXHD1, MYH14, MYO3A, MYO6, MYO7A,
MYO15A, PCDH15, POU4F3, PTPRQ, OTOF, RDX, SERPINB6, STRC, TFCP2L3, TJP2, TMC1, TMHS, TRIOBP, USH1C, and WFS1. 2, Outer hair cells: ACTG1,
CCDC50, CDH23, CLDN14, GIPC3, GJA1, ILDR1, KCNQ4, LOXHD1, MYH9, MYH14, MYO3A, MYO6, MYO7A, MYO15A, OTOF, PCDH15, POU4F3, PTPRQ, PRES,
RDX, STRC, SLC26A5, TFCP2L3, TJP2, TMC1, TMHS, TRIOBP, USH1C, and WFS1. 3, Supporting cells: CLDN14, ESRRB, GJA1, GJB2, GJB6, MYH14, PCDH15,
SLC26A4, TFCP2L3, TMPRSS3, and WFS1. 4, Stereocilia: CDH23, DFNB18, ESPN, PCDH15, STRC, TMIE, and WHRN. 5, Interdental cells: ATP6B1, GJA1,
GJB2, TFCP2L3, and WFS1. 6, Spiral limbus: COCH, COL9A1, CRYM, ESRRB, GJB2, GJB3, and GJB6. 7, Tectorial membrane: COL11A2 OTOA, OTOG, and
TECTA. 8, Cochlear nerve: CCDC50, ESRRB, and GJB3. 9, Spiral ganglion: ESRRB, GIPC3, GJB1, KCNQ4, MPZ, NDP, NDRG1, OTOF, PCDH15, PJVK, PMP22,
SBF2, SLC26A4, TMPRSS3, and WFS1. 10, Reissner's membrane: ESRRB, MYH9, MYH14, POU3F4A, TFCP2L3, and WFS1. 11, Stria vascularis: ATP6B1,
BSND, CCDC50, CLCNKA, CLCNKB, DFNA5, EDN3, ESRRB, GJB2, GJB6, KCNE1, KCNQ1, MITF, MYH14, TFCP2L3, and TMPRSS3. 12, Marginal cells: KCNE1
and KCNQ1. 13, Spiral prominence: ESRRB, MYH14, SLC26A4, and WFS1. 14, Spiral ligament: COCH, COL9A1, CRYM, ESRRB, GJB2, GJB3, GJB6, MYH9,
MYH14, POU3F4, and WFS1. (Modified from Morton CC, Nance WE: Newborn hearing screening: a silent revolution. N Engl J Med 2006;354:2154-64. A, Modified
from Muller U: Harmonin mutations cause mechanotransduction defects in cochlear hair cells. Neuron 2009;62:375-387. B, Modified from Smith RJH: Sensorineural
hearing loss in children. Lancet 2005;365:879-890.)
transduction leads to an increase in cytosolic Κ+ in the outer DFNA8/12 and DFNA13 (Midfrequency Hearing Loss). Identi-
hair cells of the cochlea, the major site of KCNQ4 expression. fication of phenotype-genotype correlations is crucial in
KCNQ4 channels expressed in the base of these cells transport determining the etiology of autosomal-dominant SNHL,34
Κ+ extracellularly, where the ion is taken up by supporting cells and it has implications for prognostic and therapeutic out-
and is cycled back into the scala media.30 The consequence of comes. Some correlations are very robust, such as the low-
abnormal KCNQ4 function is apoptosis of the outer hair cells, frequency audioprofile associated with WFS1-related hearing
and the clinical manifestation of this damage is hearing loss that loss (DFNA6/14/38)35 and the “cookie-bite” (midfrequency)
is progressive and biased to the high frequencies.30 audioprofile associated with TECTA-related hearing loss
TABLE 148-4. Autosomal-Dominant Nonsyndromic Hearing Loss

DFNA1 5q31 DIAPH1 Postlingual low-frequency SNHL (first decade)220,221
DFNA2A 1p34 KCNQ4 Postlingual high-frequency SNHL (second decade)30,31
DFNA2B 1p35.1 GJB3 Postlingual high-frequency SNHL (first decade)222
DFNA3A† 13q11-q12 GJB2 Prelingual high-frequency SNHL18,223
DFNA3B 13q12 GJB6 Unknown224
DFNA4 19q13 MYH14 Postlingual SNHL with a flat or gently downsloping audioprofile225,226
CEACAM16 Unknown227
DFNA5 7p15 DFNA5 Postlingual high-frequency SNHL (first decade)228,229
DFNA6/14/38‡ 4p16.1 WFS1 Prelingual low-frequency SNHL230-232
DFNA8/12† 11q22-24 TECTA Prelingual midfrequency SNHL36
DFNA9 14q12-q13 COCH Postlingual high-frequency SNHL (second decade)233,234
DFNA10 6q22-23 EYA4 Postlingual SNHL with a flat or gently downsloping audioprofile
(third or fourth decade)235,236
DFNA11 11q12.3-q21 MYO7A Postlingual SNHL (first decade)169,237
DFNA13 6p21 COL11A2 Postlingual midfrequency SNHL (second decade)238,239
DFNA15 5q31 POU4F3 Postlingual high-frequency SNHL240-244
DFNA17 22q MYH9
DFNA20/26 17q25 ACTG1
DFNA22 6q13 MYO6
DFNA25 12q21-24 SLC17A8 Postlingual high-frequency SNHL245,246
DFNA28 8q22 GRHL2 Postlingual SNHL with a flat or gently downsloping audioprofile175,247
DFNA36 9q13-q21 TMC1
DFNA39 4q21.3 DSPP Postlingual high-frequency SNHL248
DFNA44 3q28 CCDC50 Postlingual SNHL that is moderate in all frequencies249
DFNA48 12q13-q14 MYO1A Postlingual SNHL250,251
DFNA50 7q32.2 MIRN96 Postlingual, mild to profound, progressive SNHL252,253
DFNA51 9q21 TJP2 Postlingual high-frequency SNHL254
DFNA64 12q24.31-32 SMAC/DIABLO Postlingual moderate to severe SNHL255
†Most autosomal-dominant loci cause postlingual hearing impairment. Some exceptions are DFNA3, DFNA8, and DFNA12.
‡DFNA6/14 is noteworthy because the hearing loss primarily affects the low frequencies.
(DFNA8/12),36 whereas other correlations, such as high- DFNA13 families and were predicted to affect the triple helical

frequency hearing loss, are more difficult to define. Hearing domain of the collagen protein.43,44 A Col11a2−/− mouse model
loss at the DFNA8/12 locus is unusual among dominant forms, displayed moderate to severe hearing loss and an enlarged
because midfrequencies are predominantly affected, it is con- tectorial membrane attributable to disorganized and widely
genital, and it is nonprogressive.37 The causative gene at this spaced collagen fibrils.44 Defects in genes that encode compo-
locus, α-tectorin (TECTA), was identified in Austrian DFNA837 nents of the collagenous and noncollagenous regions of the
and Belgian DFNA1236 families. In both families, missense tectorial membrane can induce autosomal-dominant midfre-
mutations were identified that are thought to have a dominant- quency hearing impairment.
negative effect that leads to disruption of the structure of the
tectorial membrane.36,39 DFNA6/14/38 (Low-Frequency Hearing Loss). Mutations in the
α-Tectorin is the major noncollagenous component of the Wolfram syndrome 1 gene (WFS1) at the DFNA6/14/38
tectorial membrane of the inner ear. A mouse mutant gener- locus are a common cause of low-frequency SNHL. WFS1
ated with a TECTA missense mutation showed elevated neural was originally identified in human disease as a cause of Wol-
thresholds, broadened neural tuning, and decreased sensitivity fram syndrome, an autosomal-recessive neurodegenerative dis-
of the tip of the neural tuning curve, indicating that the tecto- order comprising diabetes mellitus, optic atrophy, and often
rial membrane enables the motion of the basilar membrane to deafness.45 Later, WFS1 was implicated in autosomal-dominant
optimally drive the inner hair cells at their best frequency.40 NSHL at the DFNA6/14 locus in six families, segregating
TECTA has also been implicated in recessive deafness at the delayed-onset, slowly progressive, low-frequency SNHL.45 These
DFNB21 locus.41,42 Hearing loss in these families was also con- families all carried missense mutations located in a region of
genital, but it was severe to profound across all frequencies exon 8 that encodes the C-terminal domain.46 Although the
rather than restricted to the midfrequencies. protein is known to contain nine putative transmembrane
DFNA13 is a related form of dominant hearing impairment domains, its function and role in causing low-frequency SNHL
also characterized by initial midfrequency loss and disruption remain unclear. One of the original WFS1 mutations, V779M,
of the tectorial membrane. In this case, missense mutations was identified in 1 of 336 control individuals.47 This frequency
were identified in the COL11A2 gene of American and Dutch is comparable to that of heterozygous carriers of Wolfram
TABLE 148-5. X-Linked Nonsyndromic Hearing Loss

DFNX1 Xq22.3 PRPS1 Prelingual profound SNHL in all frequencies256
DFNX2 Xq21.1 POU3F4 Mixed variable prelingual hearing loss that progresses
to profound hearing loss in all frequencies53
DFNX4 Xp22.12 SMPX Prelingual progressive, severe SNHL in all frequencies257
syndrome, which has been estimated to be 0.3% to 1%.48 SYNDROMIC HEARING
Because an increased risk of SNHL had been reported for these
carriers,48 it was predicted that WFS1 was a common cause of
IMPAIRMENT
low-frequency SNHL. This assumption has been supported by Syndromic forms of hereditary SNHL (Table 148-7) are less
the subsequent discovery of frequent WFS1 mutations in fami- common than nonsyndromic forms. Syndromic hearing impair-
lies with low-frequency SNHL from different populations.49,50 ment refers to deafness that cosegregates with other features to
form a recognizable constellation of findings known as a syn-
X-Linked Nonsyndromic Hearing Impairment drome. Sensorineural deafness has been associated with more
X-linked nonsyndromic hearing impairment accounts for less than 400 syndromes. A discussion of a few of the more common
than 2% of NSHL.51 Five loci and three causative genes have syndromes follows.
been identified (Table 148-5). Reexamination of the original
family used to map DFN1 has revealed other cosegregating fea-
tures, including mental retardation. This type of deafness is AUTOSOMAL-DOMINANT SYNDROMIC
now recognized as a form of X-linked syndromic hearing loss.52 HEARING IMPAIRMENT
Of the remaining DFN loci, DFN3 is most common and is due
to mutations in a transcription factor called POU3F453; it mani- Branchio-oto-renal Syndrome
fests as congenital stapes fixation with radiologic findings that Melnick coined the term branchio-oto-renal (BOR) syndrome in
include widening of the lateral internal auditory canal and dila- 1975 to describe the cosegregation of branchial, otic, and renal
tion of the vestibule.54 Hearing loss is usually mixed, and stape- anomalies in deaf individuals.63 Inheritance is autosomal domi-
dectomy is typically attended by a perilymph gusher.55 The nant, penetrance is nearly 100%, and prevalence is estimated at
hearing impairment associated with the other loci is variable.56,57 1 in 40,000 newborns.64 BOR affects 2% of profoundly deaf
children.64 Otologic findings can involve the external, middle,
Mitochondrial Nonsyndromic Hearing Impairment or inner ear. External ear anomalies include preauricular pits
Mitochondrial nonsyndromic deafness can be caused by various (82%) or tags, auricular malformations (32%), microtia, and
mtDNA mutations, although the 1555 A-to-G mtDNA has been external auditory canal narrowing65,66; middle ear anomalies
characterized best (Table 148-6). As mentioned earlier, this include ossicular malformation (fusion, displacement, underde-
mutation is also associated with aminoglycoside ototoxicity. As velopment), facial nerve dehiscence, absence of the oval window,
a cause of nonsyndromic deafness, the phenotype is similar to and reduction in the size of the middle ear cleft65; and inner
aminoglycoside ototoxicity with a mild, high-frequency loss that ear anomalies include cochlear hypoplasia and dysplasia.67
shows progression.58 The loss is generally of later onset in indi- Enlargement of the cochlear or vestibular aqueducts may be
viduals who have not been exposed to aminoglycosides.3 seen66 as may hypoplasia of the lateral semicircular canal.67
Presbycusis, or age-related hearing loss, also may have a Hearing impairment is the most common feature of BOR
mitochondrial basis.59-62 Because mtDNA mutations accumulate syndrome and is reported in almost 90% of affected individu-
at several times the rate of nuclear DNA mutations, mitochon- als.64 The loss can be conductive (30%) or sensorineural (20%)
drial function ultimately may be impaired, resulting in age- but is most often mixed (50%). It is severe in one third of indi-
related cochlear dysfunction.60 In support of this hypothesis, an viduals and is progressive in one quarter.64 Branchial anomalies
increase in the mtDNA mutation load has been shown in aged occur in the form of laterocervical fistulas, sinuses, and cysts;
cochlea.62 renal anomalies range from agenesis to dysplasia and are found
TABLE 148-6. Mitochondrial Nonsyndromic Hearing Loss

Gene Symbol Mutation Phenotype*
MTRNR1 961 (different Aminoglycoside induced/worsened
mutations) Often secondary to aminoglycoside use with variable severity and
highly variable penetrance141,258
MTRNR1 c.1494 C>T Aminoglycoside induced/worsened
MTRNR1 c.1555 A>G Aminoglycoside induced/worsened
MTTS1 c.7445 A>G Palmoplantar keratoderma
Variably severe hearing loss with highly variable penetrance259-262
MTTS1 c.7472 ins C Neurologic dysfunction includes ataxia, dysarthria, and myoclonus
MTTS1 c.7510 T>C No additional symptoms reported
MTTS1 c.7511 T>C No additional symptoms reported
TABLE 148-7. Syndromic Forms of Hearing Loss

Syndrome or Disease/ Syndrome or Disease/
Locus Name Location Gene* Locus Name Location Gene*
Autosomal Dominant Usher syndrome
Branchio-oto-renal USH1A 14q32 Unknown270,271
syndrome
USHIB 11q13.5 MYO7A118
BOR1 8q13.3 EYA168
USH1C 11p15.1 USH1C272-274
BOR2 19q13.3 SIX569
USH1D 10q22.1 CDH2339,275,276
1q31 Unknown263
USH1E 21q21 Unknown277
BOR3 14q21.3-q24.3 SIX170,264
USH1F 10q21-q22 PCDH1547,278
Waardenburg
syndrome USH1G 17q24-q25 SANS279,280
WS1 2q35 PAX388 USH1H 15q22-q23 Unknown281
WS2† 3p14.1-p12.3 MITF 89
USH2A 1q41 USH2A119,282
SNAI290 USH2B 3p23-p24.2 Unknown283
WS3 (Klein- 2q35 PAX391 USH2C 5q14.3-q21.3 VLGR1284,285
Waardenburg
syndrome) USH2D 9q32 WHRN286
WS4† 13q22 EDNRB 92 USH3 3q21-q25 USH3A287,288
265
10q24.31 PDZD7289
Shah-Waardenburg or 20q13.2-q13.3 EDN3
Waardenburg Jervell and Lange-
syndrome– Nielsen syndrome
Hirschsprung disease JLNS1 11p15.5 KCNQ1108,109
22q13 SOX1093
JLNS2 21q22.1-q22.2 KCNE1110
Stickler syndrome
Biotinidase deficiency 3p25 BTD290
SS1 12q13.11-q13.2 COL2A179
Refsum disease 10pter-p11.2 PAHX291
SS2 1p21 COL11A180 6q22-q24 PEX7122
SS3 6p21.3 COL11A281 Alport syndrome 2q36-2q37 COL4A3/
6q13 COL9A182 COL4A4292
1p34.2 COL9A2266
X-Linked
Neurofibromatosis
Alport syndrome Xq22 COL4A5126
NF2 22q12 NF2267
Mohr-Tranebjaerg Xq22 TIMM8A293
Treacher Collins syndrome
syndrome
Norrie disease Xp11.3 NDP294,295
TCOF1 5q32-q33.1 TCOF1268
Mitochondrial
Autosomal Recessive
MELAS and MIDD mtDNA MTTL1296,297
Pendred syndrome
MERRF mtDNA MTTK298-300
PDS 7q21-q34 SLC26A4/PDS98
Kearns-Sayre mtDNA Several large
PDS 5q35.1 FOXI1106 syndrome deletions136
PDS 1q23.2 KCNJ10269 MIDD mtDNA Several large
deletions/
duplication301
†Although Waardenburg syndrome (WS) is usually inherited in an autosomal-dominant manner, sometimes WS2 can be inherited in an autosomal-
recessive manner. WS4 is always inherited in an autosomal-recessive manner.
MELAS, mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with red ragged fibers; MIDD, mater-
nally inherited diabetes and deafness; mtDNA, mitochondrial DNA.
in 25% of individuals.64 Less common phenotypic findings Neurofibromatosis Type 2
include lacrimal duct aplasia, short palate, and retrognathia.64 Neurofibromatosis type 2 (NF2) is characterized by the devel-
One causative gene is EYA1, the human homologue of the opment of bilateral vestibular schwannomas and other intracra-
Drosophila eyes absent gene.68 The gene contains 16 exons that nial and spinal tumors that include schwannomas, meningiomas,
encode for 559 amino acids.68 EYA1 mutations are found in gliomas, and ependymomas. In addition, patients may have
approximately 25% of patients with a BOR phenotype, and this posterior subcapsular lenticular opacities. Diagnostic criteria
phenotype is hypothesized to reflect a reduction in the amount include 1) bilateral vestibular schwannomas that usually develop
of the EYA1 protein. Mutations in two additional genes, SIX1 by the second decade of life, or 2) a family history of NF2 in
and SIX5, also have been shown more recently to cause BOR a first-degree relative, plus one of the following: unilateral
syndrome.69,70 Both genes act within the genetic network of the vestibular schwannomas before age 30 or any two of meningi-
EYA and PAX genes to regulate organogenesis. oma, glioma, schwannoma, or juvenile posterior subcapsular
lenticular opacities/juvenile cortical cataract. The causative

gene is a 17-exon gene that codes for a 595–amino acid protein Waardenburg Syndrome
named merlin on chromosome 22q12.71 Merlin is a tumor sup- In 1951, Waardenburg published an article that defined an
pressor that regulates the actin cytoskeleton.72,73 Although its auditory-pigmentary disease.86 Now known as Waardenburg syn-
mechanism of action is not completely understood, microarray drome (WS), it is classified under four types and has an aggre-
analysis has identified numerous other genes that become gate incidence of 1 per 10,000 to 1 per 20,000 population.87
deregulated during tumorigenesis.74 WS1 is recognized by SNHL; white forelock; pigmentary distur-
The incidence of NF2 is 1 per 40,000 to 90,000 population.73 bances of the iris; and dystopia canthorum, a specific displace-
Hearing loss is usually high frequency and sensorineural; ment of the inner canthi and lacrimal puncti.86 Other features
vertigo, tinnitus, and facial nerve paralysis may be associated include synophrys, broad nasal root, hypoplasia of the alae
findings. The diagnosis rests on the clinical and family history, nasi, patent metopic suture, and a square jaw. WS1 is caused by
physical examination, and imaging studies (magnetic reso- mutations in PAX3, a DNA-binding transcription factor homol-
nance imaging). Treatment of the vestibular schwannomas ogous to mouse Pax-3, the gene implicated in the Splotch
usually consists of surgery, although Gamma Knife surgery is mouse mutant.88 PAX3 is expressed in neural crest cells in early
considered in selected cases.75 Auditory brainstem implants development, and strial melanocytes are absent in affected
have been used with success in patients with vestibular individuals.88
schwannomas, although their use is limited if the patient has a WS2 is distinguished from WS1 by the absence of dystopia
history of Gamma Knife treatment.75,76 canthorum. Approximately 15% of WS2 cases are caused by
mutations in MITF, a transcription factor also involved in mela-
Stickler Syndrome nocyte development.89 Mutations in SNAI2, a zinc-finger tran-
In 1965, Stickler described a family followed at the Mayo Clinic scription factor expressed in migratory neural crest cells, have
for five generations that segregated syndromic features that also been shown to cause WS2.90 WS3 is also called Klein-
included myopia, clefting, and hearing loss.77 The disease, now Waardenburg syndrome, and it is characterized by WS1 features
known eponymously as Stickler syndrome (SS), has an incidence with the addition of hypoplasia or contracture of the upper
of 1 per 10,00078 and is caused by mutations in the COL2A1, limbs. PAX3 is the causative gene.91 WS4 is also known as Shah-
COL11A2, or CO11A1 genes that encode for the constituent Waardenburg syndrome, and it involves the association of WS
proteins of type II and type XI collagen.79-82 On the basis of with Hirschsprung disease. Three genes have been implicated:
criteria set forth by Snead and Yates,83 the diagnosis of SS endothelin 3 (EDN3), endothelin receptor B gene (EDNRB),
requires 1) a congenital vitreous anomaly, and 2) any three of and SOX10.92,93 Although WS types 1 through 3 are inherited
the following: myopia with onset before age 6 years, rhegmatog- as dominant diseases, WS of the fourth type is autosomal reces-
enous retinal detachment or paravascular pigmented lattice sive (see Table 148-7).
degeneration, joint hypermobility with abnormal Beighton The hearing loss in WS shows considerable variability
score, SNHL (audiometric confirmation), or midline clefting. between and within families. Congenital hearing impairment is
Other manifestations include craniofacial anomalies such as present in 36% to 66.7% of cases of WS1 versus 57% to 85% of
midfacial flattening, mandibular hypoplasia, a short upturned cases of WS2.87 Most commonly, the loss affects individuals with
nose, or a long philtrum. Micrognathia is common; if severe, it more than one pigmentation abnormality and is profound,
leads to the Robin sequence with cleft palate (28% to 65%).84 bilateral, and stable over time. Audiogram configuration varies,
Clefting may be complete, with a U-shaped cleft palate second- and low-frequency loss is more common. Nadol and Merchant94
ary to Robin sequence, but it is more commonly limited to a examined the inner ear of a 76-year-old woman with WS1 and
submucous cleft.85 found intact neurosensory structures only in the basal turn of
SS1 is caused by mutations in COL2A1.79 This phenotype the cochlea. Temporal bone imaging is typically normal,
includes the classic ocular findings with a “membranous” vitre- although cochlear hypoplasia and malformation of the semicir-
ous. SS2 is due to missense or in-frame deletion mutations in cular canals can be found.95 Risk chance prediction of the
COL11A2,81 and it is unique in that no ocular abnormalities findings associated with WS is difficult because of variability in
are present, because COL11A2 is not expressed in the vitreous. disease expression.
SS3 is caused by mutations in COL11A2, COL9A1, and
COL9A2.81,82,266 The vitreous in these patients shows irregularly Treacher Collins Syndrome
thickened fiber bundles that may be visualized on slit-lamp Treacher Collins syndrome is an autosomal-dominant syn-
examination.80,83 drome characterized by abnormalities of craniofacial develop-
The hearing loss associated with SS can be conductive, sen- ment. The phenotype includes maldevelopment of the maxilla
sorineural, or mixed. If it is conductive, the loss typically reflects and mandible with abnormal canthi placement, ocular colobo-
the eustachian tube dysfunction that commonly occurs with mas, choanal atresia, and conductive hearing loss secondary to
palatal clefts. The incidence of SNHL increases with age. Its ossicular fixation.96 The causative gene is TCOF, which encodes
pathogenesis is incompletely understood, but possible mecha- for the protein treacle.96
nisms include primary neurosensory deficits because of altera-
tions in the pigmented epithelium of the inner ear or AUTOSOMAL-RECESSIVE SYNDROMIC
abnormalities of inner ear collagen (see Fig. 148-4).84 Computed HEARING IMPAIRMENT
tomography has not shown gross structural abnormalities.
Patients with SS3 tend to have moderate to severe hearing Pendred Syndrome
loss, whereas patients with SS1 have either normal hearing or The most common syndromic form of hereditary SNHL,
only a mild impairment; patients with SS2 fall in between.78 Pendred syndrome (PS), was described by Pendred in 1896.97
The ocular findings in SS are the most prevalent feature The condition is autosomal recessive, and affected individuals
and warrant special discussion.85 Most affected individuals are also have goiter.98 The prevalence of PS is estimated at 7.5 to
myopic,83 but they may also have vitreoretinal degeneration, 10 per 100,000 individuals, suggesting that the syndrome may
retinal detachment, cataract, and blindness.77 Retinal detach- account for 10% of hereditary deafness.98 The hearing loss is
ment leading to blindness is the most severe ocular complication usually congenital and severe to profound, although progressive
and affects approximately 50% of individuals with SS.84 Detach- mild to moderate SNHL is sometimes seen.98 Bilateral dilation
ment typically occurs in adolescence or early adulthood. of the vestibular aqueduct is common and may be accompanied
by cochlear hypoplasia. Most cases of PS result from mutations vestibular dysfunction, and retinal degeneration that begins in
in the SLC26A4 gene that encodes an anion transporter known the third to fourth decade; and type 3 is characterized by pro-
as pendrin, which is expressed in the inner ear (see Fig. 148-4), gressive hearing loss, variable vestibular dysfunction, and vari-
thyroid, and kidney.99 Expression of SLC26A4 has been shown able onset of retinitis pigmentosa. Within each subtype, genetic
throughout the endolymphatic duct and sac, in distinct areas of heterogeneity is found, and numerous subtypes are recognized,
the utricle and saccule, and in the external sulcus region within although the two most common forms are Usher syndrome
the developing cochlea.100 Pendrin is thought to be involved in type 1B (USH1B) and Usher syndrome type 2A (USH2A),
chloride and iodide transport and not sulfate transport.101 which account for 75% to 80% of the Usher syndromes.117
Affected individuals develop goiter in their second decade, USH1B accounts for 75% of Usher syndrome type 1 cases and
although they usually remain euthyroid.99 Thyroid dysfunction is caused by mutations in an unconventional myosin called
can be shown with a perchlorate discharge test, in which radio- MYO7A.118 USH2A is the most common form, and the causative
active iodide and perchlorate are administered. Mutations in gene encodes a 1551–amino acid protein named usherin, a
SLC26A4 prevent rapid movement of iodide from the thyrocyte putative extracellular matrix molecule.119 Numerous other
to the colloid, and perchlorate blocks the Na/I symporter that genes have been implicated in Usher syndrome subtypes, and
moves iodide from the bloodstream into the thyrocyte. The net these are listed in Table 148-7. Cochlear expression patterns of
effect is that iodide in the thyrocyte washes back into the blood- Usher syndrome–related genes are shown in Figure 148-4.
stream in affected individuals, with a release of greater than
10% radioactivity considered diagnostic for PS.97,102 The sensi- Biotinidase Deficiency
tivity of this test is low, which makes genetic testing the pre- Biotinidase deficiency is secondary to an absence of the water-
ferred diagnostic method.97 The hearing impairment is usually soluble B-complex vitamin biotin. Biotin covalently binds to
prelingual, bilateral, and profound, although it can be progres- four carboxylases that are essential for gluconeogenesis, fatty
sive.97 Radiologic studies always show a temporal bone anomaly, acid synthesis, and catabolism of several branched-chain amino
either dilated vestibular aqueducts or Mondini dysplasia.97,103 acids. If biotinidase deficiency is not recognized and corrected
Mutations in SLC26A4 also cause a type of nonsyndromic by daily addition of biotin to the diet, affected individuals
autosomal-recessive deafness called DFNB4.104,105 Whether the develop neurologic features such as seizures, hypertonia, devel-
phenotype is syndromic or nonsyndromic may reflect the opmental delay, ataxia, and visual problems. In at least 75% of
degree of residual function in the abnormal protein. PS and children who become symptomatic, SNHL develops and can be
DFNB4 can be diagnosed by screening this gene for mutations. profound and persistent even after treatment is initiated.120
More recently, mutations in the transcription factor FOXI1 have Cutaneous features are also present and include a skin rash,
also been shown to cause PS in patients heterozygous for a alopecia, and conjunctivitis. With treatment that consists of
mutation in SLC26A4.106 biotin replacement, the neurologic and cutaneous manifesta-
tions resolve; however, the hearing loss and optic atrophy are
Jervell and Lange-Nielsen Syndrome usually irreversible. If a child is brought to medical attention
In 1957, Jervell and Lange-Nielsen described a syndrome char- with episodic or progressive ataxia and progressive sensorineu-
acterized by congenital deafness, prolonged QT interval, and ral deafness, with or without neurologic or cutaneous symp-
syncopal attacks.107 Long QT syndrome itself can be dominantly toms, biotinidase deficiency should be considered. To prevent
or recessively inherited. The dominant disease is called Romano- metabolic coma, diet and treatment should be initiated as soon
Ward syndrome. It is more common and does not include the as possible.120,121 If untreated, 75% of affected infants develop
deafness phenotype.107 The recessive disease is known as Jervell hearing loss that can be profound, and it persists despite the
and Lange-Nielsen syndrome (JLNS). subsequent initiation of treatment.120
JLNS is genetically heterogeneous, and mutations in KVLQT1
and KCNE1 cause this phenotype.108-110 These genes encode for Refsum Disease
subunits of a potassium channel expressed in the heart and Refsum disease is a postlingual, severe, progressive SNHL asso-
inner ear. Hearing impairment is due to changes in endolymph ciated with retinitis pigmentosa, peripheral neuropathy, cere-
homeostasis caused by malfunction of this channel, and it is bellar ataxia, and elevated protein levels in the cerebrospinal
congenital, bilateral, and severe to profound.108-110 Although fluid without an increase in the number of cells.122 It is caused
the prevalence of JLNS among children with congenital deaf- by defective phytanic acid metabolism, and the diagnosis is
ness is only 0.21%,111 it is an important diagnosis to consider established by determining the serum concentration of phy-
because of its cardiac manifestations. The prolonged QT inter- tanic acid. Two genes, PHYH and PEX7, have been implicated
val can lead to ventricular arrhythmias, syncopal episodes, and in most cases of Refsum disease, although a few patients exist
death in childhood.111 Effective treatment with β-adrenergic in whom mutations have not been found.122 Although Refsum
blockers reduces mortality rate from 71% to 6%.111 disease is extremely rare, it is important that it be considered
in the evaluation of a deaf person because it can be easily
Usher Syndromes treated with dietary modification and plasmapheresis.
The Usher syndromes are a genetically and clinically heteroge-
neous group of diseases characterized by SNHL, retinitis pig- X-LINKED SYNDROMES
mentosa, and often vestibular dysfunction.112 The incidence is
estimated at 4.4 per 100,000 population in the United States, Alport Syndrome
and 3% to 6% of congenitally deaf individuals carry this diag- Alport syndrome is a disease of type IV collagen that is mani-
nosis.113 This estimate has recently been revised upward to 1 fested by hematuric nephritis, hearing impairment, and ocular
per 6000 in the United States,114 where it causes 50% of con- changes. The inheritance pattern, although predominantly
comitant deafness and blindness.113 X-linked (~80%), can be autosomal recessive or dominant.123
Three clinical variants of Usher syndrome are recog- Prevalence is estimated at 1 per 5000 in the United States, and
nized.115,116 Type 1 is phenotypically distinguished by the pres- a significant proportion of renal transplant patients have Alport
ence of severe to profound congenital hearing loss, vestibular syndrome.124 Diagnostic criteria include at least three of the
dysfunction, and retinitis pigmentosa that develops in child- following four characteristics: 1) positive family history of
hood; type 2 is distinguished by moderate to severe congenital hematuria with or without chronic renal failure, 2) progressive
hearing loss, with uncertainty related to progression, no high-tone sensorineural deafness, 3) typical eye lesion (anterior
lenticonus and/or macular flecks), and 4) histologic changes involves progressive external ophthalmoplegia, atypical retinal

of the glomerular basement membrane of the kidney.125 pigmentation, and heart block that typically starts before age
Mutations in COL4A5 are the cause of X-linked Alport syn- 20.137,138 SNHL is present in 50% of patients with KSS,60,134 and
drome.126 Type IV collagen is the major component of base- temporal bone histopathologic findings show cochleosaccular
ment membranes and is formed by the trimerization of various degeneration.136
combinations of six type IV collagen genes. Deficiency of this MIDD is another syndromic mitochondrial disease that
protein results in complete or partial deficiency of the trimer- affects an estimated 0.5% to 2.8% of diabetic patients.139 The
ized 3-4-5 complex in the basement membranes of the kidney, hearing loss occurs late and is progressive, bilateral, and high
cochlea, and eye.126 More than 300 disease-causing mutations frequency; its presence is correlated with the level of hetero-
of COL4A5 have been identified, and 9.5% to 18% arise de plasmy for the 3243 A-to-G mtDNA mutation.60,133,140
novo.124,127 Susceptibility to aminoglycoside ototoxicity is also mater-
The disease phenotype is more pronounced in males, as nally inherited. It is caused by the 1555 A-to-G mtDNA muta-
would be expected for X-linked diseases. Gross or microscopic tion, a nucleotide change found in 17% to 33% of individuals
hematuria is the hallmark of disease, and all males ultimately with aminoglycoside-induced hearing loss.141,142 This mutation
have end-stage renal disease, although the rate of progression changes the 12S rRNA gene, altering its structure to make
depends on the underlying mutation.128 Ocular manifestations it more similar to bacterial rRNA, the natural target of amino-
are present in one third of patients and are characterized by glycosides.141,142 Hearing loss develops even when aminoglyco-
anterior lenticonus, an anomaly in which the central portion sides are administered at normal doses, and residual thresholds
of the lens protrudes into the anterior chamber of the eye, vary widely among individuals. Hearing losses can be seen
causing myopia.128 End-stage renal disease develops before age months after aminoglycoside exposure. Outer hair cells in the
30 in patients with anterior lenticonus.124 Maculopathy and basal turn of the cochlea are affected first, but damage eventu-
corneal lesions may also be found in patients with Alport syn- ally extends to include apical outer hair cells and inner hair
drome. Diffuse esophageal leiomyomatosis has been associated cells.143 The same mutation causes nonsyndromic mitochon-
with deletion mutations of COL4A5 and COL4A6.125,128 drial hearing loss.3
Hearing impairment is common in Alport syndrome and is
usually a symmetric, high-frequency sensorineural loss that can
be detected by late childhood and that progresses to involve all PATIENT MANAGEMENT
frequencies.128 Pathogenesis is thought to be related to the loss
of the 3-4-5 network, which is important for radial tension on DIAGNOSIS
the basilar membrane. Diagnosis currently relies on clinical The evaluation of a deaf patient should involve a team of
and histopathologic confirmation, although genetic confirma- health care professionals that includes an audiologist, clinical
tion can allow the stratification and prediction of severity of the genet icist, ophthalmologist, and otolaryngologist, with the
disease phenotype. otolaryngologist most frequently coordinating overall care. A
well-performed history, physical examination, and audiologic
Mohr-Tranebjaerg Syndrome evaluation are keys to assessing the cause of hearing loss.144
Mohr-Tranebjaerg syndrome was first described in a large Nor- Broadly speaking, the goal in the evaluation of individuals with
wegian family with apparent progressive postlingual nonsyn- hearing loss is to determine whether the hearing loss is envi-
dromic hearing impairment and classified as DFN1.129 ronmental (acquired) or genetic and, if genetic, whether it is
Reevaluation of this family revealed additional findings, nonsyndromic or syndromic hearing loss; these answers will
however, including visual disability, dystonia, fractures, and guide further workup and counseling.
mental retardation—an indication that this form of hearing The American College of Medical Genetics has released
impairment is syndromic rather than nonsyndromic.52 The genetic evaluation guidelines for the diagnosis of congenital
gene for this syndrome, TIMM8A, is involved in the transloca- hearing loss.145 Specific details of the family history that should
tion of proteins from the cytosol across the inner mitochondrial be covered include a pedigree with attention to consanguinity
membrane system and into the mitochondrial matrix.130,131 and hearing status of first-degree relatives. Ethnicity, inheritance
patterns, audiometric characteristics, and an inquiry into syn-
dromic versus nonsyndromic features are necessary.145 To assess
MITOCHONDRIAL SYNDROMES for the presence of a syndrome-related to hearing loss, questions
Mitochondrial diseases typically cause a phenotype in tissues and physical examination regarding endocrine abnormalities
with high energy demands, such as muscle, retina, brainstem, (diabetes, thyroid nodules), pigmentary anomalies (white fore-
pancreas, and cochlea.58,60 The process by which mitochondrial lock, heterochromic irides), visual anomalies (retinitis pigmen-
diseases lead to SNHL is debated and is confounded by the tosa, retinal detachment), craniofacial anomalies (dystopia
demonstration that nuclear modifier genes have an impact on canthorum, aural atresia, cleft palate, branchial anomalies),
the outcome.132 Syndromic mitochondrial diseases are usually cardiac manifestations (syncope, arrhythmias, sudden death),
multisystemic, and hearing loss is present in 70% of affected indi- and renal anomalies.145,146 The patient history and physical
viduals.60 Examples include MELAS (mitochondrial enceph- examination also should include a search for acquired causes
alopathy, lactic acidosis, and strokelike episodes) syndrome, of hearing loss, such as intrauterine infections, meningitis,
MERRF (myoclonic epilepsy with red ragged fibers) syndrome, hypoxia, and ototoxic drugs. The most frequent intrauterine
Kearns-Sayre syndrome (KSS), and maternally inherited diabe- infection causing deafness is cytomegalovirus infection, a diag-
tes and deafness (MIDD; see Table 148-7). nosis that can be made definitively only in the neonatal period
In MELAS syndrome, hearing loss is sensorineural, progres- before postnatally acquired CMV, which can confound the diag-
sive, and bilateral and more severely affects the higher nosis of a congenital infection.147
frequencies133-135; temporal bone histopathologic findings show The audiologic evaluation is a crucial part of the initial
severe atrophy of the stria vascularis.94 MERRF syndrome is diagnostic workup. In infants, behavioral testing is often impos-
characterized by hearing loss, ataxia, dementia, optic nerve sible. Electrophysiologic tests such as ABR and otoacoustic
atrophy, and short stature. In contrast to MELAS and MERRF, emissions provide a means of objectively documenting hearing
which are caused by point mutations in mtDNA, KSS is caused impairment and can be used to provide information regarding
by several large deletions.136 First described in 1958, KSS auditory thresholds. Behavioral tests can be used when infants
reach 6 months of age. A trained pediatric audiologist can adoption of new genomic sequencing technologies has been
measure hearing losses of 20 dB in the better-hearing ear. The especially rapid for genetic hearing loss, because the need has
frequency of testing is usually decided on a case-by-case basis, been great. Interested readers are referred elsewhere for a
although Tomaski and Grundfast148 recommend a more rigid more in-depth review of these genomic technologies and their
schedule in cases of confirmed SNHL in children. They recom- impact on genetic testing for hearing loss.153
mend testing every 3 months in the first year of life, followed Several recent studies have shown the effectiveness of com-
by every 6 months during the preschool years and once a year prehensive, multigene panels for diagnosis of NSHL using
while in school. various different MPS technologies.154-157 This research has
To determine the cause of hearing loss, past recommenda- rapidly been translated into clinical diagnostic tests. In general,
tions included a battery of tests such as thyroid function studies, multigene panels sequence the more than 60 known NSHL
urinalysis, electrocardiogram, ophthalmologic consultation, genes and often include genes that cause Usher and Pendred
and temporal bone imaging. Today, however, genetic testing syndromes. Besides the technology used, differences among
should be ordered instead. Indeed, after a detailed history, these panels typically include the number of genes offered and
physical examination, and audiometric analysis, genetic testing the turnaround time. A listing of clinical laboratories that offer
should be the next test ordered in the evaluation of an indi- these tests is available on the Genetic Testing Registry (http://
vidual with apparent NSHL. This approach limits unnecessary www.ncbi.nlm.nih.gov/gtr).
costly and time-consuming tests and makes focused and Another method for sequencing all known deafness genes
directed testing possible. Apparent syndromic cases can be is whole-exome sequencing, whereby the exons of all 20,000 or so
evaluated with tests relevant to the syndrome on the differen- genes in the human genome are sequenced simultaneously,
tial diagnosis. A notable exception to this is cases of Usher and analysis is focused on known deafness genes. This method
syndrome, which commonly manifest as a nonsyndromic mimic has been effectively used for diagnosis of NSHL.158 These new
prior to progression of retinopathy. For this reason, several diagnostic methods have already improved the diagnostic rate
NSHL screening panels include the genes that cause Usher for NSHL, and it will only improve further as the methods are
syndrome. refined.
Whole-exome and multigene MPS panels are alike in that
Genetic Testing they use similar technology and in both cases uncover many
In the United States, congenital SNHL occurs about three possible causative mutations. This makes interpretation of
times more frequently than Down syndrome, six times more the variants to determine the causative mutation paramount.
frequently than spina bifida, and more than 50 times more However, two key differences exist between multigene panel
frequently than phenylketonuria, making it the most frequently testing and whole-exome sequencing: 1) cost will be highest for
occurring birth defect.149 An estimated 4000 infants are born whole-exome sequencing, and multigene panels are less expen-
each year with severe to profound bilateral hearing loss,150,151 sive, although this difference will be erased or reduced in the
and another 8000 are born with unilateral or mild to moderate next several years; and 2) secondary genomic findings—for
bilateral SNHL.5 At least 50% of congenital hearing loss cases instance, genetic risk factors for other diseases—are more of a
have an underlying genetic cause; this is a compelling reason concern as more genes of the genome are sequenced, which
to provide genetic testing services to all children diagnosed raises ethical concerns that are reduced or mitigated with more
with congenital hearing loss. The implementation of the Early focused genetic tests such as multigene panels.
Hearing Detection and Intervention (EHDI) program in the Based on these advances in genetic testing technologies, the
United States and similar universal hearing screening programs current approach to evaluation of an individual with NSHL
around the world has facilitated increased detection, genetic should proceed as follows: history, physical examination, and
diagnosis, and intervention for these children.152 In addition, audiometry are followed by genetic testing using a multigene
advances in genetic technologies have led to an increase in panel or whole-exome sequencing. In cases of apparent syn-
the availability of genetic diagnostic services for infants with dromic hearing loss, pertinent clinical examination findings
hearing loss.152 and tests will guide genetic screening, typically by single genes,
Genetic testing has undergone rapid change since the com- to arrive at a diagnosis.
pletion of the Human Genome Project, which took 11 years to
sequence the entire genome of a single person—at a cost of
roughly $3 billion and with the coordination of several large
PRENATAL TESTING
sequencing centers. Today, the same sequence can be generated Prenatal diagnosis for some forms of hereditary hearing loss is
in 24 hours for several thousand dollars because of the advent of technically possible by analysis of DNA extracted from fetal
new genomic sequencing technologies called massively parallel cells. Fetal material can be obtained by amniocentesis at 15 to
sequencing (MPS). These advances are especially applicable to a 18 weeks’ gestation or by chorionic villus sampling at 10 to 12
genetic disorder with extreme genetic heterogeneity, such as weeks’ gestation. Gestational age is expressed as menstrual
hearing loss. As could be expected, similarly vast changes in weeks calculated from the first day of the last normal menstrual
scale have also occurred in the clinical genetic testing arena: the period or by ultrasound measurements. The deafness-causing
first genetic tests for deafness that became available in the 1990s allele of a deaf family member must be identified before pre-
focused on detecting a single mutation; in the late 1990s and natal testing can be performed.
early 2000s, sequencing of a single exon or whole gene was Requests for prenatal testing for conditions such as hearing
made available; and in the last 5 years, multigene screening loss are uncommon. Differences in perspective may exist among
panels, and now whole-exome (every exon of the genome) and medical professionals and within families regarding the use of
whole-genome sequencing, have become available on a clinical prenatal testing, particularly if the testing is being considered
basis. for the purpose of pregnancy termination rather than early
As described above, more than 60 different genes with more diagnosis. Although most centers would consider decisions
than a thousand reported mutations are known to cause NSHL. about prenatal testing to be the choice of the parents, careful
The previous status quo, searching for the genetic cause of discussion of these issues is appropriate. Preimplantation
deafness in an individual by assaying for a single causative muta- genetic diagnosis may be available for families in which the
tion or by sequencing a single hearing loss gene, was under- deafness-causing mutation has been identified in a deaf family
standably a low-yield endeavor. It is for this reason that the member.
TREATMENT CULTURAL CONSIDERATIONS

When a diagnosis is made, directed treatment is possible. Having discussed the management of a patient with hearing
Appropriate consultation and management of the associated loss, a mention of the Deaf (written with a capital “D”) culture
conditions should be considered. A diagnosis of Jervell and is necessary. Individuals who identify with the Deaf culture
Lange-Nielsen syndrome may necessitate therapy with β-blockers consider themselves as culturally Deaf and understandably wish
to reduce the chance of life-threatening arrhythmias. If Usher to preserve their culture. Generally, members of the Deaf com-
syndrome is considered, close ophthalmologic follow-up is munity look on genetics negatively.164,165 A study by Middleton
mandatory. In contrast, a genetic diagnosis of GJB2-related and colleagues165 found that 55% of deaf respondents at a
deafness requires no other consultation, because no comorbid- conference on the “Deaf Nation” thought genetics would do
ity is associated. more harm than good, and 46% thought that the use of genet-
Genetic counseling should be offered to patients and their ics may devalue deaf people. This response may represent
families by a professional trained in clinical genetics. Most sample bias, however, because a study by Stern and associates164
otolaryngologists do not have an adequate understanding of found that most deaf individuals have a positive view of the field
recurrence chances to provide accurate data.159 Green and of genetics. These studies highlight an important point—that
coworkers23 have estimated the recurrence chance for a normal- attitudes about hearing loss, or more specifically deafness, are
hearing couple with a deaf child to have a second deaf child at culturally dependent. The medical community must under-
17.5%, much higher than earlier estimates of 9.8%. Factors that stand and appreciate this perspective and must try to offer
explain this increase include an improved ability to identify advances in diagnosis, counseling, and treatment in a nonjudg-
syndromic forms of deafness and a decrease in congenitally mental manner.
acquired deafness.23 A well-trained genetic counselor can also
help to interpret medical data and potential treatment options.
Counseling sessions should occur before and after genetic
ACKNOWLEDGMENT
testing has been done. We thank Katy Nash Krahn, MS, CGC, at the University of Iowa
Management of hearing loss should be directed at provid- Hospitals and Clinics Department of Pediatrics for her help in
ing appropriate amplification as soon as possible. Hearing aids preparing the pedigrees of the various forms of hearing impair-
provide significant benefits to individuals with mild to moder- ment. We also thank Hiu Tung Wong for help in preparing the
ate hearing loss. Cochlear implantation is becoming an figures. This work was supported in part by National Institutes
increasingly important option for individuals with severe to of Health grants DC02842 and DC03544 (R.J.H.S.).
profound deafness.27 The Joint Committee on Infant Hearing
recommends that diagnosis and rehabilitation be instituted by
6 months of age to minimize delays in communicative lan- For a complete list of references, see expertconsult.com.
guage development. Coupled with this recommendation, uni-
versal screening is becoming a reality throughout the United SUGGESTED READINGS
States. For the detection of congenital hearing loss, the U.S.
government has facilitated the creation of EHDI programs for Abdelhak S, Kalatzis V, Heilig R, et al: A human homologue of
the Drosophila eyes absent gene underlies branchio-oto-renal (BOR)
early newborn hearing screening (http://www.infanthearing syndrome and identifies a novel gene family. Nat Genet 15:157–164,
.org). EHDI programs aim to screen neonates for hearing loss 1997.
immediately after birth or before hospital discharge. The pro- Chang EH, Van Camp G, Smith RJ: The role of connexins in human
grams include a follow-up arm to confirm hearing loss in neo- disease. Ear Hear 24:314–323, 2003.
nates who do not pass the initial screening test so that Der Kaloustian VM: Congenital anomalies of ear, nose and throat. In
intervention can be initiated to prevent delayed language Tewfik TL, Der Kaloustian VM, editors: Introduction to medical genetics
acquisition.160 and dysmorphology, New York, 1997, Oxford University Press.
EHDI program guidelines include three phases: screening, Duncan RD, Prucka S, Wiatrak BJ, et al: Pediatric otolaryngologists’ use
audiologic evaluation, and intervention. In the first phase, new- of genetic testing. Arch Otolaryngol Head Neck Surg 133:231–236,
2007.
borns are screened with otoacoustic emissions and ABR to Ensink RJ, Huygen PL, Cremers CW: The clinical spectrum of mater-
detect permanent bilateral or unilateral sensory or conductive nally transmitted hearing loss. Adv Otorhinolaryngol 61:172–183,
hearing loss that averages 30 to 40 dB SPL or more in the fre- 2002.
quency region important for speech recognition. In the second Everett LA, Glaser B, Beck JC, et al: Pendred syndrome is caused by
phase, all infants who do not pass the initial screen are evalu- mutations in a putative sulphate transporter gene (PDS). Nat Genet
ated with a series of diagnostic audiologic tests, preferably 17:411–422, 1997.
before age 3 months. In the third phase, early intervention Fischel-Ghodsian N: Genetic factors in aminoglycoside toxicity. Ann N
services are implemented before age 6 months for all infants Y Acad Sci 884:99–109, 1999.
with confirmed hearing loss.160 Green GE, Scott DA, McDonald JM, et al: Performance of cochlear
implant recipients with GJB2-related deafness. Am J Med Genet 109:
167–170, 2002.
PREVENTION OF HEARING IMPAIRMENT Gross O, Netzer KO, Lambrecht R, et al: Meta-analysis of genotype-
phenotype correlation in X-linked Alport syndrome: impact on clini-
Although experimental methodologies to restore auditory cal counselling. Nephrol Dial Transplant 17:1218–1227, 2002.
function are currently being developed and tested,161-163 no Joint Committee on Infant Hearing, American Academy of Audiology,
effective therapy is clinically available. Existing measures must American Academy of Pediatrics, American Speech-Language-Hear-
focus on the prevention of hearing loss to decrease the fre- ing Association, and Directors of Speech and Hearing Programs in
quency of acquired and genetic hearing loss.1 Improved imple- State Health and Welfare Agencies: Year 2000 position statement:
mentation of vaccination programs in developing nations, principles and guidelines for early hearing detection and interven-
tion programs. Joint Committee on Infant Hearing, American
avoidance of exacerbating factors such as noise, and focused Academy of Audiology, American Academy of Pediatrics, American
genetic counseling and health education in populations with Speech-Language-Hearing Association, and Directors of Speech and
a high incidence of consanguinity are several methods that Hearing Programs in State Health and Welfare Agencies. Pediatrics
would reduce the incidence of acquired and hereditary hear- 106:798–817, 2000.
ing loss. Jorde L: Medical genetics, St Louis, 1995, Mosby-Year Book.
Kelsell DP, Dunlop J, Stevens HP, et al: Connexin 26 mutations in Shibata SB, Raphael Y: Future approaches for inner ear protection and
hereditary non-syndromic sensorineural deafness. Nature 387:80–83, repair. J Commun Disord 43:295–310, 2010.
1997. Smith RJ, Bale JF, Jr, White KR: Sensorineural hearing loss in children.
Kubisch C, Schroeder BC, Friedrich T: KCNQ4, a novel potassium Lancet 365:879–890, 2005.
channel expressed in sensory outer hair cells, is mutated in dominant Strachan T, Read AP: Human molecular genetics, ed 4, New York, 2011,
deafness. Cell 96:437–446, 1999. Garland Science.
Morton CC, Nance WE: Newborn hearing screening: a silent revolu- Tekin M, Arnos KS, Pandya A: Advances in hereditary deafness. Lancet
tion. N Engl J Med 354(20):2151–2164, 2006. 358:1082–1090, 2001.
Morton NE: Genetic epidemiology of hearing impairment. Ann N Y Van Camp G, Smith RJ: Hereditary Hearing Loss Homepage. http://
Acad Sci 630:16–31, 1991. hereditaryhearingloss.org.
Nowak CB: Genetics and hearing loss: A review of Stickler syndrome. Yang T, Vidarsson H, Rodrigo-Blomqvist S, et al: Transcriptional control
J Commun Disord 31:437–453, 1998. of SLC26A4 is involved in Pendred syndrome and nonsyndromic
Pennings RJ, Wagenaar M, van Aarem A, et al: Hearing impairment in enlargement of vestibular aqueduct (DFNB4). Am J Hum Genet 80:
Usher’s syndrome. Adv Otorhinolaryngol 61:184–191, 2002. 1055–1063, 2007.
Read AP, Newton VE: Waardenburg syndrome. J Med Genet 34:656–665,
1997.
148 | GENETIC SENSORINEURAL HEARING LOSS 2300.e1
28. Petersen MB: Non-syndromic autosomal-dominant deafness. Clin
REFERENCES Genet 62(1):1–13, 2002.
1. Smith RJ, Bale JF, Jr, White KR: Sensorineural hearing loss in 29. Liu X, Xu L: Nonsyndromic hearing loss: an analysis of audio-
children. Lancet 365(9462):879–890, 2005. grams. Ann Otol Rhinol Laryngol 103(6):428–433, 1994.
2. Morton CC, Nance WE: Newborn hearing screening–a silent revo- 30. Kubisch C, Schroeder BC, Friedrich T, et al: KCNQ4, a novel
lution. N Engl J Med 354(20):2151–2164, 2006. potassium channel expressed in sensory outer hair cells, is
3. Estivill X, Govea N, Barcelo E, et al: Familial progressive sensori- mutated in dominant deafness. Cell 96(3):437–446, 1999.
neural deafness is mainly due to the mtDNA A1555G mutation 31. Coucke PJ, Van Hauwe P, Kelley PM, et al: Mutations in the
and is enhanced by treatment of aminoglycosides. Am J Hum Genet KCNQ4 gene are responsible for autosomal dominant deafness in
62(1):27–35, 1998. four DFNA2 families. Hum Mol Genet 8(7):1321–1328, 1999.
4. Gorga M, Worthington D: Stimulus calibration in ABR measure- 32. Denoyelle F, Lina-Granade G, Plauchu H, et al: Connexin 26 gene
ments. In Jacobson JT, editor: The Auditory Brainstem Response, linked to a dominant deafness. Nature 393(6683):319–320, 1998.
London, 1985, Taylor & Francis. 33. Kharkovets T, Dedek K, Maier H, et al: Mice with altered KCNQ4
5. Maki-Torkko EM, Lindholm PK, Vayrynen MR, et al: Epidemiol- K+ channels implicate sensory outer hair cells in human progres-
ogy of moderate to profound childhood hearing impairments in sive deafness. EMBO J 25(3):642–652, 2006.
northern Finland. Any changes in ten years? Scand Audiol 27(2): 34. Huygen PPR, Cremers C: Audiometric profiles associated with
95–103, 1998. genetic nonsyndromal hearing impairment: a review and pheno-
6. Fortnum HM, Summerfield AQ, Marshall DH, et al: Prevalence type analysis. In Martini MS, Read D, et al, editors: Genes, Hearing
of permanent childhood hearing impairment in the United and Deafness: From Molecular Biology to Clinical Practice, London, UK,
Kingdom and implications for universal neonatal hearing screen- 2007, Informa HealthCare, pp 185–204.
ing: questionnaire based ascertainment study. Br Med J 323(7312): 35. Cryns K, Pfister M, Pennings RJ, et al: Mutations in the WFS1 gene
536–540, 2001. that cause low-frequency sensorineural hearing loss are small non-
7. Barsky-Firkser L, Sun S: Universal newborn hearing screenings: a inactivating mutations. Hum Genet 110(5):389–394, 2002.
three-year experience. Pediatrics 99(6):E4, 1997. 36. Verhoeven K, Van Laer L, Kirschhofer K, et al: Mutations in the
8. Parving A: The need for universal neonatal hearing screening– human alpha-tectorin gene cause autosomal dominant non-
some aspects of epidemiology and identification. Acta Paediatrica syndromic hearing impairment. Nat Genet 19(1):60–62, 1998.
88(432):69–72, 1999. 37. Kirschhofer K, Kenyon JB, Hoover DM, et al: Autosomal-dominant,
9. Vega Cuadri A, Alvarez Suarez MY, Blasco Huelva A, et al: Oto- prelingual, nonprogressive sensorineural hearing loss: localiza-
acoustic emissions screening as early identification of hearing loss tion of the gene (DFNA8) to chromosome 11q by linkage in an
in newborns [in Spanish]. Acta Otorrinolaringol Esp 52(4):273–278, Austrian family. Cytogenet Cell Genet 82(1-2):126–130, 1998.
2001. 38. Verhoeven K, Van Camp G, Govaerts PJ, et al: A gene for autoso-
10. Lin HC, Shu MT, Chang KC, et al: A universal newborn hearing mal dominant nonsyndromic hearing loss (DFNA12) maps to
screening program in Taiwan. Int J Pediat Otorhinolaryngol 63(3): chromosome 11q22-24. Am J Hum Genet 60(5):1168–1173, 1997.
209–218, 2002. 39. Bork JM, Peters LM, Riazuddin S, et al: Usher syndrome 1D and
11. Van Camp G SR: Hereditary Hearing Loss. Available at http:// nonsyndromic autosomal recessive deafness DFNB12 are caused
hereditaryhearingloss.org. by allelic mutations of the novel cadherin-like gene CDH23. Am J
12. Der Kaloustian VM, Kurban AK: Genetic diseases of the skin, Berlin– Hum Genet 68(1):26–37, 2001.
New York, 1979, Springer. 40. Legan PK, Lukashkina VA, Goodyear RJ, et al: A deafness muta-
13. Strachan T, Read AP: Human molecular genetics, ed 4, New York, tion isolates a second role for the tectorial membrane in hearing.
2011, Garland Science. Nat Neurosci 8(8):1035–1042, 2005.
14. Jorde LB, White RL, Carey JC: Medical genetics, St. Louis, 1995, 41. Mustapha M, Weil D, Chardenoux S, et al: An alpha-tectorin gene
Mosby. defect causes a newly identified autosomal recessive form of sen-
15. Li XC, Friedman RA: Nonsyndromic hereditary hearing loss. Oto- sorineural pre-lingual non-syndromic deafness, DFNB21. Hum
laryngol Clin North Am 35(2):275–285, 2002. Mol Genet 8(3):409–412, 1999.
16. Sundstrom RA, Van Laer L, Van Camp G, et al: Autosomal reces- 42. Meyer NC, Alasti F, Nishimura CJ, et al: Identification of three
sive nonsyndromic hearing loss. Am J Med Genet 89(3):123–129, novel TECTA mutations in Iranian families with autosomal reces-
1999. sive nonsyndromic hearing impairment at the DFNB21 locus. Am
17. Guilford P, Ben Arab S, Blanchard S, et al: A non-syndrome form J Med Genet Part A 143A(14):1623–1629, 2007.
of neurosensory, recessive deafness maps to the pericentromeric 43. Brown MR, Tomek MS, Van Laer L, et al: A novel locus for auto-
region of chromosome 13q. Nat Genet 6(1):24–28, 1994. somal dominant nonsyndromic hearing loss, DFNA13, maps to
18. Kelsell DP, Dunlop J, Stevens HP, et al: Connexin 26 mutations in chromosome 6p. Am J Hum Genet 61(4):924–927, 1997.
hereditary non-syndromic sensorineural deafness. Nature 387 44 McGuirt WT, Prasad SD, Griffith AJ, et al: Mutations in COL11A2
(6628):80–83, 1997. cause non-syndromic hearing loss (DFNA13). Nat Genet 23(4):413–
19. Steel KP: Perspectives: biomedicine. The benefits of recycling. 419, 1999.
Science 285(5432):1363–1364, 1999. 45. Inoue H, Tanizawa Y, Wasson J, et al: A gene encoding a trans-
20. Smith RJ, Robin NH: Genetic testing for deafness–GJB2 and membrane protein is mutated in patients with diabetes mellitus
SLC26A4 as causes of deafness. J Commun Disord 35(4):367–377, and optic atrophy (Wolfram syndrome). Nat Genet 20(2):143–148,
2002. 1998.
21. Kenneson A, Van Naarden Braun K, Boyle C: GJB2 (connexin 26) 46. Khan SY, Ahmed ZM, Shabbir MI, et al: Mutations of the RDX
variants and nonsyndromic sensorineural hearing loss: a HuGE gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum
review. Genet Med 4(4):258–274, 2002. Mutat 28(5):417–423, 2007.
22. Chang EH, Van Camp G, Smith RJ: The role of connexins in 47. Ahmed ZM, Riazuddin S, Bernstein SL, et al: Mutations of the
human disease. Ear Hear 24(4):314–323, 2003. protocadherin gene PCDH15 cause Usher syndrome type 1F. Am
23. Green GE, Scott DA, McDonald JM, et al: Carrier rates in the J Hum Genet 69(1):25–34, 2001.
midwestern United States for GJB2 mutations causing inherited 48. Ohata T, Koizumi A, Kayo T, et al: Evidence of an increased risk
deafness. JAMA 281(23):2211–2216, 1999. of hearing loss in heterozygous carriers in a Wolfram syndrome
24. Morell RJ, Kim HJ, Hood LJ, et al: Mutations in the connexin 26 family. Hum Genet 103(4):470–474, 1998.
gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive 49. Fukuoka H, Kanda Y, Ohta S, et al: Mutations in the WFS1 gene
deafness. N Engl J Med 339(21):1500–1505, 1998. are a frequent cause of autosomal dominant nonsyndromic low-
25. Abe S, Usami S, Shinkawa H, et al: Prevalent connexin 26 gene frequency hearing loss in Japanese. J Hum Genet 52(6):510–515,
(GJB2) mutations in Japanese. J Med Genet 37(1):41–43, 2000. 2007.
26. Choung YH, Moon SK, Park HJ: Functional study of GJB2 in 50. Hansen L, Eiberg H, Barrett T, et al: Mutation analysis of the
hereditary hearing loss. Laryngoscope 112(9):1667–1671, 2002. WFS1 gene in seven Danish Wolfram syndrome families; four new
27. Green GE, Scott DA, McDonald JM, et al: Performance of cochlear mutations identified. Eur J Hum Genet 13(12):1275–1284, 2005.
implant recipients with GJB2-related deafness. Am J Med Genet 51. Morton NE: Genetic epidemiology of hearing impairment. Ann N
109(3):167–170, 2002. Y Acad Sci 630:16–31, 1991.
2300.e2 PART VII | OTOLOGY, NEUROTOLOGY, AND SKULL BASE SURGERY
52. Tranebjaerg L, Schwartz C, Eriksen H, et al: A new X linked reces- 79. Ahmad NN, Ala-Kokko L, Knowlton RG, et al: Stop codon in the

sive deafness syndrome with blindness, dystonia, fractures, and procollagen II gene (COL2A1) in a family with the Stickler syn-
mental deficiency is linked to Xq22. J Med Genet 32(4):257–263, drome (arthro-ophthalmopathy). Proc Natl Acad Sci U S A 88(15):
1995. 6624–6627, 1991.
53. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, et al: Associa- 80. Richards AJ, Yates JR, Williams R, et al: A family with Stickler
tion between X-linked mixed deafness and mutations in the POU syndrome type 2 has a mutation in the COL11A1 gene resulting
domain gene POU3F4. Science 267(5198):685–688, 1995. in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.
54. Glasscock ME, 3rd: The stapes gusher. Arch Otolaryngol 98(2):82– Hum Mol Genet 5(9):1339–1343, 1996.
91, 1973. 81. Vikkula M, Mariman EC, Lui VC, et al: Autosomal dominant and
55. Cremers CW, Hombergen GC, Scaf JJ, et al: X-linked progressive recessive osteochondrodysplasias associated with the COL11A2
mixed deafness with perilymphatic gusher during stapes surgery. locus. Cell 80(3):431–437, 1995.
Arch Otolaryngol 111(4):249–254, 1985. 82. Van Camp G, et al: A new autosomal recessive form of Stickler
56. del Castillo I, Villamar M, Sarduy M, et al: A novel locus for non- syndrome is caused by a mutation in the COL9A1 gene. Am J Hum
syndromic sensorineural deafness (DFN6) maps to chromosome Genet 79(3):449–457, 2006.
Xp22. Hum Mol Genet 5(9):1383–1387, 1996. 83. Snead MP, Yates JR: Clinical and Molecular genetics of Stickler
57. Lalwani AK, Brister JR, Fex J, et al: A new nonsyndromic X-linked syndrome. J Med Genet 36(5):353–359, 1999.
sensorineural hearing impairment linked to Xp21.2. Am J Hum 84. Nowak CB: Genetics and hearing loss: a review of Stickler syn-
Genet 55(4):685–694, 1994. drome. J Commun Disord 31(5):437–453, 1998.
58. Usami S, Abe S, Kasai M, et al: Genetic and clinical features of 85. Webb AC, Markus AF: The diagnosis and consequences of Stickler
sensorineural hearing loss associated with the 1555 mitochondrial syndrome. Br J Oral Maxillofac Surg 40(1):49–51, 2002.
mutation. Laryngoscope 107(4):483–490, 1997. 86. Read AP, Newton VE: Waardenburg syndrome. J Med Genet 34(8):
59. Christensen K, Frederiksen H, Hoffman HJ: Genetic and environ- 656–665, 1997.
mental influences on self-reported reduced hearing in the old 87. Newton VE: Clinical features of the Waardenburg syndromes. Adv
and oldest old. J Am Geriatr Soc 49(11):1512–1517, 2001. Otorhinolaryngol 61:201–208, 2002.
60. Ensink RJ, Camp GV, Cremers CW: Mitochondrial inherited 88. Tassabehji M, Read AP, Newton VE, et al: Waardenburg’s syn-
hearing loss. Clin Otolaryngol Allied Sci 23(1):3–8, 1998. drome patients have mutations in the human homologue of the
61. Gates GA, Couropmitree NN, Myers RH: Genetic associations in Pax-3 paired box gene. Nature 355(6361):635–636, 1992.
age-related hearing thresholds. Arch Otolaryngol Head Neck Surg 89. Tassabehji M, Newton VE, Read AP: Waardenburg syndrome type
125(6):654–659, 1999. 2 caused by mutations in the human microphthalmia (MITF)
62. Jacobs HT: Mitochondrial deafness. Ann Med 29(6):483–491, 1997. gene. Nat Genet 8(3):251–255, 1994.
63. Melnick M, Bixler D, Silk K, et al: Autosomal dominant branchioo- 90. Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, et al:
torenal dysplasia. Birth Defects Orig Artic Ser 11(5):121–128, 1975. SLUG (SNAI2) deletions in patients with Waardenburg disease.
64. Smith RJ, Schwartz C: Branchio-oto-renal syndrome. J Commun Hum Mol Genet 11(25):3231–3236, 2002.
Disord 31(5):411–420; quiz 421, 1998. 91. Hoth CF, Milunsky A, Lipsky N, et al: Mutations in the paired
65. Kalatzis V, Petit C: Branchio-Oto-Renal syndrome. Adv Otorhinolar- domain of the human PAX3 gene cause Klein-Waardenburg syn-
yngol 56:39–44, 2000. drome (WS-III) as well as Waardenburg syndrome type I (WS-I).
66. Chen A, Francis M, Ni L, et al: Phenotypic manifestations of Am J Hum Genet 52(3):455–462, 1993.
branchio-oto-renal syndrome. Am J Med Genet 58(4):365–370, 92. Attie T, Till M, Pelet A, et al: Mutation of the endothelin-receptor
1995. B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet
67. Ceruti S, Stinckens C, Cremers CW, et al: Temporal bone anoma- 4(12):2407–2409, 1995.
lies in the branchio-oto-renal syndrome: detailed computed tomo- 93. Pingault V, Bondurand N, Kuhlbrodt K, et al: SOX10 mutations
graphic and magnetic resonance imaging findings. Otol Neurotol in patients with Waardenburg-Hirschsprung disease. Nat Genet
23(2):200–207, 2002. 18(2):171–173, 1998.
68. Abdelhak S, Kalatzis V, Heilig R, et al: A human homologue of 94. Nadol JB, Jr, Merchant SN: Histopathology and molecular genet-
the Drosophila eyes absent gene underlies branchio-oto-renal ics of hearing loss in the human. Int J Pediatr Otorhinolaryngol
(BOR) syndrome and identifies a novel gene family. Nat Genet 61(1):1–15, 2001.
15(2):157–164, 1997. 95. Oysu C, Oysu A, Aslan I, et al: Temporal bone imaging findings
69. Hoskins BE, Cramer CH, Silvius D, et al: Transcription factor SIX5 in Waardenburg’s syndrome. Int J Pediatr Otorhinolaryngol 58(3):
is mutated in patients with branchio-oto-renal syndrome. Am J 215–221, 2001.
Hum Genet 80(4):800–804, 2007. 96. Positional cloning of a gene involved in the pathogenesis of
70. Ruf RG, Xu PX, Silvius D, et al: SIX1 mutations cause branchio- Treacher Collins syndrome. The Treacher Collins Syndrome Col-
oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. laborative Group. Nat Genet 12(2):130–136, 1996.
Proc Natl Acad Sci U S A 101(21):8090–8095, 2004. 97. Stinckens C, Huygen PL, Van Camp G, et al: Pendred syndrome
71. Rouleau GA, Merel P, Lutchman M, et al: Alteration in a new gene redefined. Report of a new family with fluctuating and progressive
encoding a putative membrane-organizing protein causes neuro- hearing loss. Adv Otorhinolaryngol 61:131–141, 2002.
fibromatosis type 2. Nature 363(6429):515–521, 1993. 98. Everett LA, Glaser B, Beck JC, et al: Pendred syndrome is caused
72. Bashour AM, Meng JJ, Ip W, et al: The neurofibromatosis type 2 by mutations in a putative sulphate transporter gene (PDS). Nat
gene product, merlin, reverses the F-actin cytoskeletal defects in Genet 17(4):411–422, 1997.
primary human Schwannoma cells. Mol Cell Biol 22(4):1150–1157, 99. Kopp P: Pendred’s syndrome: identification of the genetic defect
2002. a century after its recognition. Thyroid 9(1):65–69, 1999.
73. Kang BS, Cooper DR, Devedjiev Y, et al: The structure of the 100. Everett LA, Morsli H, Wu DK, et al: Expression pattern of the
FERM domain of merlin, the neurofibromatosis type 2 gene mouse ortholog of the Pendred’s syndrome gene (Pds) suggests
product. Acta Crystallogr D Biol Crystallogr 58(Pt 3):381–391, 2002. a key role for pendrin in the inner ear. Proc Natl Acad Sci U S A
74. Welling DB, Lasak JM, Akhmametyeva E, et al: cDNA microarray 96(17):9727–9732, 1999.
analysis of vestibular schwannomas. Otol Neurotol 23(5):736–748, 101. Scott DA, Wang R, Kreman TM, et al: The Pendred syndrome
2002. gene encodes a chloride-iodide transport protein. Nat Genet
75. Bance M, Ramsden RT: Management of neurofibromatosis type 21(4):440–443, 1999.
2. Ear Nose Throat J 78(2):91–94, 96, 1999. 102. Campbell C, Cucci RA, Prasad S, et al: Pendred syndrome, DFNB4,
76. Sollmann WP, Laszig R, Marangos N: Surgical experiences in 58 and PDS/SLC26A4 identification of eight novel mutations and
cases using the Nucleus 22 multichannel auditory brainstem possible genotype-phenotype correlations. Hum Mutat 17(5):403–
implant. J Laryngol Otol Suppl (27):23–26, 2000. 411, 2001.
77. Stickler GB, Hughes W, Houchin P: Clinical features of hereditary 103. Phelps PD, Coffey RA, Trembath RC, et al: Radiological malforma-
progressive arthro-ophthalmopathy (Stickler syndrome): a survey. tions of the ear in Pendred syndrome. Clin Radiol 53(4):268–273,
Genet Med 3(3):192–196, 2001. 1998.
78. Admiraal RJ, Szymko YM, Griffith AJ, et al: Hearing impairment 104. Baldwin CT, Weiss S, Farrer LA, et al: Linkage of congenital, reces-
in Stickler syndrome. Adv Otorhinolaryngol 61:216–223, 2002. sive deafness (DFNB4) to chromosome 7q31 and evidence for
genetic heterogeneity in the Middle Eastern Druze population. 130. Jin H, May M, Tranebjaerg L, et al: A novel X-linked gene, DDP,
Hum Mol Genet 4(9):1637–1642, 1995. shows mutations in families with deafness (DFN-1), dystonia,
105. Li XC, Everett LA, Lalwani AK, et al: A mutation in PDS causes mental deficiency and blindness. Nat Genet 14(2):177–180,
non-syndromic recessive deafness. Nat Genet 18(3):215–217, 1998. 1996.
106. Yang T, Vidarsson H, Rodrigo-Blomqvist S, et al: Transcriptional 131. Koehler CM, Leuenberger D, Merchant S, et al: Human deafness
control of SLC26A4 is involved in Pendred syndrome and non- dystonia syndrome is a mitochondrial disease. Proc Natl Acad Sci U
syndromic enlargement of vestibular aqueduct (DFNB4). Am J S A 96(5):2141–2146, 1999.
Hum Genet 80(6):1055–1063, 2007. 132. Bykhovskaya Y, Yang H, Taylor K, et al: Modifier locus for mito-
107. Komsuoglu B, Goldeli O, Kulan K, et al: The Jervell and Lange- chondrial DNA disease: linkage and linkage disequilibrium
Nielsen syndrome. Int J Cardiol 47(2):189–192, 1994. mapping of a nuclear modifier gene for maternally inherited
108. Neyroud N, Tesson F, Denjoy I, et al: A novel mutation in the deafness. Genet Med 3(3):177–180, 2001.
potassium channel gene KVLQT1 causes the Jervell and Lange- 133. Usami S, Abe S, Akita J, et al: Sensorineural hearing loss associated
Nielsen cardioauditory syndrome. Nat Genet 15(2):186–189, 1997. with the mitochondrial mutations. Adv Otorhinolaryngol 56:203–
109. Tyson J, Tranebjaerg L, Bellman S, et al: IsK and KvLQT1: muta- 211, 2000.
tion in either of the two subunits of the slow component of the 134. Ensink RJ, Huygen PL, Cremers CW: The clinical spectrum of
delayed rectifier potassium channel can cause Jervell and Lange- maternally transmitted hearing loss. Adv Otorhinolaryngol 61:172–
Nielsen syndrome. Hum Mol Genet 6(12):2179–2185, 1997. 183, 2002.
110. Schulze-Bahr E, Wang Q, Wedekind H, et al: KCNE1 mutations 135. Zwirner P, Wilichowski E: Progressive sensorineural hearing loss
cause Jervell and Lange-Nielsen syndrome. Nat Genet 17(3):267– in children with mitochondrial encephalomyopathies. Laryngo-
268, 1997. scope 111(3):515–521, 2001.
111. Ocal B, Imamoglu A, Atalay S, et al: Prevalence of idiopathic long 136. Moraes CT, DiMauro S, Zeviani M, et al: Mitochondrial DNA dele-
QT syndrome in children with congenital deafness. Pediatr Cardiol tions in progressive external ophthalmoplegia and Kearns-Sayre
18(6):401–405, 1997. syndrome. N Engl J Med 320(20):1293–1299, 1989.
112. Keats BJ, Corey DP: The usher syndromes. Am J Med Genet 89(3): 137. Marin-Garcia J, Goldenthal MJ, Sarnat HB: Kearns-Sayre syn-
158–166, 1999. drome with a novel mitochondrial DNA deletion. J Child Neurol
113. Boughman JA, Vernon M, Shaver KA: Usher syndrome: definition 15(8):555–558, 2000.
and estimate of prevalence from two high-risk populations. 138. Katsanos KH, Pappas CJ, Patsouras D, et al: Alarming atrioven-
J Chronic Dis 36(8):595–603, 1983. tricular block and mitral valve prolapse in the Kearns-Sayre syn-
114. Kimberling WJ, Hildebrand MS, Shearer AE, et al: Frequency of drome. Int J Cardiol 83(2):179–181, 2002.
Usher syndrome in two pediatric populations: Implications for 139. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al: Maternally
genetic screening of deaf and hard of hearing children. Genet Med inherited diabetes and deafness: a multicenter study. Ann Intern
12(8):512–516, 2010. Med 134(9 Pt 1):721–728, 2001.
115. Petit C: Usher syndrome: from genetics to pathogenesis. Ann Rev 140. Newkirk JE, Taylor RW, Howell N, et al: Maternally inherited
Genomics Hum Genet 2:271–297, 2001. diabetes and deafness: prevalence in a hospital diabetic popula-
116. Reisser CF, Kimberling WJ, Otterstedde CR: Hearing loss in Usher tion. Diabet Med 14(6):457–460, 1997.
syndrome type II is nonprogressive. Ann Otol Rhinol Laryngol 141. Prezant TR, Agapian JV, Bohlman MC, et al: Mitochondrial ribo-
111(12 Pt 1):1108–1111, 2002. somal RNA mutation associated with both antibiotic-induced and
117. Pennings RJ, Wagenaar M, van Aarem A, et al: Hearing impair- non-syndromic deafness. Nat Genet 4(3):289–294, 1993.
ment in Usher’s syndrome. Adv Otorhinolaryngol 61:184–191, 2002. 142. Yoshida M, Shintani T, Hirao M, et al: Aminoglycoside-induced
118. Weil D, Blanchard S, Kaplan J, et al: Defective myosin VIIA gene hearing loss in a patient with the 961 mutation in mitochondrial
responsible for Usher syndrome type 1B. Nature 374(6517):60–61, DNA. ORL J Otorhinolaryngol Relat Spec 64(3):219–222, 2002.
1995. 143. Fischel-Ghodsian N: Genetic factors in aminoglycoside toxicity.
119. Eudy JD, Weston MD, Yao S, et al: Mutation of a gene encoding Pharmacogenomics 6(1):27–36, 2005.
a protein with extracellular matrix motifs in Usher syndrome type 144. ACMG: Genetics evaluation guidelines for the etiologic diagnosis
IIa. Science 280(5370):1753–1757, 1998. of congenital hearing loss. Genetic Evaluation of Congenital
120. Wolf B, Spencer R, Gleason T: Hearing loss is a common feature Hearing Loss Expert Panel. ACMG statement. Genet Med 4(3):162–
of symptomatic children with profound biotinidase deficiency. 171, 2002.
J Pediatr 140(2):242–246, 2002. 145. Greinwald JH, Jr, Hartnick CJ: The evaluation of children with
121. Heller AJ, Stanley C, Shaia WT, et al: Localization of biotinidase sensorineural hearing loss. Arch Otolaryngol Head Neck Surg
in the brain: implications for its role in hearing loss in biotinidase 128(1):84–87, 2002.
deficiency. Hear Res 173(1-2):62–68, 2002. 146. Tekin M, Arnos KS, Pandya A: Advances in hereditary deafness.
122. van den Brink DM, Brites P, Haasjes J, et al: Identification of PEX7 Lancet 358(9287):1082–1090, 2001.
as the second gene involved in Refsum disease. Am J Hum Genet 147. Green GE, Cunniff C: Genetic evaluation and counseling for con-
72(2):471–477, 2003. genital deafness. Adv Otorhinolaryngol 61:230–240, 2002.
123. Dagher H, Buzza M, Colville D, et al: A comparison of the clinical, 148. Tomaski SM, Grundfast KM: A stepwise approach to the diagnosis
histopathologic, and ultrastructural phenotypes in carriers of and treatment of hereditary hearing loss. Pediatric Clin North Am
X-linked and autosomal recessive Alport’s syndrome. Am J Kidney 46(1):35–48, 1999.
Dis 38(6):1217–1228, 2001. 149. White KR: The current status of EHDI programs in the United
124. Jais JP, Knebelmann B, Giatras I, et al: X-linked Alport syndrome: States. Ment Retard Dev Disabil Res Rev 9(2):79–88, 2003.
natural history in 195 families and genotype-phenotype correla- 150. Mohr PE, Feldman JJ, Dunbar JL: The societal costs of severe to
tions in males. J Am Soc Nephrol 11(4):649–657, 2000. profound hearing loss in the United States. Policy Anal Brief H Ser
125. Plant KE, Green PM, Vetrie D, et al: Detection of mutations in 2(1):1–4, 2000.
COL4A5 in patients with Alport syndrome. Hum Mutat 13(2):124– 151. Thompson DC, McPhillips H, Davis RL, et al: Universal newborn
132, 1999. hearing screening: summary of evidence. JAMA 286(16):2000–
126. Barker DF, Hostikka SL, Zhou J, et al: Identification of mutations 2010, 2001.
in the COL4A5 collagen gene in Alport syndrome. Science 152. White KR: Early hearing detection and intervention programs:
248(4960):1224–1227, 1990. opportunities for genetic services. Am J Med Genet Part A 130A(1):
127. Gross O, Netzer KO, Lambrecht R, et al: Meta-analysis of genotype- 29–36, 2004.
phenotype correlation in X-linked Alport syndrome: impact on 153. Shearer AE, Hildebrand MS, Sloan CM, et al: Deafness in the
clinical counselling. Nephrol Dial Transplant 17(7):1218–1227, genomics era. Hear Res 282(1-2):1–9, 2011.
2002. 154. Brownstein Z, Friedman LM, Shahin H, et al: Targeted genomic
128. Kashtan CE: Familial hematuric syndromes–Alport syndrome, capture and massively parallel sequencing to identify genes for
thin glomerular basement membrane disease and Fechtner/ hereditary hearing loss in Middle Eastern families. Genome Biol
Epstein syndromes. Contrib Nephrol (136):79–99, 2001. 12(9):R89, 2011.
129. Mohr J, Mageroy K: Sex-linked deafness of a possibly new type. 155. Tang W, Qian D, Ahmad S, et al: A low-cost exon capture method
Acta Genet Stat Med 10:54–62, 1960. suitable for large-scale screening of genetic deafness by the
massively-parallel sequencing approach. Genet Testing Mol Biomark- 178. Scott HS, Kudoh J, Wattenhofer M, et al: Insertion of beta-satellite

ers 16(6):536–542, 2012. repeats identifies a transmembrane protease causing both con-
156. Schrauwen I, Sommen M, Corneveaux JJ, et al: A sensitive and genital and childhood onset autosomal recessive deafness. Nat
specific diagnostic test for hearing loss using a microdroplet PCR- Genet 27(1):59–63, 2001.
based approach and next generation sequencing. Am J Med Genet 179. Yasunaga S, Grati M, Cohen-Salmon M, et al: A mutation in
Part A 161A(1):145–152, 2013. OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a
157. Shearer AE, DeLuca AP, Hildebrand MS, et al: Comprehensive nonsyndromic form of deafness. Nat Genet 21(4):363–369, 1999.
genetic testing for hereditary hearing loss using massively parallel 180. Chaib H, Place C, Salem N, et al: A gene responsible for a senso-
sequencing. Proc Natl Acad Sci U S A 107(49):21104–21109, 2010. rineural nonsyndromic recessive deafness maps to chromosome
158. Diaz-Horta O, Duman D, Foster J, 2nd, et al: Whole-exome 2p22-23. Hum Mol Genet 5(1):155–158, 1996.
sequencing efficiently detects rare mutations in autosomal reces- 181. Chaib H, Place C, Salem N, et al: Mapping of DFNB12, a gene for
sive nonsyndromic hearing loss. PloS One 7(11):e50628, 2012. a non-syndromal autosomal recessive deafness, to chromosome
159. Duncan RD, Prucka S, Wiatrak BJ, et al: Pediatric otolaryngolo- 10q21-22. Hum Mol Genet 5(7):1061–1064, 1996.
gists’ use of genetic testing. Arch Otolaryngol Head Neck Surg 133(3): 182. Ain Q, Nazli S, Riazuddin S, et al: The autosomal recessive non-
231–236, 2007. syndromic deafness locus DFNB72 is located on chromosome
160. Joint Committee on Infant Hearing, American Academy of Audi- 19p13.3. Hum Genet 122(5):445–450, 2007.
ology, American Academy of Pediatrics, et al: Year 2000 position 183. Rehman AU, Gul K, Morell RJ, et al: Mutations of GIPC3 cause
statement: principles and guidelines for early hearing detection nonsyndromic hearing loss DFNB72 but not DFNB81 that also
and intervention programs. Joint Committee on Infant Hearing, maps to chromosome 19p. Hum Genet 130(6):759–765, 2011.
American Academy of Audiology, American Academy of Pediat- 184. Charizopoulou N, Lelli A, Schraders M, et al: Gipc3 mutations
rics, American Speech-Language-Hearing Association, and Direc- associated with audiogenic seizures and sensorineural hearing loss
tors of Speech and Hearing Programs in State Health and Welfare in mouse and human. Nat Commun 2:201, 2011.
Agencies. Pediatrics 106(4):798–817, 2000. 185. Verpy E, Masmoudi S, Zwaenepoel I, et al: Mutations in a new
161. Shibata SB, Raphael Y: Future approaches for inner ear protection gene encoding a protein of the hair bundle cause non-syndromic
and repair. J Commun Disord 43(4):295–310, 2010. deafness at the DFNB16 locus. Nat Genet 29(3):345–349, 2001.
162. Akil O, Seal RP, Burke K, et al: Restoration of hearing in the 186. Ouyang XM, Xia XJ, Verpy E, et al: Mutations in the alternatively
VGLUT3 knockout mouse using virally mediated gene therapy. spliced exons of USH1C cause non-syndromic recessive deafness.
Neuron 75(2):283–293, 2012. Hum Genet 111(1):26–30, 2002.
163. Oshima K, Shin K, Diensthuber M, et al: Mechanosensitive hair 187. Jain PK, Lalwani AK, Li XC, et al: A gene for recessive nonsyn-
cell-like cells from embryonic and induced pluripotent stem cells. dromic sensorineural deafness (DFNB18) maps to the chromo-
Cell 141(4):704–716, 2010. somal region 11p14-p15.1 containing the Usher syndrome type
164. Stern SJ, Arnos KS, Murrelle L, et al: Attitudes of deaf and hard 1C gene. Genomics 50(2):290–292, 1998.
of hearing subjects towards genetic testing and prenatal diagnosis 188. Zwaenepoel I, Mustapha M, Leibovici M, et al: Otoancorin, an
of hearing loss. J Med Genet 39(6):449–453, 2002. inner ear protein restricted to the interface between the apical
165. Middleton A, Hewison J, Mueller RF: Attitudes of deaf adults surface of sensory epithelia and their overlying acellular gels, is
toward genetic testing for hereditary deafness. Am J Hum Genet defective in autosomal recessive deafness DFNB22. Proc Natl Acad
63(4):1175–1180, 1998. Sci U S A 99(9):6240–6245, 2002.
166. Dodson KM, Blanton SH, Welch KO, et al: Vestibular dysfunction 189. Khan SY, Ahmed ZM, Shabbir MI, et al: Mutations of the RDX
in DFNB1 deafness. Am J Med Genet Part A 155A(5):993–1000, 2011. gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum
167. del Castillo I, Villamar M, Moreno-Pelayo MA, et al: A deletion Mutat 28(5):417–423, 2007.
involving the connexin 30 gene in nonsyndromic hearing impair- 190. Schraders M, Lee K, Oostrik J, et al: Homozygosity mapping
ment. N Engl J Med 346(4):243–249, 2002. reveals mutations of GRXCR1 as a cause of autosomal-recessive
168. Guilford P, Ayadi H, Blanchard S, et al: A human gene responsible nonsyndromic hearing impairment. Am J Hum Genet 86(2):138–
for neurosensory, non-syndromic recessive deafness is a candidate 147, 2010.
homologue of the mouse sh-1 gene. Hum Mol Genet 3(6):989–993, 191. Shahin H, Walsh T, Sobe T, et al: Mutations in a novel isoform of
1994. TRIOBP that encodes a filamentous-actin binding protein are
169. Liu XZ, Walsh J, Mburu P, et al: Mutations in the myosin VIIA responsible for DFNB28 recessive nonsyndromic hearing loss. Am
gene cause non-syndromic recessive deafness. Nat Genet 16(2):188– J Hum Genet 78(1):144–152, 2006.
190, 1997. 192. Riazuddin S, Khan SN, Ahmed ZM, et al: Mutations in TRIOBP,
170. Wang A, Liang Y, Fridell RA, et al: Association of unconventional which encodes a putative cytoskeletal-organizing protein, are asso-
myosin MYO15 mutations with human nonsyndromic deafness ciated with nonsyndromic recessive deafness. Am J Hum Genet
DFNB3. Science 280(5368):1447–1451, 1998. 78(1):137–143, 2006.
171. Friedman TB, Liang Y, Weber JL, et al: A gene for congenital, 193. Wilcox ER, Burton QL, Naz S, et al: Mutations in the gene encod-
recessive deafness DFNB3 maps to the pericentromeric region of ing tight junction claudin-14 cause autosomal recessive deafness
chromosome 17. Nat Genet 9(1):86–91, 1995. DFNB29. Cell 104(1):165–172, 2001.
172. Pourova R, Janousek P, Jurovcik M, et al: Spectrum and frequency 194. Walsh T, Walsh V, Vreugde S, et al: From flies’ eyes to our ears:
of SLC26A4 mutations among Czech patients with early hearing mutations in a human class III myosin cause progressive nonsyn-
loss with and without enlarged vestibular aqueduct (EVA). Ann dromic hearing loss DFNB30. Proc Natl Acad Sci U S A 99(11):7518–
Hum Genet 74(4):299–307, 2010. 7523, 2002.
173. Naz S, Giguere CM, Kohrman DC, et al: Mutations in a novel 195. Mustapha M, Chouery E, Chardenoux S, et al: DFNB31, a reces-
gene, TMIE, are associated with hearing loss linked to the DFNB6 sive form of sensorineural hearing loss, maps to chromosome
locus. Am J Hum Genet 71(3):632–636, 2002. 9q32-34. Eur J Hum Genet 10(3):210–212, 2002.
174. Fukushima K, Ramesh A, Srisailapathy CR, et al: An autosomal 196. Mburu P, Mustapha M, Varela A, et al: Defects in whirlin, a PDZ
recessive nonsyndromic form of sensorineural hearing loss maps domain molecule involved in stereocilia elongation, cause deaf-
to 3p-DFNB6. Genome Res 5(3):305–308, 1995. ness in the whirler mouse and families with DFNB31. Nat Genet
175. Kurima K, Peters LM, Yang Y, et al: Dominant and recessive deaf- 34(4):421–428, 2003.
ness caused by mutations of a novel gene, TMC1, required for 197. Collin RW, Kalay E, Tariq M, et al: Mutations of ESRRB encoding
cochlear hair-cell function. Nat Genet 30(3):277–284, 2002. estrogen-related receptor beta cause autosomal-recessive nonsyn-
176. Jain PK, Fukushima K, Deshmukh D, et al: A human recessive dromic hearing impairment DFNB35. Am J Hum Genet 82(1):125–
neurosensory nonsyndromic hearing impairment locus is poten- 138, 2008.
tial homologue of murine deafness (dn) locus. Hum Mol Genet 198. Naz S, Griffith AJ, Riazuddin S, et al: Mutations of ESPN cause
4(12):2391–2394, 1995. autosomal recessive deafness and vestibular dysfunction. J Med
177. Veske A, Oehlmann R, Younus F, et al: Autosomal recessive non- Genet 41(8):591–595, 2004.
syndromic deafness locus (DFNB8) maps on chromosome 21q22 199. Ahmed ZM, Morell RJ, Riazuddin S, et al: Mutations of MYO6 are
in a large consanguineous kindred from Pakistan. Hum Mol Genet associated with recessive deafness, DFNB37. Am J Hum Genet
5(1):165–168, 1996. 72(5):1315–1322, 2003.
200. Schultz JM, Khan SN, Ahmed ZM, et al: Noncoding mutations of 223. Chaib H, Lina-Granade G, Guilford P, et al: A gene responsible
HGF are associated with nonsyndromic hearing loss, DFNB39. Am for a dominant form of neurosensory non-syndromic deafness
J Hum Genet 85(1):25–39, 2009. maps to the NSRD1 recessive deafness gene interval. Hum Mol
201. Borck G, Ur Rehman A, Lee K, et al: Loss-of-function mutations Genet 3(12):2219–2222, 1994.
of ILDR1 cause autosomal-recessive hearing impairment DFNB42. 224. Grifa A, Wagner CA, D’Ambrosio L, et al: Mutations in GJB6 cause
Am J Hum Genet 88(2):127–137, 2011. nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat
202. Riazuddin S, Ahmed ZM, Fanning AS, et al: Tricellulin is a tight- Genet 23(1):16–18, 1999.
junction protein necessary for hearing. Am J Hum Genet 79(6): 225. Chen AH, Ni L, Fukushima K, et al: Linkage of a gene for domi-
1040–1051, 2006. nant non-syndromic deafness to chromosome 19. Hum Mol Genet
203. Chen W, Kahrizi K, Meyer NC, et al: Mutation of COL11A2 causes 4(6):1073–1076, 1995.
autosomal recessive non-syndromic hearing loss at the DFNB53 226. Donaudy F, Snoeckx R, Pfister M, et al: Nonmuscle myosin heavy-
locus. J Med Genet 42(10):e61, 2005. chain gene MYH14 is expressed in cochlea and mutated in
204. Delmaghani S, del Castillo FJ, Michel V, et al: Mutations in the patients affected by autosomal dominant hearing impairment
gene encoding pejvakin, a newly identified protein of the afferent (DFNA4). Am J Hum Genet 74(4):770–776, 2004.
auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 227. Zheng J, Miller KK, Yang T, et al: Carcinoembryonic antigen-
38(7):770–778, 2006. related cell adhesion molecule 16 interacts with alpha-tectorin
205. Liu XZ, Ouyang XM, Xia XJ, et al: Prestin, a cochlear motor and is mutated in autosomal dominant hearing loss (DFNA4). Proc
protein, is defective in non-syndromic hearing loss. Hum Mol Genet Natl Acad Sci U S A 108(10):4218–4223, 2011.
12(10):1155–1162, 2003. 228. van Camp G, Coucke P, Balemans W, et al: Localization of a gene
206. Ahmed ZM, Masmoudi S, Kalay E, et al: Mutations of LRTOMT, for non-syndromic hearing loss (DFNA5) to chromosome 7p15.
a fusion gene with alternative reading frames, cause nonsyn- Hum Mol Genet 4(11):2159–2163, 1995.
dromic deafness in humans. Nat Genet 40(11):1335–1340, 2008. 229. Van Laer L, Huizing EH, Verstreken M, et al: Nonsyndromic
207. Du X, Schwander M, Moresco EM, et al: A catechol-O-methyl- hearing impairment is associated with a mutation in DFNA5. Nat
transferase that is essential for auditory function in mice and Genet 20(2):194–197, 1998.
humans. Proc Natl Acad Sci U S A 105(38):14609–14614, 2008. 230. Bespalova IN, Van Camp G, Bom SJ, et al: Mutations in the
208. Shabbir MI, Ahmed ZM, Khan SY, et al: Mutations of human Wolfram syndrome 1 gene (WFS1) are a common cause of low
TMHS cause recessively inherited non-syndromic hearing loss. frequency sensorineural hearing loss. Hum Mol Genet 10(22):2501–
J Med Genet 43(8):634–640, 2006. 2508, 2001.
209. Tlili A, Mannikko M, Charfedine I, et al: A novel autosomal reces- 231. Lesperance MM, Hall JW, 3rd, Bess FH, et al: A gene for autoso-
sive non-syndromic deafness locus, DFNB66, maps to chromo- mal dominant nonsyndromic hereditary hearing impairment
some 6p21.2-22.3 in a large Tunisian consanguineous family. Hum maps to 4p16.3. Hum Mol Genet 4(10):1967–1972, 1995.
Hered 60(3):123–128, 2005. 232. Young TL, Ives E, Lynch E, et al: Non-syndromic progressive
210. Kalay E, Li Y, Uzumcu A, et al: Mutations in the lipoma HMGIC hearing loss DFNA38 is caused by heterozygous missense muta-
fusion partner-like 5 (LHFPL5) gene cause autosomal recessive tion in the Wolfram syndrome gene WFS1. Hum Mol Genet
nonsyndromic hearing loss. Hum Mutat 27(7):633–639, 2006. 10(22):2509–2514, 2001.
211. Waryah AM, Rehman A, Ahmed ZM, et al: DFNB74, a novel auto- 233. Manolis EN, Yandavi N, Nadol JB, Jr, et al: A gene for non-
somal recessive nonsyndromic hearing impairment locus on chro- syndromic autosomal dominant progressive postlingual sensori-
mosome 12q14.2-q15. Clin Genet 76(3):270–275, 2009. neural hearing loss maps to chromosome 14q12-13. Hum Mol
212. Ahmed ZM, Yousaf R, Lee BC, et al: Functional null mutations Genet 5(7):1047–1050, 1996.
of MSRB3 encoding methionine sulfoxide reductase are associ- 234. Robertson NG, Lu L, Heller S, et al: Mutations in a novel cochlear
ated with human deafness DFNB74. Am J Hum Genet 88(1):19–29, gene cause DFNA9, a human nonsyndromic deafness with vestibu-
2011. lar dysfunction. Nat Genet 20(3):299–303, 1998.
213. Grillet N, Schwander M, Hildebrand MS, et al: Mutations in 235. O’Neill ME, Marietta J, Nishimura D, et al: A gene for autosomal
LOXHD1, an evolutionarily conserved stereociliary protein, dominant late-onset progressive non-syndromic hearing loss,
disrupt hair cell function in mice and cause progressive hearing DFNA10, maps to chromosome 6. Hum Mol Genet 5(6):853–856,
loss in humans. Am J Hum Genet 85(3):328–337, 2009. 1996.
214. Rehman AU, Morell RJ, Belyantseva IA, et al: Targeted capture 236. Wayne S, Robertson NG, DeClau F, et al: Mutations in the tran-
and next-generation sequencing identifies C9orf75, encoding scriptional activator EYA4 cause late-onset deafness at the DFNA10
taperin, as the mutated gene in nonsyndromic deafness DFNB79. locus. Hum Mol Genet 10(3):195–200, 2001.
Am J Hum Genet 86(3):378–388, 2010. 237. Tamagawa Y, Kitamura K, Ishida T, et al: A gene for a dominant
215. Li Y, Pohl E, Boulouiz R, et al: Mutations in TPRN cause a progres- form of non-syndromic sensorineural deafness (DFNA11) maps
sive form of autosomal-recessive nonsyndromic hearing loss. Am J within the region containing the DFNB2 recessive deafness gene.
Hum Genet 86(3):479–484, 2010. Hum Mol Genet 5(6):849–852, 1996.
216. Walsh T, Shahin H, Elkan-Miller T, et al: Whole exome sequencing 238. Brown MR, Tomek MS, Van Laer L, et al: A novel locus for auto-
and homozygosity mapping identify mutation in the cell polarity somal dominant nonsyndromic hearing loss, DFNA13, maps to
protein GPSM2 as the cause of nonsyndromic hearing loss chromosome 6p. Am J Hum Genet 61(4):924–927, 1997.
DFNB82. Am J Hum Genet 87(1):90–94, 2010. 239. McGuirt WT, Prasad SD, Griffith AJ, et al: Mutations in COL11A2
217. Schraders M, Oostrik J, Huygen PL, et al: Mutations in PTPRQ cause non-syndromic hearing loss (DFNA13). Nat Genet 23(4):413–
are a cause of autosomal-recessive nonsyndromic hearing impair- 419, 1999.
ment DFNB84 and associated with vestibular dysfunction. Am J 240. Melchionda S, Ahituv N, Bisceglia L, et al: MYO6, the human
Hum Genet 86(4):604–610, 2010. homologue of the gene responsible for deafness in Snell’s waltzer
218. Liu XZ, Xia XJ, Xu LR, et al: Mutations in connexin31 underlie mice, is mutated in autosomal dominant nonsyndromic hearing
recessive as well as dominant non-syndromic hearing loss. Hum loss. Am J Hum Genet 69(3):635–640, 2001.
Mol Genet 9(1):63–67, 2000. 241. Vahava O, Morell R, Lynch ED, et al: Mutation in transcription
219. Sirmaci A, Erbek S, Price J, et al: A truncating mutation in factor POU4F3 associated with inherited progressive hearing loss
SERPINB6 is associated with autosomal-recessive nonsyndromic in humans. Science 279(5358):1950–1954, 1998.
sensorineural hearing loss. Am J Hum Genet 86(5):797–804, 2010. 242. Lalwani AK, Goldstein JA, Kelley MJ, et al: Human nonsyndromic
220. Leon PE, Raventos H, Lynch E, et al: The gene for an inherited hereditary deafness DFNA17 is due to a mutation in nonmuscle
form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U myosin MYH9. Am J Hum Genet 67(5):1121–1128, 2000.
S A 89(11):5181–5184, 1992. 243. van Wijk E, Krieger E, Kemperman MH, et al: A mutation in
221. Lynch ED, Lee MK, Morrow JE, et al: Nonsyndromic deafness the gamma actin 1 (ACTG1) gene causes autosomal domi-
DFNA1 associated with mutation of a human homolog of the nant hearing loss (DFNA20/26). J Med Genet 40(12):879–884,
Drosophila gene diaphanous. Science 278(5341):1315–1318, 1997. 2003.
222. Xia JH, Liu CY, Tang BS, et al: Mutations in the gene encoding 244. Zhu M, Yang T, Wei S, et al: Mutations in the gamma-actin gene
gap junction protein beta-3 associated with autosomal dominant (ACTG1) are associated with dominant progressive deafness
hearing impairment. Nat Genet 20(4):370–373, 1998. (DFNA20/26). Am J Hum Genet 73(5):1082–1091, 2003.
245. Greene CC, McMillan PM, Barker SE, et al: DFNA25, a novel locus 267. Trofatter JA, MacCollin MM, Rutter JL, et al: A novel moesin-,
for dominant nonsyndromic hereditary hearing impairment, ezrin-, radixin-like gene is a candidate for the neurofibromatosis
maps to 12q21-24. Am J Hum Genet 68(1):254–260, 2001. 2 tumor suppressor. Cell 72(5):791–800, 1993.
246. Ruel J, Emery S, Nouvian R, et al: Impairment of SLC17A8 encod- 268. Positional cloning of a gene involved in the pathogenesis of
ing vesicular glutamate transporter-3, VGLUT3, underlies nonsyn- Treacher Collins syndrome. The Treacher Collins Syndrome Col-
dromic deafness DFNA25 and inner hair cell dysfunction in null laborative Group. Nat Genet 12(2):130–136, 1996.
mice. Am J Hum Genet 83(2):278–292, 2008. 269. Yang T, Gurrola JG, 2nd, Wu H, et al: Mutations of KCNJ10
247. Peters LM, Anderson DW, Griffith AJ, et al: Mutation of a tran- together with mutations of SLC26A4 cause digenic nonsyndromic
scription factor, TFCP2L3, causes progressive autosomal domi- hearing loss associated with enlarged vestibular aqueduct syn-
nant hearing loss, DFNA28. Hum Mol Genet 11(23):2877–2885, drome. Am J Hum Genet 84(5):651–657, 2009.
2002. 270. Gerber S, Bonneau D, Gilbert B, et al: USH1A: chronicle of a slow
248. Xiao S, Yu C, Chou X, et al: Dentinogenesis imperfecta 1 with or death. Am J Hum Genet 78(2):357–359, 2006.
without progressive hearing loss is associated with distinct muta- 271. Kaplan J, Gerber S, Bonneau D, et al: A gene for Usher syndrome
tions in DSPP. Nat Genet 27(2):201–204, 2001. type I (USH1A) maps to chromosome 14q. Genomics 14(4):979–
249. Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, et al: A novel 987, 1992.
locus for autosomal dominant nonsyndromic hearing loss 272. Bitner-Glindzicz M, Lindley KJ, Rutland P, et al: A recessive con-
(DFNA44) maps to chromosome 3q28-29. Hum Genet 112(1):24– tiguous gene deletion causing infantile hyperinsulinism, enter-
28, 2003. opathy and deafness identifies the Usher type 1C gene. Nat Genet
250. Donaudy F, Ferrara A, Esposito L, et al: Multiple mutations of 26(1):56–60, 2000.
MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. 273. Verpy E, Leibovici M, Zwaenepoel I, et al: A defect in harmonin,
Am J Hum Genet 72(6):1571–1577, 2003. a PDZ domain-containing protein expressed in the inner ear
251. D’Adamo P, Pinna M, Capobianco S, et al: A novel autosomal sensory hair cells, underlies Usher syndrome type 1C. Nat Genet
dominant non-syndromic deafness locus (DFNA48) maps to 26(1):51–55, 2000.
12q13-q14 in a large Italian family. Hum Genet 112(3):319–320, 274. Smith RJ, Lee EC, Kimberling WJ, et al: Localization of two genes
2003. for Usher syndrome type I to chromosome 11. Genomics 14(4):995–
252. Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, et al: A novel 1002, 1992.
locus for autosomal dominant nonsyndromic hearing loss, 275. Wayne S, Der Kaloustian VM, Schloss M, et al: Localization of the
DFNA50, maps to chromosome 7q32 between the DFNB17 and Usher syndrome type ID gene (Ush1D) to chromosome 10. Hum
DFNB13 deafness loci. J Med Genet 41(2):e14, 2004. Mol Genet 5(10):1689–1692, 1996.
253. Mencia A, Modamio-Hoybjor S, Redshaw N, et al: Mutations in 276. Bolz H, von Brederlow B, Ramirez A, et al: Mutation of CDH23,
the seed region of human miR-96 are responsible for nonsyn- encoding a new member of the cadherin gene family, causes
dromic progressive hearing loss. Nat Genet 41(5):609–613, 2009. Usher syndrome type 1D. Nat Genet 27(1):108–112, 2001.
254. Walsh T, Pierce SB, Lenz DR, et al: Genomic duplication and 277. Chaib H, Kaplan J, Gerber S, et al: A newly identified locus for
overexpression of TJP2/ZO-2 leads to altered expression of apop- Usher syndrome type I, USH1E, maps to chromosome 21q21.
tosis genes in progressive nonsyndromic hearing loss DFNA51. Am Hum Mol Genet 6(1):27–31, 1997.
J Hum Genet 87(1):101–109, 2010. 278. Alagramam KN, Yuan H, Kuehn MH, et al: Mutations in the novel
255. Cheng J, Zhu Y, He S, et al: Functional mutation of SMAC/ protocadherin PCDH15 cause Usher syndrome type 1F. Hum Mol
DIABLO, encoding a mitochondrial proapoptotic protein, causes Genet 10(16):1709–1718, 2001.
human progressive hearing loss DFNA64. Am J Hum Genet 89(1): 279. Mustapha M, Chouery E, Torchard-Pagnez D, et al: A novel locus
56–66, 2011. for Usher syndrome type I, USH1G, maps to chromosome 17q24-
256. Tyson J, Bellman S, Newton V, et al: Mapping of DFN2 to Xq22. 25. Hum Genet 110(4):348–350, 2002.
Hum Mol Genet 5(12):2055–2060, 1996. 280. Weil D, El-Amraoui A, Masmoudi S, et al: Usher syndrome type I
257. Abdelfatah N, Merner N, Houston J, et al: A novel deletion in G (USH1G) is caused by mutations in the gene encoding SANS,
SMPX causes a rare form of X-linked progressive hearing loss in a protein that associates with the USH1C protein, harmonin. Hum
two families due to a founder effect. Hum Mutat 34(1):66–69, Mol Genet 12(5):463–471, 2003.
2013. 281. Ahmed ZM, Riazuddin S, Khan SN, et al: USH1H, a novel locus
258. Zhao H, Li R, Wang Q, et al: Maternally inherited aminoglycoside- for type I Usher syndrome, maps to chromosome 15q22-23. Clin
induced and nonsyndromic deafness is associated with the novel Genet 75(1):86–91, 2009.
C1494T mutation in the mitochondrial 12S rRNA gene in a large 282. Kimberling WJ, Weston MD, Moller C, et al: Localization of Usher
Chinese family. Am J Hum Genet 74(1):139–152, 2004. syndrome type II to chromosome 1q. Genomics 7(2):245–249, 1990.
259. Reid FM, Vernham GA, Jacobs HT: A novel mitochondrial point 283. Hmani M, Ghorbel A, Boulila-Elgaied A, et al: A novel locus for
mutation in a maternal pedigree with sensorineural deafness. Usher syndrome type II, USH2B, maps to chromosome 3 at p23-
Hum Mutat 3(3):243–247, 1994. 24.2. Eur J Hum Genet 7(3):363–367, 1999.
260. Tiranti V, Chariot P, Carella F, et al: Maternally inherited hearing 284. Pieke-Dahl S, Moller CG, Kelley PM, et al: Genetic heterogeneity
loss, ataxia and myoclonus associated with a novel point mutation of Usher syndrome type II: localisation to chromosome 5q. J Med
in mitochondrial tRNASer(UCN) gene. Hum Mol Genet 4(8):1421– Genet 37(4):256–262, 2000.
1427, 1995. 285. Weston MD, Luijendijk MW, Humphrey KD, et al: Mutations in
261. Hutchin TP, Parker MJ, Young ID, et al: A novel mutation in the the VLGR1 gene implicate G-protein signaling in the pathogen-
mitochondrial tRNA(Ser(UCN)) gene in a family with non- esis of Usher syndrome type II. Am J Hum Genet 74(2):357–366,
syndromic sensorineural hearing impairment. J Med Genet 37(9): 2004.
692–694, 2000. 286. Ebermann I, Scholl HP, Charbel Issa P, et al: A novel gene for
262. Friedman RA, Bykhovskaya Y, Sue CM, et al: Maternally inherited Usher syndrome type 2: mutations in the long isoform of whirlin
nonsyndromic hearing loss. Am J Med Genet 84(4):369–372, 1999. are associated with retinitis pigmentosa and sensorineural hearing
263. Kumar S, Deffenbacher K, Marres HA, et al: Genomewide search loss. Hum Genet 121(2):203–211, 2007.
and genetic localization of a second gene associated with autoso- 287. Joensuu T, Hamalainen R, Yuan B, et al: Mutations in a novel gene
mal dominant branchio-oto-renal syndrome: clinical and genetic with transmembrane domains underlie Usher syndrome type 3.
implications. Am J Hum Genet 66(5):1715–1720, 2000. Am J Hum Genet 69(4):673–684, 2001.
264. Ruf RG, Berkman J, Wolf MT, et al: A gene locus for branchio-otic 288. Sankila EM, Pakarinen L, Kaariainen H, et al: Assignment of an
syndrome maps to chromosome 14q21.3-q24.3. J Med Genet 40(7): Usher syndrome type III (USH3) gene to chromosome 3q. Hum
515–519, 2003. Mol Genet 4(1):93–98, 1995.
265. Edery P, Attie T, Amiel J, et al: Mutation of the endothelin-3 gene 289. Ebermann I, Phillips JB, Liebau MC, et al: PDZD7 is a modifier
in the Waardenburg-Hirschsprung disease (Shah-Waardenburg of retinal disease and a contributor to digenic Usher syndrome.
syndrome). Nat Genet 12(4):442–444, 1996. J Clin Invest 120(6):1812–1823, 2010.
266. Baker S, Booth C, Fillman C, et al: A loss of function mutation in 290. Blanton SH, Pandya A, Landa BL, et al: Fine mapping of the
the COL9A2 gene causes autosomal recessive Stickler syndrome. human biotinidase gene and haplotype analysis of five common
Am J Med Genet Part A 155A(7):1668–1672, 2011. mutations. Hum Hered 50(2):102–111, 2000.
291. Mihalik SJ, Morrell JC, Kim D, et al: Identification of PAHX, a 297. van den Ouweland JM, Lemkes HH, Ruitenbeek W, et al: Muta-
Refsum disease gene. Nat Genet 17(2):185–189, 1997. tion in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree
292. Mochizuki T, Lemmink HH, Mariyama M, et al: Identification of with maternally transmitted type II diabetes mellitus and deafness.
mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in Nat Genet 1(5):368–371, 1992.
autosomal recessive Alport syndrome. Nat Genet 8(1):77–81, 1994. 298. Shoffner JM, Lott MT, Lezza AM, et al: Myoclonic epilepsy and
293. Roesch K, Curran SP, Tranebjaerg L, et al: Human deafness dys- ragged-red fiber disease (MERRF) is associated with a mitochon-
tonia syndrome is caused by a defect in assembly of the DDP1/ drial DNA tRNA(Lys) mutation. Cell 61(6):931–937, 1990.
TIMM8a-TIMM13 complex. Hum Mol Genet 11(5):477–486, 2002. 299. Zeviani M, Muntoni F, Savarese N, et al: A MERRF/MELAS
294. Berger W, van de Pol D, Warburg M, et al: Mutations in the can- overlap syndrome associated with a new point mutation in the
didate gene for Norrie disease. Hum Mol Genet 1(7):461–465, mitochondrial DNA tRNA(Lys) gene. Eur J Hum Genet 1(1):80–87,
1992. 1993.
295. Chen ZY, Hendriks RW, Jobling MA, et al: Isolation and charac- 300. Kameoka K, Isotani H, Tanaka K, et al: Novel mitochondrial DNA
terization of a candidate gene for Norrie disease. Nat Genet mutation in tRNA(Lys) (8296A–>G) associated with diabetes.
1(3):204–208, 1992. Biochem Biophys Res Commun 245(2):523–527, 1998.
296. Goto Y, Nonaka I, Horai S: A mutation in the tRNA(Leu)(UUR) 301. Ballinger SW, Shoffner JM, Hedaya EV, et al: Maternally transmit-
gene associated with the MELAS subgroup of mitochondrial ted diabetes and deafness associated with a 10.4 kb mitochondrial
encephalomyopathies. Nature 348(6302):651–653, 1990. DNA deletion. Nat Genet 1(1):11–15, 1992.
Otologic Manifestations 149
of Systemic Disease
Saumil N. Merchant† | Joseph B. Nadol Jr
Key Points
■ A wide variety of systemic diseases can affect the temporal bone, including granulomatous and
infectious diseases, neoplasms, disorders of bone, storage and metabolic diseases, and autoimmune
and immunodeficiency disorders.
■ Otologic manifestations of a particular systemic disease are determined by location and extent of
involvement within the temporal bone and the nature of the disease. Any part of the temporal
bone may be affected, and the clinical features may include conductive or sensorineural hearing
loss, vestibular manifestations, otalgia, and facial nerve paralysis.
■ Systemic disease may mimic more common otologic disorders, such as acute or chronic otitis
media, sudden idiopathic deafness, and Bell palsy.
■ Otologic manifestations may constitute a small part of a wider constellation of symptoms and signs,
or they may be the sole and initial presenting feature of a systemic disease.
■ Diagnosis may be challenging, and it requires a high level of suspicion and use of ancillary tests such
as laboratory studies, radiographic evaluation, and biopsy.
■ Management of otologic symptoms must be individualized and often requires coordinated care
across multiple disciplines.
S ystemic diseases that may involve the ear include granuloma- well as the prognosis and treatment, differ greatly. Histopatho-
tous and infectious processes, tumors, bone disorders, storage logically, the primary lesion of LCH is formed by collections of
diseases, collagen vascular and autoimmune diseases, and pathologic Langerhans cells with variable numbers of eosino-
immunodeficiency disorders (Box 149-1). In some of these dis- phils, macrophages, and lymphocytes. Diagnostic characteris-
eases, the initial clinical symptoms may occur in the temporal tics of the pathologic Langerhans cells include nuclei that
bone and may be confused with other diseases limited to the ear. appear deeply indented and elongated on light microscopy,
cytoplasm that is pale and abundant, Birbeck granules on elec-
GRANULOMATOUS AND tron microscopy, expression of CD1 on the cell surface, and
positive immunostaining for S100 protein and for the langerin
INFECTIOUS DISEASES protein.2,3 The etiology and pathogenesis of LCH remain
Chronic otitis media with otorrhea, inflammation, and granula- unknown, although more recent research has begun to shed
tion of the middle ear and mastoid is one of the most common some light on these.2,4,5 Current thinking favors the notion
entities treated by otolaryngologists. Several more generalized that LCH results from immunologic dysfunction that leads to
disease entities—such as Langerhans cell histiocytosis, tubercu- unchecked proliferation of pathologic Langerhans cells.5
losis, Wegener granulomatosis, and mycotic diseases—may Unifocal eosinophilic granuloma, which occurs in children
closely mimic the symptoms of chronic suppurative otitis media, and young adults, shows a male predominance and appears
whereas others, such as Lyme disease and sarcoidosis, may as a solitary osteolytic lesion in the femora, pelvis, scapulae,
mimic idiopathic cranial neuropathy. vertebrae, ribs, mandible, maxilla, or skull, which includes the
temporal bone. The lesion may be asymptomatic, or it may
cause pain, local swelling, or pathologic fracture. No systemic
LANGERHANS CELL HISTIOCYTOSIS manifestations have been reported. The clinical course is
Langerhans cell histiocytosis (LCH), formerly called histiocytosis X, typically benign, the prognosis is excellent, and spontaneous
refers to a group of disorders characterized by a proliferation regression may occur. Local curettage with or without low-dose
of cytologically benign histiocytes. The term histiocytosis X was irradiation (approximately 60 Gy)6 is usually curative, although
proposed by Lichtenstein,1 who considered eosinophilic granu- temporary splinting or casting may be necessary for weight-
loma, Hand-Schüller-Christian disease, and Letterer-Siwe bearing bones. Follow-up examination with a radiographic skel-
disease to be related disorders because of the similarity of their etal survey should be performed to detect lesions at other sites;
pathologic lesions. However, the severity of these diseases, as such lesions are almost always found within 1 year.
Hand-Schüller-Christian disease may be best understood as
a multifocal form of LCH. It usually occurs in children younger
†
Deceased. than 5 years of age, and it is characterized by multifocal
2301
marrow transplantation or hematopoietic stem cell transplanta-
Box 149-1. SYSTEMIC DISEASES THAT AFFECT THE EAR
tion has been reported to be successful in a few advanced
Granulomatous and Infectious Diseases refractory cases of LCH.8
Langerhans cell histiocytosis
Tuberculosis Otologic Manifestations
Wegener granulomatosis The mastoid is a common site of involvement in LCH. When
Sarcoidosis small, the lesion is asymptomatic. As it expands, it may manifest
Syphilis in several ways: by erosion of the posterior bony canal wall; by
Lyme disease
erosion through the cortex of the mastoid, zygomatic, or squa-
Mycotic diseases
Cytomegalic inclusion disease mous portions; or by secondary infection.9 The otic capsule and
facial nerve are relatively resistant. Although sensorineural
Neoplastic Diseases
hearing loss (SNHL), vertigo, and facial nerve paralysis can
Multiple myeloma occur, they are infrequent. Similarly, extension beyond the tem-
Leukemia
poral bone to the jugular fossa and skull base is rare.
Lymphoma
Metastatic neoplasms The reported incidence of otologic manifestations in
patients with LCH is 15% to 61%,7 and they may be the first
Diseases of Bone
sign of the disease. The most common symptom is otorrhea,
Paget disease (osteitis deformans) followed by postauricular swelling, hearing loss, and vertigo.10,11
Osteogenesis imperfecta
The most common sign is granulation tissue or aural polyps
Fibrous dysplasia
Osteopetroses in the external auditory canal. The disease may manifest with
Osteitis fibrosa cystica perforation of the tympanic membrane, otitis media, otitis
externa, fistula between the mastoid and the external canal, or
Storage and Metabolic Diseases
nontender postauricular swelling. Occasionally, inner ear symp-
Mucopolysaccharidoses
toms and a positive fistula test are found in the presence of an
Gout
Ochronosis intact tympanic membrane. The disease often mimics chronic
otitis media, and mastoid surgery is frequently performed
Collagen Vascular and Autoimmune Diseases
before the diagnosis is made.9
Multiple sclerosis Diagnosis of LCH is suggested by 1) an inflammatory disor-
Susac disease
der of the middle ear and mastoid that does not respond to
Immunodeficiency Disorders routine antibiotic therapy, 2) bilateral destructive ear disease,
Primary or Congenital 3) an elevated erythrocyte sedimentation rate (ESR) in the
Humoral immunodeficiency disorders absence of acute infection, 4) exuberant granulation tissue
Cellular immunodeficiency disorders after mastoid surgery with a persistently draining cavity, and 5)
Disorders of phagocyte function associated skin and systemic lesions. Radiographs show destruc-
Complement system defects tive lesions in the mastoid and temporal bones (Figs. 149-1 and
Acquired 149-2).9,10,12 The diagnosis is established by biopsy; because the
Acquired immunodeficiency syndrome surface of the granulation tissue often shows infection, necro-
Other sis, and fibrosis, tissue should be acquired from deeper parts of
Genetically determined defects the lesion.13 Microscopic findings include sheets of histiocytes
osteolytic lesions with limited extraskeletal involvement of skin,
lymph nodes, and viscera. Multiple lesions are evident at diag-
nosis or develop within 6 months after a unifocal lesion appears.
Systemic manifestations include fever, anorexia, recurrent
upper respiratory infections, anterior cervical lymphadenopa-
thy, otitis media, and hepatosplenomegaly. The classic triad of
osteolytic skull lesions, exophthalmos as a result of orbital bone
involvement, and diabetes insipidus secondary to pituitary
disease may be seen in 25% of patients.7 Chest radiograph
may show diffuse pulmonary infiltration, particularly in
central and perihilar areas. Hilar lymphadenopathy is rare.
Diagnosis requires biopsy of an accessible lesion. Spontaneous
regression may occur, but the disease is typically chronic, and
low-dose chemotherapy may be required to control systemic
manifestations.
Letterer-Siwe disease is a disseminated form of LCH that occurs
in children younger than 3 years old and manifests with the
diffuse involvement of multiple organs. Manifestations include
fever, seborrheic or eczema-like rash, oral lesions, lymphade-
nopathy, hepatosplenomegaly, multiple bony lesions, diffuse
replacement of marrow with resulting blood dyscrasias, and
pulmonary infiltration with respiratory failure. The disease is
virulent, with a poor prognosis and a high mortality rate. Treat-
ment consists of varying combinations of corticosteroids and
cytotoxic drugs such as methotrexate, mercaptopurine, vincris- FIGURE 149-1. Multiple eosinophilic granulomas in a 32-year-old woman.
tine, vinblastine, chlorambucil, cyclophosphamide, and etopo- Two lytic lesions of the skull show beveled edges (arrows) and nonsclerotic
side. High-dose chemotherapy and radiation followed by bone margins, which are typical of this disease.
149 | OTOLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE 2303
FIGURE 149-4. A higher-powered view of part of the middle ear area

shown in Figure 149-3. The infiltrate consists of histiocytes, eosinophils, and
FIGURE 149-2. Irregular lytic lesion in the mastoid bone (arrows) of a multinucleated cells. The incus (arrow) has been partially resorbed (×45).
13-year-old boy with unifocal eosinophilic granuloma.
inoculation through a perforation of the tympanic membrane
with a variable number of eosinophils, plasma cells, polymor- is also possible. Middle ear involvement in the absence of active
phonuclear leukocytes, and multinucleated cells (Figs. 149-3 pulmonary disease is rare but may occur.
through 149-5). Areas of hemorrhage and necrosis are common. During the early stages of tuberculous otitis media, the
A definitive diagnosis of LCH is usually made on the basis of tympanic membrane becomes thickened, and the otoscopic
immunohistochemistry and electron microscopic studies.2,4 landmarks become obliterated. Conductive hearing loss results
from middle ear effusion, thickening of the tympanic mem-
brane and middle ear mucosa, and destruction of the ossicles
TUBERCULOSIS (Figs. 149-6 and 149-7). No characteristic pain or tenderness is
The incidence of tuberculous otitis media has decreased dra- evident, but lymphadenopathy in the high jugular chain occurs
matically. During the early part of the twentieth century, 1.3% early. Multiple small perforations of the tympanic membrane
to 18.6% of all cases of chronic otitis media were reportedly may occur, with seropurulent drainage. The perforations
caused by tuberculosis, whereas more recent studies report quickly coalesce to cause loss of the tympanic membrane. Like-
tuberculous otitis media rates of 0.05% to 0.9%.14 The last 20 wise, a myringotomy site in an intact tympanic membrane may
years have witnessed an increase in incidence of tuberculosis, enlarge quickly. The middle ear mucosa appears to be hyper-
however, caused in part by the aggressive nature of tuberculosis emic with polypoid granulation. Osseous involvement results in
in individuals infected with human immunodeficiency virus the sequestration of bone and the destruction of the inner ear,
(HIV) and by an emerging resistance to antituberculosis the facial nerve, or both. Destruction of the mastoid tip may
drugs.15 Mycobacterium tuberculosis is the infective organism in result in an asymptomatic, nontender Bezold abscess (a “cold”
most cases; occasionally, atypical mycobacteria (e.g., M. avium abscess). Rarely, tuberculosis can also manifest as primary
and M. fortuitum) are responsible.16 tuberculous petrositis17 or as SNHL caused by chronic labyrin-
Tuberculosis of the middle ear and mastoid may occur as a thitis and tuberculous meningitis.18
result of hematogeneous or lymphatic spread or by extension
to the middle ear cleft through the eustachian tube. Direct
H
P
ME
M
PA
FIGURE 149-3. Granulation tissue typical of histiocytosis is seen in lytic FIGURE 149-5. Eosinophilic granuloma of the external ear canal with
lesions within the mastoid (M), middle ear (ME), and petrous apex (PA) of a plasma cells (P), eosinophils, and histiocytes (H), which show “folded” nuclei,
4-year old boy with Letterer-Siwe disease of the temporal bone (×4). a morphology peculiar to the histiocytoses (×640).
Multiple perforations of the tympanic membrane, exuber-

TM ant polypoid granulation within the middle ear, and early loss
of inner ear function also are seen in Wegener granulomatosis
(WG). These two diseases are distinguished on the basis of skin
tests for tuberculosis, histologic demonstration of acid-fast
M organisms of tuberculosis in granulation tissue, cultures of the
middle ear, the presence of antineutrophil cytoplasmic anti-
MA
bodies (ANCAs) in WG, and the systemic manifestations of
each process.
I
The mainstay of management of tuberculosis of the middle
ear and mastoid is the systemic use of standard antituberculous
chemotherapy.14 Mastoid surgery may be required to remove
FN sequestrated bone. Reconstructive surgery of the ossicles and
tympanic membrane is feasible after the infection has been
controlled.
FIGURE 149-6. Tuberculous granulation tissue filled the middle ear of a WEGENER GRANULOMATOSIS
57-year-old man who died of miliary tuberculosis (×12.35). FN, facial nerve; Wegener granulomatosis is a granulomatous inflammatory
I, incus; M, malleus; MA, mastoid; TM, tympanic membrane.
process with necrotizing vasculitis. It primarily affects the upper
and lower respiratory tracts and kidneys, but it can involve
essentially any organ in the body. The disease occurs equally
The diagnosis of tuberculous involvement of the middle ear in men and women, and the mean age of onset is 40 years.
is usually delayed. The characteristic signs and symptoms Common presenting symptoms include headache, sinusitis, rhi-
include 1) multiple perforations of the tympanic membrane norrhea, otitis media, fever, and arthralgia.20,21 Upper airway
that quickly coalesce to form total tympanic membrane loss, and sinus involvement occurs in 75% to 90% of cases. Pulmo-
2) nontender cervical lymphadenopathy, 3) intractable otitis nary manifestations include cough, pleuritic chest pain, hemop-
media with polypoid granulation, and 4) bony sequestration. tysis, and nodular or cavitary infiltrates on chest radiography.
These should alert the physician to this possible diagnosis. Otic Pulmonary manifestations occur in 65% to 85% of cases. Other
capsule involvement with resultant loss of auditory and vestibu- manifestations include glomerulonephritis (60% to 75% of
lar function may be the first symptom and indicates a process cases); eye involvement in the form of conjunctivitis, iritis, scle-
that differs from the more typical chronic otitis media. Defini- ritis, or proptosis (15% to 50% of cases); and dermatologic
tive diagnosis is made by histopathologic examination of tissue findings of necrotic ulcerations, vesicles, or petechiae.
from the middle ear or mastoid, which shows a granulomatous Laboratory findings in WG may include normochromic nor-
process with multinucleated giant cells (Langerhans cells; see mocytic anemia; thrombocytosis; positive rheumatoid factor;
Figs. 149-6 and 149-7) and histologic demonstration of acid-fast and hyperglobulinemia, particularly of IgA. The ESR is almost
organisms of tuberculosis. The accurate identification of the always elevated. The discovery in 1985 of autoantibodies
mycobacterial species and drug-resistant isolates by culture is directed against the cytoplasmic constituents of neutrophils
still the gold standard, although culture is time consuming and (antineutrophil cytoplasmic antibody [ANCA] and cytoplasmic
takes several weeks. The process is facilitated by the use of ANCA [c-ANCA]) in patients with WG was a major advance in
several different types of nucleic acid amplification tests that the diagnosis and understanding of WG.22 A positive ANCA test,
have been approved by the U.S. Food and Drug Administration especially proteinase 3–specific c-ANCA, is very helpful in estab-
for rapid identification of M. tuberculosis.15,19 lishing or supporting a diagnosis of WG. The specificity of posi-
tive c-ANCA testing in WG is greater than 95%; the sensitivity
is variable and depends on the phase and type of WG. In more
than 90% of patients with systemic and active WG, c-ANCA is
positive; whereas in limited WG (e.g., ear or head and neck
only or inactive disease), the sensitivity of c-ANCA is only 65%
to 70%. In addition, the antibody titer parallels the activity of
the disease, although data conflict about the value in using the
titer as a guide for immunosuppressive therapy.
The diagnosis of WG is made histologically by the presence
of necrosis, granulomatous inflammation with multinucleated
TM giant cells, vasculitis, and microabscess formation (Figs. 149-8
and 149-9). Small biopsy specimens, however, such as those
obtained from the ear or upper airway, may lack all of the
various diagnostic features. In such cases, a diagnosis of WG
can be made on the basis of the clinical presentation, ANCA
G testing, and repeat biopsy specimens taken from the same or
related sites.
The etiology and pathogenesis of WG are unknown. Infec-
tious, genetic, and environmental risk factors and combina-
tions thereof have been proposed. The evidence to date
suggests that WG is a complex, immune-mediated disorder in
FIGURE 149-7. A magnified view of the tympanic membrane (TM) seen in which tissue injury results from the interplay of an initiating
Figure 149-6. The TM is intact but greatly thickened by tuberculous granula- inflammatory event and a highly specific immune response.23
tion tissue that contains the typical epithelioid, round, and multinucleated Part of this response consists of the production of ANCA,
giant (G) cells (×100). directed against antigens present within the primary granules
ET
EAC
TT
ME
CO
IAC
FIGURE 149-10. Bilateral hilar adenopathy and linear parenchymal densi-
FIGURE 149-8. Wegener granulomatosis causing blockage of the eusta- ties in a 56-year-old woman with pulmonary sarcoidosis.
chian tube (ET) and infiltration of the middle ear (ME) in a 41-year-old man
(×10). CO, cochlea; EAC, external auditory canal; IAC, internal auditory
canal; TT, tensor tympani. (Courtesy Leslie Michaels, MD, Institute of Laryngol-
ogy and Otology, London, United Kingdom.) others may have frank granulomatous involvement of the
middle ear and mastoid. The process can extend to involve the
facial nerve and inner ear, and this usually manifests as rapidly
progressive SNHL and loss of vestibular function. Otologic
of neutrophils and monocytes; these antibodies produce tissue disease may be the sole and initial presenting feature in some
damage by interacting with primed neutrophils and endothe- patients with WG.
lial cells.
The prognosis of WG has dramatically improved from a
mortality rate of 82% before the era of immunosuppressive
SARCOIDOSIS
therapy to the current remission rate of more than 75% with Sarcoidosis is a chronic multisystem disorder of unknown etiol-
appropriate medical therapy.24 Induction of remission is usually ogy characterized by the presence of noncaseating granulomas.
achieved with high doses of corticosteroids, cyclophosphamide, It most frequently affects the lungs, although almost all body
or methotrexate given for 3 to 6 months. Maintenance of remis- parts can be affected. The disease shows a female predominance
sion is achieved with lower doses of corticosteroids and less and is 10 times more common in blacks than in whites. The
toxic alternatives to cyclophosphamide, such as azathioprine, onset of disease is usually during the third to fourth decade of
methotrexate, trimethoprim-sulfamethoxazole, or other drug life. Common presenting manifestations include bilateral hilar
combinations. Other therapies that have been used include adenopathy on chest radiography, cough, and granulomatous
leflunomide, mycophenolate mofetil, and the tumor necrosis skin rash. Other manifestations include iridocyclitis, keratocon-
factor inhibitors etanercept and infliximab. junctivitis, peripheral lymphadenopathy, hepatosplenomegaly,
cardiac failure, myalgia, and arthralgia. Neurologic involvement
Otologic Manifestations includes central and peripheral manifestations, and the facial
The middle ear and mastoid are the most common sites within and optic nerves are the most commonly affected cranial nerves.
the temporal bone that are involved in patients with WG,20,25 Either peripheral mononeuritis or polyneuritis may be seen.
and WG may cause obstruction of the eustachian tube with Laboratory findings may include hilar adenopathy on chest
resultant serous otitis media and conductive hearing loss (see radiography (Fig. 149-10), hypercalcemia, and elevated serum
Fig. 149-8). Some patients also have purulent otitis media, and angiotensin-converting enzyme. The histopathologic feature of
GR
G
L
A B
FIGURE 149-9. Wegener granulomatosis in lung biopsy specimen. A, Arteriole shows necrotizing vasculitis with obliteration of the lumen (L) and infiltration
of the vessel wall with polymorphonuclear leukocytes (elastic stain; ×256). B, Vessel wall shows fibrin deposit (F), giant cells (G), and granuloma (GR) (hema-
toxylin and eosin stain; ×256).
FIGURE 149-11. Sarcoidosis in a lymph node specimen. Noncaseating

granulomas with giant cells (G), histiocytes (H), and lymphocytes (L) are
shown (×79).
the sarcoid lesion is noncaseating epithelioid granulomas

(Fig. 149-11).
The etiology and pathogenesis of sarcoidosis are unknown.
The initial pulmonary lesion is an alveolitis characterized by
the accumulation of CD4+ T cells; this is followed by develop-
ment of noncaseating granulomas. The antigenic stimulus that FIGURE 149-12. Section of the incus in a patient with acquired syphilis. An
initiates the disease process remains elusive. Several possible active round cell osteitis (O) with involvement of the periosteum is shown
associations have been investigated that include mycobacteria, (×120).
certain human leukocyte antigen complexes, abnormalities of
T cells and the T-cell antigen receptor, and involvement of
several different cytokines.26 necrosis. A gumma of the ear canal or middle ear may result
Spontaneous resolution occurs in many patients. Cortico- in perforation of the tympanic membrane and a granuloma-
steroids are beneficial for patients with progressive symptoms tous appearance of the middle ear mucosa. Definitive diagnosis
or with ocular, cardiac, or central nervous system (CNS) of syphilis of the middle ear requires a positive serologic test
involvement. For patients who cannot tolerate or do not and a histologic demonstration of Treponema pallidum. Syphilitic
respond to corticosteroids, alternative drugs include metho- involvement of the tympanic membrane and middle ear may
trexate, cyclophosphamide, azathioprine, chlorambucil, cyclo- mimic tuberculosis, and superinfection may result in chronic
sporine, chloroquine, pentoxifylline, and antagonists of human otitis media.
tumor necrosis factor-α, such as etanercept and infliximab.27 Inner ear involvement may occur in the absence of macro-
scopic changes in the tympanic membrane or middle ear. The
Otologic Manifestations
Otologic manifestations of sarcoidosis include SNHL, vestibu-
lar dysfunction, facial nerve paralysis, and occasionally granu-
lomatous disease of the external or middle ear and mastoid.28-31
The facial nerve is the most commonly affected cranial nerve
and is usually involved as part of the symptom complex of
uveoparotid fever (Heerfordt syndrome) characterized by par-
otitis, uveitis, facial nerve paralysis, and mild pyrexia. The facial
paralysis may be sudden in onset, is often bilateral, and may
resolve spontaneously. Histopathology of the temporal bone in
sarcoidosis has been reported in only one case; the main find-
ings were perivascular lymphocytic infiltration and granuloma-
tous inflammation that involved the cochlear, vestibular, and
facial nerves within the internal auditory canal.32
SYPHILIS
Congenital and acquired syphilis may affect the middle ear in
the late latent and tertiary forms. In the late latent form, the
middle ear and mastoid may be affected by a rarefying osteitis
with leukocytic infiltration of the ossicles and mastoid bone FIGURE 149-13. Area of active bone resorption in a 43-year-old patient
(Figs. 149-12 and 149-13). A similar but larger lesion of tertiary with congenital syphilis. The inflammatory infiltrate includes lymphocytes,
syphilis, the gumma, shows obliterative arteritis and central plasma cells, and multinucleated giant cells (×396).
Hennebert sign, which is the induction of ocular deviation with a specific antibody to B. burgdorferi by enzyme-linked immuno-

positive or negative pressure in the external auditory canal, was sorbent assay and Western blotting.35 The antibody test must
believed to indicate a true fistula between the middle and inner be interpreted properly using the criteria of the Centers for
ear as a result of rarefying osteitis of the otic capsule. The more Disease Control and Prevention, because false-negative and
probable cause is fibrous adhesions, however, between the false-positive results can occur. In addition, B. burgdorferi may
stapes footplate and the membranous labyrinth as a result of cause asymptomatic infection, in which case the symptoms
endolymphatic hydrops.33 Combined antibiotic and corticoste- caused by another disease may be wrongly attributed to Lyme
roid therapy is beneficial for the management of SNHL.34 borreliosis.
The spirochete is highly sensitive to doxycycline but only
moderately so to penicillin. Other effective antibiotics include
LYME DISEASE amoxicillin, erythromycin, cefuroxime, ceftriaxone, and. Ste-
Lyme disease is a multisystem inflammatory disorder that pri- roids have been used for severe carditis and arthritis. Among
marily affects the skin, nervous system, heart, and joints. It is patients managed early in the course of the disease, the specific
caused by the spirochete Borrelia burgdorferi, which is transmit- antibody response usually disappears within months, and
ted to humans by certain Ixodes ticks that are part of the Ixodes patients may become reinfected in the future. Among patients
ricinus complex. The known primary reservoirs of the disease with late manifestations, such as arthritis, titers decline after
are white-footed mice and white-tailed deer. The disease was successful management, but patients remain seropositive.
initially recognized in 1975 because of a clustering of patients Although two vaccines were developed and found to be effec-
with arthritis in Lyme, Connecticut, but it is now known that tive in clinical trials, they are not currently being marketed.37
Lyme disease has been present for several decades in Europe,
where it is called Bannwarth syndrome. Otologic Manifestations
Infection is usually acquired in the summer, and individuals Facial nerve paralysis is the most common otologic manifesta-
of all ages and both sexes can be affected. Three clinical stages tion, with a reported incidence of 3% to 11%38,39; it may be
similar to the stages seen with cases of syphilis are recognized.35 bilateral in 25% of cases. This type of paralysis is seen in the
The first stage, early localized infection, begins 3 to 33 days second stage of the disease, and it affects patients of all ages
after a tick bite with a characteristic skin lesion (erythema and both sexes. The onset is acute, the duration is weeks to a
migrans). This lesion occurs in 60% to 80% of patients and few months, and the return of function is spontaneous and is
may be accompanied by minor constitutional symptoms. The usually complete. There may be a history of preceding otalgia,
second stage, early disseminated infection, occurs within days ipsilateral facial pain, or paresthesias.40 Although other neuro-
or weeks after inoculation and begins with hematogeneous logic features of the second stage may be seen, facial nerve
dissemination of the organism from the site of inoculation. paralysis can occur as the sole neurologic abnormality.
The symptoms, which mimic a systemic viral illness, include Antibiotics and steroids do not seem to influence the dura-
fever, migratory arthralgia, myalgia, headache, meningismus, tion or outcome of facial paralysis,38 but they are recommended
generalized lymphadenopathy, malaise, fatigue, and secondary to treat concurrent symptoms and to prevent the more serious
annular skin lesions. late complications. There is no role for surgery. The precise
After hematogenous spread, B. burgdorferi seems to be able cause and histopathology of facial nerve palsy have not been
to sequester itself in certain niches and can cause localized elucidated. Histology from other involved peripheral nerves
inflammation in the nervous system, heart, or joints. Neuro- shows perineural and perivascular infiltration by lymphocytes
logic involvement is manifested by meningitis, encephalitis, and plasma cells. In chronic and severe neuropathies, demye-
cerebrospinal fluid lymphocytosis, peripheral neuropathy, lination and loss of nerve fibers similar to wallerian degenera-
myelitis, or cranial neuropathy that includes facial nerve paraly- tion occur.36 It is unclear whether neural lesions result from
sis. Cardiac manifestations include atrioventricular block or an inflammatory response to the spirochete or represent an
other arrhythmias, myocarditis, and pericarditis. Joint disease immune-mediated epiphenomenon.
manifests as brief attacks of asymmetric oligoarticular arthritis, A well-documented otologic manifestation is an unusual
primarily in large joints and especially the knee. The third skin lesion called a lymphocytoma, in which intensely red and
stage, late or persistent infection, occurs more than 1 year violet nodules occur on the earlobe during the second stage of
after onset and can result in chronic, prolonged arthritis; disease.35 The lesion consists of benign but hyperplastic lym-
chronic encephalomyelitis; chronic axonal peripheral polyra- phocytic follicles in the dermis.36
diculopathy; keratitis, similar to syphilis; acrodermatitis chron- Auditory and vestibular manifestations such as SNHL,
ica atrophicans; and localized scleroderma-like lesions. A sudden hearing loss, positional vertigo, and Meniere-like symp-
patient may experience one or all of the stages, and the infec- toms have been described.41-44 More clinical data and temporal
tion may not become symptomatic until the second or third bone studies are needed to substantiate these preliminary
stage. Affected tissues show infiltration by lymphocytes and observations.
plasma cells. Mild vasculitis and hypercellular vascular occlu-
sion can occur, but tissue necrosis generally does not. Granu-
lomas, gummas, multinucleated giant cells, and fibrinoid
MYCOTIC DISEASES
necrosis have not been observed, in contrast to the findings in Fungi are ubiquitous in the environment and are of low intrin-
patients with syphilis.36 sic virulence. Systemic invasive clinical disease reflects some
In recent years, the complete genome of the spirochete has defect in host defenses, such as diabetic ketoacidosis, chemo-
been sequenced, and animal models have been developed for therapy for malignancy, corticosteroid therapy, or acquired
studying the pathogenesis of Lyme disease using mice and immunodeficiency syndrome (AIDS). Aspergillosis, mucormy-
primates. The animal models have shown that inflammatory cosis, candidiasis, cryptococcosis, coccidioidomycosis, and his-
innate immune responses are critical in the pathogenesis of the toplasmosis are systemic mycoses that can cause disseminated
disease and that genetic factors may be important in determin- disease and may involve the temporal bone. Diagnosis is made
ing the severity of some of the manifestations. by biopsy and culture, and treatment consists of control of
The diagnosis of Lyme disease is usually based on the rec- the underlying predisposing condition, surgical debridement
ognition of the characteristic clinical features, a history of expo- of necrotic tissues, and systemic chemotherapy, usually with
sure in an area where the disease is endemic, and detection of amphotericin B.
Otologic Manifestations 1.0 mm
The middle ear and mastoid can be involved as a result of
ascending infection along the eustachian tube and tensor
tympani, which is often seen in mucormycosis (Fig. 149-14), Cytomegalovirus
or through superinfection of existing chronic otitis media.45 inclusions
Destruction of the middle ear cleft ensues, often with extension
to the surrounding structures, including thrombosis or rupture Crista lateral
of the internal carotid artery.46 Other routes of infection include semicircular
hematogeneous embolic dissemination, which can result in canal
multiple granulomas throughout the temporal bone, and
through cryptococcal involvement of the CNS, which can cause
invasion and degeneration of the nerve trunks in the internal
auditory canal.47
CYTOMEGALIC INCLUSION DISEASE

Cytomegalic inclusion disease is caused by infection by the A
cytomegalovirus (CMV). Cochlear involvement may be con-
genital or reactivated from a latent state, particularly in immu-
nocompromised patients. In the congenital form, infection
may result in hepatic injury, brain injury, mental retardation,
blindness, and deafness. The hearing loss caused by cytome-
galic inclusion disease is variable and may be progressive or
sudden in onset.48,49
Temporal bone histopathology of cytomegalic inclusion
disease shows characteristic inclusions within the middle and
inner ears that includes the nonsensory elements of both
cochlear and vestibular systems (Fig. 149-15).
NEOPLASTIC DISEASES
Although neoplasms of the temporal bone are discussed else-
where (see Chapters 176 and 177), three neoplasms—multiple Cytomegalovirus
myeloma, leukemia, and metastatic tumors—warrant mention inclusions
here, because temporal bone manifestations can occur with
these diseases. 200 µm
B
MULTIPLE MYELOMA FIGURE 149-15. Cytology of the temporal bone of a full-term male infant
Multiple myeloma is a malignancy of plasma cells derived from who died in the first day after birth of disseminated cytomegalic inclusion
disease and necrotizing enterocolitis. Although the right temporal bone was
B lymphocytes, and its major feature is the demonstration of normal, numerous cytomegalic inclusions were apparent within the vestibu-
an abnormal monoclonal protein (M component) in blood, lar labyrinth on the left side, here in the lateral semicircular canal. In this case,
urine, or both. There is a slight male predominance, and the no inclusions were found within the cochlea on either side.
median age of onset is 60 years. Clinical manifestations are the
result of multiple plasma cell tumors and consist of severe bone
pain, pathologic fractures, failure of the bone marrow, renal
EAC failure, hypercalcemia, and recurrent infections.
Laboratory findings include the demonstration of the M
component on serum or urine electrophoresis, normochromic
normocytic anemia, hypercalcemia, and elevated blood urea
nitrogen levels. Typical radiographic findings include punched-
EF
out osteolytic lesions, which are particularly well seen on lateral
skull radiography. Bone marrow aspirates show infiltration by
plasma cells. For decades, the mainstay of therapy has been the
use of alkylating agents, such as melphalan and corticosteroids;
with this regimen, the median survival is approximately 3 years.
TT Important advances have been made more recently that have
substantially altered therapy for patients with myeloma. These
FN advances include the use of hematopoietic cell transplantation;
improved supportive care measures, such as the use of bisphos-
phonates and erythropoietin; and novel agents such as thalido-
mide, lenalidomide, and bortezomib.50,51
FIGURE 149-14. Mucormycosis in a 37-year-old man with diabetes. Inflam- Occasionally, only one plasma cell tumor (without marrow
matory cells have invaded and destroyed the tensor tympani muscle (TT), plasmacytosis) can be found. These lesions can occur in bone
and a hemorrhagic effusion (EF) is apparent in the mesotympanum (×12.35). (solitary bone plasmacytoma) or soft tissue (extramedullary
EAC, external auditory canal; FN, facial nerve. plasmacytoma), including the temporal bone. Both lesions can
CL
FIGURE 149-18. One of several osteolytic lesions of the temporal bone of

a 69-year-old woman with multiple myeloma. The lesion shows sharp bony
margins and consists of immature plasma cells (×39.6).
FIGURE 149-16. Coronal computed tomography scan shows a large, microscopic level, the marrow spaces of the petrous bone are

destructive lytic lesion (arrows) of the clivus (CL), petrous temporal bone, commonly replaced by myeloma cells, and discrete lytic bone
middle ear, and jugular foramen area caused by multiple myeloma in a lesions may be seen in the otic capsule (Fig. 149-18).52 Symp-
72-year-old man. The presenting symptoms were facial nerve paralysis and toms referable to temporal bone involvement are usually over-
otorrhea.
shadowed by manifestations of diffuse disease. Occasionally,
these symptoms may be the presenting feature of myeloma,53
affect younger individuals, are associated with an M component or they may be the only evidence of disease (plasmacytoma of
in less than 30% of the cases, and have an indolent course with the temporal bone).54 Symptoms are nonspecific and include
survival rates of 10 years or more. Local radiotherapy (40 Gy) hearing loss, tinnitus, vertigo, otalgia, and facial paralysis.55
is usually sufficient management. Periodic evaluation of serum
and urine globulins and a skeletal radiographic survey should
be performed to detect conversion to multiple myeloma.
LEUKEMIA
Leukemic infiltrates may occur in the temporal bone. They are
Otologic Manifestations common in the submucosa of the pneumatized areas of the
The temporal bone is frequently involved in cases of multiple middle ear and mastoid, including the tympanic membrane
myeloma. Radiography may show rounded lytic lesions of the (Fig. 149-19), and in the bone marrow of the petrous apex (Fig.
calvaria and temporal bone (Figs. 149-16 and 149-17). At a 149-20).56,57 Secondary bacterial infection of the middle ear and
mastoid often results from an immunocompromised state that
is a result of either the disease itself or chemotherapy. Hemor-
rhage commonly occurs in association with infiltrates and can
TM
PF
UN
FIGURE 149-19. Acute lymphocytic leukemia in a 9-year-old boy. Ten days

FIGURE 149-17. Coronal computed tomography scan with contrast before his death, the patient reported ear pain. Otoscopic examination
enhancement and a soft tissue technique in the same patient from Figure revealed a hyperemic tympanic membrane (TM). The TM and mucosa of the
149-16 shows a slightly enhancing mass that has destroyed the mastoid bone middle ear are infiltrated by tumor cells (T), and the middle ear space con-
and extends to the posterior fossa (PF) and upper neck (UN). tains a purulent exudate (×12.35).
1.0 mm
TM HLI
ME
PA
T
FIGURE 149-20. Acute myelogenous leukemia in a 38-year-old man. Leu-

kemic infiltrates (T) are seen in the tympanic membrane (TM), middle ear
(ME), and marrow spaces of the petrous apex (PA; ×6.7). A
1.0 mm
occur in the middle ear, mastoid, or inner ear. Clinical mani-
festations include middle ear effusion, acute and chronic sup-
puration in the middle ear and mastoid, thickening of the HLI
tympanic membrane, conductive hearing loss, SNHL (includ-
ing sudden SNHL), vertigo, facial paralysis, and skin lesions in
the auricle or external auditory canal.58,59
Granulocytic sarcoma, or chloroma, is a localized extramed-
ullary tumor composed of immature myeloid cells. It is related
to acute or chronic myelogenous leukemia, and its appearance
may precede, coincide with, or follow the diagnosis of leukemia.
Such a lesion can occur in the temporal bone,60-62 and otologic
manifestations can constitute the initial presentation. Manage-
ment is by local irradiation and systemic chemotherapy.
LYMPHOMA
Similar to leukemic infiltrates in the inner ear, both Hodgkin B
and non-Hodgkin lymphomas may result in hearing loss by
either hemorrhagic or malignant infiltrative lesions of the FIGURE 149-21. A, Cytology from a 58-year old man who died of non-
middle and inner ear (Fig. 149-21).63 Hodgkin follicular lymphoma diagnosed at age 52. He was treated with radia-
tion and chemotherapy. At age 58, he developed sudden total hearing loss
in the left ear, a rapidly progressive loss in the right ear, and vertigo. Audi-
METASTATIC NEOPLASMS ometry demonstrated profound loss on the left and a severe to profound
loss on the right. Hemorrhagic and lymphatic infiltration (HLI) was apparent
Secondary malignant tumors usually involve the temporal bone in the perilymphatic scalae of the cochleae. B, HLI of the perilymphatic space
through hematogeneous dissemination. The most common of the lateral semicircular canal.
sites of origin, in order of decreasing frequency, are the breast,
lung, prostate, and skin.64 The lesions are usually destructive
and osteolytic (Fig. 149-22); however, some lesions, such as
those from the prostate or breast, may be osteoblastic. The
petrous apex and internal auditory canal seem to be sites of
predilection for metastases, although any part of the temporal
bone may be involved (Fig. 149-23). The otic capsule seems to
be resistant to neoplastic invasion.65
Although otologic manifestations infrequently are the first
evidence of malignant disease, more often they are preceded
by other systemic symptoms. Involvement of the external canal,
middle ear cleft, or eustachian tube may cause conductive
hearing loss and pain; involvement of the otic capsule may
produce SNHL, vertigo, and facial nerve paralysis. In menin-
geal carcinomatosis, rapidly progressive unilateral or bilateral
SNHL is a common presenting symptom.66 Unilateral SNHL
may mimic a cerebellopontine angle tumor, and bilateral SNHL
may mimic immune-mediated inner ear disease. Diagnosis is
made by cytology of the cerebrospinal fluid.
DISEASES OF THE BONE

FIGURE 149-22. Axial computed tomography scan of an 82-year-old
Several generalized bone diseases affect the middle ear and woman with metastatic breast adenocarcinoma showing a large lytic lesion
temporal bone, and occasionally the initial symptoms of the (arrows) destroying the mastoid, squamosa, otic capsule, and labyrinth.
EAC
ME
MA
PA
FC
IAC
FIGURE 149-23. Metastatic breast adenocarcinoma in a 75-year-old

woman involving the nerve trunks in the internal auditory canal (IAC), FIGURE 149-24. Lateral skull radiograph of a patient with Paget disease.
petrous apex (PA), subcutaneous tissues of the external auditory canal (EAC), Findings include thickening of the skull table, multiple patchy densities, and
facial canal (FC), middle ear (ME), and mastoid (MA; ×4.5). platybasia.
disease occur in the temporal bone. Paget disease, osteogenesis decade; greater SNHL, with a descending pattern; enlarged

imperfecta, and osteopetrosis can sometimes mimic the clinical calvaria; enlargement and tortuosity of the superficial temporal
features of otosclerosis. artery and its anterior branches70; elevated serum alkaline phos-
phatase level; and radiographic evidence of pagetic changes in
the temporal bones.
PAGET DISEASE None of the many published clinical and histologic reports
Paget disease of bone (osteitis deformans) is a chronic and have clearly identified a consistent pathologic basis for these
sometimes progressive disease of unknown etiology character- hearing losses72; specifically, the apparent conductive hearing
ized by osteolytic and osteoblastic changes that mainly affect loss is not caused by ossicular fixation, and SNHL is not caused
the axial skeleton. Genetic factors play a role in the pathogen- by the compression of cochlear nerve fibers. Attempts at the
esis of Paget disease, which may be inherited in an autosomal- surgical correction of conductive loss are generally not consid-
dominant manner with high penetrance. Four susceptibility loci ered worthwhile. Monsell and colleagues73,74 reported a statisti-
have been identified, one on chromosome 18, one on chromo- cally significant correlation between the bone mineral density
some 6, and two on chromosome 5.67 Mutations in the SQSTM1 of the cochlear capsule (measured in vivo by quantitative com-
gene that encodes the sequestosome 1 protein have been found puted tomography) and the high-frequency pure tone air-
in some individuals. Viral infection also seems to play a role in conduction thresholds and the air-bone gap in patients with
the etiology of Paget disease, based on electron microscopy and Paget disease of the skull. It is unclear whether this finding is
immunohistochemical studies.68,69 It is possible that the disease only a marker of disease effect or a phenomenon closely related
develops from a slow virus infection in susceptible individuals to the mechanism of hearing loss.
who have an underlying genetic predisposition.
Paget disease affects 3% of the population aged 40 years and
older and 11% of the population aged 80 years and older.70
Men are affected more commonly than women. The onset of
clinical manifestations is usually in the sixth decade of life and
includes enlarging skull; progressive kyphosis; and deformities
of the pelvis, femur, and tibia. Radiographic findings (Figs.
149-24 and 149-25) include a thickened skull table; patchy, ill-
defined densities of the skull; and poor definition of the corti-
cal margins of the inner ear and internal auditory canal,
particularly in the lytic phase of the disease. The bisphospho-
nates, which inhibit the resorption of bone, constitute the
mainstay of medical therapy for symptomatic Paget disease.71
Other antipagetic drugs include calcitonin, mithramycin, ipri-
flavone, and gallium nitrate.
Clinical manifestations of Paget disease include hearing loss,
tinnitus, and mild vestibular dysfunction. The facial nerve is
spared. Hearing loss occurs in 5% to 44% of patients70 and may
be sensorineural, mixed, or, rarely, conductive only. Most often,
the loss is mixed, with a descending pattern for bone conduc-
tion and relatively flat air-conduction thresholds. Hearing
losses are progressive and are greater than those of age-matched
healthy subjects. Distinguishing features of Paget disease— FIGURE 149-25. Axial computed tomography scan of a 75-year-old man
compared with otosclerosis, which is the most common differ- with Paget disease. Diffuse expansion of the skull table and involvement of
ential diagnosis—include a later age of onset, in the sixth both temporal bones with patchy demineralization is apparent.
IAC
FIGURE 149-26. Pagetic involvement of the temporal bone in a 70-year-old

man. The pagetic bone encroaches on the posterior margin (arrow) of the
internal auditory canal (IAC). The mastoid is largely replaced by pagetic bone
(×6.7).
FIGURE 149-27. Lateral radiograph of the skull in a patient with osteogen-

The histopathologic appearance of pagetic bone is variable esis imperfecta. Wormian bone is seen, particularly in the posterior table.
and depends on the relative osteoclastic and osteoblastic activ-
ity. Typical findings include osteoclastic resorption of marrow-
containing bone with an increase in vascularity and formation
of fibrous tissue. New bone formation occurs in an irregular (normal). Hearing loss is less common than it is with type 1
manner and produces its typical mosaic pattern as a result of and occurs in 10% to 30% of cases.75,76
irregular and curved cement lines (Fig. 149-26). Pagetic bone Management consists of the treatment of fractures, ortho-
changes occur in three phases: 1) an initial osteolytic phase, 2) pedic surgery to correct deformities, use of orthotic devices,
a mixed or combined phase, and 3) an osteoblastic or “burnt- and physical and occupational therapy. Bisphosphonate therapy
out” phase. In the temporal bone, a fourth phase can be identi- is being increasingly used, because these drugs are potent
fied, which is the remodeling of inactive pagetic bone into inhibitors of bone resorption and bone turnover.77 Other thera-
normal-appearing lamellar bone.72 The disease usually begins pies under investigation include use of growth hormone and
in periosteal bone and extends to involve enchondral and end- allogeneic bone marrow transplantation.
osteal bone.
Conductive hearing loss and SNHL occur in patients with OI.
OSTEOGENESIS IMPERFECTA Severe SNHL has been estimated to occur in approximately
Osteogenesis imperfecta (OI), also known as van der Hoeve–de 40% of patients and has a high correlation with gray or white
Kleyn syndrome, is a genetically determined disorder of the sclerae. Conductive hearing loss usually accompanies blue
connective tissue characterized clinically by fragile bones that sclerae, which first becomes apparent by 20 to 25 years of age
break with minor trauma. Approximately 80% to 90% of and then becomes severe enough to cause the patient to seek
patients with OI have mutations of one of the two type 1 col- medical attention 15 to 20 years later.78 No relationship has
lagen genes, COL1A1 and COL1A2. Many hundreds of unique been found between hearing loss and frequency or severity of
mutations of these two genes have been identified in individu- fractures.76 Some patients with mild OI come to medical atten-
als with OI. The older terms osteogenesis imperfecta congenita and tion with conductive hearing loss similar to that seen with oto-
osteogenesis imperfecta tarda have been replaced by a classification sclerosis. Early age of onset of hearing loss, high compliance
system that defines four types of OI based on clinical features, values on tympanometry, a history of fractures after minor
radiologic criteria, and mode of inheritance.
OI type 1 has an autosomal-dominant mode of inheritance.
It is the mildest form and is associated with blue sclerae, non-
deforming fractures, and normal stature. Hearing loss is
common and occurs in 30% to 50% of cases. OI type 2 is the
most severe form, in which multiple fractures occur in utero
and often result in stillbirth. This type either is acquired as a
sporadic new mutation or is inherited in an autosomal-recessive
manner. OI type 3 is characterized by multiple fractures, pro-
gressive bone deformity during childhood and adolescence,
and sclerae that are bluish at birth but white later in life.
Hearing loss occurs in about 50% of individuals. The long
bones may be slender and bowed with abrupt widening near
the epiphyses. Kyphoscoliosis, pectus excavatum, weak joints,
dental abnormalities, and wormian bone in the skull table are
common (Figs. 149-27 and 149-28). The mode of inheritance
varies; it may be autosomal dominant, autosomal recessive, or FIGURE 149-28. Radiograph of the arm of a patient with osteogenesis
the result of a new mutation. OI type 4 is a dominantly inherited imperfecta. A pathologic fracture, demineralization of the humerus, and gross
form; it is similar to OI type 1 except that the sclerae are white abnormalities of the elbow joint are evident.
otic capsule (see Fig. 149-29) and may result in the fixation of
OI
M the stapes footplate.
FIBROUS DYSPLASIA
Fibrous dysplasia is a benign, chronic, slowly progressive bone
disorder of unknown etiology characterized by the replacement
of normal bone with a variable amount of fibrous tissue and
woven bone. It may occur as part of Albright syndrome—
characterized by multiple bony lesions, abnormal pigmenta-
tion, endocrine dysfunction, and precocious puberty in
girls—or it may exist alone in the monostotic or polyostotic
form. The monostotic form is more common and usually occurs
in the skull, ribs, proximal femur, or tibia. In the polyostotic
form, skull lesions are seen in more than 50% of patients.
Clinical manifestations of fibrous dysplasia include bony
deformity, pathologic fracture, and cranial nerve palsies. The
disease starts early in life, usually in childhood; the monostotic
FIGURE 149-29. Osteogenesis imperfecta in a 15-year-old girl. The osteo-
genesis has replaced the enchondral and periosteal layers of the otic capsule. form may become quiescent at puberty, whereas the polyostotic
The neck of the malleus (M) is also involved (×8.5). form can continue to progress. Sarcomatous transformation
can occur, and incidence is estimated at 0.4%.88 Laboratory
findings include an elevated serum alkaline phosphatase level
trauma in childhood that ceased after puberty, a family history in 30% of patients with polyostotic fibrous dysplasia, with
of OI, and blue sclerae are helpful diagnostic clues. usually normal serum calcium and phosphorus levels. The
The conductive loss reflects structural changes in the ossi- typical radiographic findings include a radiolucent area with a
cles. Microfractures of the manubrium,79 fragility of the long well-defined smooth or scalloped edge and a ground-glass
process of the incus, and fracture or resorption of the crura of appearance. Areas of increased radiodensity may also be seen
the stapes have been reported.78,80,81 The stapedial footplate is (Figs. 149-31 and 149-32). The histopathology of fibrous dys-
typically described as thick, soft, and chalklike or granular, plasia consists of the replacement of normal cancellous bone
and it is usually fixed.82 Rehabilitation can be accomplished by by a fibrous stroma arranged in a whorled pattern. A variable
amplification or surgery.83-85 A stapedectomy can give results amount of irregularly arranged spicules of woven bone cause
similar to those seen with otosclerosis, but the procedure is the ground-glass radiographic changes (Fig. 149-33).
extremely delicate. Crimping the prosthesis around the incus Advances have been made toward understanding the cellu-
may cause a pathologic fracture, and a platinum ribbon is pre- lar and molecular basis of fibrous dysplasia. The lesion is com-
ferred to stainless steel wire.78 posed of immature mesenchymal osteoblastic precursor cells.
Histopathology of the temporal bone (Figs. 149-29 and An activating mutation is present in the gene that encodes the
149-30) in cases of OI type 2 has shown deficient ossification α-subunit of stimulatory G protein.89 Elevated levels of cyclic
of the endochondral layer of the otic capsule, which shows
increased amounts of fibrous tissue with numerous blood
vessels. The periosteal layer is often thin and deficient (see Fig.
149-30), and the stapes crura are often thin and incomplete.
The otopathology in cases of OI type 2 is very similar if not
identical to that seen in cases of otosclerosis.86,87 The abnormal
bone involves the periosteal and endochondral layers of the
ED
L
EC
FIGURE 149-30. Osteogenesis imperfecta involving the otic capsule of a

newborn boy. The enchondral (EC) and periosteal (P) layers have been FIGURE 149-31. Lateral radiograph of the skull of a patient with fibrous
replaced by finely trabeculated bone with an increase in fibrous tissue and dysplasia showing lytic (L) and fibrous (F) phases of disease. Spicules of new
vascular spaces. The endosteal layer (ED) is normal (×60). bone are responsible for the ground-glass appearance of the fibrous phase.
deficits. Stenosis of the external canal often requires surgical

removal with canalplasty and meatoplasty. Restenosis as a result
of regrowth of fibrous dysplasia occurs, and multiple proce-
dures are sometimes needed. Compared with simple canal-
plasty, a postauricular canal-wall-down mastoidectomy with
wide canalplasty and skin grafting gives better results, with long-
term canal patency. Radiotherapy is contraindicated because of
R L an increased rate of malignant degeneration.88 Long-term
follow-up is indicated because of the potential for facial nerve
FIGURE 149-32. Coronal tomographic radiograph of a patient with fibrous involvement and for the progression of conductive hearing loss
dysplasia. New bone formation causes a dense appearance of the involved to profound SNHL.90
left temporal bone.
OSTEOPETROSES
adenosine monophosphate result that affect the transcription Osteopetroses are rare genetic disorders characterized by
and expression of multiple downstream genes, which ultimately greatly increased bone density.95-97 Osteopetroses result from
result in the pathologic lesion.90 Treatment consists of bisphos- the defective function of osteoclasts, which leads to a failure
phonate therapy and orthopedic surgery for correction of of normal bone resorption, while normal bone formation by
deformities and treatment of pathologic fractures.91 osteoblasts continues with deposition of excessive mineralized
osteoid and cartilage. Four types of osteopetrosis have been
Otologic Manifestations defined, although patients with atypical symptoms are numer-
The temporal bone occasionally may be involved in cases of ous, which suggests that additional types likely exist.
fibrous dysplasia, with about 100 cases reported to date.92-94 Of Malignant osteopetrosis is an autosomal-recessive form that
these, the monostotic form occurred in 70%, the polyostotic manifests in infancy, is rapidly progressive, and has a high mor-
form occurred in 23%, and Albright syndrome occurred in 7%. tality rate. Many cases have been shown to be due to mutations
All parts of the temporal bone can be involved, but the process in the gene that encodes for the TCIRG1 subunit of the vacu-
generally begins as a painless, slowly progressive swelling that olar proton pump within osteoclasts. The disease is character-
involves the mastoid or squama. Progressive narrowing of the ized by the encroachment of bone marrow that leads to anemia,
external auditory canal with conductive hearing loss is the most thrombocytopenia, hepatosplenomegaly, increased susceptibil-
common manifestation and occurs in about 80% of cases. This ity to infection, and encroachment of the neural foramina,
narrowing may be mistaken for exostoses, but fibrous dysplasia which causes neural degeneration. Optic atrophy, facial paraly-
is encountered during the second or third decade of life; at sis, SNHL, hydrocephalus, and mental retardation are common,
surgery, it is vascular with a characteristic soft, spongy, and gritty and death usually occurs during the first or second decade of
consistency. Entrapment of keratin debris medial to a stenotic life. The only effective treatment is bone marrow transplanta-
canal can cause an external canal cholesteatoma. Involvement tion. Another type of autosomal-recessive osteopetrosis is due
of the middle ear and ossicles or obstruction of the eustachian to a mutation in the gene for cytoplasmic carbonic anhydrase
tube also can cause conductive hearing loss. Erosion of the fal- II. This type is very rare (approximately 50 cases have been
lopian canal with facial nerve paralysis or erosion of the otic reported), and it is associated with distal renal tubular
capsule with SNHL and vertigo is seen occasionally. An isolated acidosis.
lesion of the mesotympanic bone can simulate a glomus tym- Autosomal-dominant type 2 osteopetrosis, also known as Albers-
panicum tumor that can manifest as a reddish mass behind Schönberg disease and marble bone disease, is the most frequent
an intact tympanic membrane, with pulsatile tinnitus and hear- type. It is associated with normal life expectancy and may be
ing loss. asymptomatic. Many cases have been shown to result from
Management of fibrous dysplasia is symptomatic. Operative mutations in the CLCN7 chloride-channel gene.95 Clinical
procedures should be limited to biopsy and relief of functional manifestations include an increased incidence of fractures
(osteopetrotic bone is fragile despite its solid appearance);
osteomyelitis of the mandible from dental infection; progres-
sive enlargement of the head and mandible; clubbing of the
long bones; and cranial neuropathies such as progressive optic
atrophy, trigeminal hypesthesia, recurrent facial paralysis, and
SNHL. Patients may have syndactyly of the fingers or toes and
abnormal fingernails; these abnormalities can aid the physician
in making the clinical diagnosis. Radiographic evaluation
reveals a great increase in the density of all bones.
Autosomal-dominant osteopetrosis type 1 is an extremely rare
type reported in only three families, and it seems to be linked
to a locus on chromosome 11q12-13.97 Patients with this type
of osteopetrosis are often asymptomatic, but some have pain
and hearing loss. This is the only type of osteopetrosis not
associated with an increased rate of fractures.
The endochondral layer of the otic capsule and ossicles in the
temporal bones of infants and children with the malignant
recessive form of osteopetrosis consist mainly of dense calcified
cartilage.98 The mastoid is not pneumatized, and the stapes
FIGURE 149-33. Fibrous dysplasia. The irregularly arranged spicules of persists in fetal form (Figs. 149-34 and 149-35). The inner ears
woven bone in a fibrovascular stroma show a whorled pattern (×64). appear normal. Dehiscence of the tympanic segment of the
M
FC I
LSCC
A
FIGURE 149-34. Recessive osteopetrosis of the temporal bone of a

15-month-old boy. The endochondral layer of the otic capsule and stapes is FIGURE 149-36. Osteopetrosis in a 30-year-old man shows overgrowth of
composed of calcified cartilage (×12.3). dense lamellar bone around the epitympanum with jamming of the malleus
(M) and incus (I). The facial nerve canal (FC) is narrowed (×9). A, antrum;
LSCC, lateral semicircular canal.
facial nerve, often with herniation of the nerve into the oval
window niche, has been a consistent finding.98-100 However, no should be performed in any child or young adult with recurrent
observable nerve compression is evident. These children often facial nerve paralysis to determine the possibility of osteopetro-
have recurrent episodes of acute otitis media, serous otitis sis. Total decompression of the facial nerve has been advocated
media, stenosis of the external auditory canal, conductive to ameliorate recurrent palsies.104,105
hearing loss or SNHL, and unilateral or bilateral facial nerve
paralysis.101,102
In the more benign adult form (autosomal-dominant type 2
OSTEITIS FIBROSA CYSTICA
osteopetrosis), the temporal bone is markedly sclerotic with Osteitis fibrosa cystica, also known as von Recklinghausen disease,
obliteration of the mastoid air cells and a narrowing of the is a bone lesion caused by excess parathyroid hormone, and it
eustachian tube and the external and internal auditory canals. is characterized in classic cases by osteoclastic bone resorption,
Exostotic overgrowth of the periosteal bone surrounding the marrow fibrosis, bone cysts, bone pain, and fractures. In most
tympanic cavity can occur (Fig. 149-36), with ankylosis of the cases, it is caused by primary hyperparathyroidism, usually
ossicles and obliteration of the oval and round window niches because of an adenoma. Other manifestations relate to hyper-
(Fig. 149-37). These changes explain the common finding of calcemia and hypercalciuria. Although the temporal bone can
conductive hearing loss. SNHL also occurs, but the inner ears be affected in this disorder,106,107 it is very rare in clinical prac-
appear normal. Narrowing of the eustachian tube predisposes tice. The otic capsule is replaced by abnormal bone composed
a patient to serous otitis media.103 Recurrent acute facial nerve of loosely arranged trabeculae of varying sizes and shapes inter-
paralysis that is similar to Bell palsy, involving one or both sides, spersed with marrow spaces that contain fibrous tissue. SNHL
is a frequent manifestation. The tendency is toward progressive has been attributed to osteitis fibrosa that involves the temporal
residual weakness with each episode. Radiographic studies bone.
CC
RWM RWN
FIGURE 149-35. Higher magnification of the temporal bone shown in FIGURE 149-37. Osseous obliteration of the round window niche (RWN)
Figure 149-34. The calcified cartilage (CC) of endochondral bone appears as of the patient shown in Figure 149-36. Fluid is apparent in the niche adjacent
densely staining, round-to-ovoid profiles (×396). to the round window membrane (RWM; ×18).
STORAGE AND METABOLIC

DISEASES
MUCOPOLYSACCHARIDOSES
The mucopolysaccharidoses (MPS) are a group of diseases
caused by an inherited deficiency of one of several lysosomal
enzymes that degrade mucopolysaccharides. As a result, under- EF
graded mucopolysaccharides accumulate intracellularly, which SM
gives rise to large cells with vacuolated cytoplasm. Ten enzyme
deficiencies have been identified to date and are classified into
PM
seven types or syndromes. All are transmitted as autosomal-
recessive traits except for Hunter syndrome (MPS 2), which is
X-linked recessive. Diagnosis is made either by an assay of the
specific enzyme in plasma or serum or by tissue culture using
fibroblasts or leukocytes. Management is mainly supportive and
symptomatic; however, mucopolysaccharidoses are potentially
amenable to enzyme replacement therapy and to procedures FIGURE 149-38. Hunter syndrome in a 24-year-old man. The middle ear
such as bone marrow transplantation or gene transfer.108 contains an effusion (EF) as a result of eustachian tube dysfunction. The
Hurler syndrome (MPS 1) is caused by a deficiency of submucosa (SM) is thickened, and the posterior mesotympanum (PM) con-
l-iduronidase that leads to the accumulation of heparan sulfate tains unresorbed mesenchymal tissue (×11).
and dermatan sulfate. Clinical manifestations include corneal
clouding, abnormal facies, hepatosplenomegaly, mental retar-
dation, dysostosis multiplex, joint stiffness, and hernias. Radio-
graphic features include a broadening and shortening of
long bones; hypoplasia and fractures of the lumbar vertebrae, include alcohol use, exposure to lead, use of diuretics, hyper-
causing kyphosis; and enlargement of the sella turcica. Death tension, and renal insufficiency.
usually occurs during the first decade of life. The clinical manifestations of gout include acute gouty
Hunter syndrome (MPS 2) results from a deficiency of arthritis, aggregates of crystal in connective tissue (tophi), urate
iduronate-2-sulfatase, which leads to an accumulation of urolithiasis, and, rarely, gouty nephropathy. Laboratory abnor-
heparan sulfate and dermatan sulfate. The syndrome is similar malities include hyperuricemia, leukocytosis, and an elevated
to Hurler syndrome, but corneal clouding is not seen. Survival ESR. The diagnosis of gout depends on the identification of
to adulthood may occur. urate crystals within joint fluid or within tophi under polarized
Morquio syndrome (MPS 4) is attributable to a deficiency light. The treatment of acute gouty arthritis includes bed
of N-acetylgalactosamine-6-sulfatase or of β-galactosidase, which rest, nonsteroidal antiinflammatory agents, and colchicine. Uri-
results in excessive urinary excretion of keratan sulfate. Clinical cosuric drugs such as probenecid are useful for patients with
manifestations include spondyloepiphyseal dysplasia. Spinal hyperuricemia as a result of the decreased renal clearance of
cord compression caused by hypoplasia of the odontoid process uric acid. Xanthine oxidase inhibitors such as allopurinol are
and cervical dislocation are common and may be the cause of useful if excess production of uric acid is the basis of the
death. hyperuricemia.
OTOLOGIC Tophaceous deposits can occur in multiple areas in the head
and neck.114 The helical rim of the pinna is the classic site of
Manifestations involvement. Such tophi are usually asymptomatic and do not
Hearing loss in MPS is usually conductive and sensorineural. require any treatment.
The conductive component is attributable to serous otitis
media as a result of dysfunction of the eustachian tube and
chronic thickening of the mucosa of the middle ear (Fig.
OCHRONOSIS
149-38). Unresorbed mesenchyme has been described in the Ochronosis is a rare disease caused by an inherited lack of the
middle ear and mastoid in Hurler syndrome,109 and large cells enzyme homogentisic acid oxidase. The presence of homogen-
with vacuolated cytoplasm have been described in the middle tisic acid in urine is called alkaptonuria. The result of this inborn
ear mucosa in both Hunter110 and Hurler syndromes.111 The error of metabolism is the deposition of a dark pigment in
cause of SNHL is unknown, but it has been attributed to abnor- tissues that are rich in collagen. Patients often come to medical
mal metabolism within neural elements.110-113 attention with symptoms and signs during the third decade of
life. Manifestations include ochronotic arthropathy, ocular and
Gout cutaneous pigmentation, obstruction of the genitourinary tract
Gout is a metabolic disease that results from the deposition of by ochronotic calculi, and cardiovascular manifestations as a
crystals of monosodium urate within joint spaces and cutane- result of ochronosis that affects the aortic valve. There is no
ous structures.114,115 The crystals stimulate production of effective management or cure for the condition, and treatment
interleukin-1 and other cytokines by monocytes and macro- is based on symptomatic therapy.117
phages, which leads to inflammation and tissue damage.
Patients with gout invariably have hyperuricemia (serum urate Otologic Manifestations
level >7 mg/dL). Genetic factors influence the renal clearance Ochronosis has manifestations in the external ear, and cartilage
of uric acid and may be involved in the familial incidence of is a site of predilection for the deposition of the pigment of
hyperuricemia and gout. More recent studies have implicated ochronosis. Blue or mottled-brown macules can appear on the
loci on the X chromosome and on chromosome 16 in the pinna and in other areas of the head and neck, including the
pathogenesis of hyperuricemia.116 Other risk factors for gout nose, buccal mucosa, tonsils, pharynx, larynx, and esophagus.
COLLAGEN VASCULAR AND IMMUNODEFICIENCY DISORDERS

Infections of the middle ear and mastoid can occur as part of
AUTOIMMUNE DISEASES the clinical spectrum of congenital and acquired immunodefi-
The ear may be a target organ in several systemic (non–organ- ciency disorders. Occasionally, otologic manifestations may
specific) diseases thought to be autoimmune in nature (e.g., constitute the presenting feature of the disease.
polyarteritis nodosa, relapsing polychondritis, Cogan syn-
drome), or it may be the sole target of an immune-mediated
(organ-specific) inner ear process that causes progressive PRIMARY OR CONGENITAL
SNHL with or without vestibular dysfunction. The latter was
described by McCabe,118 although the theoretic concept was
IMMUNODEFICIENCY DISORDERS
proposed by Lehnhardt in 1958.119 Histopathologic findings in Primary or congenital immunodeficiency disorders constitute
the temporal bone in both groups of disorders are similar and a diverse group of conditions that can be subdivided into four
include destruction and degeneration of the inner ear tissues; broad categories. Humoral immunodeficiency disorders are char-
scattered infiltrates of lymphocytes, plasma cells, and macro- acterized by the inability to produce antigen-specific antibod-
phages; focal or diffuse proliferation of fibrous tissue and bone; ies. Patients commonly have recurrent and chronic respiratory
and a variable degree of endolymphatic hydrops.120 The oto- tract infections owing to high-grade extracellular bacteria,
logic manifestations of these diseases have been discussed in such as Haemophilus influenzae, Streptococcus pneumoniae, and
published reviews.121-123 S. pyogenes. Diagnosis is based on the analysis of immunoglob-
ulin subtypes and the assessment of specific antibody produc-
tion. Management is symptomatic with appropriate antibiotics
MULTIPLE SCLEROSIS and replacement therapy with immune human serum globu-
Multiple sclerosis (MS) is a demyelinating disease of the brain lin. Individual syndromes within the group are classified
and spinal cord. Most investigators believe that MS is an according to the type of immunoglobulin (Ig) deficiency, the
immune-mediated disorder. The incidence of MS is 2 to 150 mode of genetic transmission, and the specific clinical fea-
per 100,000 population with a female predominance. Although tures, including X-linked infantile agammaglobulinemia
the constellation of symptoms is vast, the principal effects (Bruton), autosomal-recessive agammaglobulinemia, acquired
related to the ear are hearing loss, particularly loss of word agammaglobulinemia (common variable immunodeficiency),
recognition ability, and vestibular symptoms. It is not clear X-linked immunodeficiency with hyper-IgM, and selective IgA
whether these symptoms can be attributed to peripheral or deficiency.
central auditory and vestibular neural pathways.124 The Cellular immunodeficiency disorders exhibit partial or severe
studies of Hausler and Levine125 describe abnormal auditory deficiencies in the function of T lymphocytes. Patients with
brainstem potentials in MS that imply interference with the these disorders typically have recurrent infections owing to
ability to make intraaural time discriminations within the audi- intracellular, low-grade, opportunistic pathogens that include
tory CNS.125 viruses, fungi, protozoa, and some bacteria. Diagnosis is based
Ward and colleagues126 presented a case report of a 48-year on quantitative and qualitative tests of T-cell function, and an
old woman with MS in which the temporal bones and CNS associated deficiency of antibody production is often present.
pathology were available for study. Although the patient had Syndromes include thymic hypoplasia (DiGeorge syndrome),
no documented auditory symptoms, she did have a well- Wiskott-Aldrich syndrome, ataxia-telangiectasia, chronic muco-
documented history of vertigo. The inner ear structures, both cutaneous candidiasis, hyperimmunoglobulinemia E ( Job syn-
auditory and vestibular, were normal, and the vestibular symp- drome), and severe combined immunodeficiency.
tomatology was attributed to plaques within the vestibular path- Disorders of phagocyte function are primarily disorders of neu-
ways in the CNS. trophils that leave patients vulnerable to pyogenic bacterial or
fungal infections of varying severity and chronicity. This group
includes neutropenia, which may be inherited or acquired; if
SUSAC SYNDROME severe, it can cause fulminant sepsis, chemotactic defects that
Susac syndrome is considered to be a microangiopathy that result in pyogenic respiratory infections, and microbicidal dis-
affects the brain, retina, and cochlea.127 Symptoms include orders such as chronic granulomatous disease and Chédiak-
encephalopathy, visual defects as a result of branch retinal Higashi syndrome. Therapy includes antibiotics, neutrophil
artery occlusion, and SNHL. The pattern of hearing loss transfusions, and bone marrow transplantation.
varies considerably and may be rapid or progressive; a low-tone Complement system defects include deficiencies of the individ-
audiometric predominance is common. Magnetic resonance ual components or of the regulatory proteins, and all comple-
imaging shows supratentorial lesions of the white matter ment defects are inherited (generally autosomal recessive).
and involvement of the corpus callosum. Treatment includes Clinical features vary with the type of defect and include recur-
immunosuppressive therapy and, if indicated, cochlear rent Neisseria infections (C5, C6, C7, and C9 deficiency), recur-
implantation.128 rent staphylococcal infections (C3b inactivator deficiency),
Temporal bone findings in a case of Susac syndrome have lupuslike syndromes (C1, C4, and C2 deficiency), and angio-
recently been published.129 The patient in this report, a 51-year- edema (C1 esterase inhibitor deficiency). Management of these
old woman, had bilateral low-frequency SNHL. Findings on is symptomatic and supportive.
magnetic resonance imaging were consistent with Susac syn- Major advances have been made in the understanding of the
drome. Temporal bone histopathology consisted of widespread genetic basis and molecular mechanisms of immunodeficiency
degeneration within the apical portion of both cochleae and disorders.130,131 As a result, most of the more than 100 primary
included the inner and outer hair cells, tectorial membranes, immunodeficiency diseases can be diagnosed by molecular
stria vascularis, spiral ligament, and spiral limbus. Capillary techniques. These molecular approaches have also resulted in
occlusion within the stria vascularis was also evident, and in significant insight into the pathophysiology of the various con-
contrast, the cochlear neurons were normal in appearance. No ditions, which has permitted early diagnosis of many of these
evidence of endolymphatic hydrops was found, and the vestibu- conditions by neonatal screening of umbilical cord blood. The
lar end organs were normal. immunodeficiency syndromes have also played a major role in
the development of human gene therapy, which is being actively of cases, severe otitis media in 20%, CMV inclusion-bearing
pursued in many centers. cells in the inner and middle ears in 24%, labyrinthine crypto-
coccosis in 8%, and Kaposi sarcoma deposits in the eighth
Otologic Manifestations cranial nerve in 4%. They concluded that the ear is no less
Otologic disease has been described in all four categories of susceptible to AIDS-associated diseases than any other organ
immunodeficiency disorders. Humoral immune defects result and that it is particularly prone to CMV infection. The spec-
in recurrent and persistent acute and serous otitis media. trum of otologic manifestations and their pathophysiologic
Chronic suppurative otitis media and its attendant complica- mechanisms in AIDS is most likely to expand as more clinical
tions may develop and is often refractory to medical and surgi- and histopathologic data accrue.
cal therapy.132,133 A subgroup consists of children with selective
IgG subclass 2 deficiency, who have been shown to be suscep-
tible to recurrent episodes of otitis media.134 DiGeorge syn- GENETICALLY DETERMINED
drome, T-cell deficiency as a result of thymic hypoplasia, can
manifest varying degrees of anomalies of the external, middle,
DEFECTS
and inner ears with conductive, sensorineural, or mixed hearing Numerous syndromic disorders secondary to genetic defects
losses135; a high incidence of Mondini dysplasia is also seen may have otologic manifestations that consist of hearing loss or
in these ears. Recurrent episodes of acute and chronic otitis vestibular dysfunction or both. Examples include syndromes
media have also been described with neutrophil chemotactic caused by mutations in single genes (autosomal or sex linked),
defects,136 microbicidal disorders (chronic granulomatous mutations in mitochondrial genes, or chromosomal abnormali-
disease),137 and complement system defects.138 ties. Such disorders are beyond the scope of this chapter, and
the reader is referred to Chapter 147 or other sources.147
ACQUIRED IMMUNODEFICIENCY
SYNDROME
For a complete list of references, see expertconsult.com.
Acquired immunodeficiency syndrome (AIDS), which was first
recognized in 1981, is caused by HIV, a lymphotropic virus
that primarily attacks T-helper lymphocytes and renders the SUGGESTED READINGS
patient susceptible to numerous opportunistic infections (see Agrup C, Luxon LM: Immune-mediated inner-ear disorders in neuro-
Chapter 11). otology. Curr Opin Neurol 19:26–32, 2006.
Cunningham MJ, Curtin HD, Jaffe R, et al: Otologic manifestations of
Otologic Manifestations Langerhans’ cell histiocytosis. Arch Otolaryngol Head Neck Surg 115:807,
Otologic manifestations are infrequent in patients with AIDS 1989.
except in children, in whom serous otitis media is common.139 Harris JP, South MA: Immunodeficiency diseases: head and neck mani-
When otologic disease does occur, the microbiology is similar festations. Head Neck Surg 5:114, 1982.
to that of non-AIDS patients, with the addition of unusual Khetarpal U, Schuknecht HF: In search of pathologic correlates of
hearing loss and vertigo in Paget’s disease: a clinical and histopatho-
opportunistic organisms, such as protozoa, fungi, viruses, and logic study of 26 temporal bones. Ann Otol Rhinol Laryngol Suppl
mycobacteria. 145:1, 1990.
Middle ear and mastoid manifestations include acute otitis McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol Rhinol
media, acute mastoiditis, serous otitis media, and bullous myr- Laryngol 88:585, 1979.
ingitis; the severity of these infections varies and depends on McCaffrey TV, McDonald TJ, Facer GW, et al: Otologic manifestations
the immune status of the patient. External ear disease such as of Wegener’s granulomatosis. Otolaryngol Head Neck Surg 88:586,
otitis externa and Kaposi sarcoma can also occur. Tissue diag- 1980.
nosis by biopsy or tympanocentesis is indicated to identify the McGill TJI: Mycotic infection of the temporal bone. Arch Otolaryngol
causative agent before initiating therapy. Head Neck Surg 104:140, 1978.
McKenna MJ, Kristiansen AG, Bartley ML, et al: Association of COL1A1
Pneumocystis jiroveci is an unusual opportunistic protozoan and otosclerosis: evidence for a shared genetic etiology with mild
that is a common cause of middle ear and external ear disease osteogenesis imperfecta. Am J Otol 19:604, 1998.
in patients with AIDS. Subcutaneous masses in the external Megerian CA, Sofferman RA, McKenna MJ, et al: Fibrous dysplasia of
canal or aural polyps that arise from the canal, the tympanic the temporal bone: ten new cases demonstrating the spectrum of
membrane, or the mesotympanum can result in conductive otologic sequelae. Am J Otol 16:408, 1995.
hearing loss, otorrhea, or otalgia. Presumed routes of infection Michaels L, Suocek S, Liang J: The ear in the acquired immunodefi-
include hematogenous spread from another source (e.g., pul- ciency syndrome, 1: temporal bone histopathologic study. Am J Otol
monary), ascending infection through the eustachian tube 15:515, 1994.
from pharyngeal colonization, or airborne transmission of Monsell EM: The mechanism of hearing loss in Paget’s disease of bone.
Laryngoscope 114:598–606, 2004.
the aerosolized organism directly to the external canal.140,141 A Nadol JB, Jr: Positive “fistula sign” with an intact tympanic membrane.
biopsy specimen shows the characteristic organism, and the Arch Otolaryngol Head Neck Surg 100:273, 1974.
infection responds to treatment with oral trimethoprim- Rinaldo A, Brandwein MS, Devaney KO, et al: AIDS-related otological
sulfamethoxazole. Otologic disease that results from P. jiroveci lesions. Acta Otolaryngol 123:672–674, 2003.
may be the initial and only presenting symptom of AIDS.140-142 Ryan AF, Harris JP, Keithley EM: Immune-mediated hearing loss: basic
Inner ear symptoms can occur such as vertigo, tinnitus, and mechanisms and options for therapy. Acta Otolaryngol Suppl 548:38–
SNHL that includes fluctuating and sudden hearing loss.143,144 43, 2002.
SNHL is ascribed to various causes that include otosyphilis, Schuknecht HF: Pathology of the ear, ed 2, Philadelphia, 1993, Lea &
cryptococcal meningitis, tuberculous meningitis, CNS toxoplas- Febiger.
Skolnik PR, Nadol JB, Jr, Baker AS: Tuberculosis of the middle ear:
mosis, and ototoxic medication.142,145 HIV is neurotropic and review of the literature with an instructive case report. Rev Infect Dis
may itself be the primary cause of SNHL, and the facial nerve 8:403, 1986.
can be involved by herpes zoster (Ramsay Hunt syndrome). Zoller M, Wilson WR, Nadol JB, Jr: Treatment of syphilitic hearing loss,
In a study of 49 temporal bones from 25 patients with AIDS, combined penicillin and steroid therapy in 29 patients. Ann Otol
Michaels and colleagues146 found low-grade otitis media in 60% Rhinol Laryngol 88:160, 1979.
149 | OTOLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE 2318.e1
28. Hybels RL, Rice DH: Neuro-otologic manifestations of sarcoidosis.

REFERENCES Laryngoscope 86:1873, 1976.
1. Lichtenstein L: Histiocytosis X: integration of eosinophilic granu- 29. Cohen JP, Lachman LJ, Hammerschlag PE: Reversible facial paral-
loma of bone, “Letterer-Siwe disease,” and “Schüller-Christian ysis in sarcoidosis. Arch Otolaryngol Head Neck Surg 109:832, 1983.
disease” as related manifestations of a single nosologic entity. Arch 30. Banerjee AS, Gleeson MJ: Mesotympanic sarcoidosis. J Laryngol
Pathol 56:84, 1953. Otol 119:733–736, 2005.
2. Schmitz L, Favara BE: Nosology and pathology of Langerhans cell 31. Adelola OA, Fernandez R, Ahmad R, et al: Sarcoidosis of the
histiocytosis. Hematol Oncol Clin North Am 12:221, 1998. external ear—literature review and report of a case. J Laryngol Otol
3. Valladeau J, Ravel O, Dezutter-Dambuyant C, et al: Langerin, a 121:289–292, 2007.
novel C-type lectin specific to Langerhans cells, is an endocytic 32. Babin RW, Liu C, Aschenbrener C: Histopathology of neurosen-
receptor that induces the formation of Birbeck granules. Immunity sory deafness in sarcoidosis. Ann Otol Rhinol Laryngol 93:389, 1984.
12:71–81, 2000. 33. Nadol JB, Jr: Positive “fistula sign” with an intact tympanic mem-
4. Herzog KM, Tubbs R: Langerhans cell histiocytosis. Adv Anat brane. Arch Otolaryngol Head Neck Surg 100:273, 1974.
Pathol 5:347, 1998. 34. Zoller M, Wilson WR, Nadol JB, Jr: Treatment of syphilitic hearing
5. McClain KL: Langerhans cell histiocytosis (histiocytosis X, eosino- loss, combined penicillin and steroid therapy in 29 patients. Ann
philic granuloma). http://www.uptodateonline.com; version 9.0, Otol Rhinol Laryngol 88:160, 1979.
2013. Accessed May 6, 2014. 35. Steere AC: Lyme disease. N Engl J Med 321:586, 1989.
6. Smith DG, Nesbit ME, Jr, D’Angio GJ, et al: Histiocytosis X: role 36. Duray PH, Steere AC: Clinical pathologic correlations of Lyme
of radiation therapy in management with special reference to disease by stage. Ann N Y Acad Sci 539:65, 1988.
dose levels employed. Radiology 106:419, 1973. 37. Sigal LH, Eisen R: Prevention of Lyme disease. http://www
7. Cunningham MJ, Curtin HD, Jaffe R, et al: Otologic manifesta- .uptodateonline.com; version 13.0, 2012. Accessed May 6, 2014.
tions of Langerhans’ cell histiocytosis. Arch Otolaryngol Head Neck 38. Clark JR, Carlson RD, Sasaki CT, et al: Facial paralysis in Lyme
Surg 115:807, 1989. disease. Laryngoscope 95:1341, 1985.
8. Arceci RJ, Brenner MK, Pritchard J: Controversies and new 39. Petersen LR, Sweeney AH, Checko PJ, et al: Epidemiological and
approaches to treatment of Langerhans cell histiocytosis. Hematol clinical features of 1,149 persons with Lyme disease identified by
Oncol Clin North Am 12:339, 1998. laboratory-based surveillance in Connecticut. Yale J Biol Med 62:
9. Schuknecht HF, Perlman HB: Hand-Schüller-Christian disease 253, 1989.
and eosinophilic granuloma of the skull. Ann Otol Rhinol Laryngol 40. Pachner AR, Steere AC: The triad of neurologic manifestations of
57:643, 1948. Lyme disease: meningitis, cranial neuritis, and radiculoneuritis.
10. Tos M: A survey of Hand-Schüller-Christian’s disease in otolaryn- Neurology 35:47, 1985.
gology. Acta Otolaryngol (Stockh) 62:217, 1966. 41. Rosenhall U, Hanner P, Kaijser B: Borrelia infection and vertigo.
11. McCaffrey TV, McDonald TJ: Histiocytosis X of the ear and tem- Acta Otolaryngol (Stockh) 106:111, 1988.
poral bone: review of 22 cases. Laryngoscope 89:1735, 1979. 42. Hanner P, Rosenhall U, Edström S, et al: Hearing impairment
12. Hudson WR, Kenan PD: Otologic manifestations of histiocytosis in patients with antibody production against Borrelia burgdorferi
X. Laryngoscope 79:678, 1969. antigen. Lancet 1:13, 1989.
13. Schuknecht HF, Papaspyrou S: Histiocytosis X. Otolaryngol Head 43. Fox GM, Heilskov T, Smith JL: Cogan’s syndrome and seroreactiv-
Neck Surg 88:544, 1980. ity to Lyme borreliosis. J Clin Neuroophthalmol 10:83, 1990.
14. Skolnik PR, Nadol JB, Jr, Baker AS: Tuberculosis of the middle 44. Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifes-
ear: review of the literature with an instructive case report. Rev tations of Lyme disease. N Engl J Med 323:1438, 1990.
Infect Dis 8:403, 1986. 45. Stanley RJ, McCaffrey TV, Weiland LH: Fungal mastoiditis in
15. Cleary KR, Batsakis JG: Pathology consultation: mycobacterial the immunocompromised host. Arch Otolaryngol Head Neck Surg
disease of the head and neck: current perspective. Ann Otol Rhinol 114:198, 1988.
Laryngol 104:830, 1995. 46. Gussen R, Canalis RF: Mucormycosis of the temporal bone. Ann
16. Wardrop PA, Pillsbury HC, III: Mycobacterium avium acute mastoid- Otol Rhinol Laryngol 91:27, 1982.
itis. Arch Otolaryngol Head Neck Surg 110:686, 1984. 47. McGill TJI: Mycotic infection of the temporal bone. Arch Otolar-
17. Sethi A, Sabherwal A, Gulati A, et al: Primary tuberculous petro- yngol Head Neck Surg 104:140, 1978.
sitis. Acta Otolaryngol 125:1236–1239, 2005. 48. Woolf, NK: Experimental congenital cytomegalovirus labyrinthitis
18. Kuan CC, Kaga K, Tsuzuku T: Tuberculous meningitis-induced and sensorineural hearing loss. Am J Otolaryngol 11:299–303, 1990.
unilateral sensorineural hearing loss: a temporal bone study. Acta 49. Stagno S, Pass RF, Dworsky ME, et al: Congenital and perinatal
Otolaryngol 127:553–557, 2007. cytomegalovirus infections. Semin Perinatol 7:31–42, 1983.
19. Bernardo J: Diagnosis of pulmonary tuberculosis in HIV-negative 50. Rajkumar SV, Gertz MA, Kyle RA, et al: Mayo Clinic Myeloma,
patients. http://www.uptodateonline.com; versin 24.0, 2014. Amyloid, and Dysproteinemia Group: Current therapy for multi-
Accessed May 6, 2014. ple myeloma. Mayo Clin Proc 77:813, 2002.
20. Rasmussen N: Management of the ear, nose and throat manifesta- 51. Brenner T, Duggan S, Natale J, et al: Treatment protocols for
tions of Wegener granulomatosis: an otorhinolaryngologist’s per- multiple myeloma. http://www.uptodateonline.com; version 5.0,
spective. Curr Opin Rheumatol 13:3, 2001. 2013. Accessed May 6, 2014.
21. Yi ES, Colby TV: Wegener’s granulomatosis. Semin Diagn Pathol 18: 52. Li W, Schachern PA, Morizono T, et al: The temporal bone in
34, 2001. multiple myeloma. Laryngoscope 104:675–680, 1994.
22. van der Woude FJ, Rasmussen N, Lobatto S, et al: Autoantibodies 53. Lavine FR, Mattucci KF, Merten CW: Multiple myeloma of the
against neutrophils and monocytes: tool for diagnosis and temporal bone. Ear Nose Throat J 58:210, 1979.
marker of disease activity in Wegener’s granulomatosis. Lancet 1: 54. Noorani MA: Plasmacytoma of middle ear and upper respiratory
425, 1985. tract. J Laryngol Otol 89:105, 1975.
23. Levine SM, Stone JH: Pathogenesis of Wegener’s granulomatosis 55. Quinodoz D, Dulguerov P, Kurt AM, et al: Multiple myeloma
and related vasculitides. http://www.uptodateonline.com; version presenting with external ear canal mass. J Laryngol Otol 112:469–
10.0, 2013. Accessed May 6, 2014. 471, 1998.
24. Regan MJ, Hellmann DB, Stone JH: Treatment of Wegener’s 56. Zechner G, Altmann F: The temporal bone in leukemia: histologi-
granulomatosis. Rheum Dis Clin North Am 27:1, 2001. cal studies. Ann Otol Rhinol Laryngol 78:375, 1969.
25. McCaffrey TV, McDonald TJ, Facer GW, et al: Otologic manifesta- 57. Paparella MM, Berlinger NT, Oda M, et al: Otological manifesta-
tions of Wegener’s granulomatosis. Otolaryngol Head Neck Surg 88: tions of leukemia. Laryngoscope 83:1510, 1973.
586, 1980. 58. Druss JG: Aural manifestations of leukemia. Arch Otolaryngol Head
26. Fontenot A, King TE, Jr: Pathogenesis of sarcoidosis. http:// Neck Surg 42:267, 1945.
www.uptodateonline.com; version 12.0, 2013. Accessed May 6, 59. Gotay V: Unusual otologic manifestation of chronic lymphocytic
2014. leukemia. Laryngoscope 86:1856, 1976.
27. King TE, Jr: Treatment of pulmonary sarcoidosis with alternatives 60. Todd NW, Jr, Bowman CA: Acute myelogenous leukemia present-
to glucocorticoids. http://www.uptodateonline.com; version 9.0, ing as atypical mastoiditis with facial paralysis. Int J Pediatr Otorhi-
2013. Accessed May 6, 2014. nolaryngol 7:173, 1984.
61. Levy R, Shvero J, Sandbank J: Granulocytic sarcoma (chloroma) 89. Marie PJ: Cellular and molecular basis of fibrous dysplasia. Histol

of the temporal bone. Int J Pediatr Otorhinolaryngol 18:163, 1989. Histopathol 16:981, 2001.
62. Gokcan MK, Batikhan H, Calguner M, et al: Unilateral hearing 90. Weinstein LS: G(s)alpha mutations in fibrous dysplasia and
loss as a presenting manifestation of granulocytic sarcoma (chlo- McCune-Albright syndrome. J Bone Miner Res (Suppl 2):120–124,
roma). Otol Neurotol 27:106–109, 2006. 2006.
63. Okura SI, Kaga K: Temporal bone pathology of leukemia and 91. DiCaprio MR, Enneking WF: Fibrous dysplasia: pathophysiology,
malignant lymphoma with middle ear effusion. Auris Nasus Larynx evaluation, and treatment. J Bone Joint Surg Am 87:1848–1864,
21:1–7, 1994. 2005.
64. Gloria-Cruz TI, Schachern PA, Paparella MM, et al: Metastases to 92. Nager GT, Kennedy DW, Kopstein E: Fibrous dysplasia: a review
temporal bones from primary nonsystemic malignant neoplasms. of the disease and its manifestations in the temporal bone. Ann
Arch Otolaryngol Head Neck Surg 126:209, 2000. Otol Rhinol Laryngol Suppl 92:1, 1982.
65. Schuknecht HF, Allam AF, Murakami Y: Pathology of secondary 93. Megerian CA, Sofferman RA, McKenna MJ, et al: Fibrous dysplasia
malignant tumors of the temporal bone. Ann Otol Rhinol Laryngol of the temporal bone: ten new cases demonstrating the spectrum
77:5, 1968. of otologic sequelae. Am J Otol 16:408, 1995.
66. Berlinger NT, Koutroupas S, Adams G, et al: Patterns of involve- 94. Lustig LR, Holliday MJ, McCarthy EF, et al: Fibrous dysplasia
ment of the temporal bone in metastatic and systemic malignancy. involving the skull base and temporal bone. Arch Otolaryngol Head
Laryngoscope 90:619, 1980. Neck Surg 127:1239, 2001.
67. Selton M: Clinical manifestations and diagnosis of Paget’s 95. Cleiren E, Bénichou O, Van Hul E, et al: Albers-Schönberg disease
disease of bone. http://www.uptodateonline.com; version 6.0, (autosomal dominant osteopetrosis, type II) results from muta-
2013. Accessed May 6, 2014. tions in the CICN7 chloride channel gene. Hum Mol Genet 10:2861,
68. Mills BG, Singer FR: Nuclear inclusions in Paget’s disease of bone. 2001.
Science 194:201, 1976. 96. de Vernejoul MC, Benichou O: Human osteopetrosis and other
69. Mirra JM: Pathogenesis of Paget’s disease based on viral etiology. sclerosing disorders: recent genetic developments. Calcif Tissue Int
Clin Orthop 217:162, 1987. 69:1, 2001.
70. Davies DG: Paget’s disease of the temporal bone: a clinical and 97. Van Hul E, Gram J, Bollerslev J, et al: Localization of the gene
histopathological survey. Acta Otolaryngol Suppl (Stockh) 242:1, causing autosomal dominant osteopetrosis type I to chromosome
1968. 11q12-13. J Bone Miner Res 17:1111, 2002.
71. Hadjipavlou AG, Gaitanis IN, Kontakis GM: Paget’s disease of the 98. Myers EN, Stool S: The temporal bone in osteopetrosis. Arch
bone and its management. J Bone Joint Surg Br 84:160, 2002. Otolaryngol Head Neck Surg 89:44, 1969.
72. Khetarpal U, Schuknecht HF: In search of pathologic correlates 99. Suga F, Lindsay JR: Temporal bone histopathology of osteopetro-
of hearing loss and vertigo in Paget’s disease: a clinical and histo- sis. Ann Otol Rhinol Laryngol 85:15, 1976.
pathologic study of 26 temporal bones. Ann Otol Rhinol Laryngol 100. Hawke M, Jahn AF, Bailey D: Osteopetrosis of the temporal bone.
Suppl 145:1, 1990. Arch Otolaryngol Head Neck Surg 107:278, 1981.
73. Monsell EM, Cody DD, Bone HG, et al: Hearing loss in Paget’s 101. Wong ML, Balkany TJ, Reeves J, et al: Head and neck manifesta-
disease of bone: the relationship between pure-tone thresholds tions of malignant osteopetrosis. Otolaryngology 86:585, 1978.
and mineral density of the cochlear capsule. Hear Res 83:114, 102. Dozier TS, Duncan IM, Klein AJ, et al: Otologic manifestations of
1995. malignant osteopetrosis. Otol Neurotol 26:762–766, 2005.
74. Monsell EM: The mechanism of hearing loss in Paget’s disease of 103. Milroy CM, Michaels L: Temporal bone pathology of adult type
bone. Laryngoscope 114:598–606, 2004. osteopetrosis. Arch Otolaryngol Head Neck Surg 116:79, 1990.
75. Paterson CR, Monk EA, MacAllion SJ: How common is hearing 104. Hamersma H: Total decompression of the facial nerve in osteo-
impairment in osteogenesis imperfecta? J Laryngol Otol 115:280, petrosis. ORL J Otorhinolaryngol Relat Spec 36:21, 1973.
2001. 105. Hamersma H, Hofmeyr L: Too much bone: the middle ear in
76. Kuurila K, Kaitila I, Johansson R, et al: Hearing loss in Finnish sclerosing bone dysplasias. Adv Otorhinolaryngol 65:61–67, 2007.
adults with osteogenesis imperfecta: a nationwide survey. Ann Otol 106. Ruedi L: Are there cochlear shunts in Paget’s and Recklinghau-
Rhinol Laryngol 111:939, 2002. sen’s disease? Acta Otolaryngol (Stockh) 65:13, 1968.
77. Beary JF, 3rd, Chines AA: Management and prognosis of osteo- 107. Lindsay JR, Suga F: Sensorineural deafness due to osteitis fibrosa.
genesis imperfecta. http://www.uptodateonline.com; version 7.0, Arch Otolaryngol Head Neck Surg 102:37, 1976.
2013. Accessed May 6, 2014. 108. Schiffmann R, Brady RO: New prospects for the treatment of
78. Armstrong BW: Stapes surgery in patients with osteogenesis lysosomal storage disease. Drugs 62:733, 2002.
imperfecta. Ann Otol Rhinol Laryngol 93:634, 1984. 109. Schachern PA, Shea DA, Paparella MM: Mucopolysaccharidosis
79. Berger G, Hawke M, Johnson A, et al: Histopathology of the tem- I-H (Hurler’s syndrome) and human temporal bone histopathol-
poral bone in osteogenesis imperfecta congenita: a report of ogy. Ann Otol Rhinol Laryngol 93:65, 1984.
5 cases. Laryngoscope 95:193, 1985. 110. Zechner G, Altmann F: The temporal bone in Hunter’s syndrome
80. Zajtchuk JT, Lindsay JR: Osteogenesis imperfecta congenita and (gargoylism). Arch Klin Exp Ohren Nasen Kehlkopfheilkd 192:137,
tarda: a temporal bone report. Ann Otol Rhinol Laryngol 84:350, 1968.
1975. 111. Friedmann I, Spellacy E, Crow J, et al: Histopathological studies
81. Nager GT: Osteogenesis imperfecta of the temporal bone and its of the temporal bones in Hurler’s disease (mucopolysaccharidosis
relation to otosclerosis. Ann Otol Rhinol Laryngol 97:585, 1988. [MPS] IH). J Laryngol Otol 99:29, 1985.
82. Patterson CN, Stone HB, 3rd: Stapedectomy in van der Hoeve’s 112. Wolff D: Microscopic study of temporal bones in dysostosis multi-
syndrome. Laryngoscope 80:544, 1970. plex (gargoylism). Laryngoscope 52:218, 1942.
83. van der Rijt AJ, Cremers CW: Stapes surgery in osteogenesis 113. Komura Y, Kaga K, Ogawa Y, et al: ABR and temporal bone pathol-
imperfecta: results of a new series. Otol Neurotol 24:717–722, 2003. ogy of Hurler’s disease. Int J Pediatr Otorhinolaryngol 43:179, 1998.
84. Kuurila K, Pynnonen S, Grenman R: Stapes surgery in osteogen- 114. Stark TW, Hirokawa RH: Gout and its manifestations in the head
esis imperfecta in Finland. Ann Otol Rhinol Laryngol 113:187–193, and neck. Otolaryngol Clin North Am 15:659, 1982.
2004. 115. Touart DM, Purnima S: Cutaneous deposition disease, part II.
85. Doi K, Nishimura H, Ohta Y, et al: Stapes surgery in Japanese J Am Acad Dermatol 39:527, 1998.
patients with osteogenesis imperfecta. Adv Otorhinolaryngol 65: 116. Agudelo CA, Wise CM: Gout: diagnosis, pathogenesis, and clinical
226–230, 2007. manifestations. Curr Opin Rheumatol 13:234, 2001.
86. Sando I, Myers D, Harada T, et al: Osteogenesis imperfecta tarda 117. Van Offel JF, De Clerck LS, Francx LM, et al: The clinical mani-
and otosclerosis: a temporal bone histopathology report. Ann Otol festations of ochronosis: a review. Acta Clin Belg 50:358, 1995.
Rhinol Laryngol 90(3 Pt 1):199, 1981. 118. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol
87. McKenna MJ, Kristiansen AG, Bartley ML, et al: Association of Rhinol Laryngol 88:585, 1979.
COL1A1 and otosclerosis: evidence for a shared genetic etiology 119. Lehnhardt E: Sudden hearing disorders occurring simultaneously
with mild osteogenesis imperfecta. Am J Otol 19:604, 1998. or successively on both sides. Z Laryngol Rhinol Otol 37:1–16, 1958.
88. Schwartz DT, Alpert M: The malignant transformation of fibrous 120. Schuknecht HF: Ear pathology in autoimmune disease. Adv Oto-
dysplasia. Am J Med Sci 247:1, 1964. rhinolaryngol 46:50, 1991.
149 | OTOLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE 2318.e3
121. Stephens SDG, Luxon L, Hinchcliffe R: Immunological disorders 136. Hill HR, Book LS, Hemming VG, et al: Defective neutrophil che-

and auditory lesions. Audiology 21:128, 1982. motactic responses in patients with recurrent episodes of otitis
122. Ryan AF, Harris JP, Keithley EM: Immune-mediated hearing loss: media and chronic diarrhea. Am J Dis Child 131:433, 1977.
basic mechanisms and options for therapy. Acta Otolaryngol Suppl 137. Blayney AW, Bunch C: Mastoid surgery in chronic granulomatous
548:38–43, 2002. disease. J Laryngol Otol 98:187, 1984.
123. Ruckenstein MJ: Autoimmune inner ear disease. Curr Opin Otolar- 138. Alper CA, Abramson N, Johnston RB, Jr, et al: Increased suscep-
yngol Head Neck Surg 12:426–430, 2004. tibility to infection associated with abnormalities of complement
124. Oh YM, Oh DH, Jeong SH, et al: Sequential bilateral hearing loss mediated functions and of the third component of complement
in multiple sclerosis. Ann Otol Rhinol Laryngol 117:186–191, 2008. (C3). N Engl J Med 282:349, 1970.
125. Hausler R, Levine RA: Brainstem auditory evoked potentials are 139. Smith ME, Canalis RF: Otologic manifestations of AIDS: the oto-
related to intra-aural time discrimination in patients with multiple syphilis connection. Laryngoscope 99:365, 1989.
sclerosis. Brain Res 191:589–594, 1980. 140. Breda SD, Hammerschlag PE, Gigliotti F, et al: Pneumocystis carinii
126. Ward PH, Cannon D, Lindsay JR: The vestibular system in multi- in the temporal bone as a primary manifestation of the acquired
ple sclerosis, a clinical-histopathological study. Laryngoscope 75: immunodeficiency syndrome. Ann Otol Rhinol Laryngol 97(4 Pt 1):
1031–1047, 1965. 427, 1988.
127. O’Halloran HS, Pearson PA, Lee WB, et al: Microangiopathy of 141. Gherman CR, Ward RR, Bassis ML: Pneumocystis carinii otitis media
the brain, retina and cochlea (Susac’s syndrome). A report of 5 and mastoiditis as the initial manifestation of the acquired immu-
cases and a review of the literature. Ophthal 105:1038–1044, 1998. nodeficiency syndrome. Am J Med 85:250, 1988.
128. Grover N, Whiteside OJ, Ramsden JD: Susac syndrome: outcome 142. Kohan D, Rothstein SG, Cohen NL: Otologic disease in patients
of unilateral cochlear implantation. J Laryngol Otol 125:856–858, with acquired immunodeficiency syndrome. Ann Otol Rhinol Lar-
2011. yngol 97:636, 1988.
129. Francis HW, Makary C, Halpin C, et al: Temporal bone findings 143. Chandrasekhar SS, Connelly PE, Brahmbhatt SS, et al: Otologic
in a case of Susac’s syndrome. Otol & Neurotol 32:1198–1204, 2011. and audiologic evaluation of human immunodeficiency virus-
130. Candotti F: Gene therapy for immunodeficiency. Curr Allergy infected patients. Am J Otolaryngol 21:1–9, 2000.
Asthma Rep 1:407, 2001. 144. Teggi R, Giordano L, Pistorio V, et al: Vestibular function in HIV
131. Fischer A: Primary immunodeficiency diseases: an experimental patients: preliminary report. Acta Otorhinolaryngol Ital 26:140–146,
model for molecular medicine. Lancet 357:1863, 2001. 2006.
132. Sasaki CT, Askenase P, Dwyer J, et al: Chronic ear infection in the 145. Rinaldo A, Brandwein MS, Devaney KO, et al: AIDS-related oto-
immunodeficient patient. Arch Otolaryngol 107:82, 1981. logical lesions. Acta Otolaryngol 123:672–674, 2003.
133. Harris JP, South MA: Immunodeficiency diseases: head and neck 146. Michaels L, Suocek S, Liang J: The ear in the acquired immuno-
manifestations. Head Neck Surg 5:114, 1982. deficiency syndrome, 1: temporal bone histopathologic study. Am
134. Oxelius V: Immunoglobulin G (IgG) subclasses and human J Otol 15:515, 1994.
disease. Am J Med 76:7, 1984. 147. Toriello HV, Reardon W, Gorlin RJ, editors: Hereditary Hearing
135. Ohtani I, Schuknecht HF: Temporal bone pathology in DiGeorge’s Loss and Its Syndromes, ed 2, New York, 2004, Oxford University
syndrome. Ann Otol Rhinol Laryngol 93:220, 1984. Press.
Sensorineural Hearing 150
Loss in Adults
H. Alexander Arts
Key Points
■ Sensorineural hearing loss (SNHL) is one of the most common clinical disorders and is associated
with a multitude of etiologies.
■ Because of the wide range of genetic, infectious, vascular, neoplastic, traumatic, toxic, iatrogenic,
degenerative, and immunologic and inflammatory pathologies that can affect the cochlea, a
systematic approach to assessment is crucial to identification of the responsible etiology.
Audiologic, serologic, radiologic, and blood chemistry testing can be used strategically for a
cost-effective approach to diagnosis of SNHL.
■ SNHL results from cochlear hair cell or auditory nerve dysfunction. Psychophysical abnormalities
that result from impaired auditory physiology combine to challenge effective listening.
■ Sudden SNHL is a clinical syndrome with a lengthy differential diagnosis. Prompt assessment and
management of sudden SNHL may offer the opportunity to reverse or ameliorate the hearing loss
using more recently developed therapeutic protocols.
S ensorineural hearing loss (SNHL) is an extremely common for associated symptoms such as tinnitus, vertigo, dysequilib-

disorder, and it has a spectrum of effect that ranges from an rium, otalgia, otorrhea, or headache, and ophthalmologic or
almost undetectable degree of disability to a profound altera- neurologic complaints should be sought. A sensation of aural
tion in the ability to function in society. Because its onset is fullness or pressure may be present and may be the patient’s only
often insidious, and because it is frequently accompanied by complaint.
subtle compensatory strategies, hearing loss is often overlooked A thorough medical history should be obtained with particu-
by physicians and patients. The auditory system is complex, and lar attention to cardiovascular, rheumatologic, endocrine, neu-
it depends on the performance of many different systems for rologic, and renal disorders and to any exposure to potentially
its continued function. Normal hearing function depends on ototoxic drugs. Surgical history should be evaluated, and a
the mechanical integrity of the middle ear mechanism and history of skull trauma, penetrating trauma to the ear canal,
cochlear duct, micromechanical and cellular integrity of the and compressive force applied to the ear canal (e.g., slap injury)
organ of Corti, homeostasis of the inner ear biochemical and should be queried. The patient’s history of exposure to noise,
bioelectric environment, and adequate function of the central occupational and otherwise, should be specifically addressed.
nervous system (CNS) pathways and nuclei. These depend on The type of noise, its estimated level, duration of exposure, and
normal vascular, hematologic, metabolic, and endocrine func- use of hearing protection should be documented; patients and
tion. As a result, disease of almost any human physiologic physicians often underestimate the importance of a patient’s
system has the potential to affect auditory function. occupational noise exposure and avocational exposures, such
This chapter addresses the clinical evaluation, differential as hunting and power tool use. Finally, family history with regard
diagnosis, natural history, and pathogenesis of SNHL in adults, to hearing loss is particularly important and often overlooked.
and it provides a systematic review of the broad array of etiolo-
gies of SNHL. Inevitably, some overlap will occur with other
chapters in this text, and in these cases, the reader is referred
PHYSICAL EXAMINATION
elsewhere for a more detailed discussion. Physical examination of the ears in patients with SNHL is often
unrevealing. The whisper test and tuning fork testing can be
used to estimate the degree of hearing loss and to determine
CLINICAL EVALUATION OF THE whether the loss is predominantly conductive or sensorineural.
PATIENT WITH HEARING LOSS With the exception of these findings, no abnormality generally
is seen in patients with SNHL. Otoscopic examination of the
HISTORY ears should exclude the possibility of acute or chronic otitis
Evaluation of patients with sudden SNHL begins with a careful media (OM). Neoplasm within the middle ear may rarely be
history. The degree of loss from the patient’s perspective should noted. Pulsatile tinnitus may be heard by the examiner with a
be assessed, which includes its laterality (unilateral or bilateral) standard or Toynbee stethoscope. Other cranial nerve abnor-
and chronicity (sudden onset, rapidly progressive, slowly pro- malities and stigmata of associated systemic disease or heredi-
gressive, fluctuating, or stable). Patients should be questioned tary abnormalities should be specifically sought. The nonotologic
2319
portion of the physical examination is more likely to reveal emission. If the stimulus consists of continuous pure tones of
positive findings. two separate frequencies (F1 and F2), the resulting emission is a
continuous tone of frequency (2F1-F2) and is termed a
distortion product otoacoustic emission. OAEs are clearly generated
AUDIOMETRIC TESTING within the cochlea and are believed to be a byproduct of the
Only a brief discussion of audiometric testing is presented here. “cochlear amplifier,” which is dependent on outer hair cell func-
Conventional audiometric testing is discussed more thoroughly tion. They depend highly on the physiologic state of the cochlea
in Chapter 133, and electrophysiologic testing is addressed in and, if present, suggest normal cochlear function. OAEs are
Chapter 134. rarely present with hearing thresholds greater than 30 dB
Audiometric testing serves to verify and quantify the degree hearing loss regardless of etiology. In addition, for an OAE to be
of hearing loss. Air conduction, bone conduction, and speech present, the middle ear mechanism must be functioning nor-
audiometry and tympanometry measurements constitute the mally, because the stimulus and the response must traverse the
minimum test battery in patients with suspected SNHL. Bone- middle ear. The presence of an OAE in an ear with SNHL sug-
conduction and air-conduction pure tone audiometry helps to gests a retrocochlear etiology or possible pseudohypacusis.
determine the type of hearing loss: conductive, sensorineural, Because these etiologies are extremely rare in neonates, OAEs
or mixed. Speech audiometry verifies the pure tone audiomet- also have been useful in neonatal hearing screening programs.
ric results. Speech discrimination testing with assessment of
the performance-intensity function helps to define further the
nature of the SNHL (cochlear vs. retrocochlear) and pro-
VESTIBULAR TESTING
vides essential prognostic information regarding the potential Vestibular testing can be a useful adjunct in the evaluation of
benefits of amplification. Tympanometry with acoustic reflex SNHL in selected patients. Evidence of ipsilateral peripheral
testing verifies the conductive or sensorineural nature of the vestibular hypofunction in a patient with unilateral progressive
hearing loss and provides additional clues regarding etiology. SNHL suggests the presence of a retrocochlear lesion.
Tympanometry can be especially helpful in excluding the pos-
sibility of a conductive component in patients with profound
losses or bilateral losses in the presence of a masking dilemma.
LABORATORY TESTING
Basic audiologic tests also can provide essential diagnostic Laboratory testing rarely proves to be helpful in determining
clues as to whether SNHL is cochlear or retrocochlear in the etiology of SNHL. In most patients, either the fluorescent
origin. By retrocochlear, we mean a lesion proximal to the cochlea, treponemal antibody absorption test or the microhemaggluti-
the most common retrocochlear lesion being vestibular nation test for Treponema pallidum should be obtained, because
schwannoma. The examiner should have a high degree of the prevalence of syphilis is relatively high, it is frequently
suspicion for retrocochlear etiologies when loss is asymmet- asymptomatic, it is important to manage, and it is a potentially
ric, speech discrimination is abnormally reduced or asymmet- treatable cause of SNHL. The Venereal Disease Research Labo-
ric, performance-intensity relationships (“rollover”) on speech ratory test is not helpful in this regard, because it frequently
discrimination testing is abnormal, or abnormalities in acous- becomes negative with inadequate management in the latent
tic reflex are apparent. Other cranial nerve findings, asym- phase of the disease or in neurosyphilis. Routinely obtaining
metric tinnitus, or vestibular complaints—even if mild—should hematologic, metabolic, and endocrine studies does not seem
increase the level of suspicion. to be necessary or cost-effective. Similarly, routine screening for
Auditory brainstem response (ABR) testing is useful in eval- autoimmune disorders does not seem warranted. If these dis-
uating the possibility of a retrocochlear etiology and for estab- orders are clinically significant, they typically are apparent from
lishing thresholds in difficult-to-test patients (young children the history and physical examination. In addition, no clear
or malingerers). In the past, the ABR was believed to be a highly relationship is apparent between the results of any of these tests
sensitive test for the presence of a retrocochlear lesion. It is less and the presence of autoimmune hearing loss.
commonly used in this role today because of reduced sensitivity
in patients with small vestibular schwannomas, tumors readily
detected with the high accuracy offered by magnetic resonance
RADIOGRAPHIC TESTING
imaging (MRI).1-3 New modifications of the ABR may increase Radiographic imaging is warranted in selected patients with
this study’s sensitivity.4 SNHL. MRI with gadolinium enhancement is currently the
Electrocochleography differs from ABR testing in that the gold standard in evaluating potential retrocochlear hearing
reference electrode is placed closer to the cochlea (on or close losses. The role of MRI versus ABR testing in this regard is
to the tympanic membrane or promontory). This allows mea- controversial. It is clear, however, that MRI with gadolinium is
surement of the cochlear microphonic potential, the summat- much more sensitive than ABR for diagnosis of small lesions.1-3
ing potential, and the auditory nerve action potential. Wave I Selective T2-weighted fast spin-echo MRI may be almost as
of the ABR corresponds to the action potential of electroco- sensitive as gadolinium-enhanced standard MRI and is less
chleography. Approximately two thirds of patients with classic expensive.7 Computed tomography (CT) is useful in patients
Meniere disease have an elevated summating potential/action with suspected labyrinthine anomalies, such as large vestibular
potential ratio. It is believed that such a finding suggests the aqueduct syndrome or Mondini dysplasia. CT may also be
presence of endolymphatic hydrops.5,6 Electrocochleography useful in patients with suspected labyrinthine fistula or tempo-
can also be useful in patients in whom wave I of the ABR is ral bone fractures. High-resolution CT with reformatted images
weak or not present, because the location of the reference in the plane of, and perpendicular to, the semicircular canals
electrode inherently enlarges wave I. is the study of choice for showing semicircular canal dehiscence
Otoacoustic emissions (OAEs) consist of acoustic energy syndrome.8
generated by the cochlea and recorded with a microphone in
the external auditory canal. These emissions can be spontane- ETIOLOGY OF SENSORINEURAL
ous in onset or, more commonly, they can be evoked by an
acoustic stimulus delivered to the ear canal. If the acoustic
HEARING LOSS
stimulus consists of a transient sound (a click or tone pip), the SNHL is a common clinical disorder associated with a multi-
resulting emission is termed a transient-evoked otoacoustic tude of etiologies. Because of the wide range of genetic,
150 | SENSORINEURAL HEARING LOSS IN ADULTS 2321
deficits. Three distinct groups have been defined: Type 1

accounts for 85% of all cases and is characterized by profound
congenital hearing loss, absent vestibular response, and the
development of retinitis pigmentosa by the age of 10 years. Type
2 accounts for 10% of cases and is characterized by congenital,
moderate-to-severe stable hearing loss, normal vestibular
responses, and onset of retinitis pigmentosa in patients 17 to
23 years old. Type 3 is typified by progressive hearing loss with
FIGURE 150-1. Ocular findings in Waardenberg syndrome. Note the dys-
topia canthorum, broad nasal root, confluence of the eyebrows, and hetero-
onset in childhood or late adolescence and variable onset of
chromia iridis. retinitis pigmentosa. Approximately 5% of patients have type 3
disease. The disease is transmitted in an autosomal-recessive
fashion, and it is estimated that 1 of 100 people is a carrier of
the trait.
infectious, vascular, neoplastic, traumatic, toxic, iatrogenic,
degenerative, and immunologic and inflammatory pathologies Inner Ear Anomalies
that can affect the cochlea, a systematic approach to assessment Many patterns of dysplasia of the inner ear have been described,
is crucial to identification of the responsible etiology. and most have been associated with SNHL. These dysplastic
patterns of development may be inherited, sporadic, or the
result of chromosomal abnormalities. Commonly used descrip-
DEVELOPMENTAL AND tive terms for these dysplasias include Scheibe dysplasia (cochleo-
HEREDITARY DISORDERS saccular dysplasia that involves membranous labyrinth only),
Hereditary Disorders of Adult Onset Mondini dysplasia (dysplasia of bony and membranous laby-
rinth), and common cavity deformity (otocystlike labyrinth with no
The discussion of hereditary causes of hearing loss in this cochlea or clear vestibular organs). Patterns of labyrinthine
chapter is limited to the more common etiologies primarily dysplasias form a spectrum with all manner of anomalies and
seen in adulthood. Hereditary factors frequently play a role in patterns of hearing loss.15
SNHL, and research in this area is expanding rapidly. For a
complete categorization and review of these disorders, the Large Vestibular Aqueduct Syndrome. One form of inner ear
reader is referred to the excellent and encyclopedic work by dysplasia is unique, because it has been associated with delayed
Toriello and colleagues.9 onset of SNHL. An enlarged vestibular aqueduct is commonly
seen in combination with other inner ear dysplasias, but more
Nonsyndromic Hereditary Hearing Loss. Most hereditary recently, it has been noted as an isolated finding in many ears.
SNHL is not associated with other hereditary abnormalities. These patients may have any level of hearing, from normal to
Hereditary hearing loss without associated abnormalities is a profound loss. Frequently, both ears are affected, and the
much more common than is generally appreciated and fre- losses are asymmetric. Fluctuation of hearing is common and
quently is overlooked. It is likely that genetic factors play a role usually affects one ear at a time; this may manifest as anacusis
in presbycusis and in susceptibility to noise-induced hearing in one ear with fluctuation in the other. A conductive compo-
loss (NIHL).10-13 Distinct patterns of hereditary hearing loss nent to the low-frequency hearing loss is often evident. In
transmitted in autosomal-dominant, autosomal-recessive, and patients who have been followed over time, a progressive step-
X-linked fashion have been well described. Recessive or domi- wise loss has been noted in many.15 This syndrome has been
nant isolated SNHL can be progressive or static, and it may be found to be familial in some cases, and it probably occurs much
congenital, with symptoms present at birth, manifest in child- more commonly than generally appreciated.16 It is seen in isola-
hood, or manifest in adulthood. Approximately 90% of inher- tion, as part of the Mondini malformation, and in patients with
ited SNHL is recessive. branchio-oto-renal syndrome17 and Pendred syndrome.18 It is
well shown on high-resolution CT imaging of the temporal
Waardenburg Syndrome. Waardenburg syndrome is transmit- bone (Fig. 150-2).
ted in an autosomal-dominant fashion and consists of a constel-
lation of findings that include 1) dystopia canthorum, or lateral
displacement of the medial canthi; 2) broad nasal root; 3)
confluence of the medial portions of the eyebrows; 4) partial
or total heterochromia iridis; 5) a white forelock; and 6) SNHL
(Fig. 150-1). Extreme variability is seen in the expression of this
disorder, and the hearing loss can vary from profound to none
at all. The hearing loss can be unilateral or bilateral and can
be associated with vestibular abnormalities.
Alport Syndrome. Alport syndrome is characterized by intersti-

tial nephritis, SNHL, and, much less commonly, ocular mani-
festations.14 This disease is unique, because it is more common
in women but typically is much more severe in men. In the past,
it has been thought to be transmitted in an autosomal-dominant
fashion. However, it is now clear that genetic heterogeneity is
significant. Hearing loss is progressive and variable, usually
beginning in the second decade of life. By age 20 to 40 years,
50% to 75% of men develop end-stage renal failure.
FIGURE 150-2. Computed tomography scan of temporal bone shows large
Usher Syndrome. Usher syndrome consists of the combination vestibular aqueduct syndrome. Arrow indicates the enlarged vestibular
of retinitis pigmentosa and SNHL, with or without vestibular aqueduct.
healthy children or sudden deafness in adults may be caused
INFECTIOUS DISORDERS by subclinical mumps infection in individuals without previous
Infectious disease is a leading cause of SNHL in children and immunity.
less so in adults. Infectious etiologies that cause SNHL primarily Cytomegalovirus (CMV) infection is thought by some
in adults are discussed. authors to be a common cause of congenital and progressive
hearing loss in children.24-27 It has also been proposed to be a
Labyrinthitis cause of sudden SNHL in adults.28 Hearing loss associated with
An infectious or inflammatory process within the labyrinth can acquired immunodeficiency syndrome (AIDS) may represent
take two forms pathologically: serous, sometimes referred to as reactivation of latent CMV infections.29
toxic, or suppurative. Serous labyrinthitis is defined as an abnor-
mal process within the labyrinth caused by the degradation of Syphilis
the tissue-fluid environment within the inner ear.19 It may be Congenital or acquired syphilis has been well established as a
caused by bacterial toxins or contamination of perilymph with cause of SNHL. Although hearing loss is not associated with
blood, products of tissue injury, or air at surgery. Bacterial primary acquired syphilis, its incidence has been estimated to
toxins may enter the inner ear during the course of acute or be 80% in patients with symptomatic neurosyphilis, 29% in
chronic OM, presumably through either the oval or the round patients with asymptomatic neurosyphilis, 25% in patients with
window membranes. Because both acute and chronic suppura- late latent syphilis, and 17% in patients with congenital syphi-
tive OM are common, and because SNHL associated with either lis.19 The mechanism of hearing loss in syphilis is either a
condition is rare, these membranes seem to provide an excel- meningolabyrinthitis, as seen in neurosyphilis, or an osteitis of
lent barrier to prevent transmission of bacteria or their toxins the temporal bone with secondary involvement of the laby-
to the inner ear. The principal abnormal finding in patients rinth, as seen in late congenital, late latent, or tertiary syphilis.30
with serous labyrinthitis is endolymphatic hydrops, and the Pathologically, a resorptive osteitis is seen in the temporal bone,
hearing loss and vestibular dysfunction associated with this state and progressive endolymphatic hydrops is noted within the
can be permanent or transient. labyrinth. Clinically, the presentation of syphilitic hearing loss
Commonly, a clinical diagnosis of labyrinthitis is made when often is indistinguishable from Meniere disease, with fluctuat-
patients come to medical attention with sudden onset of SNHL ing hearing loss, tinnitus, aural fullness, and episodic vertigo.
and acute vertigo. The exact etiology in cases such as this is Hennebert sign, a positive fistula test without middle ear disease,
uncertain, but it is probably identical or similar to the etiology and the Tullio phenomenon, which is vertigo or nystagmus on
of sudden SNHL. The evidence tends to support the theory exposure to high-intensity sound, have been strongly associated
that this is most commonly caused by a viral labyrinthitis.20,21 with otosyphilis.19 The generally recommended treatment con-
Suppurative labyrinthitis is caused by bacterial invasion of the sists of an antibiotic protocol adequate for neurosyphilis with
inner ear, and it is manifested by profound hearing loss and the addition of systemic corticosteroids.31
acute vertigo. The route of invasion can be otogenic, from
acute or chronic OM, most commonly caused by a fistula Rocky Mountain Spotted Fever
between the middle ear and the labyrinth. Alternatively, the Rocky Mountain spotted fever is a tick-borne infection caused
route of invasion can be meningogenic, through the cochlear by Rickettsia rickettsii. Headache, fever, myalgias, and an expand-
aqueduct or internal auditory canal. This is the most common ing petechial rash follow the tick bite by approximately 1 week.
etiology of deafness associated with meningitis. The disease results in systemic vasculitis that leads to encepha-
litis, nephritis, and hepatitis. Rapidly progressive SNHL has
Otitis Media been associated with Rocky Mountain spotted fever and may be
SNHL is rarely associated with acute OM, and no study has transient.32,33 Vasculitis that involves the auditory system has
shown a relationship between SNHL and frequency of acute been postulated to be the etiology of the hearing loss. Diagnosis
OM.22 Patients with long-standing chronic OM commonly have is made primarily by clinical presentation and is confirmed by
a mixed hearing loss. Whether the sensorineural component serologic titers. Treatment is with broad-spectrum antibiotics.
of this loss is a result of the infectious process itself or a result
of other factors, such as surgery or chronic use of ototoxic Lyme Disease
topical antibiotics, has been a long-standing controversy. When Lyme disease is a tick-borne spirochetal illness caused by Bor-
controlled for sensorineural losses associated with surgery, no relia burgdorferi. Although the most well-known otolaryngologic
increase in SNHL in patients with chronic OM is apparent.23 manifestation of the disease is facial paralysis, some evidence
suggests that the disease can be a cause of SNHL.34-37 Although
Viral Infections its true significance remains unclear, Lyme disease should be
Herpes zoster oticus is a varicella-zoster virus infection most considered a possible etiology of SNHL in endemic areas.
commonly associated with facial paralysis and a herpetic skin
eruption over the auricle or within the external auditory canal.
Although facial paralysis is the most frequent finding, hearing PHARMACOLOGIC TOXICITY
loss and vertigo can occur singly or in combination.
Measles is now rare in the developed world because of wide- Aminoglycosides
spread vaccination. In the past, measles was a common cause At least 96 different pharmacologic agents have potential oto-
of deafness in children. The hearing loss usually is bilateral and toxic side effects.38,39 Among these, aminoglycoside antibiotics
moderate to profound in degree, and vestibular function can are perhaps the most common offending agents. This group of
be similarly affected. antibiotics includes streptomycin, dihydrostreptomycin, kana-
Similar to measles, mumps is uncommon in the developed mycin, neomycin, amikacin, gentamicin, tobramycin, and netilm-
world because of widespread vaccination. Mumps is a para- icin. Ototoxic drugs are often also nephrotoxic and vice versa
myxovirus infection that causes parotitis. Complications of (aminoglycosides, loop diuretics, potassium bromates, and non-
mumps include orchitis, pancreatitis, SNHL, prostatitis, nephri- steroidal antiinflammatory drugs [NSAIDs]). Alport syndrome,
tis, myocarditis, and meningoencephalitis. SNHL resulting described earlier, is a hereditary disorder that affects the
from mumps is unique, because it is almost always unilateral. kidneys and the inner ear, and associated developmental disor-
Bilateral involvement is rare. Unilateral deafness in otherwise ders result in renal and inner ear abnormalities. The strong
association between pathology of the renal and auditory systems was available.51 Other ingredients of older ototopical prepara-
has not been well explained. tions also have ototoxic potential (e.g., polymyxin B, propylene
Aminoglycosides target the hair cells and enter the hair cell glycol, acetic acid, and antifungal agents).52,53 It seems prudent
in an energy-dependent process. The end result is death of the to use only agents specifically designed and approved for use in
hair cell. The reader is referred to excellent reviews of the the middle ear for treatment of chronic otitis.
current understanding of the mechanism of aminoglycoside
ototoxicity (see Chapter 154).40-42 The final common pathway Loop Diuretics
of hair cell damage consists of the generation of reactive oxygen The loop diuretics ethacrynic acid, bumetanide, and furosemide
species. Different aminoglycosides have affinities for differing exert their diuretic effect by blocking sodium and water reab-
groups of hair cells, which result in different patterns of oto- sorption in the proximal portion of the loop of Henle. The use
toxicity with different aminoglycosides. Kanamycin, tobramy- of these drugs has been associated with a reversible SNHL and
cin, amikacin, neomycin, and dihydrostreptomycin are more with the potentiation of aminoglycoside-induced hearing loss.
cochleotoxic than vestibulotoxic. Others, such as streptomycin The loss typically is bilateral and symmetric and may be sudden
and gentamicin, are more vestibulotoxic than cochleotoxic. in onset.54,55 These drugs seem to alter metabolism in the stria
In addition, the time course of the toxicity can vary.39 Neo- vascularis, which results in alteration of endolymphatic ion con-
mycin toxicity is typically rapid and profound, whereas a centration and endocochlear potential.56 Risk factors for loop
significant delayed effect has been noted for systemically admin- diuretic–induced ototoxicity include renal failure, rapid infu-
istered streptomycin, dihydrostreptomycin, tobramycin, amika- sion, and concomitant aminoglycoside administration.57
cin, and netilmicin and for gentamicin administered through
the middle ear.43 Antimalarials
The hearing loss may be unilateral or asymmetric and can Quinine has long been known to be associated with the devel-
progress during or after cessation of therapy. Some degree of opment of tinnitus, SNHL, and visual disturbances.58 The drug,
reversibility of the hearing loss sometimes is noted weeks to derived from the bark of the cinchona tree, has a colorful
months after treatment.39 Protective agents, including antioxi- history as an antipyretic. It was dispensed by quacks and in
dants, show promise for preventing or reducing aminoglyco- secret remedies in the seventeenth and eighteenth centuries.
side toxicity. More recently, the use of salicylates has been The syndrome of tinnitus, headache, nausea, and disturbed
proposed.44 A placebo-controlled clinical trial in China has vision is termed cinchonism. Larger doses may cause a more
shown a beneficial effect from the use of aspirin during amino- severe form of the syndrome, which also includes gastrointesti-
glycoside administration.45 nal, CNS, cardiovascular, and dermatologic manifestations.
Well-defined risk factors for aminoglycoside-induced ototox- Quinine is used as an adjunct in the treatment of malaria and
icity have been established and include 1) presence of renal nocturnal leg cramps.59 The ototoxic effect of quinine seems to
disease; 2) longer duration of therapy; 3) increased serum be primarily on hearing and usually is transient. Permanent
levels (either peak or trough levels); 4) advanced age; and 5) hearing loss may occur with large doses or in sensitive patients.
concomitant administration of other ototoxic drugs, particu- Chloroquine and hydroxychloroquine are currently used anti-
larly loop diuretics. Peak and trough serum levels should be malarial drugs structurally related to quinine. They have also
routinely monitored when these drugs are being used, and been associated with ototoxicity and retinopathy. Ototoxicity
particular attention should be paid to avoidance of dosing with these drugs seems to be rare and possibly reversible.60,61
intervals that are too short. With the more recent increased use
of prolonged home-based intravenous (IV) antibiotic therapy, Salicylates
an increase in ototoxic complications has been noted, possibly Aspirin and other salicylates are strongly associated with tinni-
a result of reduced attentiveness to serum levels and dosing tus and reversible SNHL. The hearing loss is dose dependent
intervals. and can be in the moderate-to-severe range. On discontinua-
tion of the drug, hearing returns to normal within 72 hours.58
Ototopical Preparations. Topical preparations that contain Tinnitus consistently occurs at a dose of 6 to 8 g/day of aspirin
neomycin, gentamicin, and tobramycin have long been used and at lower doses in some patients.62,63 Caloric responses also
directly in the ear for treatment of otitis externa and chronic can be reduced by salicylates.64 The site of the ototoxic effect
OM. Placement of aminoglycosides within a healthy middle ear seems to be at the level of basic cochlear mechanics, as evi-
space frequently results in cochlear or vestibular ototoxicity as denced by SNHL, loss of OAEs, reduced cochlear action poten-
shown in experimental animals and in patients. This effect is tials, and alteration of the “tips” of auditory nerve fiber tuning
now used to perform a titrated chemical labyrinthectomy for curves.65 These effects may be a result of alteration in turgidity
patients with Meniere disease.46,47 These same drugs have been and motility of outer hair cells.66
used extensively over the years in countless ears with chronic
OM, with little to no apparent clinically significant effect on Nonsteroidal Antiinflammatory Drugs
hearing or vestibular function.48,49 Reduced permeability of the NSAIDs share many of the therapeutic actions and side effects
inflamed round and oval window membranes, dilution of the of salicylates. Although there are isolated reports of hearing
toxic drugs by purulent fluids, and increased absorption into loss caused by naproxen,67 ketorolac,68 and piroxicam,69 ototox-
the vascular system by the hyperemic mucosa probably account icity as a result of NSAID use is generally rare compared with
for this decreased toxicity in the presence of OM. ototoxicity of salicylates.58,70 Similar to salicylates, animal models
It is clear, however, that use of aminoglycosides in the middle of NSAID ototoxicity show only reversible physiologic changes
ear does cause significant and predictable cochlear and vestibu- without major morphologic changes. Two large epidemiologic
lar toxicity in animals.50 Based on this toxicity, and on the now studies have shown an increased risk of hearing loss related to
widespread effective use of aminoglycosides to create a chemical acetaminophen and ibuprofen use in both men and women.71,72
labyrinthectomy, it is now generally regarded as unwise to use The increased risk appears to be both dose and duration
topical aminoglycoside antibiotics for treatment of OM. In 2004, dependent and is greater in younger subjects.
the American Academy of Otolaryngology–Head and Neck
Surgery convened a consensus panel, which after careful review Analgesics and Analgesic/Narcotic Compounds
of the literature recommended against the use of aminoglyco- The first report of SNHL associated with analgesic abuse was
sides in topical form in the middle ear unless no alternative with propoxyphene in 1978.73 Subsequently, acetaminophen/
hydrocodone abuse was found to be associated with SNHL in histologic data suggest that the lesion site in erythromycin tox-
2000.74,75 The hearing loss was severe to profound in the vast icity is the stria vascularis.94
majority of patients. All of the patients were using large amounts
of the drug, but the duration and frequency was quite variable. Cisplatin and Carboplatin
In the majority of the reports, the progression of hearing loss Cisplatin (cis-diamminedichloroplatinum) is a cell cycle–
was usually rapid and usually, but not universally, bilateral. nonspecific cancer chemotherapeutic agent that produces
These patients have generally responded very well to cochlear dose-limiting SNHL and peripheral neuropathy and a dose-
implantation, which suggests a cochlear etiology of the hearing related cumulative renal toxicity, hematologic toxicity, and gas-
loss. Since then, a number of reports have been published of trointestinal toxicity.95 The incidence of hearing loss varies in
SNHL associated with various narcotic-analgesic compounds as adults (25% to 86%) and children (84% to 100%), and chil-
well as street narcotics.76-81 The mechanism of SNHL in these dren seem to be significantly more susceptible to ototoxicity.96
patients is unclear, but it is likely multifactorial. One study The hearing loss initially is worse at high frequencies and is
points to acetominophen as the probable ototoxic agent in bilateral and irreversible. It occasionally is accompanied by tin-
acetaminophen/hydrocodone–associated hearing loss.82 nitus or vertigo. The degree of hearing loss is dose related, but
variability is considerable. Occasionally, severe hearing loss can
Phospodiesterase-5 Inhibitors occur after a single dose.97 If ultra–high-frequency hearing is
The phosphodiesterase-5 (PDE-5) inhibitors sildenafil, varde- tested, 100% of patients show a loss. Many factors influence this
nafil, and tadalafil are widely used agents for the treatment of variability, including mode of drug administration, tumor site,
erectile dysfunction. More recently, they have also shown age, renal function, diet, cranial irradiation, interaction with
some utility in the treatment of pulmonary hypertension. These aminoglycosides and loop diuretics, preexisting hearing loss,
drugs block the degradative action of PDE-5 on nitric oxide– cumulative dose, and total dose per treatment.95,98,99
activated cyclic gaunosine monophosphate in the smooth Carboplatin is a cisplatin analogue with a similar spectrum
muscle cells of the vasculature of the corpus cavernosum. Mild of antineoplastic activity. Carboplatin is less nephrotoxic than
side effects are common and include flushing, headache, nasal cisplatin. Myelosuppression is the dose-limiting toxicity with
congestion, and visual disturbances. In 2007, a case of bilateral, carboplatin. It was initially thought that carboplatin was less
sudden, severe SNHL was reported in a man after daily use of ototoxic than cisplatin, although more recent studies have
sildenafil for 15 days.83 Following this report, a U.S. Food and shown higher rates of ototoxicity than initially appreciated. In
Drug Administration investigation discovered 29 reports of a series of children, high-dose carboplatin therapy was associ-
sudden hearing loss in patients taking PDE-5 inhibitors. ated with a very high rate of ototoxicity.100
Maddox and colleagues84 reviewed these cases and added two Cisplatin and carboplatin ototoxicity seems to be due to the
additional cases. The loss was usually unilateral and partial, and creation of reactive oxygen species within the inner ear that
complete recovery was seen in one third of patients. A second target the hair cells. Cisplatin results in greater outer than
study that reviewed worldwide databases came to approximately inner hair cell damage, whereas carboplatin seems to affect the
the same conclusions.85 Although plausible causative mecha- inner hair cells preferentially.101
nisms have been postulated, whether a causative relationship
exists between PDE-5 inhibitor use and sudden SNHL is impos- Nitrogen Mustards
sible to know with certainty, given the presently available data. Nitrogen mustards are antineoplastic agents that include mech-
lorethamine, chlorambucil, cyclophosphamide, melphalan,
Vancomycin and ifosfamide. Of these drugs, only mechlorethamine has oto-
Vancomycin generally is believed to be ototoxic, but the avail- toxicity as a serious adverse effect, and it has limited usefulness
able data are difficult to evaluate.86 In clinical reports of vanco- today because of its severe toxic profile. Animal and human
mycin ototoxicity, patients almost always also received loop studies with mechlorethamine ototoxicity have revealed severe
diuretics or aminoglycosides. Vancomycin has been associated loss of outer hair cells.70 Other studies have shown shrinkage
with ototoxicity when administered intravenously but not when of the organ of Corti and loss of inner and outer hair cells.102
given orally. Auditory impairment has been reported to be
transient or permanent and is extremely unusual if serum con- Vincristine and Vinblastine
centrations are less than 30 mg/mL. In animals, vancomycin The vinca alkaloids vincristine and, to a lesser extent, vinblas-
ototoxicity does not occur, unless toxic levels are adminis- tine are notable for their potent neurotoxicity. Peripheral neu-
tered.87 Vancomycin is nephrotoxic and is excreted by the ropathy is common, and cranial neuropathies, ataxia, and
kidneys; therefore renal failure can prolong vancomycin half- hearing loss have been reported. Vincristine has been shown
life and can increase the likelihood of ototoxicity. Ototoxicity in animals to cause loss of hair cells and primary auditory
and nephrotoxicity are reputed to be less common with newer, neurons, whereas vinblastine has been shown to result in only
more purified formulations of vancomycin.88 When given orally hair cell loss.95
or in appropriate IV doses, vancomycin ototoxicity seems to
be very rare, but vancomycin may potentiate other ototoxic Eflornithine
drugs.89,90 One case of severe, irreversible hearing loss associ- Eflornithine (difluoromethylornithine) is a potent inhibitor of
ated with intrathecal administration of vancomycin has been ornithine decarboxylase and is very effective in the treatment
reported.91 of trypanosomiasis. It also has proven useful in some patients
with Pneumocystis carinii pneumonia, cryptosporidiosis, leish-
Erythromycin maniasis, and malaria. And although it has shown potential as
Numerous case reports document SNHL associated with eryth- an antineoplastic agent, eflornithine has been reported to
romycin administration.92 In almost all reports, the drug was cause major and dose-related SNHL.103
given intravenously rather than orally. The hearing loss seems
to be uncommon, and in most cases the patient recovers within Deferoxamine
1 to 3 weeks after the drug is stopped. The risk of erythromycin Deferoxamine is an iron-chelating agent used in some patients
ototoxicity seems to be greater in patients with renal or hepatic with chronic iron overload or acute, severe iron intoxication.
insufficiency. Ototoxicity associated with the newer macrolide However, auditory and visual neurotoxicity have been reported
antibiotic azithromycin has also been reported.93 Limited with its use, particularly with larger doses in younger patients.
SNHL is reversible in some patients when the dosage is 10
reduced.104
0
Percentile
Lipid-Lowering Drugs 10 50 {
Although optic and vestibulocochlear nerve degeneration
Hearing level (dB) (ANSI, 1989)

(wallerian-like degeneration) have been seen in dogs given 20 Years of
high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG- 95 { Exposure
30
CoA) reductase inhibitors, no clinically significant effect on 20
vision or hearing has been found. 40
50
40
RENAL DISORDERS 60
Numerous genetic causes of SNHL are associated with renal
70 90 dBA
abnormalities, and Alport syndrome is the most well recog-
nized.9 Acquired renal disorders have an unclear association 80 20
with SNHL. Chronic renal failure, especially when managed
with hemodialysis or renal transplantation, has been associ- 90
40
ated with progressive, fluctuating, or sudden SNHL. Oda and 100
coworkers105 found that 15% of 290 hemodialysis and renal
transplantation patients developed SNHL. The etiology of the 110
125 250 500 1000 2000 4000 8000
SNHL is difficult to determine precisely and probably is multi-
Frequency (Hz)
factorial. In addition to the electrolyte and metabolic abnor-
malities caused by the renal failure and subsequent hemodialysis, FIGURE 150-3. Predicted hearing thresholds (median and extreme values)
these patients typically receive frequent doses of loop diuretics, after 20 years and 40 years of occupational noise exposure at 90 dBA. ANSI,
aminoglycoside antibiotics, and vancomycin. Because of the American National Standards Institute. (From Dobie RA. Medical-legal evalua-
tion of hearing loss. New York: Van Nostrand Reinhold; 1993.)
altered pharmacodynamics of these drugs caused by renal
failure, their ototoxic potential is increased.
TRAUMA produces a temporary SNHL that recovers over the next 24 to
48 hours. This reversible loss is termed a temporary threshold shift
Head Injury (TTS). If the noise is of high enough intensity or is repeated
Blows to the head can cause labyrinthine injury and resultant often enough, a permanent loss of hearing results, which is
SNHL, either directly, through fracture of the labyrinth as a referred to as a permanent threshold shift (PTS). Two distinct types
result of temporal bone fracture, or indirectly, through labyrin- of hearing loss are caused by excessive noise exposure: NIHL
thine concussion. The most common type of temporal bone and acoustic trauma. NIHL is caused by repeated exposures to
fracture, longitudinal fracture, uncommonly extends through sound that is too intense or too long in duration. Each expo-
the labyrinth. The hearing loss associated with longitudinal sure is followed by a TTS, which recovers, but eventually a PTS
fractures typically is similar to that of acoustic trauma (i.e., develops. Acoustic trauma consists of a single exposure to a
limited to the high frequencies and worse at 4 kHz). Similarly, hazardous level of noise that results in a PTS without an inter-
blunt head injury alone, without temporal bone fracture, can current TTS.
result in concussive injury of the labyrinth, which can result in NIHL almost always results in a symmetric, bilateral hearing
SNHL. Transverse fractures almost always traverse the labyrinth loss; it almost never results in a profound loss. Early in the
and result in complete loss of auditory and vestibular function. course of NIHL, the loss usually is limited to the 3, 4, and 6 kHz
Penetrating injuries to the inner ear are rare, but they most range. The greatest loss usually occurs at 4 kHz. As the loss
commonly involve subluxation of the stapes into the vestibule progresses, lower frequencies become involved, but the loss at
with resultant profound SNHL. 3 to 6 kHz is always far worse. The loss progresses most rapidly
during the first 10 to 15 years of exposure and thereafter grows
Noise-Induced Hearing Loss and Acoustic Trauma at a much-reduced rate. Figure 150-3 shows the 50% and 95%
The fact that excessive noise exposure could cause hearing loss confidence limits for 20- and 40-year exposures to 90 dBA
was first recognized in the eighteenth century. In the early sound (decibel with “A” weighting that fully weights 700 to
twentieth century, noise-induced hearing loss (NIHL) was 9000 Hz). Figure 150-4 shows an example of the rate of pro-
termed “boilermaker’s deafness.” Careful descriptions of the gression of NIHL over time. The International Organization
hearing loss sustained in industry would await development of for Standardization has established standards for determining
the audiometer and were first published in the 1930s.106 NIHL and quantifying occupational hearing loss and noise-induced
is now recognized as one of the most common occupationally hearing impairment.108
induced disabilities, and noise exposure is now regulated by the Although other patterns also are seen, the hearing loss from
Occupational Health and Safety Administration (OSHA).107 acoustic trauma is similar to that from NIHL (i.e., worse at high
Noise can be defined loosely as “unwanted sound,” and it can frequencies with a 4-kHz “notch”). The other, most common
be subdivided by intensity, time course (continuous, fluctuating, patterns include flat and downsloping losses. Acoustic trauma
intermittent, impact, impulse), and spectral content (pure tone, frequently is unilateral or asymmetric, and considerable vari-
narrow band, broad band). Impact noise is noise caused by col- ability is found in hearing loss among subjects with identical
lision of two objects and is common in industry. Impulse noise is exposure. Age, gender, race, and coexisting vascular disease
that resulting from a sudden release of energy, such as an explo- have been carefully studied, and when adequately controlled
sion or weapon fire. for other factors, they have not been shown to correlate with
Hearing loss caused by noise is sensorineural in nature. susceptibility to NIHL. An attractive theory suggests that
Rarely, extremely intense impulse exposures can result in tym- patients who are more susceptible to TTS would be more sus-
panic membrane perforations, which adds a conductive com- ceptible to PTS and NIHL, although this has not been shown
ponent to the hearing loss. Most hazardous noise exposure to be the case. At present, there is no known way to predict
25 Acquired perilymphatic fistulae can result from barotrau-

Lex (dBA)
mas or direct or indirect trauma to the temporal bone, or it
may arise as a complication of stapedectomy surgery. A typical
100
history attributed to perilymphatic fistula consists of the sudden
20 development of SNHL and vertigo after a head injury, baro-
trauma, or heavy lifting or straining. The event is sometimes
0.5–1–2–3 kHz NIPTS (dB)
associated with an audible “pop.” Patients may have a positive
Hennebert sign and positional nystagmus when the involved
15
ear is placed in a dependent position.115 Some authors believe
that perilymphatic fistulae develop spontaneously.116,117
Diagnosis is made by middle ear exploration. Visualization
10
95 of fluid in the region of the oval or round windows is not defini-
tive evidence of a fistula, because serous fluid can ooze from
the middle ear mucosa, or lidocaine from the local anesthetic
can collect in the vicinity.118,119 Treatment consists of packing
90 the area in question with tissue. Because of the lack of a defini-
5
tive diagnostic test for the presence of a fistula, and because
85 even surgical exploration does not reliably diagnose or exclude
the possibility of a fistula, considerable controversy exists with
0
0 5 10 15 20 25 30 35 40
regard to the management of this entity.109,116,120,121 In the 1980s
and early 1990s, it was commonly believed that spontaneous
Duration (years)
perilymphatic fistulae were a common cause of otherwise unex-
FIGURE 150-4. Speech frequency average noise-induced permanent plained hearing loss and vertigo. Many surgical fistula repairs
threshold shift (NIPTS) as a function of duration and level of exposure (Lex) were performed as a result of this belief. It has since become
in dBA time-weighted average (TWA). (From Dobie RA. Medical-legal evalua- clear that spontaneous perilymphatic fistula is rare,122 but no
tion of hearing loss. New York: Van Nostrand Reinhold; 1993.) clear consensus exists regarding diagnosis or management.
Finally, labyrinthine fistula can result from erosion by cho-
lesteatoma, or it may develop spontaneously, as in the superior
semicircular canal dehiscence syndrome. The reader is referred
susceptibility to NIHL—with three exceptions: 1) conductive to Chapters 140 and 165 of this book for detailed descriptions
hearing losses are clearly protective for NIHL in the same way of these entities.
that earplugs or earmuffs would be; 2) the lack of an acoustic
reflex has been shown to predispose patients to NIHL (the Irradiation
protective effect of the acoustic reflex is primarily ≤2 kHz)19; The cochlea seems to be resistant to radiation injury at doses
and 3) patients with an unusually large PTS already should be less than 45 Gy. At doses greater than 45 Gy, a clear, dose-
considered to be more susceptible. TTS and PTS are commonly dependent toxicity manifests as hearing loss.123-125 Radiation
accompanied by tinnitus, and tinnitus after a noise exposure also seems to cause a dose-dependent toxicity to the auditory
should be considered a warning sign. nerve and brainstem.126 The latency period from radiation
A clinician can do little in the management of NIHL or exposure to clinical hearing loss can be 12 months or more.
acoustic trauma. The primary role of otolaryngologists and One report notes that early-onset SNHL after radiation can
audiologists is in prevention and early identification; however, recover to some degree.127 Fractionated irradiation has been
many hazardous noise exposures are not occupational in origin, used to a limited extent in the past to treat vestibular
and many employers are either unable or unwilling to provide schwannoma. Whether it has had an effect on hearing in these
hearing conservation programs. patients is difficult to determine because of the limited data
available.128 More recently, the experience with stereotactic irra-
Barotrauma and Perilymphatic Fistula diation (radiosurgery) for vestibular schwannoma has been
Otitic barotrauma consists of traumatic injury of the tympanic much more extensive; this modality seems to be associated with
membrane and middle ear caused by unequalized pressure substantial risk of SNHL, at least as high as that with microsurgi-
differentials between the middle and external ears. The injury cal removal.129
typically occurs during flying or underwater diving and consists A relative paucity of published literature exists to describe
of pain, hyperemia, possible perforation of the tympanic mem- the experimental effects of radiation on hearing. In a histologic
brane, and edema and ecchymosis of the middle ear mucosa. study in chinchillas sacrificed 2 years after fractionated irradia-
These symptoms can be followed by the development of a tion of the cochlea, Bohne and coworkers130 showed a dose-
hemotympanum or a transudative middle ear effusion, and dependent loss of inner and outer hair cells. Early studies of
conductive hearing loss may result. Any abnormality that results the effects of radiotherapy involving the cochlea on human
in compromised eustachian tube function may predispose to hearing were flawed because of a lack of controls, inadequate
barotrauma. follow-up, and the retrospective nature of the studies. However,
A perilymphatic fistula consists of a pathologic communica- many well-designed studies have now shown that radiotherapy
tion between the perilymphatic space of the inner ear and involving the cochlea causes SNHL in 50% of patients.123-125,131-133
middle ear. Perilymphatic fistulae can be congenital or acquired The hearing loss occurs in a dose-dependent fashion, and it
and can occur at either the round or the oval window.109 seems to increase significantly at doses greater than 45 Gy.
Congenital defects can occur in the stapes footplate in Advanced age, preexisting hearing loss, and adjuvant ototoxic
patients with labyrinthine anomalies such as Mondini dyspla- chemotherapeutic agents are likely to amplify the effects of
sia.110,111 These fistulae can communicate with the subarachnoid radiation. The hearing loss occurs with a latency of 0.5 to
space and result in cerebrospinal fluid leak and possible men- 2 years after treatment and is probably progressive.127 This
ingitis. Typically, these ears have a profound hearing loss. This delayed onset, and the fact that many patients do not survive
phenomenon should be a consideration in the differential for sufficient follow-up, results in underestimation of the fre-
diagnosis of patients with recurrent meningitis.112-114 quency and severity of this complication. Dose-dependent
injury to the auditory nerve and brainstem also occurs; however, understood. The most common presenting symptoms are head-
the frequency in the absence of other neurologic complications ache and visual blurring, although pulsatile tinnitus, SNHL,
is difficult to determine.126 and vertigo also may be present. It is more commonly seen in
An understanding of the effects of radiation on hearing has obese women.154,155
become much more clinically relevant more recently because The pulsatile tinnitus is usually objective and is eliminated
of the popularity of stereotactic radiotherapy for the treatment by jugular venous compression.156,157 SNHL typically is a fluctu-
of vestibular schwannoma and other similar lesions. Although ating, low-frequency loss that is unilateral or bilateral. Vertigo
many reports suggest that the risk of hearing loss is minimal, and aural fullness also may be present. The most serious mani-
these studies are limited by 1) their retrospective design, 2) lack festation of the disorder is progressive visual loss caused by
of long-term follow-up, and 3) incomplete audiologic charac- optic atrophy. The disease is characterized by remissions and
terization. In addition, it is difficult to compare the studies that relapses, and diagnosis is confirmed by documentation of pap-
are available because of differences in tumor size, radiation illedema on funduscopy or cerebrospinal fluid pressure greater
dose, radiation field, technique of radiation administration, than 200 mm H2O. ABR and electrocochleography abnor-
and follow-up. A wealth of literature is available on the treat- malities can also be seen. Management consists of weight loss,
ment outcomes after stereotactic radiotherapy; however, almost acetazolamide, furosemide, and occasionally lumbar-peritoneal
all of them are limited by one of the above-mentioned short- shunting.157,158
comings. More recent studies report hearing-preservation
rates, defined in different ways and with different follow-up
periods, between 36% and 61%.134-137 The time course of VASCULAR AND HEMATOLOGIC
hearing loss after stereotactic radiotherapy is poorly character- DISORDERS
ized; however, available data would suggest that the loss is pro-
gressive and that early results may not predict later outcomes. Migraine
Migraine is a common disorder, usually restricted to headache
NEUROLOGIC DISORDERS and sometimes the neurologic symptoms of an aura. Numerous
subtypes of migraine are associated with different neurologic
Multiple Sclerosis deficits. Basilar migraine has been associated with numerous
Multiple sclerosis (MS) is a chronic disease characterized auditory and vestibular symptoms and signs that include epi-
pathologically by multiple areas of CNS demyelination, inflam- sodic vertigo, SNHL, tinnitus, aural fullness, distortion, and
mation, and glial scarring. The clinical course is variable and recruitment. Fairly complex and specific diagnostic criteria
ranges from a benign, almost symptom-free disease to a rapidly have been established for basilar migraine.159 In a series of
progressive, disabling disorder. Early in the patient’s course, the 50 patients who met the criteria for basilar migraine, 46% had
disease is characterized by remissions and relapses. The disease bilateral low-frequency SNHL, and an additional 34% had uni-
is said to result in dissemination of neurologic lesions in time lateral low-frequency SNHL.160 The hearing loss often fluctu-
(remissions and relapses) and in space (variability of multiple ated and occasionally was severe. Basilar migraine has been
deficits). The age at onset is typically between 20 and 30 years, implicated as an occasional cause of SNHL. Because of their
and it rarely occurs before age 10 years or after age 60 years. similarity, considerable speculation is found in the literature of
MS is more common in women than in men. The racial and an etiologic association between basilar migraine and Meniere
geographic differences in prevalence are striking, with the disease.
disease being most common in whites and in individuals living Migraine headache can be managed with β-blockers, calcium
at higher latitudes. The cause is unknown but seems to be channel blockers, acetazolamide, NSAIDs, and antiserotonin
related to genetic factors, autoimmune mechanisms, and viral agents. No systematic study to evaluate the use of these drugs
infection. in patients with basilar migraine is currently available. The
SNHL develops in 4% to 10% of patients with MS.138,139 The reader is referred to the excellent reviews of Olsson160 and
hearing loss can be progressive or sudden in onset and can be Harker161 and to Chapter 165 for a more detailed discussion.
bilateral, unilateral, symmetric, or asymmetric.140-143 Frequently,
the loss is sudden and unilateral, and it can recover after days Vertebrobasilar Arterial Occlusion
or weeks.57,144 Audiometrically, speech discrimination can be Several eponyms have been applied to brainstem syndromes,
normal or reduced out of proportion to the increase of pure but all apply to neoplasms with the exception of Wallenberg
tone thresholds. Abnormal patterns of acoustic reflexes can be syndrome (lateral medullary syndrome). Classic brainstem
seen in some patients.141,145,146 Abnormalities of the ABR fre- infarction patterns are seen less often than incomplete or
quently are seen and are a diagnostic criterion for MS. Patterns mixed clinical pictures. To result in SNHL, the occlusion gener-
of abnormality vary and include latency prolongation of wave ally has to involve the anterior inferior cerebellar artery (AICA).
I or the later waves, absence or poor morphology of waveforms, Occlusion of the AICA results in ischemic infarction of the
and waveform abnormalities with increased stimulus presenta- regions of the brainstem supplied by this artery. The occlusion
tion rate.140,143,145,147-149 MRI is often abnormal in MS and typi- typically results from thrombosis or embolism and, rarely, from
cally reveals periventricular white matter plaques on T2-weighted other vascular disorders or surgical occlusion of the vessel. The
images. Plaques can be seen in the cochlear nucleus or inferior area infarcted includes the inferior pons, and many of the find-
colliculus in patients with SNHL.150-153 ings are similar to those of Wallenberg syndrome. In addition,
the AICA usually gives rise to the internal auditory artery, which
Benign Intracranial Hypertension is the principal blood supply to the labyrinth. The findings in
Benign intracranial hypertension, also known as pseudotumor cerebri, patients with acute AICA infarction include acute vertigo with
probably is better termed idiopathic intracranial hypertension, associated nausea and vomiting, facial paralysis, SNHL, tinni-
because it is not always benign in nature. The disorder consists tus, ipsilateral gaze paralysis, ipsilateral loss of pain and tem-
of increased intracranial pressure without evidence of mass perature sensation on the face, contralateral partial loss of pain
lesion, obstructive hydrocephalus, intracranial infection, or and temperature sensation on the trunk and extremities, and
hypertensive encephalopathy. It is associated with a long list ipsilateral Horner syndrome. The vertigo and hearing loss are
of medical disorders but frequently manifests as an isolated caused by ischemic injury of the cochlear and vestibular nuclei
phenomenon. The underlying pathophysiology is poorly in the brainstem and in the labyrinth itself.19 Isolated cerebellar
infarction can result in hearing loss, vertigo, facial pain or Polyarteritis Nodosa. Polyarteritis nodosa consists of a nec-
numbness, headache, and ataxia.162 rotizing vasculitis of small-sized and medium-sized arteries. It
can manifest with myriad findings that include weight loss,
Rheologic Disorders and Blood Dyscrasias fatigue, fever, anorexia, arthritis, neuropathy, hypertension,
Waldenström macroglobulinemia is a plasma cell disorder in renal failure, abdominal pain, and SNHL. Diagnosis is made by
which abnormally large amounts of immunoglobulin M (IgM) demonstration of the necrotizing vasculitis on a biopsy speci-
are synthesized and circulate in the plasma. The result is men of involved tissue. SNHL may precede the development
increased blood viscosity and subsequent ischemic lesions. Pro- of systemic symptoms, or it may occur late in the disease.
gressive and sudden hearing losses caused by this disorder have Hearing loss may be unilateral or bilateral and is either rapidly
been reported, and some patients with SNHL have responded or slowly progressive. Facial paralysis also may be seen. Aggres-
to treatment with alkylating agents or plasmapheresis.163 sive doses of steroids and immunosuppressive drugs are given
Cryoglobulinemia results from immune-complex disease, in for management.181,182
which the resulting immune complexes are soluble at body
temperature and precipitate at lower temperatures. The depo- Relapsing Polychondritis. Relapsing polychondritis consists of
sition of these complexes results in glomerulonephritis, vascu- an inflammatory reaction in multiple cartilages. The auricles
litis, and arthritis. The disorder can be associated with usually are the first cartilages to be affected, although arthritis
progressive or sudden SNHL.164 and eye findings are commonly present. The disorder fre-
Sickle cell disease is associated with an increased incidence quently is seen in conjunction with other autoimmune diseases.
of SNHL,165-167 and it has been estimated that SNHL is present The associated hearing loss may be conductive, sensorineu-
in 22% of patients with sickle cell disease.168 The hearing loss ral, or mixed. SNHL can be sudden or progressive in onset
may be progressive or sudden and may be associated with sickle and may be associated with vestibular disturbances. Therapy
cell crises.169-171 Leukemias and lymphomas also have been asso- includes steroids, immunosuppressive drugs, or dapsone.183,184
ciated with SNHL caused by either leukemic infiltrates or hem-
orrhage within the inner ear or by vascular occlusion and Wegener Granulomatosis. Wegener granulomatosis is a syn-
resulting labyrinthine ischemia.19 drome of necrotizing granulomatous vasculitis that principally
Cardiopulmonary bypass has been associated with a slightly involves the lungs, airway, and kidneys. Hearing loss usually is
increased risk of SNHL.172-174 The loss most often is sudden, but conductive because of involvement of the eustachian tube or
one study suggests an increased incidence of bilateral high- middle ear. SNHL may be present if the granulomatous disease
frequency loss postoperatively.175 The etiology would seem to or secondary infection extends into the inner ear.185-187
relate to either an embolic phenomenon or to reduced perfu-
sion of the inner ear. Other Autoimmune Disorders. Other systemic autoimmune
Vascular loops within the cerebellopontine angle (CPA) or disorders less commonly associated with SNHL include sclero-
internal auditory canal have been proposed to be a cause derma,188 temporal arteritis,189 systemic lupus erythemato-
not only of SNHL but also of tinnitus, vertigo, and Meniere sus,190,191 sarcoidosis,192,193 and Vogt-Koyanagi-Harada syndrome.
disease.176-179 Although the concept of vascular compression of
cranial nerves causing intermittent neurologic dysfunction has Primary Autoimmune Inner Ear Disease
been reasonably well accepted in trigeminal neuralgia and McCabe194 first described patients with bilateral SNHL who
hemifacial spasm, it has achieved far less support in auditory were responsive to immunosuppressive drugs. The loss can be
and vestibular dysfunction. Vessel loops are found in contact sudden or progressive in onset and usually involves both ears,
with these nerves routinely during CPA surgery for other either simultaneously or alternately. The hearing loss frequently
reasons, and these patients seem to be suffering no ill effects is associated with vestibular symptoms and can strongly mimic
as a result. The entire CNS is subjected to such pulsation con- Meniere disease. Myriad nonspecific tests of humoral autoim-
tinuously. To date, nothing other than anecdotal evidence has munity may be abnormal. The hallmark of the disease is the
been published in support of this theory. responsiveness of the hearing loss to steroids or cytotoxic drugs.
In some patients, a course of drug treatment can produce a
IMMUNE DISORDERS long-lasting improvement in hearing, and in others, the hearing
improvement depends on continued use of the medications.195
Systemic Autoimmune Disorders In these patients, methotrexate is sometimes used to reduce
Various systemic (non–organ-specific) autoimmune disorders the need for continued high-dose steroids and their resultant
have been associated with SNHL. side effects.196 In still others, SNHL progresses despite aggres-
sive treatment.
Cogan Syndrome. Cogan syndrome is perhaps the prototypic Sera of many of these patients have been shown to contain
autoimmune disorder to affect the inner ear. It consists of an antibody to a 68-kD protein of bovine or guinea pig inner
attacks of acute nonsyphilitic interstial keratitis together with ear extracts. The responsiveness of SNHL to steroid treatment
auditory and vestibular dysfunction. The ocular inflammation correlates with the presence of this antibody.197-200 This 68-kD
may be limited to interstial keratitis but may also include scle- protein has been shown to be a member of the heat shock
ritis and/or uveitis. Cogan syndrome can be associated with protein 70 (HSP70) family.201,202 A significant percentage of
systemic vasculitis, especially of the medium and large vessels, patients with Meniere disease show similar reactivity, which
and aortic involvement is seen in 10% of patients. SNHL may suggests that autoimmunity may play a role in at least a subset
be unilateral or bilateral, and it can be associated with severe of patients with Meniere disease.203,204 Chapter 149 contains a
vertigo, nausea, vomiting, and tinnitus. If treated early enough, full discussion of autoimmune inner ear disease.
SNHL is often responsive to aggressive treatment with steroids
and/or other immunosuppressive medications. If untreated, Acquired Immunodeficiency Syndrome
the hearing loss frequently progresses to a profound loss over SNHL is among the numerous neurologic manifestations of
months. The cochlear inflammatory response can lead to oblit- AIDS. The hearing loss may be a result of an infectious com-
eration and ossification of the cochlear lumen; therefore early plication of AIDS, particularly cryptococcal meningitis or syphi-
cochlear implantation should be considered in cases that do lis, or it may be a primary neurologic manifestation of the
not respond to immunosuppressive agents.180 disease. Human immunodeficiency virus (HIV) should be a
consideration in patients with otherwise unexplained SNHL

when risk factors are present.205-212
PARANEOPLASTIC SYNDROMES
Neurologic paraneoplastic syndromes consist of neurologic
abnormalities associated with malignant neoplasms not meta-
static to the nervous system. Rarely, the abnormality may involve
the auditory or vestibular system.213
BONE DISORDERS
Otosclerosis
Otosclerosis primarily causes a conductive hearing loss, but it
is commonly associated with a progressive SNHL, especially
later in the course of the disease. The precise mechanism
remains unclear. CT images of the cochlea in these patients
often reveal a radiolucent area immediately surrounding the
cochlea. Histologically, otosclerotic bone frequently involves
the endosteum, but the degree of endosteal involvement does
not clearly correlate with the degree of SNHL.214 It is doubtful
that isolated cochlear otosclerosis without stapedial involve-
ment (and conductive hearing loss) occurs with any clinically
significant frequency.215 Treatment with sodium fluoride has FIGURE 150-5. Gadolinium-enhanced magnetic resonance image shows a
been reported to retard the progression of hearing loss in medium-sized vestibular schwannoma.
these patients,215-218 although the efficacy of this treatment
remains controversial.219-222 Patients with very advanced otoscle-
rosis can have a bilateral profound mixed hearing loss that can reduced out of proportion to the pure tone thresholds. Acoustic
be audiometrically indistinguishable from a profound SNHL. neuroma can manifest as a sudden loss in 10% of patients,
In these patients, stapedectomy can result in useful hearing although most sudden losses are not a result of acoustic
improvement.30,223,224 neuroma.230 Unilateral or asymmetric tinnitus, with or without
hearing loss, also is a common manifestation of acoustic
Paget Disease neuroma. Patients may have mild or severe vestibular symptoms,
Paget disease (osteitis deformans) is a common but poorly or they may have no symptoms. Bilateral acoustic neuromas are
understood disorder of bone. It is most common in older indi- pathognomonic for neurofibromatosis type 2 (Fig. 150-6).
viduals, with an estimated incidence that ranges from 1% in
individuals 40 to 49 years old to 19% in individuals 80 to 89
years old. Approximately 50% of patients with Paget disease
manifest hearing loss. The loss can be conductive, sensorineu-
ral, or mixed. The stapes footplate is rarely fixed, and surgical
ossicular chain reconstruction is rarely beneficial.225 The treat-
ment of Paget disease consists of calcitonin or etidronate diso-
dium. Some evidence indicates that medical treatment may
stabilize or reverse SNHL.226,227
NEOPLASMS
When patients are initially seen with unilateral or asymmetric
SNHL, particularly when the presentation is not typical for
Meniere disease, neoplasm should be a principal diagnostic
consideration. All patients with asymmetric or progressive
SNHL should be evaluated for a neoplastic etiology. Lesions that
result in SNHL usually are located within the internal auditory
canal or CPA, but tumors located anywhere in the skull base or
temporal bone can result in SNHL if the labyrinth is invaded.
Vestibular schwannoma is the most common neoplasm that
results in SNHL (Fig. 150-5). Best known as acoustic neuroma,
vestibular schwannomas originate from the vestibular nerves
within the CPA or the internal auditory canal. Acoustic neuroma
is common and constitutes 6% of all intracranial neoplasms.228
It has been estimated that 2500 new acoustic neuromas are
diagnosed in the United States annually,229 and acoustic neuro-
mas account for approximately 80% of all CPA neoplasms.228
The most common presenting feature of acoustic neuroma is
progressive unilateral SNHL. Any pattern of hearing loss can FIGURE 150-6. Gadolinium-enhanced magnetic resonance image shows
occur, but most frequently the loss initially involves principally bilateral vestibular schwannomas pathognomonic for neurofibromatosis
the high frequencies. Commonly, speech discrimination is type 2.
found between the presence of diabetes and SNHL when

adjusted for expected hearing loss as a result of age.231
Although there is a definite association between SNHL and
congenital hypothyroidism, little to no evidence suggests that
adult-onset acquired hypothyroidism can result in SNHL.232-235
Similarly, reports have suggested that an association exists
between hypoparathyroidism and hyperlipidemia, although no
convincing studies have shown either association.236-238
PSEUDOHYPACUSIS
Pseudohypacusis is simply a factitious or exaggerated hearing
loss and is common, especially in situations in which there is
secondary gain to patients. Pseudohypacusis should be consid-
ered whenever the pattern of loss does not fit the clinical
picture. Discordance between the speech reception threshold
and the pure tone average is a strong indicator of a factitious
loss. Other audiometric studies—such as the Stenger test, ABR,
and OAEs—are helpful in clarifying such situations.
DISORDERS OF UNKNOWN ETIOLOGY

FIGURE 150-7. Gadolinium-enhanced magnetic resonance image shows a
large cerebellopontine angle meningioma. This patient had tinnitus and
Presbycusis
normal hearing after surgical removal of the lesion. SNHL associated with the aging process is termed presbycusis.
In the strictest sense, only SNHL specifically caused by the
aging process—and not by genetic factors, accumulated noise
Meningiomas account for approximately 15% of CPA neo- injury, vascular and metabolic factors, and so on—should be
plasms, and the manifestation of CPA meningiomas is very attributed to presbycusis. Because of the limitations of con-
similar to that of acoustic neuromas. For reasons that are trolled studies in such a situation, it is difficult, if not impossi-
unclear, meningiomas generally have less effect on hearing for ble, to establish absolutely the existence of presbycusis. A better
a given size than do acoustic neuromas (Fig. 150-7). The term for such a loss is age-related hearing loss, and this applies to
remaining 5% of CPA lesions include dermoid cysts (congenital any loss associated with age without other apparent etiology.
cholesteatoma), lipomas, arachnoid cysts, cholesterol granulo- Age-related hearing loss is a major public health issue. Actual
mas, and hemangiomas. Metastatic lesions, particularly adeno- prevalence of age-related hearing loss depends on its definition
carcinoma, also can occur in the internal auditory canal. and is difficult to determine. It has been difficult in large epi-
Tumors that occur elsewhere in the skull base that can cause demiologic studies to exclude NIHL from study groups.
SNHL by involvement of the labyrinth include paragangliomas, Approximately 30% of individuals older than 65 years admit to
chondrosarcoma, hemangioma, middle ear adenoma, rhabdo- a hearing loss.107 Because at least 12% of the population is older
myosarcoma, lymphoma, and leukemia.19 than 65 years, more than 9 million people in the United States
probably have age-related hearing loss.
ENDOCRINE AND METABOLIC Age-related hearing loss typically is worse for high frequen-
cies and is more severe in men.239 The rate of loss accelerates
DISORDERS with time; so the older patient is, the greater the threshold shift
It would seem logical that the diffuse large and small vessel that can be expected in the future. Many large studies docu-
atherosclerotic disease that results from diabetes would be asso- ment the degree and prevalence of age-related hearing loss.
ciated with an increased incidence of SNHL; however, this has Figure 150-8 shows the median pure tone thresholds of a group
not proven to be the case. No significant association has been highly screened to exclude noise exposure.
Age-related permanent threshold shift (dB)
0 0
10 10
20 20
Females Males
30 30
Age (years)
Age (years)
30 30
40 40
50 50 FIGURE 150-8. Median audiograms
40 40
60 60 for patients with little to no noise
exposure as a function of gender, fre-
quency, and age. (From Dobie RA.
50 50
0.5 1 2 3 4 6 0.5 1 2 3 4 6 Medical-legal evaluation of hearing loss.
New York: Van Nostrand Reinhold;
Frequency (kHz) Frequency (kHz) 1993.)
Schuknecht19 has defined four separate types of presbycusis hypertension. This regimen of sodium restriction and diuretics
on the basis of pathologic findings in human temporal bones. was first proposed by Furstenberg and has since gained wide
In sensory presbycusis, hair cells are progressively lost beginning acceptance.245,246 Despite this wide acceptance, few studies have
at the base of the cochlea. Patients with this abnormal pattern been able to show definitively any beneficial therapeutic effect
tend to have steeply sloping high-frequency hearing losses. with regard to improvement or preservation of hearing.247-249
Neural presbycusis implies a loss of auditory nerve fibers; these The creation of an intralabyrinthine shunt (cochleosaccu-
patients tend to have reduced speech discrimination out of lotomy) has been proposed as a mechanism to control the
proportion to their pure tone thresholds. Atrophy of the stria hydrops and prevent the recurrent membrane ruptures thought
vascularis was seen in strial presbycusis, and these patients have to traumatize the organ of Corti. This procedure has been
relatively flat audiograms. Finally, Schuknecht19 described a shown to be beneficial in controlling vertigo but has been
fourth type of presbycusis termed cochlear conductive or mechani- associated with an unacceptably high incidence of severe
cal presbycusis. No light-microscopic abnormalities are seen in hearing loss.250,251 Surgical decompression of the endolym-
these specimens, and Schuknecht theorized that an age-related phatic sac, with or without shunting of the sac into the mastoid
change in the stiffness of the basilar membrane resulted in the or the subarachnoid space, has been proposed as a way to
hearing loss. These patients have gradually descending (approx- correct the presumed defective sac physiology. Although excel-
imately 25 dB/octave) pure tone thresholds.19 These patterns lent results have been reported, double-blind randomized
are not useful clinically because of the variability of audiometric studies to compare endolymphatic sac with mastoid shunt pro-
shape and severity in individuals with age-related hearing loss, cedures with mastoidectomy alone have failed to show any
and clinically the losses do not fall naturally into these significant difference in maintenance of hearing or control of
patterns.240 vertigo.252-256 The unpredictable, fluctuating nature of Meniere
disease, the lack of an objective diagnostic test, and the high
Meniere Disease and Endolymphatic Hydrops incidence of spontaneous resolution of symptoms make it
Meniere disease is a common disorder that consists of fluctuat- extremely difficult to come to valid statistical conclusions with
ing SNHL, tinnitus, episodic vertigo, and aural fullness. The regard to therapeutic efficacy in Meniere disease.
hearing loss typically begins as a fluctuating low-frequency loss Meniere disease may be considered to be idiopathic endo-
that progresses, gradually or quickly, to a permanent loss that lymphatic hydrops. Although it is the most common cause of
can involve any or all frequencies. The tinnitus is most com- endolymphatic hydrops, many other entities result in similar
monly described as “buzzing” or “roaring,” and it can fluctuate clinical presentations and pathologic findings. The syndrome
in loudness and character. The aural fullness perhaps is the of delayed endolymphatic hydrops consists of the initial devel-
most consistent and stable complaint, but it also typically fluctu- opment of a profound SNHL in one ear, followed by develop-
ates. The vertigo of Meniere disease is the most disabling aspect ment of symptoms of endolymphatic hydrops years later in
of the disorder. either the ipsilateral ear (ipsilateral delayed endolymphatic
The typical presentation consists of episodic, spontaneous hydrops) or the contralateral ear (contralateral delayed endo-
attacks of severe, spinning vertigo that lasts for several hours. lymphatic hydrops).257 Other pathologic processes have been
The attacks frequently are associated with nausea, vomiting, associated with development of endolymphatic hydrops, includ-
and diaphoresis. After the attacks, patients usually are fatigued ing syphilis, temporal bone trauma, serous labyrinthitis, stape-
for 24 hours or more. The attacks of vertigo may be associated dectomy, and autoimmune disease.19 The reader is referred to
with a concomitant or preceding change in hearing loss, tin- Chapter 165 for a more extensive discussion of Meniere disease.
nitus, or aural fullness. Many patients also have various combi-
nations of dysequilibrium or motion-provoked vertigo between
the classic attacks. Subtypes of Meniere disease are described SUDDEN SENSORINEURAL
that have only vestibular symptoms (vestibular Meniere disease)
or auditory symptoms (cochlear Meniere disease).
HEARING LOSS
The hallmark of Meniere disease is variability and unpredict- A subset of patients with SNHL develops hearing loss rapidly,
ability, and this holds true for the hearing loss associated with awakening with it in the morning or developing a progressive
the disease. The hearing loss may fluctuate wildly or may be loss over 12 hours or less. This commonly is a frightening expe-
quite stable over many years. It also may manifest as a sudden, rience for the patient, who might assume that this is a life-
permanent loss. Although most patients progress over the threatening disorder or that it will lead to profound bilateral
years to a moderate to severe loss, many do not, and progres- deafness. Neither scenario typically is the case. The etiology and
sion to a profound loss is rare. The low frequencies are more appropriate evaluation and management of this common syn-
commonly involved than are the middle or high frequencies, drome have been the subject of much debate over the years,
especially in the early stages of the disease, but variability illustrated by the fact that more than 100 etiologies have been
is considerable. The disease is bilateral in perhaps 30% of proposed for this disorder.258
cases.241-244 Patients who have bilateral disease usually develop
bilaterality early in the course of the disease. Patients who
maintain hearing loss in only one ear for the first few years PREVALENCE, NATURAL HISTORY,
rarely develop it in the contralateral ear. This finding supports
the idea that the syndrome we have labeled as Meniere disease
AND PROGNOSIS
is actually the manifestation of several different pathologies. Sudden SNHL is a syndrome and not a diagnosis. Most com-
Although vestibular destructive therapy (chemical or surgical monly, the syndrome has been referred to as sudden deafness or
labyrinthectomy, vestibular nerve section) is effective in control- sudden sensorineural hearing loss, and it has many possible etiolo-
ling the episodic vertigo associated with Meniere disease, no gies. In most patients, the cause is idiopathic. Among patients
therapy to date has been proven to be effective in the treatment who reveal no identifiable etiology, several different pathoge-
of the hearing loss. The most widely accepted medical therapy netic mechanisms seem to be responsible. In reviewing the
for Meniere disease, a sodium-restricted diet and diuretic natural history of the disorder, it should be kept in mind that
administration, is based on the hypothesis that the hydropic the described natural history is most likely the sum of the his-
distension of the membranous labyrinth can be reduced by tories of patients with differing abnormalities. Because of this,
altering body water distribution, as in the management of and because of the difficulty of studying such an entity, either
in clinical trials or in animal models, much remains to be hearing loss.260,264 With the possible exception of mumps par-
learned about sudden SNHL. otitis and herpes zoster infections, however, the clinical diagno-
A universal definition of sudden SNHL does not exist, and sis of viral infections is unreliable. Azimi and colleagues265
the rate of progression of SNHL can vary from seconds to days. reported that 53% of mumps meningoencephalitis occurs
For purposes of this discussion, sudden SNHL develops over 12 without parotitis. Other evidence for a viral etiology for sudden
hours or less. This rate of progression can sometimes be unclear SNHL includes studies that document increased viral titers in
in the history, because some patients notice their loss only when such patients,264 pathology consistent with viral infection,266-269
using a telephone. In other patients, sensation of fullness or and viral seroconversion studies.270-273 These seroconversion
tinnitus is the patient’s primary initial complaint. The inci- studies showed a mixture of viruses that included herpes
dence of sudden SNHL has been estimated to range from 5 to simplex, herpes zoster, CMV, influenza, parainfluenza, mumps,
20 per 100,000 persons per year.259 In a typical otologic practice, measles, and adenovirus. The studies failed to show a relation-
this may account for 2% to 3% of unselected outpatient visits. ship between titer results and severity of hearing loss or fre-
Any age group can be affected, but the peak incidence seems quency of recovery.
to be in the sixth decade. The male/female distribution is For some viruses, the evidence of a causative relationship is
essentially equal.260 Bilateral involvement is rare, and simultane- more convincing. The mumps virus has been isolated from the
ous bilateral involvement is very rare.261 perilymph of patients with sudden SNHL,274 and experimental
The most common presentation is a patient noticing a uni- mumps labyrinthitis has been reproduced in hamsters by inocu-
lateral hearing loss on awakening. Others notice a sudden, lation of the subarachnoid space with mumps virus.274,275 Lassa
stable hearing loss or a rapidly progressive loss. Occasionally, fever, an arenavirus infection endemic in West Africa, has been
patients note a fluctuating hearing loss, but most patients have shown to be associated with sudden SNHL in approximately
a stable loss. A sensation of aural fullness in the affected ear is two thirds of the patients.276 The time course, the results of
common and frequently is the only complaint. Tinnitus is audiometric testing, and the patterns of recovery in Lassa fever
present in the ear to a variable degree, and the hearing loss are very similar to that in idiopathic sudden SNHL.277 Measles
sometimes is preceded by the onset of tinnitus. Vertigo or dys- and rubella also are well-documented causes of labyrinthitis,268
equilibrium is present to a variable degree in approximately but these cases rarely manifest in a manner typical of sudden
40% of patients.262 SNHL. Herpes zoster oticus also can cause sudden SNHL,
Four variables seem to affect the prognosis of untreated although it is a clinical entity distinct from idiopathic sudden
idiopathic sudden SNHL: 1) severity of loss, 2) audiogram SNHL. The evidence that herpes zoster may be associated with
shape, 3) presence of vertigo, and 4) age. The more severe the idiopathic sudden SNHL is limited to viral seroconversion
loss, the lower the prognosis for recovery, and profound losses studies. Sudden hearing loss associated with infectious mono-
have an exceptionally poor prognosis. Upsloping and midfre- nucleosis is rare but has been reported.278 For a few viruses,
quency losses recover more frequently than downsloping and strong evidence suggests they may be an occasional cause of
flat losses. The presence of vertigo, particularly with a downslop- idiopathic sudden SNHL. For most other viruses, an association
ing loss, is a poor prognostic indicator, although not all studies with idiopathic sudden SNHL is found, although convincing
concur on this point. Reduced speech discrimination carries a evidence of a causal relationship is lacking.
poor prognosis. Finally, most studies show that children and
adults older than 40 years have a poorer prognosis than Meningitis. Meningitis is a well-recognized and common etiol-
others.259,260,262,263 Most recovery occurs within the first 2 weeks ogy of acquired severe to profound SNHL. It is possible that
after onset; as a corollary, the prognosis for recovery decreases rare cases of idiopathic sudden SNHL may be caused by sub-
the longer the loss persists. Without treatment of any kind, a clinical meningoencephalitis.
significant proportion (30% to 65%) of patients experience
complete or partial recovery.262,263 Syphilis. It has been estimated that the incidence of syphilis in
patients with sudden SNHL is 2% or less. Syphilitic hearing loss
may manifest at any stage of the disease, and it may be associ-
ETIOLOGY OF SUDDEN SENSORINEURAL ated with other manifestations of syphilis, with vestibular symp-
toms, or alone. It may also manifest with unilateral or bilateral
HEARING LOSS sudden SNHL. More typical presentations of syphilitic hearing
The management of sudden SNHL should be focused on loss are discussed in other sections of this chapter. It is impor-
excluding known causes of the syndrome, especially conditions tant to consider the possibility of reactivation of syphilis in
that require treatment. Similar to causes of SNHL in general, patients with HIV infection.209,211
these disorders can be conveniently broken down into infec-
tious, neoplastic, traumatic, ototoxic, immunologic, vascular, Lyme Disease. Lyme disease is a well-established etiology of
developmental, psychogenic, and idiopathic etiologies. Despite acute facial paralysis, and it would not be unreasonable to
a thorough search for an etiology, most cases remain idio- assume that it could also cause SNHL. Hearing loss has not
pathic. Considerable debate continues as to the pathogenesis been strongly associated with Lyme disease, however. The litera-
of the disease in these patients. Principal theories include viral ture contains several descriptions of associations between posi-
infection, vascular occlusion, intracochlear membrane breaks, tive Lyme titers and acute or chronic SNHL, but a causal
and autoimmunity. relationship seems doubtful. In one large study, Lyme titers
were found in 21% of patients with sudden SNHL, and despite
Infectious Disorders antibiotic treatment of all seropositive patients, no difference
Viral Infection. Viral neuritis or cochleitis has long been was reported in outcome between patients with positive titers
thought to be the most common cause of sudden SNHL, and those without.279 Reports of hearing loss in patients with
although much of the evidence for this is circumstantial. SNHL Lyme disease with improved hearing after antibiotic treatment
can complicate clinically evident infections with mumps, are limited to a few case reports.35,280
measles, herpes zoster, and infectious mononucleosis and with
congenital rubella and CMV. Of patients who come to medical Acquired Immunodeficiency Syndrome. At autopsy, 88% of
attention with sudden SNHL, 28% report a viral-like upper HIV-positive patients have evidence of CNS involvement,281 and
respiratory infection within 1 month before the onset of their approximately 10% of patients with AIDS come to medical
attention because of neurologic symptoms.205 It is not surpris- the presence of such a fistula, and even surgical exploration is
ing that sudden SNHL may be associated with HIV infection; subject to error.295 Except in poststapedectomy patients, it is
it is not a common manifestation of AIDS, but it has been well doubtful that perilymph fistula is a significant cause of SNHL.
documented in the literature.206-209,212,282 In the presence of HIV
infection, sudden SNHL may occur with or without the pres- Intracochlear Membrane Breaks. Intracochlear membrane
ence of opportunistic infection, and it may occur without clini- ruptures and fistulae have been documented pathologically in
cal evidence of AIDS. Sudden SNHL caused by reactivation of patients with endolymphatic hydrops.19 Such breaks have been
latent syphilis may complicate any stage of HIV infection.208,209,211 proposed to be an etiology of SNHL.296 Schuknecht and
As previously mentioned, some cases of sudden SNHL associ- Donovan268 found no evidence of such breaks in a series of
ated with AIDS may be the result of reactivation of latent CMV temporal bones from patients with sudden SNHL; however,
infection. Gussen297-299 found evidence to support the membrane break
theory in a few temporal bones.
Neoplasms
Acoustic Neuroma. It is common for sudden SNHL to be the Pharmacologic Toxicity
initial manifestation of a vestibular schwannoma (acoustic Toxicity from any of the drugs discussed in the previous section
neuroma). According to Moffat and associates,230 10.2% of on ototoxic causes of SNHL may result in the relatively sudden
acoustic neuromas initially manifest with sudden SNHL. The onset of hearing loss. In addition to these drugs, others have
prevalence of acoustic neuroma among patients with sudden been associated with sudden SNHL. Interferon has been associ-
SNHL is less clear, although estimates range from 0.8%261 to ated with SNHL that has been reversible in most patients.300,301
3%.283,284 No clear criteria suggest that sudden SNHL may be a The insecticides malathion and methoxychlor have been associ-
result of an acoustic neuroma. The presence of tinnitus in the ated with bilateral SNHL.302
ipsilateral ear before sudden SNHL is suggestive, but it is not
present in most cases.284 In addition, midfrequency and high- Immunologic Disorders
frequency hearing loss are more commonly associated with The finding that many patients with SNHL seem to benefit
acoustic neuroma than are low-frequency losses, and electro- from glucocorticoid therapy and the finding of cross-reacting
nystagmography abnormalities are more common with acoustic circulating antibodies in many patients with sudden and rapidly
neuroma.284 progressive SNHL suggest that at least a subset of SNHL cases
Responsiveness of the hearing loss to treatment with steroids are caused by inner ear autoimmunity.200 In addition, many
is not a reliable indicator that a retrocochlear lesion can be well-known autoimmune diseases have been associated with
ruled out. Many cases have been reported of steroid-responsive SNHL, including Cogan syndrome,303,304 systemic lupus erythe-
SNHL and SNHL with spontaneous recovery that have been matosus,190 temporal arteritis, and polyarteritis nodosa.
found to be caused by acoustic neuroma.284,285 The clinician
should have a high level of suspicion for acoustic neuroma in Vascular Disorders
any patient with SNHL. Most investigators recommend that Sudden hearing loss can occur with occlusion of the cochlear
ABR or gadolinium-enhanced MRI be obtained in patients with blood supply. Because of the abruptness of onset of SNHL and
sudden SNHL,286 although no relationship has been found the fact that the cochlea depends on a single terminal branch
between tumor size and SNHL.284 Because of this and the of the posterior cerebral circulation, vascular occlusion has
numerous more recent reports of false-negative ABR tests in been thought by some authors to be an attractive hypothetic
patients with small acoustic neuromas,3,287-289 it seems warranted etiology for idiopathic sudden hearing losses. Other aspects
to evaluate all patients with sudden SNHL with gadolinium- that argue against a circulatory etiology include high incidence
enhanced MRI. of spontaneous recovery, significant incidence in young
patients, lack of an apparent increased incidence in diabetics,
Other Neoplasms. Neoplasms of the CPA or internal auditory the fact that the loss frequently is limited to just a few frequen-
canal other than acoustic neuromas have also been associated cies, and the fact that most patients do not have vertigo. Similar
with SNHL. These include meningioma,290 cholesteatoma, to viral etiologies, a few cases of SNHL are clearly a result of
hemangioma,291 arachnoid cyst, and metastatic neoplasms. In vascular occlusion, but most cases remain idiopathic. Temporal
addition, skull base neoplasms that erode into the inner ear bone studies have not found evidence of vascular occlusion in
can rarely manifest with SNHL. cases of idiopathic SNHL.19 Series of patients with idiopathic
SNHL have been evaluated for hemostatic abnormalities, but
Trauma and Membrane Ruptures no significant association has been found.305 The role of vascu-
Head Injury. Sensorineural hearing loss of any degree can lar occlusion versus viral infection in these idiopathic cases has
occur after closed or open head injury. The mechanism of been the subject of extensive debate over the years. At this
injury in such patients has been shown pathologically to vary point, it seems doubtful that a significant proportion of cases
from mild loss of outer or inner hair cells or cochlear mem- of idiopathic sudden SNHL have a vascular etiology.
brane breaks to fracture across the labyrinth or intralabyrin- Migraine,160,306,307 hemoglobin sickle cell disease,166,168-171 and
thine hemorrhage.19 Many of these injuries are pathologically macroglobulinemia163,164 have been documented to be associ-
indistinguishable from injuries of acoustic trauma.292 Some ated with sudden SNHL. Rare cases of thromboangiitis obliter-
patients experience a variable degree of recovery from head ans (Buerger disease) have been associated with sudden
injury–induced hearing loss, a process probably equivalent to SNHL.308 Small cerebellar infarctions may mimic labyrinthine
the temporary threshold shift seen with acoustic trauma. lesions, including sudden onset of hearing loss.309 Cardiopul-
monary bypass173,174 and noncardiac surgery172 have been associ-
Perilymphatic Fistula. Round or oval window fistulae can occur ated with an increased risk of sudden SNHL. Sudden SNHL
congenitally, after stapedectomy, or after barotrauma. SNHL is has also been reported after spinal manipulation with probable
well described after events that cause barotrauma.293,294 Some injury to the vertebrobasilar arterial system.310
investigators theorize that these fistulae can occur after heavy It has long been believed that patients with diabetes have a
lifting or straining or even spontaneously. Patients with such higher incidence of idiopathic sudden SNHL than people
fistulae can have sudden or fluctuating SNHL and varying without diabetes. This belief has been based on the higher
degrees of vestibular symptoms. No test is reliable for detecting incidence of other acute cranial neuropathies and on the
diffuse vascular abnormalities found in patients with diabetes. at tapering doses. They found that all patients (n = 14) with
Histologic studies of human temporal bones from patients with midfrequency losses (loss at 4 kHz better than 8 kHz) had a
diabetes mellitus have not consistently found any abnormal complete recovery regardless of treatment. They noted that
alterations.19,311 In a careful study of the relationship of idio- among patients with losses greater than 90 dB HL at all fre-
pathic sudden SNHL to diabetes, Wilson28 found that diabetic quencies, no difference in recovery was reported between the
patients with idiopathic sudden SNHL were less likely to recover steroid-treated versus placebo-treated groups. Among the
hearing at higher frequencies. No significant difference was remaining patients (nonprofound losses with hearing at 4 kHz
reported in audiologic patterns between diabetic and nondia- better than at 8 kHz), a significant increase in recovery was
betic patients with idiopathic sudden SNHL. An attempt to reported in the steroid-treated group. Of patients in the steroid-
compare the incidence of diabetes in patients with idiopathic treated group, 78% experienced complete or partial recovery
sudden SNHL with a control population was inconclusive. compared with 38% in the placebo-treated group.
In a similar study, Moskowitz and colleagues315 confirmed a
Developmental Abnormalities significantly improved recovery rate in a steroid-treated group
Large vestibular aqueduct syndrome is associated with SNHL compared with a nontreated control group. Direct steroid treat-
and frequently occurs in a stepwise fashion associated with ment to the inner ear via middle ear instillation or round
minor head trauma. It seems plausible that other, as yet unde- window microcatheter has seen increasing use on an empiric
fined developmental abnormalities may predispose individuals basis. This treatment has the potential advantage of very high
to sudden SNHL, either spontaneously or after minor head steroid concentrations within the inner ear without the associ-
trauma. ated systemic side effects. Anecdotal reports indicate that this
treatment may be more effective than orally administered ste-
Idiopathic Disorders roids and that local complications are infrequent.316 Refer to
Meniere Disease. Some patients seen with typical sudden Chapter 155 for a more complete discussion.
SNHL ultimately may develop a history more suggestive of An alternative management regimen proposed by some
endolymphatic hydrops or even frank Meniere disease; this investigators involves attempts to improve blood flow or oxy-
probably constitutes only 5% of all patients with sudden SNHL. genation to the inner ear. Vasodilators have been used exten-
In a review of 1270 patients with Meniere disease, Hallberg312 sively in the treatment of sudden SNHL. Any proposed
found that only 4.4% had initially been seen with sudden vasodilator would have to cross the blood-brain barrier and
SNHL. A subset of these patients very likely had an autoim- have an effect on intracranial circulation. IV histamine infu-
mune etiology of their hearing loss. sion, oral papaverine, and oral nicotinic acid have been used
most frequently. Fisch and Nagahara others317,318 have shown
Multiple Sclerosis. MS is a demyelinating disorder of the CNS that breathing a gas mixture with increased partial pressures of
manifested by differing neurologic lesions separated by space oxygen and carbon dioxide (carbogen) results in increased
and time. Sudden SNHL is a rare initial manifestation of perilymph oxygen tension in cats and humans.
MS.140,152,313 Among patients with MS, auditory abnormalities Other agents proposed to improve cochlear blood flow
are common.142,145 include low-molecular-weight dextran, mannitol, pentoxifyl-
line, and heparin. In addition, the iodinated radiographic
Sarcoidosis. CNS manifestations are rare (incidence of 1% to contrast agent diatrizoate was serendipitously noted during a
5%), although among patients with neurosarcoidosis, 20% vertebral angiogram to improve hearing in patients with sudden
have eighth cranial nerve findings. This eighth cranial nerve SNHL. Morimitsu and coworkers319 showed in the same report
involvement may manifest as sudden SNHL, although it only that in a small series, 54% of patients treated with diatrizoate
rarely is an isolated finding.193 had a complete recovery compared with 19% of a control
group treated with vasodilators. It was later shown that triiodin-
Psychogenic Disorders ated benzoic acid derivatives such as diatrizoate have a specific
Pseudohypacusis frequently manifests as a sudden loss. In most effect on the stria vascularis, protecting the endocochlear
patients, malingering is readily apparent after initial audiologic potential from furosemide-induced depression.320
studies. Clinical studies that used the previously mentioned agents
have shown poor to mixed results. The varying definition of
recovery used by different authors complicates the interpretation
TREATMENT of these results. No controlled study has shown a beneficial
Treatment of sudden SNHL should be based on its etiology. effect from papaverine, nicotinic acid, or pentoxifylline. Don-
If an etiology is apparent, the appropriate treatment should aldson321 found no improvement with aggressive heparin
follow: antibiotics for infectious causes, withdrawal of the therapy in a series of patients. In a prospective, randomized
offending drug for ototoxicity, and so on. Most cases are idio- double-blind study, Probst and colleagues322 found no differ-
pathic, and treatment decisions should be made on the basis ence in outcome between placebo and treatment with low-
of empiric guidelines. Because of the poor understanding of molecular-weight dextran, pentoxifylline, or both. In a
idiopathic sudden SNHL, controversy surrounds its treatment. randomized prospective trial that compared papaverine/
Because of the dictum, “first, do no harm,” new or unconven- dextran infusion treatment with inhaled carbogen, the average
tional treatment protocols should be well reasoned and care- hearing improvement in the carbogen group was better,
fully applied. It seems prudent to avoid the use of potentially although no significant difference in hearing recovery was seen
harmful treatment protocols outside of controlled clinical between the two groups after 5 days of treatment.317 After 1 year
trials, because serious complications and deaths have been of treatment, a statistically significant improvement in hearing
reported after treatment of idiopathic sudden SNHL.314 was reported in the carbogen-treated group.323
Steroids in moderate doses have become the most widely Redleaf and coworkers324 reviewed their 10-year experience
accepted treatment option for idiopathic sudden SNHL. Wilson with diatrizoate and dextran and noted that 74% of their 36
and associates263 performed a double-blind randomized trial of patients showed audiometric improvement with treatment.
steroids versus placebo for idiopathic sudden SNHL. Their Only 36% improved to 50% of their premorbid hearing levels,
active drug group was treated with either a 10- or 12-day course which was very close to the 32% recovery noted in the placebo
of orally administered dexamethasone or methylprednisolone group of the Wilson study.263 Another, even more empiric
treatment protocol is the so-called shotgun regimen, which uses For a complete list of references, see expertconsult.com.

most of the proposed agents in hopes that one or more will be
beneficial. Wilkins and associates325 reviewed their results with SUGGESTED READINGS
a protocol of dextran, histamine, diatrizoate, diuretics, steroids,
Arts HA, Kileny PR, Telian SA: Diagnostic testing for endolymphatic
oral vasodilators, and carbogen inhalation. Although it was a hydrops. Otolaryngol Clin North Am 30:987, 1997.
retrospective study limited by methodologic problems, these Bakthavachalam S, Driver MS, Cox C, et al: Hearing loss in Wegener’s
authors were unable to show any difference in recovery between granulomatosis. Otol Neurotol 25:833, 2004.
patients who had the “full” protocol versus patients who had Bretlau P, Thomsen J, Tos M, et al: Placebo effect in surgery for Meniere
only portions of the total regimen. Their overall results were disease: nine-year follow-up. Am J Otol 10:259, 1989.
no better than the results expected for spontaneous recovery. Byl FM, Jr: Sudden hearing loss: eight years’ experience and suggested
Still other treatment ideas are directed at other presumed prognostic table. Laryngoscope 94:647, 1984.
etiologies. Because endolymphatic hydrops is a common final Dobie RA: Medical-legal evaluation of hearing loss, ed 2, San Diego, 2001,
Singular.
pathology for many inner ear injuries and may be associated
Friedland DR, Wackym PA: A critical appraisal of spontaneous perilym-
with some cases of sudden SNHL, some authors have advocated phatic fistulas of the inner ear. Am J Otol 20:261, 1999.
treatment with a sodium-restricted diet and a diuretic.326 Grau C, Overgaard J: Postirradiation sensorineural hearing loss: a
Because of the evidence for a viral etiology and, specifically, common but ignored late radiation complication. Int J Radiat Oncol
evidence of herpesvirus, treatment with oral antiviral medica- Biol Phys 36:515, 1996.
tions has been proposed. Because these drugs rarely have Jackler RK, Luxford WM, House WF: Congenital malformations of the
adverse side effects, many practitioners routinely treat patients inner ear: a classification based on embryogenesis. Laryngoscope 97:2,
with sudden hearing loss with antivirals in addition to steroids. 1987.
In a double-blind, randomized, placebo-controlled multicenter Matz G, Rybak L, Roland PS, et al: Ototoxicity of ototopical antibiotic
drops in humans. Otolaryngol Head Neck Surg 130:S79, 2004.
trial, Tucci and colleagues327 found no difference in hearing
Moscicki RA, San Martin JE, Quintero CH, et al: Serum antibody to
recovery outcome between patients treated with steroids and inner ear proteins in patients with progressive hearing loss: correla-
valacyclovir versus those treated with steroids and placebo. tion with disease activity and response to corticosteroid treatment.
Some authors have advocated aggressive management with very JAMA 272:611, 1994.
large (mega) doses of steroids or even cytotoxic medications. Musiek FE, Gollegly KM, Kibbe KS, et al: Electrophysiologic and behav-
Clinical studies that support the efficacy of any of these treat- ioral auditory findings in multiple sclerosis. Am J Otol 10:343, 1989.
ments have yet to be published. Paek SH, Chung H-T, Jeong SS, et al: Hearing preservation after gamma
I believe that a reasonable treatment approach to sudden knife stereotactic radiosurgery of vestibular schwannoma. Cancer
SNHL is as follows. Sudden SNHL is regarded as an otologic 104:580, 2005.
Pan CC, Eisbruch A, Lee JS, et al: Prospective study of inner ear radia-
emergency, and patients are evaluated audiometrically and
tion dose and hearing loss in head-and-neck cancer patients. Int J
by an otolaryngologist on an urgent basis. Known etiologies Radiat Oncol Biol Phys 61:1393, 2005.
are excluded by a thorough history; physical examination; Rybak LP, Ramkumar V: Ototoxicity. Kidney Int 72:931, 2007.
and appropriate laboratory, special audiologic, and radiologic Saunders JE, Luxford WM, Devgan KK, et al: Sudden hearing loss in
studies. Gadolinium-enhanced MRI of the internal auditory acoustic neuroma patients. Otolaryngol Head Neck Surg 113:23, 1995.
canal and CPA is obtained in all patients. A 10-day course of Schacht J: Biochemical basis of aminoglycoside ototoxicity. Otolaryngol
prednisone, approximately 1 mg/kg/day, is prescribed, fol- Clin North Am 26:845, 1993.
lowed by a slow taper. If a partial recovery is noted at the end Schuknecht HF: Pathology of the ear, ed 2, Philadelphia, 1993, Lea &
of the 10 days, the full dose is extended another 10 days, and Febiger.
Schweitzer VG: Ototoxicity of chemotherapeutic agents. Otolaryngol
the cycle is repeated until no further improvement is noted.
Clin North Am 26:759, 1993.
Valacyclovir (1000 mg three times daily for 10 days) also is Sismanis A: Otologic manifestations of benign intracranial hyperten-
considered, because it may be beneficial, and because the risks sion syndrome: diagnosis and management. Laryngoscope 97:1, 1987.
and side effects are minimal. A 2-g sodium diet is recommended Sismanis A, Smoker WR: Pulsatile tinnitus: recent advances in diagno-
with a hydrochlorothiazide-triamterene diuretic combination. sis. Laryngoscope 104:681, 1994.
Despite the possible efficacy of carbogen treatment, it is not Toriello HV, Reardon W, Gorlin RJ: Hereditary hearing loss and its syn-
routinely offered to patients with sudden SNHL; the treatment dromes, ed 2, Oxford, UK, 2004, Oxford University Press.
requires inpatient hospitalization, which renders it expensive Torok N: Old and new in Meniere disease. Laryngoscope 87:1870, 1977.
and inconvenient. Insurers typically regard carbogen as inves- Tucci DL, Farmer JC, Jr, Kitch RD, et al: Treatment of sudden sensori-
neural hearing loss with systemic steroids and valacyclovir. Otol Neu-
tigational, which results in significant expense to patients.
rotol 23:301, 2002.
Because of these issues and its controversial nature, most Wilkins SA, Jr, Mattox DE, Lyles A: Evaluation of a “shotgun” regimen
patients do not accept carbogen if it is offered. It would be for sudden hearing loss. Otolaryngol Head Neck Surg 97:474, 1987.
more strongly considered in exceptional situations, such as a Wilson WR, Byl FM, Laird N: The efficacy of steroids in the treatment
patient with sudden SNHL in an only-hearing ear or in a par- of idiopathic sudden hearing loss: a double-blind clinical study. Arch
ticularly motivated patient. Otolaryngol 106:772, 1980.
150 | SENSORINEURAL HEARING LOSS IN ADULTS 2335.e1
29. Meynard JL, el Amrani M, Meyohas MC, et al: Two cases of cyto-
REFERENCES megalovirus infection revealed by hearing loss in HIV-infected
1. El-Kashlan HK, Eisenmann D, Kileny PR: Auditory brain stem patients. Biomed Pharmacother 51:461, 1997.
response in small acoustic neuromas. Ear Hear 21:257, 2000. 30. Goodhill V: Syphilis of the ear: a histopathologic study. Ann Otol
2. Schmidt RJ, Sataloff RT, Newman J, et al: The sensitivity of audi- Rhinol Laryngol 48:676, 1939.
tory brainstem response testing for the diagnosis of acoustic neu- 31. Darmstadt GL, Harris JP: Luetic hearing loss: clinical presenta-
romas. Arch Otolaryngol Head Neck Surg 127:19, 2001. tion, diagnosis, and treatment. Am J Otolaryngol 10:410, 1989.
3. Wilson DF, Hodgson RS, Gustafson MF, et al: The sensitivity of 32. Dolan S, Everett ED, Renner L: Hearing loss in Rocky Mountain
auditory brainstem response testing in small acoustic neuromas. spotted fever. Ann Intern Med 104:285, 1986.
Laryngoscope 102:961, 1992. 33. Steinfeld HJ, Silverstein J, Weisburger W, et al: Deafness associated
4. Don M, Kwong B, Tanaka C, et al: The stacked ABR: a sensitive with Rocky Mountain spotted fever. Md Med J 37:287, 1988.
and specific screening tool for detecting small acoustic tumors. 34. Hanner P, Rosenhall U, Edstrom S, et al: Hearing impairment in
Audiol Neurootol 10:274, 2005. patients with antibody production against Borrelia burgdorferi
5. Arts HA, Kileny PR, Telian SA: Diagnostic testing for endolym- antigen. Lancet 1:13, 1989.
phatic hydrops. Otolaryngol Clin North Am 30:987, 1997. 35. Hyden D, Roberg M, Odkvist L: Borreliosis as a cause of sudden
6. Ruth RA, Lambert PR, Ferraro JA: Electrocochleography: methods deafness and vestibular neuritis in Sweden. Acta Otolaryngol Suppl
and clinical applications. Am J Otol 9(Suppl):1, 1988. 520:320, 1995.
7. Shelton C, Harnsberger HR, Allen R, et al: Fast spin echo mag- 36. Lesser TH, Dort JC, Simmen DP: Ear, nose and throat manifesta-
netic resonance imaging: clinical application in screening for tions of Lyme disease. J Laryngol Otol 104:301, 1990.
acoustic neuroma. Otolaryngol Head Neck Surg 114:71, 1996. 37. Moscatello AL, Worden DL, Nadelman RB, et al: Otolaryngologic
8. Belden CJ, Weg N, Minor LB, et al: CT evaluation of bone dehis- aspects of Lyme disease. Laryngoscope 101:592, 1991.
cence of the superior semicircular canal as a cause of sound- and/ 38. Huang MY, Schacht J: Drug-induced ototoxicity: pathogenesis and
or pressure-induced vertigo. Radiology 226:337, 2003. prevention. Med Toxicol Adverse Drug Exp 4:452, 1989.
9. Toriello HV, Reardon W, Gorlin RJ: Hereditary Hearing Loss and Its 39. Matz GJ: Clinical perspectives on ototoxic drugs. Ann Otol Rhinol
Syndromes. ed 2, Oxford, UK, 2004, Oxford University Press. Laryngol Suppl 148:39, 1990.
10. Davis RR, Kozel P, Erway LC: Genetic influences in individual 40. Forge A, Schacht J: Aminoglycoside antibiotics. Audiol Neurootol
susceptibility to noise: a review. Noise Health 5:19, 2003. 5:3, 2000.
11. Davis RR, Newlander JK, Ling X, et al: Genetic basis for suscepti- 41. Rybak LP, Ramkumar V: Ototoxicity. Kidney Int 72:931, 2007.
bility to noise-induced hearing loss in mice. Hear Res 155:82, 2001. 42. Schacht J: Biochemical basis of aminoglycoside ototoxicity. Otolar-
12. Garringer HJ, Pankratz ND, Nichols WC, et al: Hearing impair- yngol Clin North Am 26:845, 1993.
ment susceptibility in elderly men and the DFNA18 locus. Arch 43. Magnusson M, Padoan S: Delayed onset of ototoxic effects of
Otolaryngol Head Neck Surg 132:506, 2006. gentamicin in treatment of Meniere’s disease: rationale for
13. Johnson KR, Zheng QY, Erway LC: A major gene affecting age- extremely low dose therapy. Acta Otolaryngol 111:671, 1991.
related hearing loss is common to at least ten inbred strains of 44. Chen Y, Huang WG, Zha DJ, et al: Aspirin attenuates gentamicin
mice. Genomics 70:171, 2000. ototoxicity: from the laboratory to the clinic. Hear Res 226:178,
14. Kashtan CE: Alport syndrome: an inherited disorder of renal, 2007.
ocular, and cochlear basement membranes. Medicine (Baltimore) 45. Sha SH, Qiu JH, Schacht J: Aspirin to prevent gentamicin-induced
78:338, 1999. hearing loss. N Engl J Med 354:1856, 2006.
15. Jackler RK, Luxford WM, House WF: Congenital malformations 46. Chia SH, Gamst AC, Anderson JP, et al: Intratympanic gentamicin
of the inner ear: a classification based on embryogenesis. Laryn- therapy for Meniere’s disease: a meta-analysis. Otol Neurotol 25:544,
goscope 97:2, 1987. 2004.
16. Griffith AJ, Arts A, Downs C, et al: Familial large vestibular aque- 47. Nedzelski JM, Schessel DA, Bryce GE, et al: Chemical labyrinthec-
duct syndrome. Laryngoscope 106:960, 1996. tomy: local application of gentamicin for the treatment of unilat-
17. Stinckens C, Standaert L, Casselman JW, et al: The presence of eral Meniere’s disease. Am J Otol 13:18, 1992.
a widened vestibular aqueduct and progressive sensorineural 48. Linder TE, Zwicky S, Brandle P: Ototoxicity of ear drops: a clinical
hearing loss in the branchio-oto-renal syndrome: a family study. perspective. Am J Otol 16:653, 1995.
Int J Pediatr Otorhinolaryngol 59:163, 2001. 49. Rohn GN, Meyerhoff WL, Wright CG: Ototoxicity of topical
18. Kitamura K, Takahashi K, Noguchi Y, et al: Mutations of the agents. Otolaryngol Clin North Am 26:747, 1993.
Pendred syndrome gene (PDS) in patients with large vestibular 50. Matz G, Rybak L, Roland PS, et al: Ototoxicity of ototopical anti-
aqueduct. Acta Otolaryngol 120:137, 2000. biotic drops in humans. Otolaryngol Head Neck Surg 130:S79, 2004.
19. Schuknecht HF: Pathology of the Ear, ed 2, Philadelphia, 1993, Lea 51. Roland PS, Stewart MG, Hannley M, et al: Consensus panel on
& Febiger. role of potentially ototoxic antibiotics for topical middle ear use:
20. Stokroos RJ, Albers FW: The etiology of idiopathic sudden senso- introduction, methodology, and recommendations. Otolaryngol
rineural hearing loss: a review of the literature. Acta Otorhinolar- Head Neck Surg 130:S51, 2004.
yngol Belg 50:69, 1996. 52. Marsh RR, Tom LW: Ototoxicity of antimycotics. Otolaryngol Head
21. Stokroos RJ, Albers FW, Schirm J: The etiology of idiopathic Neck Surg 100:134, 1989.
sudden sensorineural hearing loss: experimental herpes simplex 53. Morizono T: Toxicity of ototopical drugs: animal modeling. Ann
virus infection of the inner ear. Am J Otol 19:447, 1998. Otol Rhinol Laryngol Suppl 148:42, 1990.
22. Rahko T, Karma P, Sipila M: Sensorineural hearing loss and acute 54. Koegel L, Jr: Ototoxicity: a contemporary review of aminoglyco-
otitis media in children. Acta Otolaryngol 108:107, 1989. sides, loop diuretics, acetylsalicylic acid, quinine, erythromycin,
23. Noordzij JP, Dodson EE, Ruth RA, et al: Chronic otitis media and and cisplatinum. Am J Otol 6:190, 1985.
sensorineural hearing loss: is there a clinically significant relation? 55. Matz GJ: Aminoglycoside ototoxicity. Am J Otolaryngol 7:117, 1986.
Am J Otol 16:420, 1995. 56. Rybak LP: Pathophysiology of furosemide ototoxicity. J Otolaryngol
24. Barbi M, Binda S, Caroppo S, et al: A wider role for congenital 11:127, 1982.
cytomegalovirus infection in sensorineural hearing loss. Pediatr 57. Franklin DJ, Coker NJ, Jenkins HA: Sudden sensorineural hearing
Infect Dis J 22:39, 2003. loss as a presentation of multiple sclerosis. Arch Otolaryngol Head
25. Fowler KB, Boppana SB: Congenital cytomegalovirus (CMV) Neck Surg 115:41, 1989.
infection and hearing deficit. J Clin Virol 35:226, 2006. 58. Jung TT, Rhee CK, Lee CS, et al: Ototoxicity of salicylate, nonste-
26. Pass RF: Congenital cytomegalovirus infection and hearing loss. roidal antiinflammatory drugs, and quinine. Otolaryngol Clin North
Herpes 12:50, 2005. Am 26:791, 1993.
27. Woolf NK, Koehrn FJ, Harris JP, et al: Congenital cytomegalovirus 59. Goodman LS, Gilman A, Brunton LL, et al: Goodman and Gilman’s
labyrinthitis and sensorineural hearing loss in guinea pigs. J Infect the Pharmacological Basis of Therapeutics, 11th ed, New York, 2006,
Dis 160:929, 1989. McGraw-Hill.
28. Wilson WR: The relationship of the herpesvirus family to sudden 60. Hadi U, Nuwayhid N, Hasbini AS: Chloroquine ototoxicity: an
hearing loss: a prospective clinical study and literature review. idiosyncratic phenomenon. Otolaryngol Head Neck Surg 114:491,
Laryngoscope 96:870, 1986. 1996.
61. Matz GJ, Naunton RF: Ototoxicity of chloroquine. Arch Otolaryngol 90. Gendeh BS, Gibb AG, Aziz NS, et al: Vancomycin administration

88:370, 1968. in continuous ambulatory peritoneal dialysis: the risk of ototoxic-
62. Myers EN, Bernstein JM: Salicylate ototoxicity: a clinical and ity. Otolaryngol Head Neck Surg 118:551, 1998.
experimental study. Arch Otolaryngol 82:483, 1965. 91. Klibanov OM, Filicko JE, DeSimone JA, Jr, et al: Sensorineural
63. Myers EN, Bernstein JM, Fostiropolous G: Salicylate ototoxicity: hearing loss associated with intrathecal vancomycin. Ann Pharma-
a clinical study. N Engl J Med 273:587, 1965. cother 37:61, 2003.
64. Bernstein JM, Weiss AD: Further observations on salicylate ototox- 92. Brummett RE: Ototoxic liability of erythromycin and analogues.
icity. J Laryngol Otol 81:915, 1967. Otolaryngol Clin North Am 26:811, 1993.
65. Silverstein H, Bernstein JM, Davies DG: Salicylate ototoxicity: 93. Ress BD, Gross EM: Irreversible sensorineural hearing loss as a
a biochemical and electrophysiological study. Ann Otol Rhinol result of azithromycin ototoxicity: a case report. Ann Otol Rhinol
Laryngol 76:118, 1967. Laryngol 109:435, 2000.
66. Boettcher FA, Salvi RJ: Salicylate ototoxicity: review and synthesis. 94. McGhan LJ, Merchant SN: Erythromycin ototoxicity. Otol Neurotol
Am J Otolaryngol 12:33, 1991. 24:701, 2003.
67. Chapman P: Naproxen and sudden hearing loss. J Laryngol Otol 95. Schweitzer VG: Ototoxicity of chemotherapeutic agents. Otolaryn-
96:163, 1982. gol Clin North Am 26:759, 1993.
68. Schaab KC, Dickinson ET, Setzen G: Acute sensorineural hearing 96. Pasic TR, Dobie RA: cis-platinum ototoxicity in children. Laryngo-
loss following intravenous ketorolac administration. J Emerg Med scope 101:985, 1991.
13:509, 1995. 97. Kopelman J, Budnick AS, Sessions RB, et al: Ototoxicity of high-
69. Vernick DM, Kelly JH: Sudden hearing loss associated with piroxi- dose cisplatin by bolus administration in patients with advanced
cam. Am J Otol 7:97, 1986. cancers and normal hearing. Laryngoscope 98:858, 1988.
70. Rybak LP: Drug ototoxicity. Annu Rev Pharmacol Toxicol 26:79, 98. Lautermann J, Song B, McLaren J, et al: Diet is a risk factor in
1986. cisplatin ototoxicity. Hear Res 88:47, 1995.
71. Curhan SG, Eavey R, Shargorodsky J, et al: Analgesic use and the 99. Schweitzer VG: Cisplatin-induced ototoxicity: the effect of pig-
risk of hearing loss in men. The American journal of medicine 123(3): mentation and inhibitory agents. Laryngoscope 103:1, 1993.
231–237, 2010. 100. Parsons SK, Neault MW, Lehmann LE, et al: Severe ototoxicity
72. Curhan SG, Shargorodsky J, Eavey R, et al: Analgesic use and the following carboplatin-containing conditioning regimen for autol-
risk of hearing loss in women. Am J Epidemiol 176(6):544–554, ogous marrow transplantation for neuroblastoma. Bone Marrow
2012. Transplant 22:669, 1998.
73. Harell M, Shea JJ, Emmett JR: Bilateral sudden deafness following 101. Wake M, Takeno S, Ibrahim D, et al: Selective inner hair cell
combined insecticide poisoning. The Laryngoscope 88(8 Pt 1):1348– ototoxicity induced by carboplatin. Laryngoscope 104:488, 1994.
1351, 1978. 102. Cummings CW: Experimental observations on the ototoxicity of
74. Friedman RA, House JW, Luxford WM, et al: Profound hearing nitrogen mustard. Laryngoscope 78:530, 1968.
loss associated with hydrocodone/acetaminophen abuse. The 103. Croghan MK, Aickin MG, Meyskens FL: Dose-related alpha-
American journal of otology 21(2):188–191, 2000. difluoromethylornithine ototoxicity. Am J Clin Oncol 14:331, 1991.
75. Oh AK, Ishiyama A, Baloh RW: Deafness associated with abuse of 104. Olivieri NF, Buncic JR, Chew E, et al: Visual and auditory neuro-
hydrocodone/acetaminophen. Neurology 54(12):2345, 2000. toxicity in patients receiving subcutaneous deferoxamine infu-
76. Ishiyama A, Ishiyama G, Baloh RW, et al: Heroin-induced revers- sions. N Engl J Med 314:869, 1986.
ible profound deafness and vestibular dysfunction. Addiction 105. Oda M, Preciado MC, Quick CA, et al: Labyrinthine pathology of
(Abingdon, England) 96(9):1363–1364, 2001. chronic renal failure patients treated with hemodialysis and
77. Ho T, Vrabec JT, Burton AW: Hydrocodone use and sensorineural kidney transplantation. Laryngoscope 84:1489, 1974.
hearing loss. Pain Physician 10(3):467–472, 2007. 106. Bunch C: Nerve deafness of known pathology or etiology: the
78. Blakley BW, Schilling H: Deafness associated with acetaminophen diagnosis of occupational or traumatic deafness: a historical and
and codeine abuse. J Otolaryngol Head Neck Surg 37(4):507–509, audiometric study. Laryngoscope 47, 1937.
2008. 107. Dobie RA: Medical-Legal Evaluation of Hearing Loss, ed 2, San Diego,
79. van Gaalen FA, Compier EA, Fogteloo AJ: Sudden hearing loss 2001, Singular.
after a methadone overdose. European archives oto-rhino-laryngology 108. Acoustics: Determination of Occupational Noise Exposure and Estimation
266(5):773–774, 2009. of Noise-Induced Hearing Impairment, ISO-1999: 1990, Geneva, 1990,
80. Christenson BJ, Marjala AR: Two cases of sudden sensorineural International Organization for Standardization.
hearing loss after methadone overdose. Ann Pharmacother 44(1): 109. Althaus S: Spontaneous and traumatic perilymphatic fistulas.
207–210, 2010. Laryngoscope 87:364, 1977.
81. Schweitzer VG, Darrat I, Stach BA, et al: Sudden bilateral senso- 110. Crook JP: Congenital fistula in the stapedial footplate. South Med
rineural hearing loss following polysubstance narcotic overdose. J 60:1168, 1967.
Journal of the American Academy of Audiology 22(4):208–214, 2011. 111. Guindi GM: Congenital labyrintho-tympanic fistula—a recently
82. Yorgason JG, Kalinec GM, Luxford WM, et al: Acetaminophen recognized entity in children. J Otolaryngol 10:67, 1981.
ototoxicity after acetaminophen/hydrocodone abuse: evidence 112. Desjardins R, Guerguerian AJ, Dube J, et al: Meningitis and con-
from two parallel in vitro mouse models. Otolaryngol Head Neck genital fistula of the internal ear. J Otolaryngol 11:97, 1982.
Surg 142(6):814–819, 819, e811–e812, 2010. 113. Harrington JW, Jr, Birck HG: Recurrent meningitis due to con-
83. Mukherjee B, Shivakumar T: A case of sensorineural deafness genital petrous fistula: a case report. Arch Otolaryngol 85:572, 1967.
following ingestion of sildenafil. The Journal of laryngology and 114. Hirakawa K, Kurokawa M, Yajin K, et al: Recurrent meningitis due
otology 121(4):395–397, 2007. to a congenital fistula in the stapedial footplate. Arch Otolaryngol
84. Maddox PT, Saunders J, Chandrasekhar SS: Sudden hearing loss 109:697, 1983.
from PDE-5 inhibitors: A possible cellular stress etiology. The 115. Singleton GT: Diagnosis and treatment of perilymph fistulas
Laryngoscope 119(8):1586–1589, 2009. without hearing loss. Otolaryngol Head Neck Surg 94:426, 1986.
85. Khan AS, Sheikh Z, Khan S, et al: Viagra deafness–sensorineural 116. Black FO, Pesznecker S, Norton T, et al: Surgical management of
hearing loss and phosphodiesterase-5 inhibitors. The Laryngoscope perilymphatic fistulas: a Portland experience. Am J Otol 13:254,
121(5):1049–1054, 2011. 1992.
86. Brummett RE: Ototoxicity of vancomycin and analogues. Otolar- 117. Stroud MH, Calcaterra TC: Spontaneous perilymph fistulas.
yngol Clin North Am 26:821, 1993. Laryngoscope 80:479, 1970.
87. Lutz H, Lenarz T, Weidauer H, et al: Ototoxicity of vancomycin: 118. Wilson DF, Hodgson RS: Lidocaine in the middle ear. Laryngoscope
an experimental study in guinea pigs. ORL J Otorhinolaryngol Relat 100:1059, 1990.
Spec 53:273, 1991. 119. Poe DS, Rebeiz EE, Pankratov MM: Evaluation of perilymphatic
88. New preparations of vancomycin. Med Lett Drugs Therap 28:121, fistulas by middle ear endoscopy. Am J Otol 6:529, 1992.
1986. 120. Calhoun KH, Strunk CL: Perilymph fistula. Arch Otolaryngol Head
89. Elting LS, Rubenstein EB, Kurtin D, et al: Mississippi mud in the Neck Surg 118:693, 1992.
1990s: risks and outcomes of vancomycin-associated toxicity in 121. Davis RE: Diagnosis and management of perilymph fistula: the
general oncology practice. Cancer 83:2597, 1998. University of North Carolina approach. Am J Otol 13:85, 1992.
122. Friedland DR, Wackym PA: A critical appraisal of spontaneous 149. Verma NP, Lynn GE: Auditory evoked responses in multiple scle-
perilymphatic fistulas of the inner ear. Am J Otol 20:261, 1999. rosis: wave I abnormality. Arch Otolaryngol 111:22, 1985.
123. Grau C, Møller K, Overgaard M, et al: Sensori-neural hearing loss 150. Armington WG, Harnsberger HR, Smoker WR, et al: Normal and
in patients treated with irradiation for nasopharyngeal carcinoma. diseased acoustic pathway: evaluation with MR imaging. Radiology
Int J Radiat Oncol Biol Phys 21:723, 1991. 167:509, 1988.
124. Honoré HB, Bentzen SM, Møller K, et al: Sensori-neural hearing 151. Cure JK, Cromwell LD, Case JL, et al: Auditory dysfunction caused
loss after radiotherapy for nasopharyngeal carcinoma: individual- by multiple sclerosis: detection with MR imaging. AJNR Am J Neu-
ized risk estimation. Radiother Oncol 65:9, 2002. roradiol 11:817, 1990.
125. Pan CC, Eisbruch A, Lee JS, et al: Prospective study of inner ear 152. Drulovic B, Ribaric-Jankes K, Kostic VS, et al: Sudden hearing loss
radiation dose and hearing loss in head-and-neck cancer patients. as the initial monosymptom of multiple sclerosis. Neurology 43:
Int J Radiat Oncol Biol Phys 61:1393, 2005. 2703, 1993.
126. Grau C, Møller K, Overgaard M, et al: Auditory brain stem 153. Gebarski SS, Gabrielsen TO, Gilman S, et al: The initial diagnosis
responses in patients after radiation therapy for nasopharyngeal of multiple sclerosis: clinical impact of magnetic resonance
carcinoma. Cancer 70:2396, 1992. imaging. Ann Neurol 17:469, 1985.
127. Ho WK, Wei WI, Kwong DL, et al: Long-term sensorineural 154. Sismanis A: Otologic manifestations of benign intracranial hyper-
hearing deficit following radiotherapy in patients suffering from tension syndrome: diagnosis and management. Laryngoscope 97:1,
nasopharyngeal carcinoma: a prospective study. Head Neck 21:547, 1987.
1999. 155. Sismanis A, Hughes GB, Abedi E, et al: Otologic symptoms and
128. Maire JJP, Floquet AA, Darrouzet VV, et al: Fractionated radiation findings of the pseudotumor cerebri syndrome: a preliminary
therapy in the treatment of stage III and IV cerebello-pontine report. Otolaryngol Head Neck Surg 93:398, 1985.
angle neurinomas: preliminary results in 20 cases. Int J Radiat 156. Sismanis A, Butts FM, Hughes GB: Objective tinnitus in benign
Oncol Biol Phys 23:147, 1992. intracranial hypertension: an update. Laryngoscope 100:33, 1990.
129. Arts HA, Telian SA, El-Kashlan H, et al: Hearing preservation and 157. Sismanis A, Smoker WR: Pulsatile tinnitus: recent advances in
facial nerve outcomes in vestibular schwannoma surgery: results diagnosis. Laryngoscope 104:681, 1994.
using the middle cranial fossa approach. Otol Neurotol 27:234, 158. Sugerman HJ, Felton WL, 3rd, Salvant JB, Jr, et al: Effects of surgi-
2006. cally induced weight loss on idiopathic intracranial hypertension
130. Bohne BBA, Marks JJE, Glasgow GGP: Delayed effects of ionizing in morbid obesity. Neurology 45:1655, 1995.
radiation on the ear. Laryngoscope 95:818, 1985. 159. Classification and diagnostic criteria for headache disorders,
131. Grau C, Overgaard J: Postirradiation sensorineural hearing loss: cranial neuralgias and facial pain. Headache Classification Com-
a common but ignored late radiation complication. Int J Radiat mittee of the International Headache Society. Cephalalgia 8
Oncol Biol Phys 36:515, 1996. (Suppl 7):1, 1988.
132. Herrmann FF, Dörr WW, Müller RR, et al: A prospective study on 160. Olsson JE: Neurotologic findings in basilar migraine. Laryngoscope
radiation-induced changes in hearing function. Int J Radiat Oncol 101:1, 1991.
Biol Phys 65:1338, 2006. 161. Harker LA: Migraine. In Jackler RK, Brackmann DE, editors:
133. Kwong DL, Wei WI, Sham JS, et al: Sensorineural hearing loss in Neurotology, Philadelphia, 2003, Elsevier.
patients treated for nasopharyngeal carcinoma: a prospective 162. Rubenstein RL, Norman DM, Schindler RA, et al: Cerebellar
study of the effect of radiation and cisplatin treatment. Int J Radiat infarction—a presentation of vertigo. Laryngoscope 90:505,
Oncol Biol Phys 36:281, 1996. 1980.
134. Iwai Y, Yamanaka K, Shiotani M, et al: Radiosurgery for acoustic 163. Wells M, Michaels L, Wells DG: Otolaryngological disturbances in
neuromas: results of low-dose treatment. Neurosurgery 53:282, Waldenstrom’s macroglobulinaemia. Clin Otolaryngol Allied Sci
2003. 2:327, 1977.
135. Massager N, Nissim O, Delbrouck C, et al: Irradiation of cochlear 164. Nomura Y, Tsuchida M, Mori S, et al: Deafness in cryoglobuline-
structures during vestibular schwannoma radiosurgery and associ- mia. Ann Otol Rhinol Laryngol 91:250, 1982.
ated hearing outcome. J Neurosurg 107:733, 2007. 165. Ajulo SO, Osiname AI, Myatt HM: Sensorineural hearing loss in
136. Paek SH, Chung H-T, Jeong SS, et al: Hearing preservation after sickle cell anaemia—a United Kingdom study. J Laryngol Otol 107:
gamma knife stereotactic radiosurgery of vestibular schwannoma. 790, 1993.
Cancer 104:580, 2005. 166. Friedman EM, Herer GR, Luban NL, et al: Sickle cell anemia and
137. Prasad DD, Steiner MM, Steiner LL: Gamma surgery for vestibular hearing. Ann Otol Rhinol Laryngol 89:342, 1980.
schwannoma. J Neurosurg 92:745, 2000. 167. Odetoyinbo O, Adekile A: Sensorineural hearing loss in children
138. Grenman R: Involvement of the audiovestibular system in multi- with sickle cell anemia. Ann Otol Rhinol Laryngol 96:258, 1987.
ple sclerosis: an otoneurologic and audiologic study. Acta Otolar- 168. Elwany S, Kamel T: Sensorineural hearing loss in sickle cell crisis.
yngol Suppl 420:1, 1985. Laryngoscope 98:386, 1988.
139. Noffsinger D, Olsen WO, Carhart R, et al: Auditory and vestibular 169. Hotaling AJ, Hillstrom RP, Bazell C: Sickle cell crisis and sensori-
aberrations in multiple sclerosis. Acta Otolaryngol Suppl 303:1, 1972. neural hearing loss: case report and discussion. Int J Pediatr Oto-
140. Daugherty WT, Lederman RJ, Nodar RH, et al: Hearing loss in rhinolaryngol 17:207, 1989.
multiple sclerosis. Arch Neurol 40:33, 1983. 170. O’Keeffe LJ, Maw AR: Sudden total deafness in sickle cell disease.
141. Jerger J, Oliver TA, Rivera V, et al: Abnormalities of the acoustic J Laryngol Otol 105:653, 1991.
reflex in multiple sclerosis. Am J Otolaryngol 7:163, 1986. 171. Tavin ME, Rubin JS, Camacho FJ: Sudden sensorineural hearing
142. Jerger JF, Oliver TA, Chmiel RA, et al: Patterns of auditory abnor- loss in haemoglobin SC disease. J Laryngol Otol 107:831, 1993.
mality in multiple sclerosis. Audiology 25:193, 1986. 172. Millen SJ, Toohill RJ, Lehman RH: Sudden sensorineural hearing
143. Schweitzer VG, Shepard N: Sudden hearing loss: an uncommon loss: operative complication in non-otologic surgery. Laryngoscope
manifestation of multiple sclerosis. Otolaryngol Head Neck Surg 92:613, 1982.
100:327, 1989. 173. Plasse HM, Mittleman M, Frost JO: Unilateral sudden hearing loss
144. Drulovic B, Ribaric-Jankes K, Kostic V, et al: Multiple sclerosis as after open heart surgery: a detailed study of seven cases. Laryngo-
the cause of sudden “pontine” deafness. Audiology 33:195, 1994. scope 91:101, 1981.
145. Keith RW, Garza-Holquin Y, Smolak L, et al: Acoustic reflex 174. Plasse HM, Spencer FC, Mittleman M, et al: Unilateral sudden loss
dynamics and auditory brain stem responses in multiple sclerosis. of hearing: an unusual complication of cardiac operation. J Thorac
Am J Otol 8:406, 1987. Cardiovasc Surg 79:822, 1980.
146. Wiegand DA, Poch NE: The acoustic reflex in patients with asymp- 175. Shapiro MJ, Purn JM, Raskin C: A study of the effects of cardio-
tomatic multiple sclerosis. Am J Otolaryngol 9:210, 1988. pulmonary bypass surgery on auditory function. Laryngoscope
147. Hopf HC, Maurer K: Wave I of early auditory evoked potentials 91:2046, 1981.
in multiple sclerosis. Electroencephalogr Clin Neurophysiol 56:31, 176. Benecke JE, Jr, Hitselberger WE: Vertigo caused by basilar artery
1983. compression of the eighth nerve. Laryngoscope 98:807, 1988.
148. Musiek FE, Gollegly KM, Kibbe KS, et al: Electrophysiologic and 177. Jannetta PJ: Neurovascular cross-compression in patients with
behavioral auditory findings in multiple sclerosis. Am J Otol 10:343, hyperactive dysfunction symptoms of the eighth cranial nerve.
1989. Surg Forum 26:467, 1975.
178. Jannetta PJ: Neurovascular compression in cranial nerve and sys- 207. Hart CW, Cokely CG, Schupbach J, et al: Neurotologic findings
temic disease. Ann Surg 192:518, 1980. of a patient with acquired immune deficiency syndrome. Ear Hear
179. McCabe BF, Harker LA: Vascular loop as a cause of vertigo. Ann 10:68, 1989.
Otol Rhinol Laryngol 92:542, 1983. 208. Kwartler JA, Linthicum FH, Jahn AF, et al: Sudden hearing loss
180. McDonald TJ, Vollertsen RS, Younge BR: Cogan’s syndrome: due to AIDS-related cryptococcal meningitis—a temporal bone
audiovestibular involvement and prognosis in 18 patients. Laryn- study. Otolaryngol Head Neck Surg 104:265, 1991.
goscope 95:650, 1985. 209. Little JP, Gardner G, Acker JD, et al: Otosyphilis in a patient with
181. Vathenen AS, Skinner DW, Shale DJ: Treatment response with human immunodeficiency virus: internal auditory canal gumma.
bilateral mixed deafness and facial palsy in polyarteritis nodosa. Otolaryngol Head Neck Surg 112:488, 1995.
Am J Med 84:1081, 1988. 210. Madriz JJ, Herrera G: Human immunodeficiency virus and
182. Wolf M, Kronenberg J, Engelberg S, et al: Rapidly progressive acquired immune deficiency syndrome AIDS-related hearing dis-
hearing loss as a symptom of polyarteritis nodosa. Am J Otolaryngol orders. J Am Acad Audiol 6:358, 1995.
8:105, 1987. 211. Smith ME, Canalis RF: Otologic manifestations of AIDS: the oto-
183. Cody DT, Sones DA: Relapsing polychondritis: audiovestibular syphilis connection. Laryngoscope 99:365, 1989.
manifestations. Laryngoscope 81:1208, 1971. 212. Timon CI, Walsh MA: Sudden sensorineural hearing loss as a
184. Damiani JM, Levine HL: Relapsing polychondritis—report of ten presentation of HIV infection. J Laryngol Otol 103:1071, 1989.
cases. Laryngoscope 89:929, 1979. 213. Gulya AJ: Neurologic paraneoplastic syndromes with neurotologic
185. Bakthavachalam S, Driver MS, Cox C, et al: Hearing loss in Wegen- manifestations. Laryngoscope 103:754, 1993.
er’s granulomatosis. Otol Neurotol 25:833, 2004. 214. Schuknecht HF, Barber W: Histologic variants in otosclerosis.
186. Fenton JE, O’Sullivan TJ: The otological manifestations of Wegen- Laryngoscope 95:1307, 1985.
er’s granulomatosis. J Laryngol Otol 108:144, 1994. 215. Bretlau P, Salomon G, Johnsen NJ: Otospongiosis and sodium
187. Takagi D, Nakamaru Y, Maguchi S, et al: Otologic manifestations fluoride: a clinical double-blind, placebo-controlled study on
of Wegener’s granulomatosis. Laryngoscope 112:1684, 2002. sodium fluoride treatment in otospongiosis. Am J Otol 10:20, 1989.
188. Abou-Taleb A, Linthicum FH, Jr: Scleroderma and hearing loss 216. Bretlau P, Causse J, Causse JB, et al: Otospongiosis and sodium
(histopathology of a case). J Laryngol Otol 101:656, 1987. fluoride: a blind experimental and clinical evaluation of the effect
189. Kramer MR, Nesher G, Sonnenblick M: Steroid-responsive of sodium fluoride treatment in patients with otospongiosis. Ann
hearing loss in temporal arteritis. J Laryngol Otol 102:524, 1988. Otol Rhinol Laryngol 94:103, 1985.
190. Bowman CA, Linthicum FH, Jr, Nelson RA, et al: Sensorineural 217. Causse JR, Causse JB: Early detection of otosclerosis by impedance-
hearing loss associated with systemic lupus erythematosus. Otolar- audiometry screening. Scand Audiol Suppl 17:47, 1983.
yngol Head Neck Surg 94:197, 1986. 218. Causse JR, Causse JB: Clinical studies on fluoride in otospongiosis.
191. MacFadyen DJ, Schneider RJ, Chisholm IA: A syndrome of brain, Am J Otol 6:51, 1985.
inner ear and retinal microangiopathy. Can J Neurol Sci 14:315, 219. Forquer BD, Linthicum FH, Bennett C: Sodium fluoride: effec-
1987. tiveness of treatment for cochlear otosclerosis. Am J Otol 7:121,
192. Jahrsdoerfer RA, Thompson EG, Johns MM, et al: Sarcoidosis 1986.
and fluctuating hearing loss. Ann Otol Rhinol Laryngol 90:161, 220. Kornblut AD: Sodium fluoride therapy for otosclerosis. Arch Oto-
1981. laryngol Head Neck Surg 117:450, 1991.
193. Souliere CR, Jr, Kava CR, Barrs DM, et al: Sudden hearing loss as 221. Shambaugh GE, Jr: Fluoride therapy for otosclerosis. Arch Otolar-
the sole manifestation of neurosarcoidosis. Otolaryngol Head Neck yngol Head Neck Surg 116:1217, 1990.
Surg 105:376, 1991. 222. Snow JB, Jr: Current status of fluoride therapy for otosclerosis. Am
194. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol J Otol 6:56, 1985.
Rhinol Laryngol 88:585, 1979. 223. Lippy WH, Battista RA, Schuring AG, et al: Far-advanced otoscle-
195. Hughes GB, Kinney SE, Barna BP, et al: Practical versus theoretical rosis. Am J Otol 15:225, 1994.
management of autoimmune inner ear disease. Laryngoscope 94: 224. Wiet RJ, Morgenstein SA, Zwolan TA, et al: Far-advanced otoscle-
758, 1984. rosis: cochlear implantation vs stapedectomy. Arch Otolaryngol
196. Sismanis A, Thompson T, Willis HE: Methotrexate therapy for Head Neck Surg 113:299, 1987.
autoimmune hearing loss: a preliminary report. Laryngoscope 104: 225. Harner SG, Rose DE, Facer GW: Paget’s disease and hearing loss.
932, 1994. Otolaryngology 86, 1978.
197. Harris JP: Autoimmunity of the inner ear. Am J Otol 10:193, 1989. 226. el Sammaa M, Linthicum FH, House HP, et al: Calcitonin as treat-
198. Harris JP, Sharp PA: Inner ear autoantibodies in patients with ment for hearing loss in Paget’s disease. Am J Otol 7:241, 1986.
rapidly progressive sensorineural hearing loss. Laryngoscope 100: 227. Lando M, Hoover LA, Finerman G: Stabilization of hearing loss
516, 1990. in Paget’s disease with calcitonin and etidronate. Arch Otolaryngol
199. Moscicki RA: Immune-mediated inner ear disorders. Baillieres Clin Head Neck Surg 114:891, 1988.
Neurol 3:547, 1994. 228. Zulch K: Epidemiology of brain tumors: general statistical and
200. Moscicki RA, San Martin JE, Quintero CH, et al: Serum antibody biological data. In Brain Tumors: Their Biology and Pathology, ed 3,
to inner ear proteins in patients with progressive hearing loss: Berlin, 1986, Springer-Verlag.
correlation with disease activity and response to corticosteroid 229. Jackler RK: Acoustic neuroma. In Jackler RK, Brackmann D,
treatment. JAMA 272:611, 1994. editors: Neurotology, ed 2, Philadelphia, 2005, Elsevier-Mosby.
201. Billings PB, Keithley EM, Harris JP: Evidence linking the 68 kilo- 230. Moffat DA, Baguley DM, von Blumenthal H, et al: Sudden deaf-
dalton antigen identified in progressive sensorineural hearing loss ness in vestibular schwannoma. J Laryngol Otol 108:116, 1994.
patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol 231. Harner SG: Hearing in adult-onset diabetes mellitus. Otolaryngol
104:181, 1995. Head Neck Surg 89:322, 1981.
202. Bloch DB, San Martin JE, Rauch SD, et al: Serum antibodies to 232. Anand VT, Mann SB, Dash RJ, et al: Auditory investigations in
heat shock protein 70 in sensorineural hearing loss. Arch Otolar- hypothyroidism. Acta Otolaryngol 108:83, 1989.
yngol Head Neck Surg 121:1167, 1995. 233. Debruyne F, Vanderschueren-Lodeweyckx M, Bastijns P: Hearing
203. Gottschlich S, Billings PB, Keithley EM, et al: Assessment of in congenital hypothyroidism. Audiology 22:404, 1983.
serum antibodies in patients with rapidly progressive sensorineu- 234. O’Malley BW, Jr, Li D, Turner DS: Hearing loss and cochlear
ral hearing loss and Meniere’s disease. Laryngoscope 105:1347, abnormalities in the congenital hypothyroid (hyt/hyt) mouse.
1995. Hear Res 88:181, 1995.
204. Rauch SD, San Martin JE, Moscicki RA, et al: Serum antibodies 235. Vanderschueren-Lodeweyckx M, Debruyne F, Dooms L, et al: Sen-
against heat shock protein 70 in Meniere’s disease. Am J Otol 16: sorineural hearing loss in sporadic congenital hypothyroidism.
648, 1995. Arch Dis Child 58:419, 1983.
205. Carne CA: ABC of AIDS. Neurological manifestations. BMJ (Clin 236. Garty BZ, Daliot D, Kauli R, et al: Hearing impairment in idio-
Res Ed) 294:1399, 1987. pathic hypoparathyroidism and pseudohypoparathyroidism. Isr J
206. Grimaldi LM, Luzi L, Martino GV, et al: Bilateral eighth cranial Med Sci 30:587, 1994.
nerve neuropathy in human immunodeficiency virus infection. 237. Ikeda K, Kobayashi T, Kusakari J, et al: Sensorineural hearing loss
J Neurol 240:363, 1993. associated with hypoparathyroidism. Laryngoscope 97:1075, 1987.
238. Lowry LD, Isaacson SR: Study of 100 patients with bilateral senso- 267. Lindsay JR, Davey PR, Ward PH: Inner ear pathology in deafness

rineural hearing loss for lipid abnormalities. Ann Otol Rhinol Lar- due to mumps. Ann Otol Rhinol Laryngol 69:918, 1960.
yngol 87:404, 1978. 268. Schuknecht HF, Donovan ED: The pathology of idiopathic sudden
239. Gates GA, Cooper JC, Jr, Kannel WB, et al: Hearing in the elderly: sensorineural hearing loss. Arch Otorhinolaryngol 243:1, 1986.
the Framingham cohort, 1983-1985, part I. basic audiometric test 269. Yoon TH, Paparella MM, Schachern PA, et al: Histopathology of
results. Ear Hear 11:247, 1990. sudden hearing loss. Laryngoscope 100:707, 1990.
240. Katsarkas A, Ayukawa H: Hearing loss due to aging (presbycusis). 270. Veltri RW, Wilson WR, Sprinkle PM, et al: The implication of
J Otolaryngol 15:239, 1986. viruses in idiopathic sudden hearing loss: primary infection or
241. Kitahara M, Matsubara H, Takeda T, et al: Bilateral Meniere’s reactivation of latent viruses? Otolaryngol Head Neck Surg 89:137,
disease. Adv Otorhinolaryngol 25:117, 1979. 1981.
242. Paparella MM, Griebie MS: Bilaterality of Meniere’s disease. Acta 271. Wallner KE, Sheline GE, Pitts LH, et al: Efficacy of irradiation for
Otolaryngol 97:233, 1984. incompletely excised acoustic neurilemomas. J Neurosurg 67:858,
243. Thomas K, Harrison MS: Long-term follow up of 610 cases of 1987.
Meniere’s disease. Proc R Soc Med 64:853, 1971. 272. Wilson WR, Laird N, Moo-Young G, et al: The relationship of
244. Wladislavosky-Waserman P, Facer GW, Mokri B, et al: Meniere’s idiopathic sudden hearing loss to diabetes mellitus. Laryngoscope
disease: a 30-year epidemiologic and clinical study in Rochester, 92:155, 1982.
MN, 1951-1980. Laryngoscope 94:1098, 1984. 273. Wilson WR, Veltri RW, Laird N, et al: Viral and epidemiologic
245. Boles R, Rice DH, Hybels R, et al: Conservative management of studies of idiopathic sudden hearing loss. Otolaryngol Head Neck
Meniere’s disease: Furstenberg regimen revisited. Ann Otol Rhinol Surg 91:653, 1983.
Laryngol 84:513, 1975. 274. Westmore GA, Pickard BH, Stern H: Isolation of mumps virus
246. Furstenberg AC, Lashmet FH, Lathrop F: Meniere’s symptom from the inner ear after sudden deafness. Br Med J 1:14, 1979.
complex: medical treatment. 1934. Ann Otol Rhinol Laryngol 101: 275. Davis LE, Shurin S, Johnson RT: Experimental viral labyrinthitis.
20, 1992. Nature 254:329, 1975.
247. Klockhoff I, Lindblom U: Meniere’s disease and hydrochlorothia- 276. Cummins D, McCormick JB, Bennett D, et al: Acute sensorineural
zide (Dichlotride)—a critical analysis of symptoms and therapeu- deafness in Lassa fever. JAMA 264:2093, 1990.
tic effects. Acta Otolaryngol 63:347, 1967. 277. Liao BS, Byl FM, Adour KK: Audiometric comparison of Lassa
248. Klockhoff I, Lindblom U, Stahle J: Diuretic treatment of Meniere fever hearing loss and idiopathic sudden hearing loss: evidence
disease: long-term results with chlorthalidone. Arch Otolaryngol for viral cause. Otolaryngol Head Neck Surg 106:226, 1992.
100:262, 1974. 278. Beg JJA: Bilateral sensorineural hearing loss as a complication of
249. Torok N: Old and new in Meniere’s disease. Laryngoscope 87:1870, infectious mononucleosis. Arch Otolaryngol 107:620, 1981.
1977. 279. Lorenzi MC, Bittar RS, Pedalini ME, et al: Sudden deafness and
250. Schuknecht HF: Cochleosacculotomy for Meniere’s disease: Lyme disease. Laryngoscope 113:312, 2003.
theory, technique and results. Laryngoscope 92:853, 1982. 280. Quinn SJ, Boucher BJ, Booth JB: Reversible sensorineural hearing
251. Schuknecht HF: Endolymphatic hydrops: can it be controlled? loss in Lyme disease. J Laryngol Otol 111:562, 1997.
Ann Otol Rhinol Laryngol 95:36, 1986. 281. Lantos PL, McLaughlin JE, Schoitz CL, et al: Neuropathology of
252. Bretlau P, Thomsen J, Tos M, et al: Placebo effect in surgery the brain in HIV infection. Lancet 1:309, 1989.
for Meniere’s disease: nine-year follow-up. Am J Otol 10:259, 282. Real R, Thomas M, Gerwin JM: Sudden hearing loss and acquired
1989. immunodeficiency syndrome. Otolaryngol Head Neck Surg 97:409,
253. Graham MD, Kemink JL: Surgical management of Meniere’s 1987.
disease with endolymphatic sac decompression by wide bony 283. Nedzelski JM, Dufour JJ: Acoustic neurinomas presenting as
decompression of the posterior fossa dura: technique and results. sudden deafness. ORL J Otorhinolaryngol Relat Spec 37:271, 1975.
Laryngoscope 94:680, 1984. 284. Saunders JE, Luxford WM, Devgan KK, et al: Sudden hearing loss
254. Thomsen J, Bretlau P, Tos M, et al: Meniere’s disease: endolym- in acoustic neuroma patients. Otolaryngol Head Neck Surg 113:23,
phatic sac decompression compared with sham (placebo) decom- 1995.
pression. Ann N Y Acad Sci 374:820, 1981. 285. Berenholz LP, Eriksen C, Hirsh FA: Recovery from repeated
255. Thomsen J, Bretlau P, Tos M, et al: Placebo effect in surgery for sudden hearing loss with corticosteroid use in the presence of an
Menière’s disease: three-year follow-up. Otolaryngol Head Neck Surg acoustic neuroma. Ann Otol Rhinol Laryngol 101:827, 1992.
91:183, 1983. 286. Welling DB, Glasscock ME, 3rd, Woods CI, et al: Acoustic neuroma:
256. Thomsen J, Kerr A, Bretlau P, et al: Endolymphatic sac surgery: a cost-effective approach. Otolaryngol Head Neck Surg 103:364, 1990.
why we do not do it: the non-specific effect of sac surgery. Clin 287. Chandrasekhar SS, Brackmann DE, Devgan KK: Utility of auditory
Otolaryngol Allied Sci 21:208, 1996. brainstem response audiometry in diagnosis of acoustic neuro-
257. Schuknecht HF, Suzuka Y, Zimmermann C: Delayed endolym- mas. Am J Otol 16:63, 1995.
phatic hydrops and its relationship to Meniere’s disease. Ann Otol 288. Levine SC, Antonelli PJ, Le CT, et al: Relative value of diagnostic
Rhinol Laryngol 99:843, 1990. tests for small acoustic neuromas. Am J Otol 12:341, 1991.
258. Jaffe BF: Clinical studies in sudden deafness. Adv Otorhinolaryngol 289. Telian SA, Kileny PR, Niparko JK, et al: Normal auditory brain-
20:221, 1973. stem response in patients with acoustic neuroma. Laryngoscope 99:
259. Byl FM, Jr: Sudden hearing loss: eight years’ experience and sug- 10, 1989.
gested prognostic table. Laryngoscope 94:647, 1984. 290. Nakamura M, Roser F, Dormiani M, et al: Facial and cochlear
260. Mattox DE, Lyles CA: Idiopathic sudden sensorineural hearing nerve function after surgery of cerebellopontine angle meningio-
loss. Am J Otol 10:242, 1989. mas. Neurosurg Online 57:77, 2005.
261. Shaia FT, Sheehy JL: Sudden sensori-neural hearing impairment: 291. Pensak ML, Glasscock ME, 3rd, Josey AF, et al: Sudden hearing
a report of 1,220 cases. Laryngoscope 86:389, 1976. loss and cerebellopontine angle tumors. Laryngoscope 95:1188,
262. Mattox DE, Simmons FB: Natural history of sudden sensorineural 1985.
hearing loss. Ann Otol Rhinol Laryngol 86:463, 1977. 292. Schuknecht HF: Mechanism of inner ear injury from blows to the
263. Wilson WR, Byl FM, Laird N: The efficacy of steroids in the treat- head. Ann Otol Rhinol Laryngol 78:253, 1969.
ment of idiopathic sudden hearing loss: a double-blind clinical 293. Adkisson GH, Meredith AP: Inner ear decompression sickness
study. Arch Otolaryngol 106:772, 1980. combined with a fistula of the round window: case report. Ann
264. Van Dishoeck HA, Bierman TA: Sudden perceptive deafness and Otol Rhinol Laryngol 99:733, 1990.
viral infection; report of the first one hundred patients. Ann Otol 294. Pullen FW, 2nd, Rosenberg GJ, Cabeza CH: Sudden hearing loss
Rhinol Laryngol 66:963, 1957. in divers and fliers. Laryngoscope 89:1373, 1979.
265. Azimi PH, Cramblett HG, Haynes RE: Mumps meningoencepha- 295. Poe DS, Bottrill ID: Comparison of endoscopic and surgical explo-
litis in children. JAMA 207:509, 1969. rations for perilymphatic fistulas. Am J Otol 15:735, 1994.
266. Khetarpal U, Nadol JB, Jr, Glynn RJ: Idiopathic sudden sensori- 296. Simmons FB: Theory of membrane breaks in sudden hearing loss.
neural hearing loss and postnatal viral labyrinthitis: a statistical Arch Otolaryngol 88:41, 1968.
comparison of temporal bone findings. Ann Otol Rhinol Laryngol 297. Gussen R: Sudden deafness of vascular origin: a human temporal
99:969, 1990. bone study. Ann Otol Rhinol Laryngol 85:94, 1976.
298. Gussen R: Sudden hearing loss associated with cochlear mem- 314. Zaytoun GM, Schuknecht HF, Farmer HS: Fatality following the
brane rupture: two human temporal bone reports. Arch Otolaryn- use of low molecular weight dextran in the treatment of sudden
gol 107:598, 1981. deafness. Adv Otorhinolaryngol 31:240, 1983.
299. Gussen R: Sudden deafness associated with bilateral Reissner’s 315. Moskowitz D, Lee KJ, Smith HW: Steroid use in idiopathic sudden
membrane ruptures. Am J Otolaryngol 4:27, 1983. sensorineural hearing loss. Laryngoscope 94:664, 1984.
300. Kanda Y, Shigeno K, Kinoshita N, et al: Sudden hearing loss associ- 316. Lefebvre PP, Staecker H: Steroid perfusion of the inner ear for
ated with interferon. Lancet 343:1134, 1994. sudden sensorineural hearing loss after failure of conventional
301. Kanda Y, Shigeno K, Matsuo H, et al: Interferon-induced sudden therapy: a pilot study. Acta Otolaryngol 122:698, 2002.
hearing loss. Audiology 34:98, 1995. 317. Fisch U: Management of sudden deafness. Otolaryngol Head Neck
302. Harell M, Shea JJ, Emmett JR: Bilateral sudden deafness following Surg 91:3, 1983.
combined insecticide poisoning. Laryngoscope 88:1348, 1978. 318. Nagahara K, Fisch U, Yagi N: Perilymph oxygenation in sudden
303. Cote DN, Molony TB, Waxman J, et al: Cogan’s syndrome mani- and progressive sensorineural hearing loss. Acta Otolaryngol 96:57,
festing as sudden bilateral deafness: diagnosis and management. 1983.
South Med J 86:1056, 1993. 319. Morimitsu T, Nakashima T, Matsumoto I, et al: Dysfunction of stria
304. Haynes BF, Pikus A, Kaiser-Kupfer M, et al: Successful treatment vascularis as a new theory of sudden deafness. Adv Otorhinolaryngol
of sudden hearing loss in Cogan’s syndrome with corticosteroids. 22:57, 1977.
Arthritis Rheum 24:501, 1981. 320. Hirashima N: Blocking effect of radio-contrast media on cochlear
305. Einer H, Tengborn L, Axelsson A, et al: Sudden sensorineural depression. Ann Otol Rhinol Laryngol 87:32, 1978.
hearing loss and hemostatic mechanisms. Arch Otolaryngol Head 321. Donaldson JA: Heparin therapy for sudden sensorineural hearing
Neck Surg 120:536, 1994. loss. Arch Otolaryngol 105:351, 1979.
306. Lipkin AF, Jenkins HA, Coker NJ: Migraine and sudden sensori- 322. Probst R, Tschopp K, Ludin E, et al: A randomized, double-blind,
neural hearing loss. Arch Otolaryngol Head Neck Surg 113:325, 1987. placebo-controlled study of dextran/pentoxifylline medication in
307. Viirre ES, Baloh RW: Migraine as a cause of sudden hearing loss. acute acoustic trauma and sudden hearing loss. Acta Otolaryngol
Headache 36:24, 1996. 112:435, 1992.
308. Kirikae I, Nomura Y, Shitara T, et al: Sudden deafness due to 323. Fisch U, Nagahara K, Pollak A: Sudden hearing loss: circulatory.
Buerger’s disease. Arch Otolaryngol 75:502, 1962. Am J Otol 5:488, 1984.
309. Huang CY, Yu YL: Small cerebellar strokes may mimic labyrinthine 324. Redleaf MI, Bauer CA, Gantz BJ, et al: Diatrizoate and dextran
lesions. J Neurol Neurosurg Psychiatry 48:263, 1985. treatment of sudden sensorineural hearing loss. Am J Otol 16:295,
310. Brownson RJ, Zollinger WK, Madeira T, et al: Sudden sensorineu- 1995.
ral hearing loss following manipulation of the cervical spine. 325. Wilkins SA, Jr, Mattox DE, Lyles A: Evaluation of a “shotgun”
Laryngoscope 96:166, 1986. regimen for sudden hearing loss. Otolaryngol Head Neck Surg 97:
311. Jorgensen MB: The inner ear in diabetes mellitus: histological 474, 1987.
studies. Arch Otolaryngol 74:373, 1961. 326. Hughes GB, Freedman MA, Haberkamp TJ, et al: Sudden senso-
312. Hallberg OE: Sudden deafness of obscure origin. Laryngoscope rineural hearing loss. Otolaryngol Clin North Am 29:393, 1996.
66:1237, 1956. 327. Tucci DL, Farmer JC, Jr, Kitch RD, et al: Treatment of sudden
313. Shea JJ, 3rd, Brackmann DE: Multiple sclerosis manifesting as sensorineural hearing loss with systemic steroids and valacyclovir.
sudden hearing loss. Otolaryngol Head Neck Surg 97:335, 1987. Otol Neurotol 23:301, 2002.
151 Tinnitus and Hyperacusis
Carol A. Bauer
Key Points
■ Tinnitus is a common condition that affects 30% of people older than age 55; the 5-year incidence
is 5%.
■ Disturbing tinnitus that impairs daily life activity affects 1% to 5% of those who have tinnitus.
■ Auditory deprivation from hearing loss induces central neural changes that result in tinnitus.
Mechanisms responsible for tinnitus involve peripheral triggers and central plasticity.
■ Sound therapy is an effective form of tinnitus treatment that benefits most patients when combined
with education and adjunct treatments directed toward factors that exacerbate tinnitus.
■ Tinnitus that can be modulated with somatic manipulation may respond to therapy that targets
temporomandibular joint and cervical spine disorders.
■ Medications are helpful for specific forms of tinnitus.
■ Associated comorbidities of anxiety and depression warrant referral for professional evaluation and
treatment with counseling and behavioral therapy.
■ Clinicians knowledgeable in auditory function and head and neck physiology are well equipped to
provide most tinnitus patients with effective treatment, which includes education, rehabilitation of
hearing loss, and identification and treatment of exacerbating factors.
annoying tinnitus was reported in 50% of respondents, and

TINNITUS extremely annoying tinnitus was reported in 16%. Nondahl and
Tinnitus is the perception of sound that does not arise from an colleagues1 reported a 5-year incidence of tinnitus of 5.7%
external source. Although 30 million Americans are estimated (95% confidence interval, 4.8 to 6.6), notably without an asso-
to have chronic tinnitus, for most it is not a problem sufficient ciation with either age or gender. Strong associations have been
for them to seek treatment. Tinnitus is a chronic sensation reported between cardiovascular disease, total serum choles-
virtually all would prefer not to experience, but for most, it is terol, and the prevalence and incidence of tinnitus. Notably,
not disabling. Severe or disturbing tinnitus occurs in 1% to 5% this large longitudinal study reported that nearly 40% of adults
of individuals with tinnitus.1,2 Until recently, treatments for dis-
turbing tinnitus were limited. Significant advances in auditory
neuroscience have advanced the treatment of tinnitus beyond Box 151-1. OBJECTIVE TINNITUS SUBTYPES
the traditional recommendation to instruct patients to “learn Pulsatile
to live with it.” This chapter reviews current theories and mech- Synchronous with Pulse
anisms of idiopathic subjective tinnitus. It also outlines a clini- Arterial etiologies
cal strategy for evaluating tinnitus and determining tinnitus Arteriovenous fistula or malformation
subtypes, and it reviews current management strategies. Paraganglioma (glomus tympanicum or jugulare)
Tinnitus can be classified as objective or subjective. Objective Carotid artery stenosis
tinnitus can be detected by an observer using a stethoscope or Other atherosclerotic disease (subclavian, external carotid)
ear canal microphone. These somatosounds reflect the percep- Arterial dissection (carotid, vertebral)
tion of internally generated sounds from joints, muscles, turbu- Persistent stapedial artery
lent blood flow, or, rarely, otoacoustic emissions. Objective Intratympanic carotid artery
tinnitus usually has a pulsatile or rhythmic quality. Box 151-1 Vascular compression of cranial nerve VIII
Increased cardiac output (pregnancy, thyrotoxicosis)
lists common causes of objective tinnitus. Because excellent Intraosseous (Paget disease, otosclerosis)
reviews of treatments for objective tinnitus are available in the Venous etiologies
literature, this uncommon form is not addressed further.3 Pseudotumor cerebri
In contrast to objective tinnitus, subjective tinnitus is not Venous hum
audible to an observer. Estimates of subjective tinnitus preva- Sigmoid sinus and jugular bulb anomalies
lence range from 8% to 30% and depend on the definition Asynchronous with Pulse
of tinnitus, tinnitus severity, the population sampled, and the Palatal myoclonus
assessment methodology.1,4,5 In a large population-based study Tensor tympani or stapedius muscle myoclonus
of participants 55 to 99 years old that combined detailed tin- Nonpulsatile
nitus questionnaires with audiologic assessment, 30% reported
Spontaneous otoacoustic emission
experiencing tinnitus, and prevalence was found to be related Patulous eustachian tube
to audiometric threshold but not to age or gender.5 Mildly
2336
151 | TINNITUS AND HYPERACUSIS 2337
with mild tinnitus in the initial survey had no tinnitus on 5-year to prevent the onset or progression of NIHL and may possibly
follow-up, and only 20% reported progression to moderate limit the incidence of tinnitus. Intense sound exposure triggers
or severe tinnitus. Forty-five percent of participants with tinni- a reduction of blood flow and a cascade of metabolic events in
tus rated as “significant” at baseline reported no tinnitus at the cochlea, with formation of reactive oxygen and nitrogen
follow-up (43%) or reported improvement to mild tinnitus species that damage cellular lipids, proteins, and DNA and
(57%). This rate of spontaneous improvement in tinnitus has culminate in increased cell death.11 Interventions that target
significant implications for designing clinical trials to assess the these molecular mechanisms of NIHL include antioxidant
efficacy of tinnitus interventions. therapy such as with vitamin E, salicylate, and N-acetylcysteine.12,13
Ginkgo biloba extract contains multiple compounds with vaso-
tropic, potential neuroprotective, and antioxidant effects.
SUBJECTIVE TINNITUS Although uncontrolled trials and anecdotal reports have sug-
Subjective tinnitus is the most common form that affects adults, gested the efficacy of ginkgo, results from a meta-analysis and
and it is the focus of this chapter. Subjective tinnitus is most randomized controlled trials do not support its use.14,15
commonly related to sensorineural hearing loss (SNHL) from Presbycusis is SNHL related to aging. Most cases of presby-
acoustic trauma and presbycusis, and it is less commonly the cusis cannot be strictly and solely attributed to aging but rather
result of conductive hearing loss, endolymphatic hydrops, and involve some combination of cochlear injury from additional
cerebellopontine angle neoplasms. Subjective tinnitus can be sources, such as cumulative noise injury, metabolic or vascular
subtyped based on etiology, the pattern of associated hearing dysfunction, and genetic predisposition. For example, elderly
loss, psychoacoustic features, exacerbating factors, psychologic patients with diabetes have significantly higher pure tone
comorbidities, and the presence of somatic modulators. Tin- thresholds, lower otoacoustic emission amplitude, and lower
nitus subtype classification schemes can be useful to identify speech recognition in noise16 than age-matched individuals
forms of tinnitus that are responsive to specific targeted treat- without diabetes.17 Interactions between age and other factors
ment programs. Box 151-2 lists some useful features for subtyp- that affect the cochlea and auditory pathway challenge the iden-
ing tinnitus. tification of a single mechanism for presbycusis-associated tin-
nitus and development of an effective targeted intervention.
Hearing Loss Subtypes
The two most common types of hearing loss associated with Somatic Tinnitus Subtype
tinnitus are noise-induced hearing loss (NIHL) and presbycu- Somatic tinnitus is a unique form of tinnitus in which the loud-
sis. NIHL is a significant and growing health problem. Although ness, laterality, or tonality of the tinnitus can by modulated by
reduction of exposure to occupational noise has been effec- somatic modulation. This form of tinnitus was originally
tive in the last several decades, a notable increase has been observed in a small group of patients after surgical removal of
reported in the incidence of NIHL from recreational and leisure large vestibular schwannomas.18,19 Postoperatively, these patients
activity in children and adolescents and from military combat– had the ability to modulate their chronic tinnitus by exagger-
related noise exposure in young adults.6-8 Acute transient tin- ated eye movements, leg motion, or cutaneous stimulation of
nitus is nearly universal immediately after unprotected exposure the hands or face.20 The presumed mechanism of action for
to damaging acoustic stimuli, such as gunfire and amplified this unusual form of tinnitus is neural sprouting or aberrant
music. A Web-based survey of 9693 adolescents determined that reinnervation after auditory deafferentation. Subsequent to
61% of respondents experienced hearing loss and temporary these observations, a more general form of somatosensory
tinnitus after attending concerts.9 The prevalence of chronic modulation of tinnitus has been recognized, in which tinnitus
tinnitus associated with NIHL is 50% to 70%.10 Chronic tinnitus can be modulated by maneuvers or stimulation of the head and
induced by acoustic trauma occurs at a younger age than tin- neck region. It has been reported that forceful isometric con-
nitus associated with other types of hearing loss. Consequently, traction of the head and neck muscles can modify the loudness
acoustic trauma–induced tinnitus is experienced for a longer and pitch of tinnitus in 65% to 80% of patients with idiopathic
portion of the life span than other forms of tinnitus. tinnitus.21,22 Furthermore, tinnitus can be induced by strong
NIHL and associated tinnitus are preventable. In addition to contractions of muscles in the jaw, head, or neck in 15% to 58%
obvious proactive methods, such as wearing ear-protective hard- of subjects without a history of tinnitus.22,23
ware, intervention in the periexposure period may prove useful The association between tinnitus and somatic pathology of
the head and neck is underscored by the reported higher inci-
dence of tinnitus in individuals with temporomandibular joint
(TMJ) dysfunction and normal audiometric thresholds com-
pared with controls.24 One third of patients with symptoms of
Box 151-2. SUBJECTIVE TINNITUS SUBTYPES
TMJ dysfunction reported modulation of tinnitus with jaw
Pattern of hearing loss movement or pressure applied to the TMJ.25 When tinnitus
Noise-induced hearing loss occurs in association with disorders of the head and neck—
Presbycusis such as TMJ dysfunction, unilateral facial pain, otalgia, and
Unilateral occipital or temporal headache—successful tinnitus alleviation
High-frequency hearing loss may be possible using interventions that target the somatic
Outer hair cell dysfunction
Somatic tinnitus
dysfunction.
Temporomandibular joint dysfunction Levine and colleagues26 systematically reviewed the efficacy
Cervical dysfunction of treatments that target somatosensory systems. They defined
Gaze evoked somatic tinnitus syndrome as tinnitus that is 1) perceived in the
Cutaneous evoked ear, 2) ipsilateral to the somatic trigger, and 3) not associated
General somatosensory modulated with any new hearing complaints. Tinnitus that is strongly lat-
Typewriter tinnitus eralized to one ear in the presence of symmetric hearing,
Exacerbated by sleep or rest including symmetric hearing loss, would theoretically have a
Musical/complex somatic etiologic component by the definition of Levine and
Associated affective disorder
Intrusive (versus habituated)
colleagues. The review by these authors presents evidence that
somatic tinnitus is often responsive to acupuncture, electric
stimulation of the scalp and auricle, trigger-point treatment, the perceived intensity and intrusiveness of the tinnitus.35 Func-

and treatment of TMJ dysfunction. tional imaging studies in humans have suggested that expanded
representation of frequency regions in the auditory cortex may
Typewriter Tinnitus Subtype underpin tinnitus.36-38
Typewriter tinnitus is defined, as its name implies, by the charac- Animal models have been important in studying the deaf-
teristic sensation of a staccato quality to the tinnitus, similar to ferentation hypothesis of tinnitus and have been used to evalu-
a typewriter tapping, popcorn popping, or Morse code signal- ate sound therapy for reversal of pathologic neural plasticity. A
ing. Its presence is intermittent and chronic, and the sound is key study by Norena and Eggermont39 illustrates the effect of
often triggered by specific head movements or sounds. This noise trauma and therapeutic sound stimulation on receptive
type of tinnitus may be confused with tinnitus that arises from fields of primary and secondary auditory cortex. Cats exposed
a muscular source, such as spasm of the tensor tympani or to a traumatizing noise were evaluated for changes in the loca-
stapedius muscles, or palatal myoclonus. Typewriter tinnitus is tion and responsiveness of auditory cortex neurons to acoustic
distinct from these somatic sources, as illustrated by a patient stimuli. The frequency tuning of cortical neurons was altered
with typewriter tinnitus that failed to respond to tensor tympani after the trauma, and this distorted the overall representation
and stapedius resection. The patient was successfully treated, of sound and overrepresented the frequencies that surrounded
however, with carbamazepine.27 This case illustrates the impor- the exposure sound. A second cohort of cats exposed to the
tance of accurate recognition and diagnosis of typewriter tin- same traumatizing sound was subsequently reared in an
nitus. Two small case series report successful treatment with enriched acoustic environment for several weeks before
carbamazepine, which suggests that typewriter tinnitus may be mapping the auditory cortex. The enriched environment was
caused by vascular compression of the auditory nerve ipsilateral spectrally composed to compensate for the anticipated fre-
to the tinnitus.28,29 quency distortions induced by hearing loss. Two important
outcomes were observed in the cats raised in the enriched
TINNITUS TREATMENT STRATEGIES environment: 1) their hearing loss was significantly reduced
compared with the cats with similar sound exposure raised in
Auditory Deprivation and Neural Plasticity a quiet environment, and 2) no plastic reorganization of the
Acoustic stimulation as a tinnitus treatment encompasses a auditory cortex was evident. The tonotopic organization of the
range of sounds and delivery systems. The rationale for using exposed and treated cats was similar to that of unexposed
external sound to treat tinnitus derives from the hypothesis that control cats. These results suggest that tinnitus may be partly
deafferentation (hearing loss) leads to pathologic reorganiza- the result of abnormal reorganization of the auditory cortex,
tion of the auditory pathway. Hearing loss decreases the affer- and this shows that therapeutic acoustic intervention may be
ent stream of neural activity from the cochlea to the auditory effective in reducing or eliminating the abnormal cortical orga-
cortex. Chronic deafferentation alters activity in the auditory nization associated with, and potentially responsible for, tinni-
brainstem and midbrain, which alters the tonotopic organiza- tus. The implications for tinnitus treatment using sound therapy
tion of the auditory cortex. Brainstem spontaneous activity may are obvious.
increase, and midbrain patterns may change (e.g., with aber-
rant synchronization or bursting) because of compensatory
downregulation of inhibition. Altered activity in the auditory
Using Sound to Decrease Loudness and
pathway may be responsible for the tinnitus percept. Stimulus Annoyance of Tinnitus
interventions that restore afferent input to more normal levels Acoustic stimulation is an important component of successful
may act through improved inhibition. They may also restore management of tinnitus in many patients. A wide range of acous-
cortical tonotopic organization to normative levels and may tic delivery strategies are currently available. Most patients with
reduce tinnitus. tinnitus can benefit from acoustic stimulation, including those
Phantom limb pain is a phenomenon similar to tinnitus with minimal threshold shift on standard audiometric testing.
that illustrates the concept and treatment of deafferentation- Patients with severe to profound hearing loss that is not ame-
induced cortical plasticity. The phantom limb syndrome is the nable to conventional amplification can achieve tinnitus relief
sensation of a distorted and painful limb after amputation, an from other modes of auditory pathway stimulation, such as
extreme form of deafferentation. The parallels between tinni- cochlear implantation. Appropriate patient education is crucial
tus and phantom limb pain in onset rate, persistence, and to successful treatment, and treatment failures occur because
affected ages are striking. Greater than 90% of amputees expe- patients erroneously expect complete elimination of tinnitus
rience a vivid limb phantom immediately after amputation.30 after a few days to weeks of treatment. Patients must be coun-
Phantoms are more likely to occur in adults than in children.31 seled about the time course of improvement, and they must be
In many cases, the phantom sensation fades after days or weeks, encouraged to have realistic expectations about the benefits of
but it persists chronically for decades in 30% of patients.30 sound therapy. Sound therapy can decrease the subjective loud-
It is well known that both the adult and the immature brain ness of tinnitus, which can significantly decrease the annoyance,
can undergo plastic change. Neural plasticity is the ability of a but this may require weeks to months of daily application.
neuron or neural network to change its function, organization,
and connectivity through long-term alterations in synaptic Ambient Stimulation. The simplest method of increasing affer-
efficiency.32 Neurons can significantly alter their response to ent input to reverse putative central reorganization and tinnitus
inputs, and receptive field sizes change, as a consequence of is environmental sound enrichment. Use of supplemental envi-
either decreased or increased input and training procedures, ronmental sound to treat tinnitus has been recommended for
and these changes can be extensive.33 Magnetoencephalo- over 50 years.40 Enrichment can be achieved using background
graphic studies have shown that stimulation of intact body areas music, audio relaxation programs, tabletop devices that gener-
distant from the amputation site is perceived, with correspond- ate nature sounds, or waterfalls or fountains. Patients are
ing central neural activity, at the cortical site of the amputated instructed to use a source of constant background sound to
limb.34 Similar changes of auditory cortical representation may decrease attention to their tinnitus. Sound enrichment is not
underlie tinnitus. Primary auditory cortex steady-state evoked intended to mask the tinnitus in the conventional sense of
magnetic fields were enhanced in tinnitus patients compared completely eliminating the tinnitus percept. Rather by elevating
with controls, and the degree of enhancement correlated with the level of ambient sound using a constant, spectrally rich
stimulus, the tinnitus sensation becomes less noticeable. Patients may be fruitful in optimizing sound stimulation parameters

show clear preferences for particular sounds that improve sleep that provide effective tinnitus relief.
quality with some evidence that the choices are driven by Benefits from masking therapy have been shown in a large,
emotion and cognitive factors rather than acoustic masking.41 prospective controlled study of chronic significant tinnitus in
Effective use of sound stimulation for managing tinnitus in U.S. veterans.52 Validated standardized tinnitus severity ques-
hearing-impaired patients is achieved when combined with tionnaires were used to screen and enroll 123 subjects with
appropriate amplification. Typically, amplification is achieved clinically significant tinnitus. Subjects were quasi-randomly
with hearing aids. Even without supplemental sound, the assigned to either the total masking group or a tinnitus retrain-
therapeutic effect of hearing aids for tinnitus patients is ing therapy (TRT) group. Subjects in the total masking group
well documented.42-44 Hearing aids reduce the awareness of received hearing aids, maskers, or combination instruments,
tinnitus through amplification of ambient sound, and they and all received information counseling over an 18-month
reduce the perception that tinnitus masks hearing and impedes follow-up period. Subjects in the TRT group received standard-
communication. ized TRT treatment. All subjects were evaluated for response to
Surr and coworkers45 reviewed the initial effect of hearing treatment at 6, 12, and 18 months, and subjects in both treat-
aid use on tinnitus in 124 patients. Approximately one half of ment groups showed improvement on multiple measures of
patients reported that the hearing aid reduced (26%) or elimi- tinnitus over the course of the study. Subjects in the total-
nated (29%) the tinnitus. Folmer and Carroll46 reviewed their masking group who rated their tinnitus as a “moderate”
clinical experience with 50 patients with mild to moderate problem had effect sizes between 0.27 and 0.48 compared with
SNHL fitted with hearing aids for tinnitus management. effect sizes for the TRT group of 0.77 and 1.26 at 18 months.
Patients were reevaluated 6 to 48 months after initial fitting Mean effect sizes in subjects with tinnitus rated as a “very big
(mean 18 months), and 70% reported significant improvement problem” were 0.64 in the total masking group and 1.08 in the
in their tinnitus. Similar results were obtained in a larger study TRT group. Although both therapies resulted in clinically sig-
of 1440 patients fitted with hearing aids for unilateral or bilat- nificant improvement in tinnitus with medium (>0.5) to large
eral hearing loss.47 In this study, digital hearing aids provided (>0.8) effect sizes, optimal outcomes were obtained with long-
significantly greater tinnitus relief than analog hearing aids. Of term TRT treatment.
patients fitted with digital hearing aids for unilateral hearing
loss, 65% reported greater than 50% improvement in tinnitus Acoustic Stimulation Combined with Education and Counsel-
compared with 39% who reported a similar degree of improve- ing. TRT combines sound therapy with a formalized program
ment after fitting with an analog aid. An even greater therapeu- of directive counseling to achieve habituation to tinnitus. TRT
tic effect was obtained with bilateral digital hearing aids: 85% is based on the assumption that tinnitus distress derives from
of patients reported greater than 50% improvement in tinnitus activation of an emotional and an autonomic response to tin-
compared with 30% of those fitted with bilateral analog aids. nitus.53 Within this theoretic framework, tinnitus emerges as a
result of damage or dysfunction within the auditory pathway,
Personal Listening Devices. Tinnitus management with supple- and it is detected at subcortical levels of the brain. The critical
mental acoustic stimulation can be implemented through the event that leads to clinically significant tinnitus is not its sensory
use of personal listening devices. Miniaturization, data storage, features but rather the perception and evaluation of the
and digital software have greatly expanded the available tools tinnitus-related neural activity that occurs in the auditory cortex
that clinicians and patients can use to produce a customized and subsequent cortical interaction with the limbic system, pre-
sound library. Inexpensive online sources are also available frontal cortex, and cortical association areas. According to
for downloading digital sound specifically developed for tin- Jastreboff and Hazell,53 tinnitus becomes clinically significant
nitus therapy (e.g., www.vectormediasoftware.com). Patients when a negative affective response to the tinnitus has been
can build and use a small library of sounds that may include established.
music to their liking, nature sounds, and noise bands of differ- The goals of TRT are to remove, decrease, or change the
ent spectral composition. Important key features of any regimen perception of tinnitus by promoting habituation of the reac-
of amplified sound therapy are 1) use of open-fit, nonoccluding tions to the tinnitus sensation. Habituation of the reaction to
ear-level amplifiers; 2) long-term exposure to the sounds; 3) tinnitus would reduce the derived annoyance, anxiety, and
sound spectral composition that is reasonably broad; and 4) stress. A key feature of TRT involves behavioral retraining of
sound levels below that of the perceived tinnitus. the associations induced by the tinnitus sensation. TRT uses five
distinct levels of therapy aimed at stratified patient groups.
Total Masking Therapy. Total masking therapy is the use of Stratification is based on tinnitus distress, associated hearing
sound with spectral characteristics and sufficient volume to impairment, presence of sound-induced exacerbation of tin-
render the tinnitus inaudible. This form of sound therapy has nitus, and comorbid hyperacusis (see later). The five strata
likely been used for centuries and derives from empiric experi- include patients with 1) tinnitus that causes minimal distress
ence that certain environmental sounds are efficient tinnitus (category 0); 2) tinnitus that causes distress (category 1); 3)
maskers. A formal masking therapy program was first proposed distressing tinnitus and hearing loss (category 2); 4) distressing
by Vernon and Schleuning.48 Patients are fitted with ear-level tinnitus, normal hearing, and hyperacusis (category 3); and 5)
devices that generate sound, and the devices can be adjusted distressing tinnitus, normal hearing, hyperacusis, and pro-
to have outputs with different frequency spectra and levels. No longed sound-induced exacerbation of tinnitus (category 4).
codified scheme exists for selecting effective masking charac- Treatment is specific for each patient category and uses direc-
teristics; the general fitting principle is to determine the tive counseling, auditory enrichment, hearing aids, and sound
minimum level of broadband noise that masks the tinnitus generators.
without interfering with communication. The fitting is empiric, Retrospective clinical trials to evaluate the efficacy of TRT
because there is a wide range of patient preference in the type have generally been positive, and the consensus is that TRT
and level of sound that masks the tinnitus and is not perceived reduces the annoyance and impact of tinnitus within a time
as annoying.49,50 Recent work using amplitude-modulated high- frame of 12 to 18 months.54,55 However, controlled trials to
frequency carrier tones within the range of the tinnitus pitch compare TRT with other standard treatments, such as cognitive
was successful in significantly to completely suppressing tinni- behavioral therapy or general counseling, showed comparable
tus in a moderate portion of people.51 Further work in this area improvement in tinnitus severity and distress.56,57
Acoustic Desensitization Protocol. The Acoustic Desensitiza- training, and selective attention distraction to induce habitua-

tion Protocol (Neuromonics, Bethlehem, PA) is a proprietary tion to tinnitus. It may be that defusing the emotional compo-
tinnitus treatment program that combines features of sound nent of tinnitus, as suggested by some, with or without
therapy, systematic desensitization, directive counseling, and concomitant changes in tinnitus loudness is sufficient for
supportive intervention for stress management, sleep disrup- improving patient outlook and perception.64
tion, and coping strategies. Systematic desensitization is a psy- A review of CBT as a tinnitus treatment by the Cochrane
chologic technique originally developed for the treatment of Collaboration evaluated six trials that comprised 285 partici-
phobias. Progressive gradual controlled exposure to the phobic pants.65 The primary outcome measure was subjective tinnitus
stimulus within the context of a deeply relaxed state of mind loudness, and the secondary outcome measures were improve-
results in a gradual desensitization of the phobic response to the ment in symptoms of mood disturbance and quality-of-life
stimulus.58 This technique has been adapted to the treatment of evaluation. The pooled results for the five trials that reported
tinnitus by targeting the individual’s tinnitus as the stimulus that subjective loudness before and after treatment showed no sig-
provokes the phobic, or at least negative, emotional response. nificant difference between treatment with CBT and either a
Patients listen to their tinnitus in gradual, progressive incre- waiting-list control or an alternative treatment. In addition,
ments within a background context of pleasant, relaxing thera- no significant treatment effect was found for the secondary
peutic sound. The therapeutic sound has three key features outcome measures of depression and mood disturbance.
that are fundamental to the protocol: 1) it is music spectrally However, a significant improvement was seen in the quality of
modified in accord with the patient’s hearing loss; 2) loudness life of CBT participants, as measured by a global decrease in
levels are enhanced for those frequencies at which hearing loss tinnitus severity with a standardized mean difference of 0.70
is pronounced; and 3) it reestablishes stimulation of the audi- (95% confidence interval, 0.33 to 1.08). The reviewers con-
tory pathway over a wide frequency range. Music that is nonin- clude that CBT has a significant impact on the qualitative
trusive and has a slow rhythm is used to maximize relaxation aspects of tinnitus and that it contributes positively to the man-
during treatment. The music has a dynamic component that agement of tinnitus. A larger meta-analysis of randomized con-
permits intermittent tinnitus perception alternating with tin- trolled trials of CBT included 15 trials, 10 with long-term
nitus masking. This gradual exposure to therapeutic music is follow-up; these researchers concluded that CBT is effective in
achieved using a staged treatment program. In the initial stage, reducing the annoyance and distress associated with tinnitus,
the spectrally modified music is embedded within a background and a larger treatment effect was seen in response to CBT,
sound of high-frequency noise that masks the tinnitus. In the compared with both waiting-list controls and active control
second stage, the masking noise is removed, and the tinnitus groups given only education.66
percept becomes gradually and progressively more audible. Nevertheless, controversy continues regarding the relative
Evidence for improved tinnitus severity after 6 to 12 months benefits of CBT and sound stimulation in promoting psycho-
of therapy has been demonstrated in several small, uncontrolled logic and physiologic habituation in patients who have chronic
trials and in Neuromonics-sponsored outcome studies.59-61 In tinnitus. Hiller and Haerkotter67 followed 124 outpatients with
the latter, 35 patients with moderate to severe tinnitus received chronic tinnitus randomly assigned to either CBT alone or CBT
Neuromonics tinnitus treatment and were tested for subjective combined with sound stimulation using noise generators.
(distress, awareness) and objective (minimum masking levels, Tinnitus-related distress and psychosocial functioning were sig-
loudness discomfort levels) changes at four time points after nificantly improved in both groups, with no additive benefit
therapy, including at 1 year. Within the first 6 months of treat- observed in the sound-stimulation group.
ment, 91% of participants reported an improvement in tinnitus
distress, which reflected a mean improvement of 65% in the Transcranial Magnetic Stimulation
Tinnitus Reaction Questionnaire. The reported “percent of Transcranial magnetic stimulation (TMS) has opened a novel
time aware of tinnitus” before therapy was 90%, which was sig- avenue for investigating the causal and associational aspects of
nificantly reduced to 30% after 12 months of therapy. A retro- tinnitus-related cortical activity, and it may provide an effective
spective assessment showed equivalent outcomes in tinnitus tinnitus therapy for some patients. TMS applies a brief, intense
improvement when comparing a tinnitus habituation protocol current to the scalp using a surface coil that induces a magnetic
using ear-level sound generators with the Neuromonics Acoustic field in the underlying brain. The magnetic pulse induces a
Desensitization Protocol.62 temporary focal disruption of neural activity in a discrete area
of cortex. Currently, depth of penetration of the magnetic field
Cognitive Behavioral Therapy for Tinnitus is limited to less than 2 cm.68 This “virtual lesion” briefly and
Cognitive behavioral therapy (CBT) is a well-established form reversibly disrupts cortical activity and allows the investigator to
of psychotherapy based on identification and modification determine whether the cortical region of interest contributes
of maladaptive behaviors using therapist-mediated cognitive to a specific behavior or perception.69 The effect of a single
restructuring techniques. This approach has been successfully pulse-induced magnetic field is short lived, on the order of
applied to tinnitus for many years and forms the basis of milliseconds. Repetitive TMS over seconds to minutes causes
another type of habituation therapy for tinnitus.63 CBT for tin- neuronal depolarization within the superficial cortex. Low-
nitus is based on the concept that the normal response to frequency (<1 Hz) repetitive TMS decreases cortical excit-
meaningless stimuli is habituation, and tinnitus distress results ability,70 whereas high-frequency (5 to 20 Hz) repetitive TMS
from a failure to habituate. Jakes and associates64 summarized increases cortical excitability.71 All repetitive TMS frequency
the causes of habituation failure to include emotional responses, parameters can induce long-term plastic changes in cortical
orientation to stimuli, arousal, and unfavorable signal-to-noise function that reportedly outlast the stimulation period by hours
ratio. When an individual is repeatedly presented with a mean- to days.72
ingless or neutral stimulus, responses to the stimulus—such as Early work was directed toward using functional imaging
orientation, attention, and cognitive processing—soon habitu- techniques to locate regions of interest for TMS application
ate (i.e., the responses drop out). When the same person is and to examine the effect of cortical stimulation on distant
presented repeatedly with a noxious stimulus (e.g., the cry of structures. Theoretically, TMS applied to accessible regions,
a baby), sensitization occurs (i.e., the response to the stimulus such as auditory cortex, would modulate tinnitus either through
becomes more pronounced and may have an emotional direct disruption of pathologic cortical activity or indirectly via
component). CBT uses techniques of reassurance, relaxation corticofugal neural networks relevant to tinnitus. However,
recent imaging work suggests that at least in people with non- inaudible, transdermal electric current to the mastoid emi-

bothersome tinnitus, abnormal functional connectivity that nence. Caffier and colleagues84 showed complete tinnitus sup-
links auditory, visual, attentional, and cognitive brain areas is pression in one of five patients treated with TENS. In a larger,
not evident.73 double-blind crossover study, 20 patients were treated first
The functional relevance of temporoparietal cortex activity using the active device followed by a placebo device in which
to tinnitus was first suggested by studies that examined the the internal circuitry was deactivated. Four patients (20%)
effect of repetitive TMS (rTMS) on auditory hallucinations. reported reduction with the placebo, whereas two patients
Three patients with schizophrenia and persistent auditory hal- (10%) reported tinnitus reduction with the active device. One
lucinations were studied in a double-blind crossover design of the responders was examined further with random trials of
using low-frequency (1 Hz) rTMS to the left temporoparietal either active or placebo stimulation and reported a median
cortex versus sham stimulation. All three subjects reported sig- 70% tinnitus decrease during active stimulation and a 16%
nificant improvement in severity of hallucinations after active decrease during placebo stimulation.85 A subsequent single-
treatment compared with sham stimulation. Two subjects had blind crossover study of 30 patients showed a similar proportion
near-complete cessation of hallucinations for 2 weeks after of patients that responded to stimulation.86 Levine and cowork-
treatment.74 Meta-analysis of the effect of rTMS on auditory ers34 reviewed the characteristics of tinnitus patients who
hallucinations in schizophrenic patients has supported these respond to TENS and concluded that the common finding
early results and shows a significant positive effect.75 present in all cases is tinnitus with features of somatic
Mennemeier and colleagues76 reported the effect on tinni- modulation.
tus of targeted rTMS to either the left or right temporal hemi- Folmer and Griest87 prospectively studied the effect of TENS
sphere, as directed by functional imaging using positron in 26 patients with tinnitus categorized as somatically modu-
emission tomography (PET). Tinnitus loudness measured with lated. Although the trial lacked a placebo control, a striking
a visual analog scale was reduced in 43% of subjects, without a effect was obtained in this sample from a selected population,
concomitant reduction in tinnitus severity ratings on standard- with tinnitus elimination in 23% and tinnitus improvement in
ized questionnaires. No evidence was found that PET was effec- 23%. Further analysis by tinnitus type showed that the group
tive in guiding effective treatment, nor was any treatment most responsive to TENS treatment had typewriter tinnitus,
advantage gained in stimulating one hemisphere over the and 88% experienced improved or eliminated tinnitus.
other. Other studies have failed to show any effect of rTMS on
subjective loudness ratings or severity ratings using similar Cochlear Implants. Suppression of tinnitus as a secondary
stimulation parameters in blinded trials.77,78 benefit of cochlear implantation was noted in the early days of
If TMS is effective in reversing neurogenic pathology, its cochlear implant development.88 Although a large variability
mechanism of action remains unclear. High-frequency rTMS exists in the methods of assessing and reporting tinnitus, most
can result in long-lasting clinical improvement in cases of studies report a consistent and clinically significant beneficial
chronic neurogenic pain, which suggests that the therapeutic effect of cochlear implantation on tinnitus suppression.74 A
effect may not be related to a reduction in cortical excitability significant proportion of patients (38% to 85%) report either
but rather may occur through reversal of chronic maladaptive a decrease or complete suppression of tinnitus after intraco-
plastic changes.79 The long-term effect of different rTMS stimu- chlear electrode insertion before initial stimulation.75 Although
lation rates delivered to the left temporoparietal cortex was studies have not been extensive, there does not seem to be a
assessed in 39 subjects with chronic tinnitus (duration 6 months significant difference in effective tinnitus suppression with dif-
to 25 years).80 Subjects were randomly assigned to one of four ferent device manufacturers. Cochlear stimulation has been
stimulation groups—1, 10, or 25 Hz or sham stimulation—and reported to reduce tinnitus intensity perceived in the ear con-
underwent five sessions over a 2-week period. All subjects in the tralateral and ipsilateral to the implant.75 This is not paradoxic,
active rTMS groups reported significant improvement (P < .05) because the brainstem cochlear nuclei have contralateral con-
in tinnitus severity on the standardized Tinnitus Handicap nections, and bilateral elevation of spontaneous activity in the
Inventory (THI) questionnaire at 4 months after completing dorsal cochlear nucleus has been shown in animals with tinni-
treatment compared with the sham treatment group. Tinnitus tus induced by unilateral acoustic trauma.89
improvement occurred regardless of stimulation rate for active The effectiveness of cochlear stimulation on decreasing tin-
rTMS. A greater proportion of subjects experienced an 80% or nitus loudness increases over time. Tinnitus was suppressed in
greater improvement in THI score after treatment with 10 Hz 65% of patients on initial stimulation, but after a 2-month
(29%) and 25 Hz (35%), however, than after 1 Hz (6%). As period, stimulation suppressed the tinnitus in 93% of patients.90
reported in other studies, a negative correlation was found These observations suggest that the mechanism responsible for
between tinnitus duration and percent improvement 4 months tinnitus suppression by cochlear implants may relate to reversal
after treatment. of maladaptive central plastic changes associated with auditory
deprivation. Multiple factors may contribute to the efficacy of
Electric Stimulation tinnitus suppression after cochlear implantation; these include
Electric stimulation has been used to treat tinnitus since the etiology, duration, and extent of hearing loss and also stimula-
advent of Volta’s battery in the early nineteenth century.81 tion strategy. Much remains to be learned about tinnitus mech-
Although anodal direct current has been used by multiple anisms from patients with cochlear implants; however, few
investigators to suppress tinnitus, practical use is limited by studies have systematically investigated the impact of these
tissue damage induced by chronic stimulation with direct factors.
current.82,83 Nondestructive methods of delivering electric
current required the development of improved noninvasive Pharmacologic Tinnitus Treatments
techniques, such as transcutaneous electric nerve stimulation Ancient written accounts (2660 to 2160 bce) indicate that
(TENS), and surgically implanted devices that use alternating medical treatment of tinnitus dates back to the Egyptians.91 An
current, such as cochlear implants and cortical stimulators. ear that was “bewitched” or humming would be infused with
oil, frankincense, tree sap, herbs, and soil. Mesopotamian writ-
Transcutaneous Electric Nerve Stimulation. Initial systematic ings considered the psychologic aspects of tinnitus, possibly the
attempts to decrease tinnitus using TENS used the Theraband earliest recognition that stress and emotional factors are signifi-
headset (Audimax, Allesandria, Italy), a device that delivers cant comorbidities of tinnitus dysfunction.
Until more recently, most pharmacologic interventions for neurotransmitters may be important in the distress associated
tinnitus were empirically determined. Anecdotal experience with tinnitus.
and fortuitous observations of tinnitus relief were the primary Treatment with sertraline, a SSRI, improved tinnitus loud-
sources of innovation. Over the past 50 years, pharmacologic ness (P = .014) and severity (P = .024) in a group of tinnitus
treatment of tinnitus has become more rational. Anesthetics patients with an associated depressive or anxiety disorder.103
(lidocaine, tocainide, mexiletine), anticonvulsants (carbamaze- Despite this positive evidence, it is unclear whether SSRI treat-
pine, gabapentin), and tranquilizers (diazepam, clonazepam, ment improved tinnitus directly or indirectly through allevia-
oxazepam) have been investigated as tinnitus treatments. They tion of mood disorder. A placebo-controlled trial of the SSRI
have in common the general property of facilitating neural paroxetine in a group of subjects without coexisting mood or
inhibition. Antidepressants such as trimipramine, nortriptyline, anxiety disorder did not produce improvement in any tinnitus
amitriptyline, and selective serotonin reuptake inhibitors measure over placebo.104
(SSRIs) have been tested for their ability to ameliorate the
comorbid mood disturbance associated with tinnitus. Consider-
ing only well-controlled trials, mixed results have been obtained
CLINICAL EVALUATION OF TINNITUS
for all drugs tested to date. Clinical treatment of a patient with tinnitus should begin with
The hypothesis that tinnitus emerges from increased central a general medical evaluation followed by a complete head
neural activity after loss of inhibition can be used to guide and neck examination. Objectives of the evaluation include a
pharmacologic intervention and is supported by work with descriptive characterization of the tinnitus (psychoacoustic
animal models,92-94 and it provides a rational basis for numerous properties, impact on daily life, reactive components); determi-
pharmacologic interventions that include lidocaine, carbam- nation of etiology; and identification of factors that exacerbate,
azepine, alprazolam, and gabapentin. Despite the increase in ameliorate, or trigger the tinnitus. At a minimum, the results
targeted tinnitus drug trials, use of a single agent to treat a of the examination educate the patient about the tinnitus, and
heterogeneous large sample of subjects has been for the most patient education is a powerful therapeutic component of the
part unsuccessful. Several reasons, none mutually exclusive, clinical process that should not be undervalued or underesti-
may account for this lack of success. Most tinnitus clinical trials mated. A thorough examination also facilitates development of
randomly select and assign participants to treatment groups. a directed individual treatment plan.
However, evidence is emerging that tinnitus is a heterogeneous Tinnitus can be described in terms of its psychoacoustic
disorder with variable pathologic features.34,95,96 Testing drugs properties and in terms of the affective or reactive responses to
with a single mechanism of action is unlikely to succeed when the tinnitus. The affective or reactive components include the
using randomly determined heterogeneous sample groups. For comorbid problems of depression, sleep disruption, difficulty
the same reason, trials that use small dose ranges may also fail. with concentration, sadness, anxiety, and fear. The reactive
Studies that enroll subjects with a single tinnitus etiology components of tinnitus are highly individual and are significant
may be more likely to identify successful treatments. A study factors in tinnitus disability. Careful evaluation of both compo-
that examined the effect of gabapentin on tinnitus in two spe- nents is important for the clinician to appreciate fully the
cific patient subpopulations obtained positive results.97 The impact of the tinnitus on the individual and to formulate a
study was designed to test the hypothesis that acoustic trauma directed treatment plan.
leads to a loss of inhibition in the auditory pathway mediated The qualitative features of tinnitus can be assessed using
by the inhibitory neurotransmitter γ-aminobutyric acid (GABA). standardized questionnaires and psychophysical measure-
The hypothesis was advanced after an animal experiment that ments. Relevant information includes localization (left, right,
showed gabapentin, a GABA analogue, to be effective in reduc- in the head, outside of the head), constancy (episodic, fluctuat-
ing the loudness of tinnitus in rats.93 This study used a very wide ing, constant, pulsatile), pitch, loudness, and sound quality
dose range and tested one group of patients with objective and (tonal, hissing, buzzing, clicking, ringing). This information
historic evidence of traumatic sound exposure and a second can be useful in determining etiology: pulsatile tinnitus can
group without such evidence. Gabapentin was found to reduce imply a vascular source, whereas fluctuating tinnitus may be
tinnitus annoyance significantly in the trauma group at a daily linked to specific triggers such as foods, illnesses, stress, or
dose level of 1800 to 2400 mg. In contrast, a subsequent clinical acoustic trauma. Episodic tinnitus may relate to unstable
trial to study the effect of only a single dose in a randomly hearing thresholds that derive from cochlear dysfunctions,
selected group of patients did not obtain a significant effect.98 such as hydrops or perilymph fistulae. Clicking or tapping tin-
The therapeutic effect was likely missed because only a single nitus may occur with mechanical disorders that affect either the
dose level was used, and the treatment group included various middle ear muscles (stapedial or tensor tympani spasm) or the
tinnitus etiologies. Drugs with a specific mechanism of action auditory nerve (vascular loop or demyelination). Identification
are unlikely to be effective in all subjects characterized by such of tinnitus with specific characteristics such as these is very
heterogeneity. Stratified study designs with segregation of tin- useful and can lead to a directed course of therapy.
nitus types, etiologies, and hearing characteristics should be
more successful in identifying effective drug therapies. Standardized Outcome Measures
The most extensively used drugs for tinnitus treatment are Numerous standardized questionnaires are available for mea-
antidepressants. Attempting to treat tinnitus with antidepres- suring tinnitus severity and perceived disability. Standardized
sants is sensible for two reasons: first, the association between assessment is useful for documenting clinical outcomes and
severe tinnitus and mood disorders is well recognized; second, reporting the results of clinical trials. Standardized measures
the pharmacologic mechanism of action of many antidepres- are also crucial for determining the subjective impact of tin-
sants involves receptors and neurotransmitters located in the nitus. Finally, standardized questionnaires are useful for stratify-
auditory pathway.99 Although GABA deficiency seems to con- ing patients according to the severity and impact of their
tribute to tinnitus pathology,97,100-102 the role of other neu- tinnitus, which facilitates identification of specific problems
rotransmitter systems in triggering or maintaining tinnitus is and serves to triage patient care from minimal counseling to
currently unknown. Serotonin is known to function as a modu- intensive rehabilitation.
lator of sensory systems, learning, and memory. Along with The THI is a widely used self-assessment tool.105 This 25-item
acetylcholine, serotonin can affect behavioral conditioning questionnaire has good construct validity, strong internal con-
and associated plastic changes in auditory cortex. Both sistency, and good test-retest reliability. The THI yields a total
score and three subscale scores; the subscales encompass func- migraine,95 Lyme disease,96 benzodiazepine withdrawal,97 or as
tional limitations in mental (e.g., difficulty concentrating), part of a syndrome.98 Patients with tinnitus and hyperacusis
social, occupational, and physical domains (e.g., difficulty frequently have loudness discomfort levels that are lower
sleeping); emotional responses to tinnitus (e.g., anger, depres- than those of individuals with similar levels of SNHL, again
sion, anxiety); and catastrophic reactions to tinnitus (e.g., des- indicating that these phenomena are distinctly different from
peration, loss of control, failure to cope). In addition to its recruitment.99
good internal consistency and test-retest reliability, the THI has Andersson and associates100 assessed the prevalence of
high convergent validity with the 27-item Tinnitus Handicap hyperacusis in the general population in two surveys of the
Questionnaire and the 52-item Tinnitus Questionnaire.106 The adult Swedish population. The point prevalence of hyperacusis
95% confidence interval for the THI is 20 points, which sug- was 5.9% (postal survey) and 7.7% (Internet survey). Partici-
gests that a difference in scores of 20 points or greater repre- pants who reported hearing impairment were excluded from
sents a statistically and clinically significant change. the prevalence calculations, which minimized the inclusion of
patients with cochlear damage and reduced dynamic range in
Tinnitus Comorbidities the sample. Other surveys of hyperacusis report a higher preva-
Severe, debilitating tinnitus is frequently associated with depres- lence in the general population (22%).101 The prevalence of
sion, anxiety, and other mood disorders.79,107 Comorbid emo- hyperacusis within the tinnitus population is unknown,
tional disturbance is not unique to tinnitus and has been shown although estimates range from 40% to 80%, but no systematic
to accompany many chronic illnesses.83,108 It is well recognized survey has been conducted for accurate estimation.102,103 In the
that coexisting mood disorders hamper improvement and general population and the tinnitus population, the varied
interfere with treatment of conditions such as chronic pain and prevalence estimates likely reflect the adopted operational defi-
tinnitus. The identification and treatment of comorbid condi- nition of hyperacusis.
tions in tinnitus patients is an important aspect of the clinical Objective tests of loudness discomfort or sound intolerance
evaluation. In an outpatient setting, several tools are available in patients with hyperacusis have been adapted from proce-
to screen for mood disorders, such as the Beck Depression dures developed for assessing recruitment.104,112 Several varia-
Inventory and the Hamilton Anxiety Scale. An important thera- tions exist on the technique for measuring loudness discomfort
peutic adjunct is teaching coping skills through behavior modi- levels, but no consensus or standardization has been estab-
fication and cognitive therapy.84 lished. In addition, issues of intersubject and intrasubject vari-
ability,113 test-retest reliability,114 operator dependency, and
Tinnitus and Insomnia poor face validity for test stimuli all limit the utility of adapting
Patients commonly report that tinnitus interferes with their measures of loudness intolerance to patients with hyperacusis.
ability to fall asleep, and sleep disruption is a significant comor- Very few validated, well-established self-report question-
bid condition in adults and children.85,86 A robust correlation naires specifically assess hyperacusis. Dauman and Bouscau-
has been shown between the reported loudness and severity of Faure103 developed a scale for assessing hyperacusis in patients
tinnitus and degree of sleep disruption.87,109 A positive feedback with tinnitus called the Multiple-Activity Scale for Hyperacusis,
loop may exist in which tinnitus leads to sleep deprivation, and which uses a structured interview for rating the annoyance
the sleep deprivation exacerbates somatic complaints, tinnitus induced by sound exposure from different physical and social
among them. Depression and anxiety exacerbated by sleep loss activities. They reported hyperacusis in 197 of 249 clinical
may significantly interact with and compound the cycle of tin- patients (79%) screened with the instrument and reported
nitus and poor quality sleep. Coping ability may also deteriorate substantial to severe annoyance from hyperacusis present in
as a result of sleep deprivation or lack of restorative sleep. Sleep 42%. No correlation was found between the severity of hyper-
difficulties include insufficient sleep, poor quality sleep, and acusis, as indicated by the Multiple-Activity Scale for Hyperacu-
nonrestorative sleep. Altered sleep architecture reflected in a sis, and audiometric threshold shift, which again indicates
significant decrease in time spent in stage 3 and 4 REM sleep that hyperacusis is a phenomenon distinct from loudness
was demonstrated in subjects with chronic tinnitus compared recruitment. The Hyperacusis Questionnaire is a 14-item instru-
with matched controls.110 Psychologic and behavioral management, in which hyperacusis is assessed using a four-alternative
ment of sleep disturbance is an effective treatment modality for Likert scale.115
chronic insomnia and may provide benefit for patients with The impact of hypersensitivity to sound can range from
tinnitus and concomitant sleep disturbance.111 general avoidance of social situations, such as concerts and
Pharmacologic sleep aids such as melatonin can reduce tin- restaurants, to specific sound aversions: vacuum cleaners,
nitus severity, particularly in patients with pronounced sleep traffic, clinking dishes, children playing, and so on. In extreme
difficulties.91,92 Bedside sound generators have also been shown cases, patients with severe hypersensitivity become housebound
to improve sleep quality significantly and to lessen tinnitus in an effort to control acoustic exposure, and they wear ear
distress. The bedside sounds most frequently chosen are often plugs and ear muffs for extended periods. In all cases of sound
selected for their perceived positive emotional effect.41 hypersensitivity, it is important to address the physiologic com-
ponent of loudness discomfort and reduced dynamic range and
also the psychologic component of fear, anxiety, social with-
HYPERACUSIS drawal, and maladaptation that accompanies the condition.
Hyperacusis has been defined as noise intolerance, annoyance The cognitive influence on sound sensitivity is illustrated by the
caused by ordinary sounds, and abnormal discomfort for supra- high correlation of loudness tolerance with anxiety.116 A survey
threshold sound.93 These definitions distinguish hyperacusis, of 62 Swedish patients with hyperacusis showed that nearly half
considered by many to be a central phenomenon, from recruit- had a concomitant psychiatric disorder with a predominance
ment, the rapid growth of perceived loudness with increasing of anxiety-related personality traits.117
stimulus level observed in association with cochlear hearing loss The efficacy of sound therapy for treating hyperacusis has
and outer cell dysfunction. Hyperacusis frequently occurs in had mixed results. Dauman and Bouscau-Faure103 reported that
association with tinnitus, but it can be present without tinnitus TRT was more effective in improving hyperacusis (63%) than
or any associated hearing loss. Hyperacusis can occur after the tinnitus (47%) in 32 patients evaluated at three time points
loss of the stapedial reflex in association with acute facial after therapy. They reported that hyperacusis remains a problem
paralysis94 and in association with general conditions such as for a significant proportion of patients treated with TRT. Gold
and associates118 reported a retrospective study on the effect of relaxation training and distraction on chronic tinnitus sufferers.

TRT on selected patients with reduced sound tolerance. Hyper- Behav Res Ther 24:497–507, 1986.
acusis was defined as average loudness discomfort levels for Kirsch CA, Blanchard EB, Parnes SM: Psychological characteristics of
1 kHz, 2 kHz, 4 kHz, and 8 kHz below 100 dB hearing loss and individuals high and low in their ability to cope with tinnitus. Psycho-
som Med 51:209–217, 1989.
patient reports of physical discomfort with exposure to sounds. Levine RA: Typewriter tinnitus: a carbamazepine-responsive syndrome
Hearing thresholds were unchanged between initial measures related to auditory nerve vascular compression. ORL J Otorhinolaryn-
and follow-up after 9 months of therapy; however, mean loud- gol Relat Spec 68:43–46, 2006.
ness discomfort levels were improved 12.48 dB, and the dynamic Lockwood AH, Salvi RJ, Coad ML, et al: The functional neuroanatomy
range was significantly increased by a mean 11.32 dB. A cor- of tinnitus: evidence for limbic system links and neural plasticity.
responding improvement in the number of activities avoided Neurology 50:114–120, 1998.
because of sound tolerance problems was noted as well. Mardini MK: Ear-clicking “tinnitus” responding to carbamazepine.
N Engl J Med 317:1542, 1987.
Martinez Devesa P, Waddell A, Perera R, et al: Cognitive behavioural
For a complete list of references, see expertconsult.com. therapy for tinnitus. Cochrane Database Syst Rev (1)CD005233, 2007.
Norena AJ, Eggermont JJ: Enriched acoustic environment after noise
trauma reduces hearing loss and prevents cortical map reorganiza-
SUGGESTED READINGS tion. J Neurosci 25:699–705, 2005.
Aydemir G, Tezer MS, Borman P, et al: Treatment of tinnitus with Robinson SK, Viirre ES, Bailey KA, et al: Randomized placebo-controlled
transcutaneous electrical nerve stimulation improves patients’ quality trial of a selective serotonin reuptake inhibitor in the treatment of
of life. J Laryngol Otol 120:442–445, 2006. nondepressed tinnitus subjects. Psychosom Med 67:981–988, 2005.
Bauer CA, Brozoski TJ: Effect of gabapentin on the sensation and Rosenberg SI, Silverstein H, Rowan PT, et al: Effect of melatonin on
impact of tinnitus. Laryngoscope 116:675–681, 2006. tinnitus. Laryngoscope 108:305–310, 1998.
Bauer CA, Brozoski TJ, Myers K: Primary afferent dendrite degenera- Rubinstein B, Axelsson A, Carlsson GE: Prevalence of signs and symp-
tion as a cause of tinnitus. J Neurosci Res 85:1489–1498, 2007. toms of craniomandibular disorders in tinnitus patients. J Cranioman-
Bauer CA, Brozoski TJ, Myers KS: Acoustic injury and TRPV1 expres- dib Disord 4:186–192, 1990.
sion in the cochlear spiral ganglion. Int Tinnitus J 13:21–28, 2007. Shulman A, Goldstein B: Pharmacotherapy for severe, disabling,
Davis PB, Paki B, Hanley PJ: Neuromonics tinnitus treatment: third subjective, idiopathic tinnitus: 2005-2006. Int Tinnitus J 12:161–171,
clinical trial. Ear Hear 28:242–259, 2007. 2006.
Folmer RL, Griest SE: Tinnitus and insomnia. Am J Otolaryngol 21:287– Trotter MI, Donaldson I: Hearing aids and tinnitus therapy: a 25 year
293, 2000. experience. J Laryngol Otol 122:1052–1056, 2008.
Hebert S, Carrier J: Sleep complaints in elderly tinnitus patients: a Tyler RS, ed. Tinnitus treatment: clinical protocols, New York, 2006, Thieme
controlled study. Ear Hear 28:649–655, 2007. Medical Publishers.
Herraiz C, Toledano A, Diges I: Trans-electrical nerve stimulation Zoger S, Svedlund J, Holgers KM: The effects of sertraline on severe
(TENS) for somatic tinnitus. Prog Brain Res 166:389–553, 2007. tinnitus suffering—a randomized, double-blind, placebo-controlled
Jakes SC, Hallam RS, Rachman S, et al: The effects of reassurance, study. J Clin Psychopharmacol 26:32–39, 2006.
151 | TINNITUS AND HYPERACUSIS 2344.e1
26. Levine RA, Nam ED, Oron Y, et al: Evidence for a tinnitus sub-
REFERENCES group responsive to somatosensory based treatment modalities.
1. Nondahl DM, Cruickshanks KJ, Wiley TL, et al: Prevalence and Prog Brain Res 166:195–207, 2007.
5-year incidence of tinnitus among older adults: the epidemiology 27. Mardini MK: Ear-clicking “tinnitus” responding to carbamaze-
of hearing loss study. J Am Acad Audiol 13(6):323–331, 2002. pine. N Engl J Med 317(24):1542, 1987.
2. Cooper JC, Jr: Health and Nutrition Examination Survey of 28. Levine RA: Typewriter tinnitus: a carbamazepine-responsive syn-
1971-75: Part II. Tinnitus, subjective hearing loss, and well-being. drome related to auditory nerve vascular compression. ORL J Oto-
J Am Acad Audiol 5(1):37–43, 1994. rhinolaryngol Relat Spec 68(1):43–46; discussion 46–47, 2006.
3. Sismanis A: Tinnitus : advances in evaluation and management. Oto- 29. Brantberg K: Paroxysmal staccato tinnitus: a carbamazepine
laryngologic clinics of North America, v. 36, no. 2, Philadelphia, 2003, responsive hyperactivity dysfunction symptom of the eighth
W.B. Saunders Company, pp xii, 235–407. cranial nerve. J Neurol Neurosurg Psychiatry 81(4):451–455, 2010.
4. Evered D, Lawrenson G: Tinnitus. Ciba Foundation symposium; 85, 30. Ramachandran VS, Hirstein W: The perception of phantom
Summit, NJ, 1981, Ciba Pharmaceutical Co. Medical Education limbs. The D. O. Hebb lecture. Brain 121(Pt 9):1603–1630, 1998.
Administration. viii, 325. 31. Simmel ML: Phantom experiences following amputation in child-
5. Sindhusake D, Golding M, Newall P, et al: Risk factors for tinnitus hood. J Neurol Neurosurg Psychiatry 25:69–78, 1962.
in a population of older adults: the blue mountains hearing study. 32. Moller AR: The role of neural plasticity in tinnitus. Prog Brain Res
Ear Hear 24(6):501–507, 2003. 166:37–45, 2007.
6. Barney R, Bohnker BK: Hearing thresholds for U.S. Marines: 33. Merzenich MM, Nelson RJ, Stryker MP, et al: Somatosensory corti-
comparison of aviation, combat arms, and other personnel. Aviat cal map changes following digit amputation in adult monkeys.
Space Environ Med 77(1):53–56, 2006. J Comp Neurol 224(4):591–605, 1984.
7. Helfer TM, Jordan NN, Lee RB: Postdeployment hearing loss in 34. Yang TT, Gallen CC, Ramachandran VS, et al: Noninvasive detec-
U.S. Army soldiers seen at audiology clinics from April 1, 2003, tion of cerebral plasticity in adult human somatosensory cortex.
through March 31, 2004. Am J Audiol 14(2):161–168, 2005. Neuroreport 5(6):701–704, 1994.
8. Niskar AS, Kieszak SM, Holmes AE, et al: Estimated prevalence of 35. Diesch E, Struve M, Rupp A, et al: Enhancement of steady-state
noise-induced hearing threshold shifts among children 6 to 19 auditory evoked magnetic fields in tinnitus. Eur J Neurosci 19(4):
years of age: the Third National Health and Nutrition Examina- 1093–1104, 2004.
tion Survey, 1988-1994, United States. Pediatrics 108(1):40–43, 36. Arnold W, Bartenstein P, Oestreicher E, et al: Focal metabolic
2001. activation in the predominant left auditory cortex in patients suf-
9. Chung JH, Des Roches CM, Meunier J, et al: Evaluation of noise- fering from tinnitus: a PET study with [18F]deoxyglucose. ORL J
induced hearing loss in young people using a web-based survey Otorhinolaryngol Relat Spec 58(4):195–199, 1996.
technique. Pediatrics 115(4):861–867, 2005. 37. Giraud AL, Chéry-Croze S, Fischer G, et al: A selective imaging of
10. Axelsson A, Sandh A: Tinnitus in noise-induced hearing loss. Br J tinnitus. Neuroreport 10(1):1–5, 1999.
Audiol 19(4):271–276, 1985. 38. Mirz F, Pedersen B, Ishizu K, et al: Positron emission tomography
11. Le Prell CG, Hughes LF, Miller JM: Free radical scavengers vita- of cortical centers of tinnitus. Hear Res 134(1–2):133–144, 1999.
mins A, C, and E plus magnesium reduce noise trauma. Free Radic 39. Norena AJ, Eggermont JJ: Enriched acoustic environment after
Biol Med 42(9):1454–1463, 2007. noise trauma reduces hearing loss and prevents cortical map reor-
12. Kopke R, Beilefeld E, Liu J, et al: Prevention of impulse noise- ganization. J Neurosci 25(3):699–705, 2005.
induced hearing loss with antioxidants. Acta Otolaryngol 125(3): 40. Goodhill V: The management of tinnitus. Trans Am Laryngol
235–243, 2005. Rhinol Otol Soc 54th Meeting:220–231, 1950.
13. Ewert DL, Liu J, Li W, et al: Antioxidant treatment reduces blast- 41. Handscomb L: Use of bedside sound generators by patients with
induced cochlear damage and hearing loss. Hear Res 285(1–2):29– tinnitus-related sleeping difficulty: which sounds are preferred
39, 2012. and why? Acta Otolaryngol Suppl 556:59–63, 2006.
14. Drew S, Davies E: Effectiveness of Ginkgo biloba in treating tin- 42. Bentler RA, Tyler RS: Tinnitus management. ASHA 29(5):27–32,
nitus: double blind, placebo controlled trial. BMJ 322(7278):73, 1987.
2001. 43. McNeill C, Távora-Vieira D, Alnafjan F, et al: Tinnitus pitch,
15. Rejali D, Sivakumar A, Balaji N: Ginkgo biloba does not benefit masking, and the effectiveness of hearing aids for tinnitus therapy.
patients with tinnitus: a randomized placebo-controlled double- Int J Audiol 51(12):914–919, 2012.
blind trial and meta-analysis of randomized trials. Clin Otolaryngol 44. Searchfield GD, Kaur M, Martin WH: Hearing aids as an adjunct
Allied Sci 29(3):226–231, 2004. to counseling: tinnitus patients who choose amplification do
16. Bainbridge KE, Cowie CC, Rust KF, et al: Mitigating case mix better than those that don’t. Int J Audiol 49(8):574–579, 2010.
factors by choice of glycemic control performance measure 45. Surr RK, Montgomery AA, Mueller HG: Effect of amplification on
threshold. Diabetes Care 31(9):1754–1760, 2008. tinnitus among new hearing aid users. Ear Hear 6(2):71–75, 1985.
17. Frisina ST, Mapes F, Kim S, et al: Characterization of hearing loss 46. Folmer RL, Carroll JR: Long-term effectiveness of ear-level devices
in aged type II diabetics. Hear Res 211(1–2):103–113, 2006. for tinnitus. Otolaryngol Head Neck Surg 134(1):132–137, 2006.
18. Wall M, Rosenberg M, Richardson D: Gaze-evoked tinnitus. Neurol- 47. Trotter MI, Donaldson I: Hearing aids and tinnitus therapy:
ogy 37(6):1034–1036, 1987. a 25-year experience. J Laryngol Otol 122(10):1052–1056, 2008.
19. Whittaker CK: Tinnitus and eye movement. Am J Otol 4(2):188, 48. Vernon J, Schleuning A: Tinnitus: a new management. Laryngo-
1982. scope 88(3):413–419, 1978.
20. Cacace AT, Cousins JP, Parnes SM, et al: Cutaneous-evoked tin- 49. Terry AM, Jones DM: Preference for potential tinnitus maskers:
nitus. I. Phenomenology, psychophysics and functional imaging. results from annoyance ratings. Br J Audiol 20(4):277–297, 1986.
Audiol Neurootol 4(5):247–257, 1999. 50. Vernon JA, Meikle MB: Tinnitus masking:unresolved problems.
21. Abel MD, Levine RA: Muscle contractions and auditory percep- Ciba Found Symp 85:239–262, 1981.
tion in tinnitus patients and nonclinical subjects. Cranio 22(3):181– 51. Reavis KM, Rothholtz VS, Tang Q, et al: Temporary suppression
191, 2004. of tinnitus by modulated sounds. J Assoc Res Otolaryngol 13(4):561–
22. Sanchez TG, Buera GC, Lorenzi MC, et al: The influence of vol- 571, 2012.
untary muscle contractions upon the onset and modulation of 52. Henry JA, Schechter MA, Zaugg TL, et al: Clinical trial to compare
tinnitus. Audiol Neurootol 7(6):370–375, 2002. tinnitus masking and tinnitus retraining therapy. Acta Otolaryngol
23. Levine RA, Abel M, Cheng H: CNS somatosensory-auditory inter- Suppl 556:64–69, 2006.
actions elicit or modulate tinnitus. Exp Brain Res 153(4):643–648, 53. Jastreboff PJ, Hazell JW: A neurophysiological approach to tinni-
2003. tus: clinical implications. Br J Audiol 27(1):7–17, 1993.
24. Chole RA, Parker WS: Tinnitus and vertigo in patients with tem- 54. Bartnik G, Fabijanska A, Rogowski M: Effects of tinnitus retraining
poromandibular disorder. Arch Otolaryngol Head Neck Surg 118(8): therapy (TRT) for patients with tinnitus and subjective hearing
817–821, 1992. loss versus tinnitus only. Scand Audiol Suppl 52:206–208, 2001.
25. Rubinstein B, Axelsson A, Carlsson GE: Prevalence of signs and 55. Berry JA, Gold SL, Frederick EA, et al: Patient-based outcomes in
symptoms of craniomandibular disorders in tinnitus patients. patients with primary tinnitus undergoing tinnitus retraining
J Craniomandib Disord 4(3):186–192, 1990. therapy. Arch Otolaryngol Head Neck Surg 128(10):1153–1157, 2002.
56. Westin VZ, Schulin M, Hesser H, et al: Acceptance and commit- 82. Rubinstein JT, Typer RS, Johnson A, et al: Electrical suppression

ment therapy versus tinnitus retraining therapy in the treatment of tinnitus with high-rate pulse trains. Otol Neurotol 24(3):478–485,
of tinnitus: a randomised controlled trial. Behav Res Ther 49(11): 2003.
737–747, 2011. 83. Katon WJ: The Institute of Medicine “Chasm” report: implications
57. Bauer CA, Brozoski TJ: Effect of tinnitus retraining therapy on for depression collaborative care models. Gen Hosp Psychiatry
the loudness and annoyance of tinnitus: a controlled trial. Ear 25(4):222–229, 2003.
Hear 32(2):145–155, 2011. 84. Caffier PP, Haupt H, Scherer H, et al: Outcomes of long-term
58. Yulis S, Brahm G, Charnes G, et al: The extinction of phobic outpatient tinnitus-coping therapy: psychometric changes and
behavior as a function of attention shifts. Behav Res Ther 13(2– value of tinnitus-control instruments. Ear Hear 27(6):619–627,
3):173–176, 1975. 2006.
59. Jang DW, Johnson E, Chandrasekhar SS: Neuromonics tinnitus 85. Kentish RC, Crocker SR, McKenna L: Children’s experience of
treatment: preliminary experience in a private practice setting. tinnitus: a preliminary survey of children presenting to a psychol-
Laryngoscope 120(Suppl 4):S208, 2010. ogy department. Br J Audiol 34(6):335–340, 2000.
60. Davis PB, Paki B, Hanley PJ: Neuromonics tinnitus treatment: 86. Tyler RS, Baker LJ: Difficulties experienced by tinnitus sufferers.
third clinical trial. Ear Hear 28(2):242–259, 2007. J Speech Hear Disord 48(2):150–154, 1983.
61. Vieira D, Eikelboom R, Ivey G, et al: A multi-centre study on the 87. Folmer RL, Griest SE: Tinnitus and insomnia. Am J Otolaryngol
long-term benefits of tinnitus management using Neuromonics 21(5):287–293, 2000.
tinnitus treatment. Int Tinnitus J 16(2):111–117, 2011. 88. House JW, Brackmann DE: Tinnitus: surgical treatment. Ciba
62. Newman CW, Sandridge SA: A comparison of benefit and eco- Found Symp 85:204–216, 1981.
nomic value between two sound therapy tinnitus management 89. Brozoski TJ, Bauer CA, Caspary DM: Elevated fusiform cell activity
options. J Am Acad Audiol 23(2):126–138, 2012. in the dorsal cochlear nucleus of chinchillas with psychophysical
63. Hallam RS, Rachman S, Hinchcliffe R: Psychological aspects of evidence of tinnitus. J Neurosci 22(6):2383–2390, 2002.
tinnitus. In Rachman S, editor: Contributions to medical psychology, 90. Ito J: Tinnitus suppression in cochlear implant patients. Otolaryn-
Oxford, UK, 1984, Pergamon Press, pp 31–53. gol Head Neck Surg 117(6):701–703, 1997.
64. Jakes SC, Hallam RS, Rachman S, et al: The effects of reassurance, 91. Hurtuk A, Dome C, Holloman CH, et al: Melatonin: can it stop
relaxation training and distraction on chronic tinnitus sufferers. the ringing? Ann Otol Rhinol Laryngol 120(7):433–440, 2011.
Behav Res Ther 24(5):497–507, 1986. 92. Rosenberg SI, Silverstein H, Rowan PT, et al: Effect of melatonin
65. Martinez Devesa P, Waddell A, Perera R, et al: Cognitive behav- on tinnitus. Laryngoscope 108(3):305–310, 1998.
ioural therapy for tinnitus. Cochrane Database Syst Rev (1):CD005233, 93. Mathisen H: Phonophobia after stapedectomy. Acta Otolaryngol
2007. 68(1):73–77, 1969.
66. Hesser H, Weise C, Westin VZ, et al: A systematic review and meta- 94. Citron D, 3rd, Adour KK: Acoustic reflex and loudness discomfort
analysis of randomized controlled trials of cognitive-behavioral in acute facial paralysis. Arch Otolaryngol 104(6):303–306, 1978.
therapy for tinnitus distress. Clin Psychol Rev 31(4):545–553, 2011. 95. Woodhouse A, Drummond PD: Mechanisms of increased sensitiv-
67. Hiller W, Haerkotter C: Does sound stimulation have additive ity to noise and light in migraine headache. Cephalalgia 13(6):417–
effects on cognitive-behavioral treatment of chronic tinnitus? 421, 1993.
Behav Res Ther 43(5):595–612, 2005. 96. Nields JA, Fallon BA, Jastreboff PJ: Carbamazepine in the treat-
68. Wagner T, Gangitano M, Romero R, et al: Intracranial measurement of Lyme disease-induced hyperacusis. J Neuropsychiatry Clin
ment of current densities induced by transcranial magnetic stimu- Neurosci 11(1):97–99, 1999.
lation in the human brain. Neurosci Lett 354(2):91–94, 2004. 97. Gordon AG: Abnormal middle ear muscle reflexes and audiosen-
69. Bestmann S, Ruff CC, Blakemore C, et al: Spatial attention sitivity. Br J Audiol 20(2):95–99, 1986.
changes excitability of human visual cortex to direct stimulation. 98. Johnson LB, Comeau M, Clarke KD: Hyperacusis in Williams
Curr Biol 17(2):134–139, 2007. syndrome. J Otolaryngol 30(2):90–92, 2001.
70. Chen R, Cohen LG, Hallett M: Role of the ipsilateral motor cortex 99. Stouffer JL, Tyler RS: Characterization of tinnitus by tinnitus
in voluntary movement. Can J Neurol Sci 24(4):284–291, 1997. patients. J Speech Hear Disord 55(3):439–453, 1990.
71. Pascual-Leone A, Valls-Solé J, Wassermann EM, et al: Responses 100. Andersson G, Lindvall N, Hursti T, et al: Hypersensitivity to sound
to rapid-rate transcranial magnetic stimulation of the human (hyperacusis): a prevalence study conducted via the Internet and
motor cortex. Brain 117(Pt 4):847–858, 1994. post. Int J Audiol 41(8):545–554, 2002.
72. Wang H, Wang X, Scheich H: LTD and LTP induced by transcra- 101. Rubinstein B: Tinnitus and craniomandibular disorders—is there
nial magnetic stimulation in auditory cortex. Neuroreport 7(2):521– a link? Swed Dent J Suppl 95:1–46, 1993.
525, 1996. 102. Bartnik G, Fabijanska A, Rogowski M: Experiences in the treat-
73. Wineland AM, Burton H, Piccirillo J: Functional connectivity net- ment of patients with tinnitus and/or hyperacusis using the habit-
works in nonbothersome tinnitus. Otolaryngol Head Neck Surg uation method. Scand Audiol Suppl 52:187–190, 2001.
147(5):900–906, 2012. 103. Dauman R, Bouscau-Faure F: Assessment and amelioration of
74. Brackmann DE: Reduction of tinnitus in cochlear-implant hyperacusis in tinnitus patients. Acta Otolaryngol 125(5):503–509,
patients. J Laryngol Otol Suppl 4:163–165, 1981. 2005.
75. Quaranta N, Wagstaff S, Baguley DM: Tinnitus and cochlear 104. Hawkins DB: Loudness discomfort levels: a clinical procedure for
implantation. Int J Audiol 43(5):245–251, 2004. hearing aid evaluations. J Speech Hear Disord 45(1):3–15, 1980.
76. Mennemeier M, Chelette KC, Allen S, et al: Variable changes in 105. Newman CW, Sandridge SA, Jacobson GP: Psychometric adequacy
PET activity before and after rTMS treatment for tinnitus. Laryn- of the Tinnitus Handicap Inventory (THI) for evaluating treat-
goscope 121(4):815–822, 2011. ment outcome. J Am Acad Audiol 9(2):153–160, 1998.
77. Piccirillo JF, Garcia KS, Nicklaus J, et al: Low-frequency repetitive 106. Baguley DM, Humphriss RL, Hodgson CA: Convergent validity of
transcranial magnetic stimulation to the temporoparietal junc- the tinnitus handicap inventory and the tinnitus questionnaire.
tion for tinnitus. Arch Otolaryngol Head Neck Surg 137(3):221–228, J Laryngol Otol 114(11):840–843, 2000.
2011. 107. Henry JL, Wilson PH: Coping with Tinnitus: Two Studies of
78. Anders M, Dvorakova J, Rathova L, et al: Efficacy of repetitive Psychological and Audiological Characteristics of Patients with
transcranial magnetic stimulation for the treatment of refractory High and Low Tinnitus-Related Distress. Int Tinnitus J 1(2):85–92,
chronic tinnitus: a randomized, placebo controlled study. Neuro 1995.
Endocrinol Lett 31(2):238–249, 2010. 108. Egede LE: Major depression in individuals with chronic medical
79. Halford JB, Anderson SD: Anxiety and depression in tinnitus suf- disorders: prevalence, correlates and association with health
ferers. J Psychosom Res 35(4–5):383–390, 1991. resource utilization, lost productivity and functional disability. Gen
80. Khedr EM, Rothwell JC, Ahmed MA, et al: Effect of daily repetitive Hosp Psychiatry 29(5):409–416, 2007.
transcranial magnetic stimulation for treatment of tinnitus: com- 109. Hebert S, Carrier J: Sleep complaints in elderly tinnitus patients:
parison of different stimulus frequencies. J Neurol Neurosurg Psy- a controlled study. Ear Hear 28(5):649–655, 2007.
chiatry 79(2):212–215, 2008. 110. Hebert S, Fullum S, Carrier J: Polysomnographic and quantitative
81. Grappengiesser C: Versuche den Galvanismus zur heilung einiger electroencephalographic correlates of subjective sleep complaints
Krankheiten anzuwenden. Berlin 1801. in chronic tinnitus. J Sleep Res 20(1 Pt 1):38–44, 2011.
151 | TINNITUS AND HYPERACUSIS 2344.e3
111. Espie CA, Inglis SJ, Tessier S, et al: The clinical effectiveness of 115. Khalfa S, Dubal S, Veuillet E, et al: Psychometric normalization of
cognitive behaviour therapy for chronic insomnia: implementa- a hyperacusis questionnaire. ORL J Otorhinolaryngol Relat Spec
tion and evaluation of a sleep clinic in general medical practice. 64(6):436–442, 2002.
Behav Res Ther 39(1):45–60, 2001. 116. Stephens SD: The treatment of tinnitus—a historical perspective.
112. Sherlock LP, Formby C: Estimates of loudness, loudness discom- J Laryngol Otol 98(10):963–972, 1984.
fort, and the auditory dynamic range: normative estimates, com- 117. Jüris L, Andersson G, Larsen HC, et al: Psychiatric comorbidity
parison of procedures, and test-retest reliability. J Am Acad Audiol and personality traits in patients with hyperacusis. Int J Audiol
16(2):85–100, 2005. 52(4):230–235, 2013.
113. Stephens SD, Blegvad B, Krogh HJ: The value of some supra- 118. Gold SL, Formby C, Gray WC: Celebrating a decade of evaluation
threshold auditory measures. Scand Audiol 6(4):213–221, 1977. and treatment: the University of Maryland Tinnitus & Hyperacusis
114. Bornstein SP, Musiek FE: Loudness discomfort level and reliability Center. Am J Audiol 9(2):69–74, 2000.
as a function of instructional set. Scand Audiol 22(2):125–131, 1993.
Noise-Induced Hearing Loss 152
Brenda L. Lonsbury-Martin | Glen K. Martin
Key Points
■ Noise-induced hearing loss (NIHL) is second only to age-related hearing loss as the most prevalent
form of hearing loss.
■ NIHL that results from relatively brief noise exposures can be reversible, as happens with exposure
that occurs at an evening spent in a loud entertainment venue.
■ Permanent NIHL is caused by either an acoustic trauma from a brief exposure to a very intense
blast of sound or chronic long-term exposure to loud sounds, such as those associated with a noisy
occupation.
■ An accelerating incidence of high-frequency hearing loss in younger individuals points to early,
chronic noise exposure, possibly from personal entertainment devices.
■ NIHL is a complex condition influenced by environmental and genetic factors.
■ NIHL is associated not only with cochlear injury but also with upstream damage to the auditory
pathway.
■ Genetic association studies have identified genetic factors primarily related to oxidative stress that
influence an individual’s susceptibility to NIHL.
■ Current research on the administration of certain antioxidants or dietary supplements before or
after noise exposure shows promise for developing a pharmacologic treatment for NIHL in the
near future.
■ NIHL is a preventable condition, and the otolaryngologist plays a critical role in educating patients
about protecting their ears from the adverse effects of noise overexposure.
O ne of the most common causes of permanent hearing MEASUREMENT OF NOISE
impairment is exposure to excessive sounds. Hundreds of mil- The term noise is commonly used to designate an undesirable
lions of individuals worldwide have noise-induced hearing loss sound. In the scientific and clinical fields that deal with hearing,
(NIHL), which results in a reduced quality of life because of this term has come to mean any excessively loud sound that has
social isolation and possible relentless tinnitus in addition to the potential to harm hearing. The temporal patterns of envi-
impairment in communication with family members, cowork- ronmental noise are typically described as continuous, fluctuat-
ers, and friends. In the United States alone, approximately 30 ing, intermittent, or impulsive.3 Continuous noise, or steady-state
million workers are exposed to hazardous job-related noises. noise, remains relatively constant, whereas fluctuating noise
The costs are immense: almost $250 million is spent per year increases and decreases in level over time, and intermittent noise
in terms of compensation and early retirement payments for is interrupted for varying time periods. Impulsive noise, or
work-related NIHL.1 Moreover, disability compensation associ- impact noise caused by explosive or metal-on-metal mechanical
ated with occupational hearing loss linked to military service events, have rapidly changing pressure characteristics that
represents an even greater cost to our society. In a recent report consist of intense, brief (i.e., milliseconds) wave fronts, fol-
for fiscal year 2009, the U.S. Government Accountability Office lowed by much smaller reverberations and echoes that occur
reported to Congress that some of the most common impair- over many seconds. The amount of noise, usually referred to
ments for veterans who receive disability benefits were hearing as the sound-pressure level (SPL), is conventionally measured by
related and that annual payments for such conditions exceeded a sound-level meter in decibel (dB) units using a frequency-
$1.1 billion.2 weighting formula called the A-scale. The dBA-scale metric of
This chapter presents and discusses recent perspectives on sound level essentially mimics the threshold-sensitivity curve for
the effects of excessive noise on hearing that address the scien- the human ear, so the low-frequency and high-frequency com-
tific and practical aspects of NIHL. Although NIHL has been ponents are given less emphasis as auditory hazards. Standard
studied experimentally for more than a century, only in the last sound-level meters have electronic networks designed to
few decades have some major breakthroughs occurred in our measure noise magnitude automatically in dBA, whereas to
basic understanding of the ear’s reaction to damaging sounds, measure impulse or impact noise, a more intricate peak-reading
along with a better understanding of the environmental and sound-level meter is needed that is capable of accurately mea-
genetic factors that contribute to NIHL. This steady progres- suring sounds with essentially instantaneous onset times.
sion in the knowledge base about NIHL promises to improve The personal noise dosimeter is typically used to measure
significantly the detection and treatment of this disorder over noise exposure in the workplace. This instrument provides a
the coming years. readout of the noise dose or the percent exposure experienced
2345
by a single worker, typically over a specific shift. The logging than is known about NIHL. Consequently, it is well established
dosimeter integrates a function of sound pressure over time that a single exposure to a severe sound that causes violent
and calculates the daily (8-hour) dose with respect to the changes in air pressure can produce direct mechanical damage
current permissible noise level for a continuous noise of less to the delicate tissues of the peripheral auditory apparatus,
than 90 dBA lasting 8 hours. More recently, personal noise which includes components of the middle ear (tympanic mem-
dosimeters have been offered to the consumer as a portable, brane, ossicles) and inner ear (organ of Corti). In contrast,
compact, and affordable device that can be used to protect regular exposure to less intense but still noisy sounds involves
hearing. The instrument measures and displays noise dose con- the insidious destruction of cochlear components that eventu-
tinuously for 16 hours, and the dosimeter provides an early ally and unavoidably leads to an elevation in hearing thresholds,
warning that the user is approaching overexposure and should along with other common symptoms of hearing impairment.
use hearing protection. A particular noise—such as from power Acoustic trauma was previously a relatively rare event typi-
tools, music concerts, or sporting events—can also be measured cally associated with accidental explosions in industrial settings.
for 2 minutes, and then the estimated dose per hour is calcu- However, military servicemen and servicewomen caught in
lated and displayed to determine whether permissible exposure roadside home-made bomb or improvised explosive device
levels would be exceeded. By putting valuable health informa- blasts in recent armed conflicts are returning home in epi-
tion into the hands of consumers, such easy-to-use, inexpensive demic numbers with tinnitus and profound, permanent hearing
(<$100) dosimeters empower individuals to take appropriate losses.5 Among the blast-related comorbidities is mild traumatic
steps to prevent NIHL. brain injury associated with central auditory processing com-
plaints.6 Overall, then, acoustic trauma is a hearing problem
that is increasing, at least in combat troops. Because many of
NATURE OF THE HEARING LOSS these postdeployment cases are being treated in the private
Depending on the level of the sound exposure, either revers- sector, otolaryngologists may see acoustic trauma in increasing
ible or permanent damage can occur to the peripheral auditory numbers.
end organ. The reversible loss, typically referred to as a tempo- Irreversible NIHL is a specific pathologic state that exhibits
rary threshold shift (TTS), results from exposures to moderately a recognized set of symptoms and objective findings.7 NIHL
intense sounds, such as might be encountered at a live music includes 1) a permanent sensorineural hearing loss with
event or by using noisy power tools. Hearing problems associ- damage principally to cochlear hair cells, primarily to OHCs;
ated with TTS include elevated thresholds, particularly for the 2) a history of long-term exposure to dangerous noise levels
higher midfrequency region that includes the 3- to 6-kHz fre- (i.e., >85 dBA for 8 hours/day) sufficient to cause the degree
quencies. The TTS condition is often accompanied by many and pattern of hearing loss described by audiologic findings;
other common symptoms of hearing impairment that include 3) a gradual loss of hearing over the first 5 to 10 years of expo-
tinnitus, loudness recruitment, muffled sounds, and diplacusis. sure; 4) hearing loss that involves initially the higher frequen-
Depending on the duration of the exposure, recovery from cies, from 3 to 8 kHz, before including frequencies of 2 kHz or
TTS can occur over periods that range from minutes to hours less; 5) speech-recognition scores consistent with the audiomet-
or days. ric loss; and 6) hearing loss that stabilizes after the noise expo-
After exposure, if TTS does not recover before the ear is sure is terminated.
reexposed to excessive sound, a permanent change in hearing A patient with NIHL commonly consults a physician because
can occur that is referred to as a permanent threshold shift (PTS). of difficulties in hearing and understanding ordinary speech,
In PTS, the elevation in hearing thresholds is irreversible, especially in the presence of background noise. Many variations
because lasting structural damage occurs to the critical ele- can be found in the detailed configuration of the audiogram
ments of the cochlea. The precise relationship between the of a noise-damaged ear, depending on the temporal and spec-
TTS and PTS stages of hearing loss caused by noise exposure tral distribution of the noise stimulus and on the stage of
is unknown. Although it seems logical to assume that repeated hearing loss. The pattern of hearing loss most commonly associ-
episodes of TTS would eventually lead to PTS, experimental ated with the earlier stages of NIHL is illustrated in Figure
evidence suggests that the fundamental processes that underlie 152-1, A. The beginning region of impairment involves the
the development of reversible versus permanent NIHL are sensitive midfrequency range, primarily 3 to 6 kHz, and the
unrelated. Nordmann and colleagues4 used a survival fixation corresponding hearing loss is classically described as the “4-kHz
approach to show that the histopathologic manifestations of notch.” This pattern of maximal hearing loss, with little or no
TTS and PTS noise damage to the chinchilla cochlea are dis- loss below 2 kHz, typically occurs regardless of the noise-
tinct. Specifically, TTS was correlated with a buckling of the exposure environment. The audiogram results in Figure 152-1,
supporting pillar cell bodies in the frequency region of the A, also show the sensorineural aspect of NIHL in that thresh-
maximal exposure effect. The morphologic abnormality consis- olds for bone-conducted stimuli are essentially identical to the
tently correlated with PTS was a focal loss of hair cells and a thresholds for air conduction. The profile of noise-induced
complete degeneration of the corresponding population of threshold hearing is usually symmetric for both ears, particu-
nerve fiber endings. Because PTS eventually develops from larly for individuals who have been working in noisy industrial
repeated exposures to stimuli that initially produce only TTS, settings in which “surround” sounds are present.
it is likely that the latter condition is also associated with subtle Commonly, other forms of noxious sound, such as the
changes to the sensitive outer hair cell (OHC) system that go gunfire associated with sport shooting, cause an asymmetric
undetected by conventional light microscopy. pattern of hearing loss similar to the one illustrated in Figure
Traditionally, PTS caused by acoustic overstimulation has 152-1, B. In this case, the ear pointed toward the source of noise
been separated into two distinct classes. One type, called acoustic (gun barrel)—which is the right ear of the left-handed shooter
trauma, is caused by a single, brief exposure to a very intense depicted in Figure 152-1, B—would have worse hearing than
sound (e.g., an explosive blast), and it results in a sudden, the ear directed away from the source (in this example, the left
usually painful loss of hearing. The other type of hearing loss or protected ear) by 15 to 30 dB or more and particularly at
is commonly referred to as noise-induced hearing loss (NIHL) and higher frequencies because of the absence of the protective
results from chronic exposure to less intense levels of sound. A head shadow effect.
great deal more is known about the anatomic processes that The development of a hearing loss caused by habitual expo-
underlie the symptoms of and recovery from acoustic trauma sure to moderately intense levels of noise typically consists of
152 | NOISE-INDUCED HEARING LOSS 2347
–10 –10
RE
0 0
LE
10 10
FIGURE 152-1. Audiometric patterns of <
Hearing level (dB) (ANSI 69)

20 20
hearing levels from patients in begin-
ning stages of noise-induced hearing loss. 30 30
A, Symmetric “4-kHz notch” pattern for a 40 40
44-year-old factory worker. Thresholds for 50 50
bone-conducted stimuli (arrowheads) were
similar to those determined with routine 60 < 60
air-conduction methods. B, Asymmetric 70 70
pattern for a 45-year-old a recreational rifle 80 80
shooter. For this left-handed man, greater
90 90
impairment is seen in the right ear (yellow
circles), compared with the left (red circles), 100 100
because of a protective head shadow effect. 110 110
Arrowheads, unmasked right ear. Shaded
120 120
areas represent air-conduction thresholds 250 500 1K 2K 4K 8K 250 500 1K 2K 4K 8K
for normal-hearing individuals. ANSI, Amer-
ican National Standards Institute. A Frequency (Hz) B Frequency (Hz)
two stages. Initially, the middle to high frequencies exhibit the loss worsened at the higher frequencies and spread to the lower
resulting hearing loss. As the length of time of exposure to loud frequencies. In addition, for average exposure times of less
noise increases, hearing loss becomes greater and begins to than 10 years, hearing levels for the press and hammer opera-
affect adjacent higher and lower frequencies. In a classic cross- tors who were exposed to mean levels of 108 and 99 dB SPL,
sectional study of occupational NIHL, Taylor and colleagues8 respectively, deteriorated similarly. For long-term exposures of
showed the gradual loss of hearing sensitivity in workers caused 10 years or more, the results of Taylor and colleagues8 indicated
by habitual exposure to the intense sounds of drop-forging that hearing losses that resulted from the hammer-induced
tools commonly used in foundries. Figure 152-2 illustrates the impact noise were greater than those that resulted from the
progressive effects of exposure to the wideband noise depicted more continuous noise of the press equipment. Finally, a char-
in Figure 152-2, A, of two types of forging tools, presses and acteristic feature of NIHL clearly documented in Figure 152-2,
hammers, on the magnitude of hearing loss as the length of B and C, is that hearing levels are rarely increased beyond about
exposure increased. For the operators of the press and hammer 70 to 90 dB of hearing loss on average even after more than
equipment (see Fig. 152-2, B and C, respectively), the approxi- 30 years of continuous noise exposure.
mate 10- to 20-dB threshold shifts, typically observed at the
higher frequencies during the first 1 to 2 years of exposure,
grew to be a 20-dB or greater loss, from 3 to 6 kHz, after a 3-year
COCHLEAR DAMAGE
exposure. After an 8-year exposure, a 40-dB or greater thresh- The primary site of anatomic damage is at the level of the
old shift was apparent. mechanosensory receptors of the auditory system’s end organ.
Detailed comparisons of the NIHL growth curves of Figure Loud sound damages the inner hair cells (IHCs) and OHCs of
152-2, B and C, reveal that with continuing exposure, hearing the organ of Corti, and the OHCs in particular are most affected
Noise spectrum Press operators Hammer operators

Threshold (dB HL re: ISO 1975)
Threshold (dB HL re: ISO 1975)
120 10 10
Sound pressure level (dB)
0 0
110 –10 –10
–20 –20
100 –30 –30
–40 –40
90 –50 –50
–60 –60
80 –70 –70
Hammer –80 –80
Press
70 –90 –90
.063 .125 .25 .5 1 2 4 8 0 1 2 3 4 5 6 0 1 2 3 4 5 6
A One-third octave band center B Frequency (kHz) C Frequency (kHz)
frequency (kHz)
Control 1–2 yr 2–3 yr 4–7 yr
8–15 yr 16–31 yr >31 yr

FIGURE 152-2. Development of the audiometric pattern of noise-induced hearing loss (NIHL) as a function of years of exposure to constant occupational
noises. A, Spectra of noise produced by hammer (red circles) and press (yellow circles) equipment, with maximal energy centered in 0.2- to 1-kHz and 0.125-
to 0.5-kHz regions, respectively. Resulting hearing losses are shown for press (B) and hammer (C) operators. NIHL occurred at frequencies above peak energy
in the exposure noise. Geometric symbols represent experimental subjects according to years of noise exposure. Shaded areas indicate effects of aging on
hearing levels in control subjects of similar age (i.e., 23 to 54 years old) who worked in nonnoisy parts of the same drop-forging plants. (Modified from Taylor
W, Lempert B, Pelmear P, Hemstock I, Kershaw J. Noise levels and hearing thresholds in the drop-forging industry. J Acoust Soc Am 1984;76:807-819.)
in the initial stages. In instances that involve very intense acous- of IHCs and OHCs), with its dense network of nerve fibers, to
tic stimulation, supporting-cell elements also can be directly the complete absence of hair cells and their corresponding
affected. Depending on the physical attributes of the exposure nerve fibers (the much lighter adjacent area) can be noted.
stimulus—such as time-varying characteristics or the intensity, Figure 152-3, B, graphically reconstructs the histopathologic
frequency, spectral content, duration, or schedule—noise can features of this cochlea as a cytocochleogram by depicting the
cause damage to hair cells that ranges from total destruction number of remaining hair cells, in the form of percentages,
to effects evident only in the ultrastructure of specialized sub- averaged over 1-mm sections. A typical finding in individuals
cellular regions (e.g., the fusing or bending of the individual exposed to the occupational noise exemplified in this case is
cilia that make up the stereociliary bundle). Whenever degen- the almost symmetric pattern of degeneration observed for the
erative processes or structural modifications to the cochlea two ears. The inset at the top right of the cytocochleogram
reach a significant level, an associated reduction in hearing shows the patient’s audiogram obtained about 1 year before his
capability can be detected. death, which shows the severity of the anatomic damage in
Johnsson and Hawkins9 were among the first investigators to functional terms by revealing an abrupt hearing loss for test
describe the typical patterns of cochlear injury for humans with frequencies below 2 kHz.
chronic exposure to different types of loud sound. The photo- Examination of human temporal bone specimens by other
micrograph of the cochlear tissue in Figure 152-3, A, depicts laboratories10 has yielded documentation of the progressive
some common histopathologic consequences of NIHL for a stages of noise damage as depicted by epidemiologic data such
patient with a lengthy history of industrial noise exposure. The as those of Figure 152-2. First, in the predictable sequence of
authors reported that the 50-year-old patient had worked inter- events, a small region of hair cell and nerve fiber degeneration
mittently over a 5- to 6-year period in an automotive body- appears bilaterally at a cochlear region that corresponds to the
stamping plant and that he had a long history of using 4-kHz notch. Typically, these discrete lesions gradually grow in
recreational firearms. The sharp transition in the basal end a basilar direction (i.e., toward the high-frequency extent of the
(following the uncoiling to the right) from the normal-looking cochlea) to involve a greater portion of the organ of Corti.
organ of Corti (a darkish stripe that corresponds to the region Finally, as exposure to noise continues over years, the remain-
ing sensory and neural elements in the basal end of the cochlea
are destroyed, which results in an abrupt loss of mid- to high-
frequency hearing, such as that depicted by the clinical audio-
gram inset shown in Figure 152-3, B.
RESEARCH ON NOISE-INDUCED
HEARING LOSS
Scientific interest in the damaging effects of excessive sound
on hearing has a long history for many reasons. First, the exper-
imental strategy of exposing animals to noise and examining
their ears for the sites of the resulting acoustic injury was used
in the past as the independent variable in establishing some of
our basic knowledge about hearing. Particularly, with the use
of intense tones as the damaging agent, frequency information
that relates physical distance along the basilar membrane to the
A “best” frequency of the injured region provided an initial basis
for understanding the tonotopicity of the cochlea and the
100 central projections of such frequency-related information.11
% Hair cells remaining
kHz
0.25 0.5 1 2 4 8
90
0 Additionally, noise-damage strategies have been used to con-
80
70
20
tribute to our understanding of the function of IHCs and OHCs
dB
40
60 60
80
by permitting differences in their central terminations in the
50 100
ventral and dorsal cochlear nuclei to be distinguished.12
40
30 Although useful as an analytic strategy, the major impetus
20 behind the more contemporary interest in the effects of noise
10
Nerve fibers
on hearing originates from a desire to understand the funda-
0
mental processes by which exposure to loud sound leads to
Apex 30 25 20 15 10 5 Base acoustic injury. The reward of achieving an appreciation of the
B Length of basilar membrane from basal end (mm) basic processes that underlie NIHL lies in the ability to prevent,
FIGURE 152-3. A, Low-power photomicrograph of a soft surface prepara-
or at least predict, an individual’s susceptibility to PTS or
tion of organ of Corti from the left cochlea of a 50-year-old man exposed perhaps even to initiate regeneration of damaged or lost critical
extensively to occupational noise shows a pattern of abrupt degeneration of cellular components, which would eventually lead to the recov-
the basal region. A small patch of organ of Corti (arrow) remains near the ery of hearing.
basal end. B, Modified cytocochleograms for two ears, along with an inset The research literature on the effects of noise on hearing
audiogram measured 1 year earlier, shows nerve fiber degeneration and a and on the anatomic elements of the ear is voluminous. Early
sharp pattern of hair cell degeneration expressed as percentage remaining experiments performed more than 70 years ago were straight-
per millimeter of length of basilar membrane measured from the basal end. forward anatomic studies based on the strategy of exposing
Note relative symmetry of corresponding abrupt, high-frequency loss of various animal models to intense noises, followed by a general
cochlear elements. Separate curves represent inner hair cells (solid lines) and
outer hair cells (dashed lines) averaged over three rows of outer hair cells
description of the resulting histopathology at the cellular level.
for left (X) and right (O) ears. Yellow horizontal line along the abscissa indicates More modern noise studies in animal models have attempted
presence of nerve fibers in osseous spiral lamina. (Modified from Johnsson LG, to establish a structure/function relationship between noise-
Hawkins JE. Degeneration patterns in human ears exposed to noise. Ann Otol induced morphologic damage and the inability to detect acous-
Rhinol Laryngol 1976;85:725-739.) tic signals.
In this extensive literature, a great disparity in the experi- loss of hair cells through oncosis or apoptosis sometimes occurs
mental findings to relate the effects of missing hair cells to the in noise-injured ears. However, a newly defined third death
corresponding hearing sensitivity is frequently apparent. Such pathway—associated with the lack of a basolateral plasma mem-
contrasting findings and the confusion they have caused are brane, cellular debris arranged in the shape of an intact OHC,
related to numerous confounding variables, which include and a nucleus deficient in nucleoplasm—is more commonly
poor analysis of the problem (e.g., different durations or recov- observed in noise-damaged OHCs.22
ery intervals, exposure frequencies, or bandwidths); lack of
understanding of the limitations of applied functional methods, NEW KNOWLEDGE ABOUT
such as auditory evoked potential or psychoacoustic hearing
tests, and anatomic techniques; and use of animals of unrelated CELLULAR AND MOLECULAR
ages with unknown histories, which could include animals with MECHANISMS OF NOISE-INDUCED
prior exposure to intense sound and/or ototoxic medications.
Also, such disparate studies typically exposed animal subjects
HEARING LOSS
to a single noise at levels much greater than 100 dB SPL in an It has long been known that NIHL is associated with cochlear
attempt to mimic, within a relatively brief study interval, damage damage that initially involves the loss of sensory OHCs. Never-
patterns that develop in humans from intermittent exposure to theless, recently it has been shown that moderate sound over-
much less intense noises over many years. Consequently, stimulation can also produce a more proximal injury that
although early noise studies showed that the longer an animal involves a rapid and irreversible loss of cochlear nerve termi-
was exposed to extreme levels of sound, the greater the result- nals on IHCs, which is followed by a subsequent gradual degen-
ing cochlear injury, they contributed little to our knowledge eration of spiral ganglion cells in the presence of a full recovery
concerning how NIHL develops in humans who work for long of cochlear thresholds and no permanent loss of IHCs and
periods in noisy work settings. OHCs.23,24 Although these new histopathologic findings about
In contrast, research conducted over the past few decades the noise-damaged inner ear are ground breaking, the research
has made use of more realistic experimental protocols that frontiers that currently promise to provide fresh insights into
incorporate intermittent exposure stimuli of intensities and the fundamental basis of NIHL, and eventually into the devel-
durations designed to approximate the effects of a working opment of a cure for this disorder, consist of hair cell regenera-
lifetime of exposure to occupational noise. Additionally, in tion and/or repair, “training” protocols that target the
general, more recent studies have been developed sequentially cochlear-efferent system to make hair cells more resistant, the
within a program of research so that a thorough understanding use of protective agents and strategies before and after noise
of a particular effect is achieved. exposure, and understanding the genetic basis of sus ceptibility
and resistance to the adverse effects of sound overexposure.
ANATOMIC MECHANISMS THAT HAIR CELL REGENERATION AND REPAIR

UNDERLIE NOISE DAMAGE In the late 1980s, several seminal reports on hair cell regenera-
Experimental studies have led to an increased understanding tion in avian species established that hair cells in neonatal and
of some major features of NIHL. It is well-accepted that the adult birds regenerate after exposure to either damaging levels
origin of the 4-kHz notch in the NIHL audiogram is related to of sound25,26 or ototoxic antibiotics.27 Additionally, follow-up
the resonator function of the external auditory ear canal,13 studies showed that recovery of cochlear function accompanied
rather than to indeterminable innate properties of the cochlea, the cellular recovery process.28,29 In the best-studied model for
such as a reduced vascular supply to this region of the organ hair cell regeneration, the neonatal chick, it was shown that
of Corti.14 The primary research interest has always been, new hair cells arose as progeny from an otherwise nondividing
however, in the fundamental mechanism by which the sensory supporting-cell population that was induced to proliferate by
cell degenerates or is damaged after exposure. Numerous the damaging insult.30
mechanisms15 have been proposed that include mechanical Generally, noise-induced hair cell loss in the mammalian
injury caused by severe motion of the basilar membrane, meta- cochlea is irreversible. However, experimental findings from a
bolic exhaustion of activated cells, activity-induced vascular nar- study that used in vitro cultures of neonatal mouse cochleae
rowing that causes ischemia, and ionic poisoning from showed that overexpression of mammalian atonal homolog 1
interruption of the normal chemical gradients of the cochlea (Atoh1)—formerly known as Math1, a basic helix-loop-helix
owing to minuscule disruptions in the organization of sensory transcription factor known to be necessary for hair cell differ-
and supporting cells. entiation during development—leads to an increase in the pro-
Although the many years of experimental research have not duction of extranumerary hair cells.31 Consequently, it seems
yet produced a thorough understanding of damage mecha- that certain cells in the mammalian organ of Corti, at least in
nisms, the current and most convincing morphologic evidence young animals, can be redirected toward a hair cell fate by the
supports a combination of the mechanochemical theories. overexpression of Atoh1.32 In addition, Kawamoto and col-
First, at the ultrastructural level, it is likely that alterations in leagues33 discovered that new hair cells can be grown in a
the stereocilia in the form of shortened or broken rootlets are mature mammalian ear by injecting an adenovirus that carries
involved in the initial pathologic processes that lead to TTS the Atoh1 gene directly into the endolymph of mature guinea
and, if such injuries are not repaired, PTS ensues.16-18 More pigs. Most importantly, more recent studies showed that not
recent findings showed that hair bundles are capable of rebuild- only did Atoh1 induce repair/regeneration of damaged or lost
ing their ultrastructure from top to bottom over a 24- to 48-hour stereocilia and hair cells in the deafened adult guinea pig, but
period, depending on their length.19,20 If damage is so severe substantially improved hearing thresholds were also mea-
that it overwhelms this self-repair mechanism as exposure con- sured.34 These findings that Atoh1 can direct hair cell differen-
tinues, a discrete but direct mechanical disruption likely results tiation and induce hearing function in mature nonsensory cells
in a toxic mixing of endolymph and perilymph through micro- support the notion that viral vector gene therapy based on
breaks in the structural framework of the cochlear duct,21 which expressing crucial developmental genes for cellular and func-
leads to secondary effects that include loss of hair cells and their tional restoration in damaged auditory epithelium may lead
corresponding nerve fibers. Based on morphologic criteria, the some day to a new treatment for NIHL.
PROTECTION FROM CONDITIONING Some studies44 that simply relate the presence or absence of

the contralateral acoustic stimulation-induced reduction of
THE COCHLEAR EFFERENT SYSTEM OAEs in human ears have reported that such suppression is
The outcomes of other experiments indicate that the mam- absent in most industrial workers who otherwise have normal
malian cochlea may be capable of actively adapting to certain OAEs. One implication of such an observation is that a lack of
high-level sounds by undergoing “exposure experience.” The efferent-related activity may be an early indication of cochlear
notion that the cochlea can become resistant over time to the damage from exposure to noise. Experimental studies such as
consequences of excessive sound was reported initially by these will eventually determine whether inherent efferent pro-
noting “conditioning” effects in several animal models.35,36 The cesses can account for and predict the remarkable individual
typical conditioning paradigm consists of providing a preexpo- variation in susceptibility to NIHL. The use of efferent-induced
sure training experience using a moderate-level stimulus that, suppression of evoked OAEs in predicting susceptibility to
at a more intense level, becomes the subsequent overexposure NIHL, or in monitoring of noise effects in hearing-conservation
stimulus. Together, the findings in animal models suggest that programs, represents a promising line of future investigation.
the mammalian cochlea might be capable under certain condi-
tions of dynamically adapting to excessive sound.
For humans, the practical implications of the capacity to PHARMACOLOGIC AND DIETARY
develop a “resistance” to loud sounds are obvious. A follow-up PROTECTION FROM NOISE-INDUCED
study in teenagers used a TTS-type paradigm to show the rel-
evance of resistance training to humans. In this experiment,37
HEARING LOSS
the investigators provided a preexposure training period in It has long been recognized that hypoxia is a major pathogenic
which the young subjects were exposed to 6 hours of pop/rock factor in NIHL. Based on the assumption that oxidative stress
music at around 70 dBA. Threshold shifts in response to a plays a substantial role in the genesis of noise-induced cochlear
10-minute exposure to a 105-dB SPL, one third octave-band injuries that lead to permanent hearing loss, numerous phar-
noise centered at 1 kHz were compared for pretraining versus macologic strategies have been developed, primarily in animal
posttraining intervals. The major result was that the “trained” models, to enhance the intrinsic defense mechanisms of the
ears exhibited significant decreases in TTS compared with their cochlea against this condition.45 Kopke and colleagues46 postu-
baseline values, showing that the so-called conditioning effect, lated several causes of noise-induced oxidative stress, all of
or the development of “resistance,” can be shown in human which are amenable to pharmacologic treatments. Specifically,
subjects, at least under brief TTS-exposure conditions. these investigators proposed that noise-induced oxidative stress
More recent research into the protective role of the cochlear that leads to cochlear injury is related to 1) impaired mitochon-
efferent system in NIHL has depended more on the benefits of drial function with respect to bioenergetics and biogenesis;
diagnostic testing with evoked otoacoustic emissions (OAEs)38 2) excitotoxicity induced by gluatamate, the main excitatory
to predict potential susceptibility to the aftereffects of noise neurotransmitter in the peripheral and central auditory
exposure. This simple, noninvasive, and objective procedure is systems; and 3) depletion of glutathione (GSH), an antioxidant
based on the systematic measurement of a class of cochlear that protects cells from toxins such as free radicals.
responses (i.e., the OAEs) that are primarily generated by the Related experimental work showed a reduction in NIHL and
OHCs.39 Not only are OHCs exquisitely sensitive to the initial hair cell loss in the chinchilla model after application of phar-
effects of acoustic overstimulation, which makes them excellent macologic agents specific to these oxidative stress–related states.
indicators of sound-induced ultrastructural damage, but also Acetyl-L-carnitine, an endogenous mitochondrial membrane
the final common pathway of the descending auditory-efferent compound that helps maintain mitochondrial bioenergetics
system preferentially innervates the OHCs. and biogenesis in the face of oxidative stress; carbamathione,
To take advantage of the ability of OAEs to measure efferent which acts as a glutamate antagonist for cochlear N-methyl-D-
activity, several experimental paradigms were developed, which aspartate receptors; and the GSH-repletion drug, D-methionine
includes a common one40 that uses contralateral acoustic stim- (D-met), all improved hearing in noise-exposed animals as
ulation to elicit medial olivocochlear-induced reductions of indexed by auditory brainstem responses; in addition, reduc-
transient evoked OAEs (TEOAEs) from the ipsilateral test ear. tions were noted in IHC and OHC loss compared with coun-
The other procedure41 is based on measurements of another terpart measures in saline-treated control subjects.47 Bielefeld
subtype of evoked emissions represented by distortion product and colleagues48 showed too that the GSH precursor, N-acetyl-
OAEs (DPOAEs) at the 2f1-f2 frequency. In this strategy, long- L-cysteine, protected the hearing of the chinchilla animal
lasting f1 and f2 primary tones of approximately 1 second are model from the adverse effects of noise overexposure.
applied binaurally to elicit an efferent-based fast adaptation Based on the assumption that a potential mechanism of
response that tests the ability of the combined medial and NIHL is the generation of damaging free radicals through the
lateral cochlear-efferent systems to suppress DPOAEs in the activation of reactive oxygen species such as hydrogen perox-
test ear. ide, hydroxyl radicals, and superoxide, many other studies have
Experiments in guinea pigs documented the ability of the tested the influence of antioxidants and related compounds on
fast-adaptive DPOAE response to predict vulnerability to acous- noise-induced cochlear dysfunction and organ of Corti mor-
tic injury based on the robustness of efferent activity.42 The phology. Together, all these findings support the notion that
robustness of the olivocochlear efferents was inversely corre- combating cellular oxidative stress, principally with prophylac-
lated with the degree of cochlear dysfunction after a subse- tic administration of antioxidant compounds, eliminates noise-
quent noise exposure, in that animals that exhibited large induced cochlear injury in animal models. However, more
adaptive effects showed smaller postexposure losses than those recently, a clinical open trial by some of these investigators49 in
that displayed small amounts of efferent-induced adaptation. normal-hearing individuals exposed to loud live music in a
More recent experiments replicated the earlier results by estab- nightclub did not confirm that N-acetyl-L-cysteine protected
lishing that the relationship of the strength of the adaptive humans against TTS.
activity to reducing noise-exposure aftereffects was even stron- The positive results for D-met,50 which appears to work pri-
ger in awake than in anesthetized subjects.43 It is clear from marily as an antioxidant, as an otoprotective agent for NIHL in
these latter findings that a modification of this assay could easily animal studies have led to a promising clinical trials study. A
be applied to human populations to screen for individuals most phase 3 clinical trial that is prospective, randomized, double-
at risk in noisy environments. blind (subject, caregiver, investigator, outcomes assessor), and
placebo-controlled, named D-Methionine to Reduce Noise-Induced as hypercholesterolemia, hypertriglyceridemia, diabetes, or car-

Hearing Loss (NIHL), is in progress in a cohort study population diovascular disease represented by hypertension. Although
of drill-sergeant instructor trainees at a U.S. Department of many pertinent factors have been uncovered, most data are
Defense weapons training center.51 Thus, it is likely that this inconclusive. In addition, although a few factors, such as pig-
potential otoprotective agent will at least complete the U.S. mentation,55 seem to have some relationship to potentiating
Food and Drug Administration clinical trials process within the noise damage, others, such as age, simply produce additive
next few years. At this rate of development, oral medications effects,56 although this latter relationship remains controver-
that prevent NIHL should be available soon. sial.57 Possibly, as McFadden and Wightman58 suggested in their
Another strategy toward developing a successful therapeutic review of the contribution of the psychoacoustic method toward
approach to noise-induced cochlear damage has been to supply understanding the symptoms of clinical hearing disorders, the
antioxidants from dietary sources. Using several animal models orthogonally based research approach, which assumes a causal
maintained on a combination of nutrients that produced relationship between factors, will not reveal meaningful rela-
increased levels in plasma concentrations of vitamins C and tionships. Perhaps the uncovering of interrelationships among
E and magnesium, Le Prell and colleagues52,53 effectively myriad individual differences by application of a multivariate
reduced both PTS and TTS in CBA/J mice and guinea pigs, test battery would be more successful in identifying the basic
respectively. These results suggest that antioxidative nutraceuti- factors that predict susceptibility to NIHL.
cal compounds can be effective in preventing both TTS and One of the most exciting areas in current experimental
PTS. Together, the success of these pharmacologic/dietary research is aimed at examining the genetic origin of differences
approaches essentially ensures the near-future development of in susceptibility to noise damage using the mouse model. A
a therapeutic intervention that reduces NIHL clinically. clear benefit of the mouse as an experimental animal is the
essentially complete knowledge that exists about the mouse
genome. Additionally, mice from the same inbred strain are
SUSCEPTIBILITY AND GENETIC FACTORS considered to be genetically identical. Consequently, assessing
A long-standing observation in NIHL has been that some ears individual variability to noise damage in subjects that are homo-
are more easily damaged by noise than others. Individually zygous at all chromosomal loci offers a unique opportunity to
varying susceptibilities to noise-induced hearing impairment isolate genetic factors responsible for susceptibility to NIHL.
have been found in humans and research animals. Because of For example, it is known that the inbred, mutant C57BL/6J
the widespread interest in NIHL and its prevention, it is impor- (C57) mouse strain, often used as a model of early age-related
tant to develop valid and reliable indices to predict human hearing loss, is more susceptible to noise damage than the
susceptibility to various noise levels. It is commonly assumed CBA/CaJ (CBA) strain, which is frequently used as a model of
that such variability in susceptibility is a manifestation of bio- normal hearing.59 Other observations that support the poten-
logic factors unique to each subject. A genetically based imper- tiation of noise damage by the age-related hearing loss gene,
fection in the physical characteristics of the cochlea (e.g., cadherin 23 (Cdh23, formerly Ahl), relate to the finding that
stiffness of the cochlear partition) and variability in cochlear when C57 (B6) mice are backcrossed with a mouse strain that
ultrastructure (e.g., density of hair cells) have been proposed exhibits normal aging (e.g., CAST/Ei), the progeny display
as contributing to susceptibility.54 neither age-related hearing loss nor susceptibility to noise expo-
Identifying individual differences among various factors sure aftereffects.60
has long been a focus of research interest. Numerous poten- Just as susceptible mutant mouse strains are readily avail-
tially important variables that have been investigated in the past able, strains with normal cochlear function also exist that are
and continue to be examined include age, gender, race, previ- exceptionally resistant to acoustic overstimulation, such as wild-
ous damage to the cochlea, efficiency of the acoustic reflex, type inbred MOLF/Ei (MOLF) mice. Figure 152-4 compares
smoking habits, and the influence of certain disease states such the effects of an intense noise exposure (8 hours of 105-dB SPL
CBA 65/65 MOLF 65/65

10 10
0 0
DPOAE level (dB SPL)
–10 –10
–20 –20
–30 –30
–40 –40
–50 –50
5 6 7 8 910 20 30 40 50 5 6 7 8 910 20 30 40 50
A Frequency (kHz) B Frequency (kHz)
FIGURE 152-4. A and B, Mean difference distortion product graph—that is, preexposure distortion product otoacoustic emission (DPOAE) levels minus
postexposure DPOAE levels—for 65-dB sound-pressure level (SPL) primary tones that compare effects of an extreme 8-hour exposure with a 10-kHz octave
band of noise (shaded region from approximately 7 to 14 kHz) at 105 dB SPL for 2-month-old CBA mice (A) compared with 2-month-old MOLF mice (B).
Bold horizontal dotted line at 0 indicates no change between preexposure baseline DPOAE levels and postexposure counterparts measured at 2 days (red
circles), 1 week (open yellow circles), and 2 weeks (×) after overexposure. Note the only minor recovery of DPOAEs for CBA mice between 2 days and 2
weeks after exposure, especially for frequencies below 30 kHz. In contrast, DPOAEs for MOLF mice essentially returned to baseline values. Although not
shown here, immediately after exposure, both strains exhibited essentially no DPOAEs greater than approximately 10 kHz. Noise-floor differences (dashed
lines without symbols in lower portion of plots) represent preexposure DPOAEs subtracted from postexposure noise floors to indicate maximum possible
DPOAE loss. Vertical bars represent ±1 standard deviation for 2 days after exposure. CBA, n = 10, 19 ears; MOLF, n = 8, 15 ears.
octave-band noise centered at 10 kHz) on control CBA and determine effective health criteria for controlling such noises.
MOLF mice at 2 months of age.61 Although CBA mice showed Most notably, a great disadvantage in gaining a more complete
only an expected minor recovery of DPOAEs to baseline levels understanding of NIHL in humans is that no more recent
at 2 days and 1 and 2 weeks postexposure, MOLF DPOAEs studies have been done of the hearing status of contemporary
essentially returned to their preexposure levels by 1 to 2 weeks workers, at least not in the countries of North America and
after exposure. In combination, findings in inbred mouse Europe. Reliance on data collected 30 or more years ago, such
models of NIHL provide the basis for applying suitable molecu- as those illustrated in Figure 152-2,8 has likely resulted in under-
lar techniques that permit the mapping of an NIHL gene to estimates of the amount of hearing loss that is due to occupa-
specific chromosomal loci (e.g., identifying differentially tional noise, especially for individuals with intermittent or
expressed genes using DNA microarrays or suppressive subtrac- impulsive noise exposures.
tive hybridization). Successful identification of this gene, and
perhaps its related modifier genes, would have great implica-
tions for developing a diagnostic indicator of the susceptibility EARLY DETECTION OF
of a particular human ear to the adverse effects of sound
overexposure.
NOISE-INDUCED HEARING LOSS
Genetic association studies on oxidative stress genes have One aspect of NIHL that has not received a great deal of
identified the first heritable factors that likely influence an research attention is the development of more sensitive mea-
individual’s susceptibility to NIHL. Konings and coworkers62 sures capable of detecting small, acoustically induced injuries
investigated whether variations in the form of single nucleotide to the organ of Corti (i.e., the beginning stages of NIHL) so
polymorphisms (SNPs) of the catalase gene (CAT), one of the that individuals vulnerable to the long-term damage caused by
genes involved in oxidative stress, influenced noise susceptibil- continuous exposure can be identified. In recent years, evi-
ity. By comparing audiometric data and DNA samples from the dence has been accumulating that the routine audiometric
10% most susceptible and 10% most resistant Swedish and testing of behavioral thresholds to pure tones at octave intervals
Polish noise-exposed workers, significant interactions were does not meet this need, because by the time such a loss is
observed between noise-exposure levels and several SNPs in identified using methods that test behavioral hearing sensitivity,
both populations. These findings indicate that CAT is poten- permanent cochlear damage has already occurred. Many
tially a noise susceptibility gene. Further research by these threshold and suprathreshold psychoacoustic tests to detect
investigators identified hundreds of common point mutations subtle deteriorations in hearing acuity, including psychophysi-
in the genome as susceptibility alleles for genes known to play cal tuning curves and frequency discrimination tasks, either
functional and/or morphologic roles in the cochlea. To date, have not proved to be of general usefulness or have proved to
the most promising results were obtained for genes involved in be too cumbersome methodologically to implement in a clini-
potassium recycling,63 heat shock protein 70,64 protocadherin cal or workplace setting because of the limitations associated
15, and myosin 14.65 With further development of high- with the necessarily brief evaluation periods.
throughput genotyping methods and expansion of SNP data- The diagnostic technique that incorporates OAEs is ideal
bases, the identification of NIHL susceptibility genes promises for assessing the normality of cochlear processing in ears sus-
to lead to genetic tests that identify at-risk individuals and pected of being overstimulated by loud sound because of their
permit personalized gene therapy if necessary. well-recognized sensitivity to the OHC class of receptor cell,
Although the findings of the more recent studies in particu- which is primarily involved in the initial stages of NIHL. The
lar have resulted in advancing our scientific knowledge of the functional status of OHCs in established instances of NIHL has
sound-damage process, many major empiric issues remain to been well described in many more recent studies of the practi-
be satisfied. These issues include development of low-cost tech- cal applicability of evoked OAE testing in the audiology clinic.66
nical methods for controlling noise at the source, physical pro- Numerous reports in the literature have shown that in groups
tection of individuals from excessive exposure, identification of of noise-exposed humans who have been followed serially,
individuals who are in the early stages of NIHL, prediction of reductions in OAE levels are more sensitive than pure tone
the degree of risk from potentially hazardous noises, and deter- audiometric thresholds in detecting the early states of perma-
mination of whether particular individuals or ears already nent noise-induced cochlear damage.67-69 In these studies,
damaged by noise are more susceptible to injury. decreases in emission magnitudes were measured in the
Ethical issues prevent the deliberate exposure of human absence of any change in the corresponding audiometric
subjects to extreme noises as a means of studying NIHL threshold frequencies.
experimentally. However, the complexity of measurements Figure 152-5 illustrates the ability of the two major types of
demanded by the alternate cross-sectional study design that evoked OAEs—the DPOAE, in its graphic, DP-gram form that
describes the hearing of humans exposed occupationally is depicts emission level as a function of the f2 test frequency
considerable. These difficulties include differences inherent in (lower left in Fig. 152-5), and the TEOAE, elicited by clicks, in
the population (e.g., race, gender, presence of ear disease); its spectral form (right plots in Fig. 152-5)—to describe the
problems involved in controlling concomitant exposure to non- configuration of a developing NIHL. The 43-year-old woman
occupational noise or past exposure history; and technical in this example had participated in recreational rifle shooting
problems with the descriptive techniques themselves, which for 3 years before OAE testing, and she claimed to have worn
range from variability in audiometric measures to difficulties in protective headphone devices continuously during this period.
performing valid measurements of the noise environment This right-shouldered shooter came to the otology clinic with
itself. Because of the complicated experimental designs complaints of hearing loss, tinnitus, muffled hearing, and dif-
demanded by all of these controls, few faultless clinical, epide- ficulty in understanding speech in background noise. It is clear
miologic, or experimental studies can be found of the effects from the test results that the magnitude and frequency extents
of excessive noise on hearing in humans. of the TEOAEs reflected the pattern of normal hearing illus-
The importance of performing longitudinal field studies trated by the clinical audiogram at the top left of Figure 152-5.
of communities or particular population segments—such as The DP-gram at lower left clearly shows abnormal activity:
elderly individuals, children, and chronically ill individuals— the right ear (yellow circles) shows below-average response
who have been habitually exposed to loud environmental levels, and the left ear (red circles) exhibits a significant
noises produced by road traffic or aircraft is obvious to reduction in emitted responses for frequencies above 3 kHz.
43 F TEOAE-R
–10 20
0 15 Repro by frequency

10 1 k 2 k 3 k 4 k 5 k (Hz)
TEOAE level (dB SPL)

20 10 97 93 0 0 0 (%)
30 5
40 0
50
–5
60 Right ear
70 Left ear –10
80 –15
90 –20
100
110 –25
120 –30
250 500 1K 2K 4K 8K 0 1 2 3 4 5 6
Frequency (Hz) Frequency (kHz)
TEOAE-L
20 20
Repro by frequency
15 15
1 k 2 k 3 k 4 k 5 k (Hz)

10 10 98 91 82 0 0 (%)
5 5
0 0
–5 –5
–10 –10
–15 –15
–20 –20
–25 –25
–30 –30
0.5 0.7 1 2 3 4 5 6 8 10 0 1 2 3 4 5 6
f2 frequency (kHz) Frequency (kHz)
FIGURE 152-5. Early detection of noise-induced hearing loss in a 43-year-old rifle shooter who complained of muffled hearing, tinnitus, and difficulty hearing
speech in background noise. Note normal pure tone audiogram bilaterally (top left). In corresponding distortion product (DP) graphs (lower left), greater
functional loss seen in the left ear (red circles) compared with the right ear (yellow circles), particularly for frequencies above 3 kHz, which was due to protec-
tive head shadow effect for this right-handed woman. Emission levels for 2f1-f2 distortion product otoacoustic emissions (DPOAEs) are plotted in the bottom
left in response to 75-dB sound pressure level primary tones as a function of the f2 eliciting primary tone. Spectral plots shown on the right are for the transient
(click) evoked otoacoustic emission (TEOAEs). Emitted response (open area) for the better functioning right (R) ear was more prominently distributed above
the related noise floor (shaded area) than were emissions for the left (L) ear for frequencies above 3 kHz. In addition, higher reproducibility (repro) values
for the right ear (top right of each plot) reflected its more robust activity levels. In the DPOAE plot, variability of emission level (± 1 standard deviation) in
normal-hearing ears is represented by the bold dashed lines in the top portion. Similar variability of the related noise floor is indicated by pair of dashed lines
along the bottom of the plot. ANSI, American National Standards Institute.
True to classic principles, the left ear, which was exposed more surviving OHCs in an impaired ear based on tests of OAEs, and
to the muzzle end of the gun, went unprotected by the head particularly the DP-gram, can assist the clinician in achieving
shadow effect. This example of the ability of evoked OAEs to an optimal match between the patterns of hearing-aid amplifi-
detect cochlear pathology caused by noise exposure attests to cation and an NIHL.
the potential usefulness of OAE procedures in identifying Also, especially important to hearing conservation is the
the primary site of pathology associated with hearing com- correct identification of individuals who exhibit pseudohypacu-
plaints secondary to a sensorineural loss and in monitoring the sis and seek monetary compensation for a purported work-
development of potential hearing impairments in hearing- related hearing impairment. An example of this application is
conservation programs. illustrated in Figure 152-8 for a 42-year-old man who was
Other evidence that supports the usefulness of evoked OAEs referred to the audiology clinic for assessment by a local work-
in examining patients with noise damage is illustrated in Figures er’s compensation committee. In this case, the patient claimed
152-6 and 152-7. In Figure 152-6, the results of OAE testing in to have poor hearing caused by on-the-job exposure to intense
a 21-year-old man who had just completed 3 years of military noise to the extent that he could not hear frequencies greater
service in the infantry show the precision of DPOAEs in particu- than about 4 kHz. According to the OAE findings, it is likely
lar in tracking the asymmetric pattern of hearing loss for this that the patient, a wood-lathe operator, had an asymmetric
left-handed shooter. Additionally, the OAE findings presented noise-related hearing loss that was worse in the ear that was
in Figure 152-7 show the ability of evoked emissions to reflect more exposed to the tool; in this case, the right ear. However,
accurately the magnitude and frequency extent of the more based on the type of hearing-loss data presented in Figure
severe but essentially symmetric hearing loss experienced by a 152-1, A, for an industrial worker, it is unlikely that lathe-related
49-year-old man who had been working for more than 20 years noises could cause such a profound deafness for frequencies
in a fish cannery. above 4 kHz. Additionally, the normal levels of DPOAEs and
Both examples attest to several other benefits of OAE testing TEOAEs for frequencies below 2 kHz do not support the
in NIHL patients, including hearing aid fitting and identifying patient’s claim that the elevated audiometric hearing levels
nonorganic hearing loss. A significant advantage of the digital over the low-frequency to midfrequency regions were due to
hearing aid over the older analog models is its ability to provide noise overexposure. Findings such as these support the use of
frequency-specific amplification based on the configuration of objective tests of evoked OAEs in determining the authenticity
a particular patient’s hearing loss. Knowledge of the pattern of of compensation claims for work-related hearing problems.
21 M TEOAE-R
–10 20

10 1 k 2 k 3 k 4 k 5 k (Hz)

20 10 90 0 0 0 0 (%)
30 5
40 0
50
–5
60 Right ear
70 Left ear –10
80 –15
90 –20
100
110 –25
120 –30
250 500 1K 2K 4K 8K 0 1 2 3 4 5 6
DPOAE TEOAE-L
20 20
1 k 2 k 3 k 4 k 5 k (Hz)
10

10 95 53 0 0 0 (%)
5 5
0
0
–5
–5
–10
–10
–15
–20 –15
–25 –20
–30 –25
–35 –30
0.5 0.7 1 2 3 4 5 6 8 10 0 1 2 3 4 5 6
FIGURE 152-6. Early stages of noise-induced hearing loss in a 21-year-old veteran who had just completed a 3-year tour of duty. For this left-handed infan-
tryman, greater hearing loss is evident from approximately 3 to 4 kHz for the right ear (yellow circles) depicted in the audiogram (top left). In the corresponding
distortion production (DP) graph (bottom left), abnormally low levels of distortion product otoacoustic emission (DPOAE) activity are apparent for frequencies
greater than 1.5 kHz, which were poorer for the right ear. Transient (click) evoked otoacoustic emission (TEOAE) spectra on the right also show poorer
emitted responses from 1 to 2 kHz and show lower reproducibility (repro) values for the right (R) ear. Above 2 kHz, no emitted response is seen for either
ear. In the DPOAE plot, variability of emission level (± 1 standard deviation) in normal-hearing ears is represented by the bold dashed lines in the top portion.
Similar variability of the related noise floor is indicated by pair of dashed lines along the bottom of the plot. ANSI, American National Standards Institute.
49 M TEOAE-R
–10 20
10 1 k 2 k 3 k 4 k 5 k (Hz)
20 10 99 93 0 0 0 (%)
30 5
40 0
50
–5
60 Right ear
70 Left ear –10
80 –15
90 –20
100
110 –25
120 –30
250 500 1K 2K 4K 8K 0 1 2 3 4 5 6
Frequency (kHz) Frequency (kHz)
TEOAE-L
20 20
1 k 2 k 3 k 4 k 5 k (Hz)
10
10 96 88 0 0 0 (%)
5 5
0
0
–5
–5
–10
–10
–15
–20 –15
–25 –20
–30 –25
–35 –30
0.5 0.7 1 2 3 4 5 6 8 10 0 1 2 3 4 5 6
FIGURE 152-7. More advanced stage of noise-induced hearing loss in a 49-year-old man who had worked for more than 20 years in a fish cannery. Audio-
grams at top left exhibit symmetric hearing loss for frequencies above 2 kHz. Distortion product otoacoustic emission (DPOAE) plots indicate a symmetric
pattern of dysfunction in a similar manner. Transient evoked otoacoustic emission (TEOAE) spectra on the right also show a lack of emitted responses for
frequencies above 2 kHz. In the DPOAE plot, variability of emission level (± 1 standard deviation) in normal-hearing ears is represented by the bold dashed
lines in the top portion. Similar variability of the related noise floor is indicated by pair of dashed lines along the bottom of the plot. ANSI, American National
Standards Institute; repro, reproducibility.
42 M TEOAE-R
–10 20

10 1 k 2 k 3 k 4 k 5 k (Hz)

20 10 96 87 0 0 0 (%)
30 5
40 0
50
–5
60 Right ear
70 Left ear –10
80 –15
90 –20
100
110 –25
120 –30
250 500 1K 2K 4K 8K 0 1 2 3 4 5 6
TEOAE-L
20 20
Repro by frequency
15 15
1 k 2 k 3 k 4 k 5 k (Hz)

10 10 84 87 0 91 0 (%)
5 5
0 0
–5 –5
–10 –10
–15 –15
–20 –20
–25 –25
–30 –30
0.5 0.7 1 2 3 4 5 6 8 10 0 1 2 3 4 5 6
FIGURE 152-8. A possible case of pseudohypacusis in a 42-year-old factory worker who operated a wood lathe. Audiograms at top left show a relatively
flat hearing loss up to approximately 4 kHz. For frequencies above 4 kHz, the patient claimed that test tones were inaudible. Distortion product otoacoustic
emission (DPOAE) graphs show normal-appearing function up to approximately 3 to 4 kHz, when reductions in distortion product otoacoustic emission
(DPOAE) levels are evident; this occurs initially for the right ear (yellow circles), which was more exposed to the lathe. Transient evoked otoacoustic emission
(TEOAE) spectral plots on the right also show poorer click-evoked OAEs for the right ear. Together, normal levels of evoked emissions for frequencies below
3 kHz and an asymmetric pattern of reduction in OAEs suggest that both exposure to noise and aging contributed to decreased levels of activity for frequen-
cies above 3 kHz. In the DPOAE plot, variability of emission level (± 1 standard deviation) in normal-hearing ears is represented by the bold dashed lines in
the top portion. Similar variability of the related noise floor is indicated by pair of dashed lines along the bottom of the plot. ANSI, American National Standards
Institute; repro, reproducibility.
reported. In a series of experimental studies in the rat model,
INTERACTIVE EFFECTS Fechter and colleagues78 discovered that the simultaneous
It is well established that noise in combination with certain exposure to noise and the environmental pollutants carbon
chemical agents produces stronger reactions than each stimu- monoxide or hydrogen cyanide produced more permanent
lus applied singly. The four major categories of ototoxic drugs hearing loss at the high frequencies than the sum of the losses
are 1) aminoglycoside antibiotics, 2) platinum derivative anti- produced by each agent administered alone. Various other
tumor agents, 3) loop diuretics, and 4) salicylates. The latter chemicals present in the environment as commercial products
two drug classes cause reversible effects, whereas aminoglyco- or chemical intermediaries and contaminants—such as the
sides and platinum derivatives cause permanent damage to the organic solvents toluene and hexane, the pollutants methyl
inner ear and to hearing. Many laboratories have established mercury and lead acetate, and the organic compounds trimeth-
in animal models that kanamycin, neomycin, or amikacin yltin chloride and styrene, used in the manufacture of plastics
applied in combination with different types of noise produces and polyurethane foam and rubber—have been identified as
a marked potentiating interaction.70,71 Other studies of the tem- potent ototoxic agents that can interact synergistically with
poral aspects of interactive effects indicate that the degree of excessive noise. The ototoxicity of environmental agents such
potentiating interaction is the same, whether the drug is given as metals, solvents, and asphyxiants and their interaction with
concurrently with the noise exposure or several months later.72 noise are issues that have received a great deal of attention in
Other evidence from humans73 and from controlled laboratory the literature.79 Although many of these environmental toxi-
research in a rat model74 indicates that additional loss may cants have been associated with direct injury to inner ear struc-
occur when subjects are treated with aspirin and exposed to tures, possible additional anatomic damage to more central
noise concomitantly, although other findings infer that the auditory pathways is also very likely.
combination of salicylate plus noise does not produce greater
effects than noise alone.75 Finally, experimental evidence in OTHER ADVERSE EFFECTS
several animal models showed that the heavy-metal antineoplas-
tic agent cis-diamminedichloroplatinum, commonly known as
CAUSED BY NOISE
cisplatin, significantly increased the amount of hearing and Damage to the vestibular system is a potential problem with
sensory cell losses from exposure to noise.76,77 noise, because balance receptors are coupled physically with
In recent years, the interactive effects of noise with chemical the auditory receptors; that is, they share the membranous
agents common to industry and the environment have been labyrinth. In addition to the anatomic proximity of the
vestibular labyrinth to the acoustic-energy delivery system, the helped attenuate the noise sufficiently to prevent TTS in most
great similarity in cochlear and vestibular hair cell ultrastruc- patients undergoing MRI evaluation. The use of the higher
ture, and the common arterial blood supply of the cochlea and gradient fields that are applied at faster slew rates, which are
vestibular end organs via the same end artery support the pos- used in current functional MRI, demands increased hearing-
sibility of vestibular damage associated with NIHL. Theoreti- protection systems to minimize the risk of noise trauma.91
cally, the limiting membrane, the membranous partition that Other nonauditory problems concern the general bother-
separates the utricle and semicircular canals from the rest of some or fatiguing effects of noise, which may lead to nonspe-
the vestibule, protects most vestibular sensory cells from the cific health disorders because of interference with the restorative
adverse effects of intensive stapes vibration. processes associated with rest and sleep. In conditions of
Nevertheless, some studies of industrial workers and military chronic exposure, noise is considered to act as a biologic
personnel have reported a high occurrence of vestibular symp- stressor that can lead to prolonged activation of the autonomic
toms and signs and complaints of dysequilibrium.80 Such simple nervous system and the pituitary-adrenal complex, which
correlations between noise exposure and vestibular distur- results in general health impairment.92 Noise has also been
bances are highly controversial because of the typical low inci- related to disorders that involve gastrointestinal motility, such
dence of clinical vestibular symptoms associated with gradually as peptic ulcers,93 and, as noted earlier, to circulatory problems
developing NIHL.81 A study of military personnel with mild to such as hypertension.94 Certain types of noise can be annoying
severe NIHL using sophisticated vestibular testing in the form and can lead to emotional unrest.95 Finally, noise can have a
of a computerized rotatory-chair system along with routine elec- deleterious effect on task performance, especially if speech
tronystagmographic measures of caloric responses showed understanding is involved.96 Generally, data relevant to the non-
more direct correlations between hearing loss and vestibular auditory effects of noise tend to be inconclusive, because the
upset.82 In combination, the results showed a symmetric, cen- variables are difficult to identify and isolate for objective study.
trally compensated decrease in the response of the vestibular
end organ associated with a symmetric hearing loss. A more
recent study83 that combined caloric testing with vestibular-
LEGAL ISSUES
evoked myogenic potentials in patients with chronic NIHL One practical issue that the lawmakers of industrialized societ-
showed absent or delayed electrophysiologic potentials, which ies have had to consider concerns the balancing of two conflict-
indicates that the vestibular system, especially the sacculocollic ing goals: How can laborers be protected against the hazards
reflex pathway, was damaged in addition to the cochlear portion of the workplace without placing an enormous financial burden
of the inner ear. on society, either by satisfying compensatory obligations or by
Together these findings imply that a subclinical, well- preventing such work-related effects through costly engineer-
compensated malfunction of the vestibular system is associated ing modifications of the industrial process? Over the years,
with NIHL. Beyond the medicolegal implications is the daunt- concerns about protecting the public and the work force from
ing possibility that a currently asymptomatic vestibulopathy environmental insults such as noise have been written into a
produced by noise exposure might progress to a disturbing combination of law and governmental regulations. Federal,
vertigo under certain environmental conditions.84 state, and community legislative and regulatory actions are con-
Considerable interest has been shown recently in the inter- tinually being reviewed and altered. Although the purpose of
action of vibration and noise, which are common cofactors in this review is not to detail such legal controls, regarding their
the workplace. Although most research shows that vibration historic development or current status, a brief discussion is
alone does not affect hearing, the results of epidemiologic appropriate. For a lucid analysis of governmental statutes
studies in humans and controlled laboratory studies in animal and regulations pertaining to noise control, see the review by
models indicate a synergistic interaction of concomitant vibra- Dobie.7
tion (either whole body or hand-arm vibration) and noise that The major difficulty encountered in composing regulatory
results in an increase in the degree of NIHL.85 control has been in defining in practical terms what constitutes
Exposure to infrafrequency and ultrafrequency sounds a hazardous noise. One popular approach toward expressing
outside of the human hearing range has also been studied. the danger of a particular noise by a simple number is embod-
Infrasonic or vibratory stimuli are defined as sounds in the range ied in the equal-energy principle,97 which assumes that perma-
of 0.1 to 20 Hz, and there are no known instances in which nent damage to hearing is related to total sound energy, a
infrasound alone clearly caused permanent damage to the product of the noise level in dBA and the duration of exposure.
human cochlea. However, studies in the chinchilla model One tenet of this postulate is that an equal amount of noise
showed that the presence of intense sounds in the audible energy causes an equal amount of hearing loss.
frequency range along with simultaneous infrasound increases Burns and Robinson,98 who investigated the hearing loss of
cochlear damage.86 thousands of industrial workers, concluded that the equal-
In contrast, earlier reports have shown detrimental effects energy principle could be applied to determine daily exposure
of microwaves on hearing.87 The thermal properties of ultra- doses, because hearing loss caused by work-related noise expo-
high-frequency sound waves in the gigahertz range, rather than sure seemed to be a simple function of noise energy. Atherley
mechanical energy, seem to have produced these adverse and Martin99 extended the concept to impulse noise by applica-
experimental effects. Overall, it is probably safe to conclude tion of the equivalent continuous sound level (Leq) principle.
that the auditory system’s built-in middle ear filter limits the The Leq is defined as the A-weighted level of a continuous,
extreme frequencies of sound that are hazardous to the steady sound that produces, in a specified interval, an exposure
inner ear.88 that has the same total acoustic energy as that of an actual time-
Magnetic resonance imaging (MRI) systems have acoustic varying sound over the identical interval.100 In other words, if
noise associated with their clinical scanning actions. For spe- one sound contains twice as much energy as a second sound
cific protocols that incorporate faster and noisier sequences, but lasts half as long, both sounds would be characterized by
peaks of 120 to 130 dBA have been measured, particularly the same equivalent sound level. The Leq concept holds that
during high-speed echoplanar imaging.89 Early on, Brummett these two exposures produce the same damage to the ear.
and associates90 showed that sounds generated by MRI are suf- Although notions such as the equal-energy principle have
ficiently intense to cause some TTS in a significant number of proved useful in the practical definition of noise-control vari-
patients. However, their results also showed that earplugs ables, their validity has been more difficult to establish. Over
the years, experimental evidence has been conflicting in that sure to overly intense sounds, particularly with respect to chil-
it has tended to be either for or against the equal-energy rule. dren and adolescents.
Generally, it seems that the principle cannot be generalized Although a known prevention exists, for fiscal and technical
indiscriminantly to stimuli throughout the range of noise reasons, it is unlikely that the general loud sound levels of our
parameters, because exposure to impulse or intermittent noises environment will be reduced. As previously noted, whereas
may lead to more or less degeneration in the organ of Corti clinical trials on the safety and efficacy of certain antioxidant
than would be expected according to the equal-energy princi- compounds to prevent or reverse NIHL are currently in prog-
ple. However, some aspect of the equal-energy concept has ress, to date no proven treatment or cure for noise damage
been adopted by most industrialized nations, including the exists. Consequently, detecting the early stages of NIHL is
United States, as a means of measuring the potential hazard of important to prevent further injury to the crucial sensory-cell
a particular noise exposure. Present regulations use a 5-dB receptors of the organ of Corti.
exchange rate, along with a 90-dBA time-weighted average, to The role of the otolaryngologist is first to identify the cause
define the permissible exposure limit over an 8-hour workday. and extent of a reported hearing loss through systematic
Consequently, exposure to 90 dBA for 8 hours is equivalent in medical and audiometric evaluation. As part of the course of
sound-energy terms to an exposure of 95 dBA for half that otologic management, the patient should be educated about
time. For more complete particulars, see Table G-16 at www the hazards of noise and about preventive measures to preserve
.osha.gov, which details the permissible noise exposures devel- remaining hearing. The physician should make basic decisions
oped by the U.S. Occupational Safety and Health Administra- about the appropriate aural rehabilitative course of action.
tion (OSHA).101 Finally, the otolaryngologist should be sensitive to any emo-
Currently, industries that employ laborers who work where tional problems the patient may have in accepting a hearing
noise levels are greater than 85 dBA—except for farming impairment, which may be dealt with by counseling or special
and construction workers, who work in hard-to-control provisions.
environments—implement a hearing-conservation program Although NIHL is not medically or surgically treatable, it is
that consists of several components as dictated by OSHA.101 almost entirely preventable. Its prevention requires education,
First, preemployment audiometric assessment and annual engineering, and administrative controls and the proper use of
audiometric monitoring are required so that noise-induced hearing protection. One of the otolaryngologist’s most impor-
cochlear impairment can be detected before it becomes too tant contributions is in teaching the patient to guard against
severe. When a hearing loss is identified, the worker must be further losses.106 When recommending the use of personal
notified of the disorder and counseled about the use of per- hearing protectors or reinforcing compliance with ongoing
sonal hearing protectors. The second portion of the conserva- hearing-protection measures, the physician should be aware
tion program requires workers in areas of high noise levels (≥ that the commonly used personal protectors in the form of
85 dBA) to wear ear protectors and to participate in a noise inserted earplugs or earmuffs vary considerably in effectiveness
education program that informs the employee of the hazardous and produce an attenuation that is highly frequency depen-
effects and the correct fitting of personal protectors. An impor- dent.107 When sealed correctly into the ear canal, earplugs
tant part of hearing conservation is the otologic referral, which reduce the noise that reaches the middle ear by 15 to 30 dB,
is essential when in-plant audiometry has detected a substantial and they work best for the mid to higher frequency range (i.e.,
hearing loss. 2 to 5 kHz). Earmuffs are more effective protectors, especially
for frequencies between 500 Hz and 1 kHz, in which noise is
attenuated by 30 to 40 dB.108 In areas with extremely high noise
ROLE OF THE levels, earplugs do not afford sufficient protection, and indi-
viduals should be advised to wear both earplugs and earmuffs.
OTOLARYNGOLOGIST Also, sound energy associated with high noise levels may reach
Patients with NIHL constitute a notable portion of an otolar- the inner ear by passing through vibrating bone and tissues
yngologist’s patient population, particularly for otolaryngolo- adjacent to the ear. Bone-conduction and tissue-conduction
gists who are in private practice. With the increase in the thresholds set a practical limit to the possible attenuation pro-
population older than 65 years, the psychologic, economic, and vided by hearing-protection devices.
social impact of NIHL is still growing. Modern stereo systems A final point concerning the use of hearing protectors
in the form of personal music players or personal listening should be impressed on the patient. When data are considered
devices (PLDs) such as the MP3 and iPod systems have suffi- that relate the maximal protection in dBA to the percentage of
cient noise levels and listening durations to put consumers at time that the devices are worn, it is clear that hearing protectors
risk for developing NIHL.102 Because the number of young should be worn all the time, because if they are removed for
people subject to social noise exposure has tripled since the even a few minutes, their effective cumulative attenuation capa-
early 1980s,103 the widespread use of these devices among chil- bility is severely reduced. Removing hearing protection for only
dren and adolescents is a growing worry. Such concern is sup- 15 minutes of an 8-hour shift can cut protection efficacy in half.
ported by the finding uncovered in the audiometric database Similarly, a poorly fitting hearing protector does not prevent
of a large-scale national cross-sectional survey of an accelerating hearing loss.1
prevalence of sensorineural hearing loss in young adults 20 to In many states, compensation is available for occupational
29 years old.104 This growing prevalence of high-frequency NIHL, and physicians are sometimes required to serve as expert
hearing loss in young adults may relate to an increase in PLD witnesses as to the probable cause of a claimant’s hearing loss.
use. However, the outcome of at least one relevant experimen- Such medicolegal testimony requires that the patient undergo
tal study that used similarly aged subjects, who were systemati- careful otologic and audiometric evaluation to exclude hearing
cally exposed to music from an MP3 player at their preferred losses caused by unrelated ear disorders such as cerumen
listening levels, does not agree with this explanation.105 It is impaction, middle ear effusion, aging, genetic deficits, otoscle-
clear that to demonstrate whether exposure to PLDs as teenag- rosis, and an array of other ear diseases (e.g., Meniere disease,
ers influences hearing loss in old age, long-term longitudinal acoustic neuroma). To permit the reversible effects (i.e., TTS)
cohort studies are needed.103 In any case, otolaryngologists to recover, most states require a recovery time that ranges from
are expected to continue to be prominently involved with the 14 “quiet” hours to 24 weeks away from the occupational noise
problem of NIHL and leisure-time activities that involve expo- source before audiometric assessment. By ruling out organic
disease, giving careful attention to the history of job-related and also know how much more we need to learn about basic ear
recreation-related noise exposure, and documenting the extent processes before such damage can be corrected. As our under-
and degree of involvement of both ears, an informed decision standing of the fundamental mechanisms involved in the
concerning any causal relationship between the noted disability process of NIHL progresses, developing a medical intervention
and the work environment can be made. to minimize permanent injury seems achievable. In the mean-
Hearing impairment is the medical term used to refer to the time, we know what needs to be done to prevent or check the
hearing level at which individuals begin to experience difficul- damage process. In light of the economic impracticability of
ties in everyday life. Hearing impairment manifests in practical noise control at the engineering or administrative level, espe-
terms, such as in a difficulty understanding speech. By the time cially in industry, it seems that education of the public about
an individual becomes aware of decreased speech intelligibility, the potential hazards of excessive sound and the beneficial use
considerable damage to the organ of Corti likely has occurred, of protective devices will be the major weapons against NIHL.
because speech reception is not altered greatly until a hearing Consequently, the educational role of otolaryngologists is para-
loss is more than 40 dB. The amount of loss at frequencies most mount for the conservation of hearing threatened by habitual
important to speech—at 2, 3, and 4 kHz—is used by OSHA101 as noise exposure.
a basis for calculating amounts of compensation, because NIHL
occurs initially at frequencies of 2 kHz or greater. The measure
of hearing impairment is called the hearing handicap, which is
ACKNOWLEDGMENTS
always based on the functional state of both ears. An official The authors acknowledge the long-time support of the National
guide devised by the American Academy of Otolaryngology– Institutes of Health (DC00613, DC03114) and the Veterans
Head and Neck Surgery109 provides a detailed explanation Administration (VA/RRD C7107R, C6212L) for their programs
and formula for evaluating and calculating an NIHL handicap. of research and Barden B. Stagner for conducting data analysis
Generally, the disability benefits of the U.S. Social Security and assisting with assembling the illustrations used here.
Administration110 are less generous than those for either mili-
tary veterans or typical worker’s compensation programs. For a complete list of references, see expertconsult.com.
Because of an increasingly noisy environment and the prob-
ability that many individuals will unwittingly sustain hearing
losses because of exposure to loud sounds at home, on the job, SUGGESTED READINGS
during recreational activity, and through misuse of PLDs, oto- Bao J, Hungerford M, Luxmore R, et al: Prophylactic and therapeutic
laryngologists and other health care professionals who deal functions of drug combinations against noise-induced hearing loss.
with hearing problems should educate the public about hearing Hear Res 304:33–40, 2013.
conservation. Such education is needed, especially for children Furman AC, Kujawa SG, Liberman MC: Noise-induce cochlear neu-
and adolescents, who, as noted previously, are regularly exposed ropathy is selective for fibers with low spontaneous rates. J Neuro-
physiol 110:577–586, 2013.
to the amplified music associated with personal music players, Gallun FJ, Diedesch AC, Kubli LR, et al: Performance on tests of central
dance clubs, and live concerts. A common image that can be auditory processing by individuals exposed to high-intensity blasts.
used to motivate the public and workers in industry to be aware J Rehabil Res Dev 49:1005–1025, 2012.
of the insidious damage of noise exposure is the grass meta- Gallun FJ, Lewis MS, Folmer RL, et al: Implications of blast exposure
phor that represents the sensory cells of the inner ear. Typically, for central auditory function: a review. J Rehabil Res Dev 49:1059–1074,
blades of grass straighten up after they have been bent by being 2012.
walked on. However, if the same patch is walked on day after Guthrie OW, Xu H: Noise exposure potentiates the subcellular distribu-
day, the grass eventually dies and leaves a bare spot; this is tion of nucleotide excision repair proteins within spiral ganglion
similar to what happens to the ear’s hair cells when assaulted neurons. Hear Res 294:21–30, 2012.
Konings A, Van Laer L, Van Camp G: Genetic studies on noise-induced
continually by high-intensity sounds. hearing loss: a review. Ear Hear 30:151–159, 2009.
The physician can be particularly effective in teaching indi- Le Prell CG, Dell S, Hensley B, et al: Digital music exposure reliably
viduals how to recognize the danger signals of potential NIHL, induces temporary threshold shift in normal-hearing human sub-
including the need to shout to be heard and the development jects. Ear Hear 33:e44–e58, 2012.
of the sensation of pain, muffled sound, and tinnitus.111,112 The Maison SF, Usubuchi H, Liberman MC: Efferent feedback minimizes
influence of otolaryngologists as hearing experts in the areas cochlear neuropathy from moderate noise exposure. J Neurosci 33:
of education and motivation can be an important force in pre- 5542–5552, 2013.
venting NIHL. National Institutes of Health: It’s a Noisy Planet: Protect Their Hearing.
Accessed September 3, 2013 at www.noisyplanet.nidcd.nih.gov.
Sliwinska-Kowalska M, Pawelczyk M: Contribution of genetic factors to
SUMMARY noise-induced hearing loss: a human studies review. Mutat Res 752:
61–65, 2013.
We know more now than ever about the workings of the human Verbeek JH, Kateman E, Morata TC, et al: Interventions to prevent
ear, including how it responds initially to excessive sound, and occupational noise-induced hearing loss. Cochrane Database Syst Rev
how it eventually fails to reverse the progressive damage. We 10:CD006396, 2012.
152 | NOISE-INDUCED HEARING LOSS 2358.e1
29. Tucci DL, Rubel EW: Physiologic status of regenerated hair cells
REFERENCES in the avian inner ear following aminoglycoside ototoxicity. Oto-
1. National Institute of Occupational Safety and Health. Available at laryngol Head Neck Surg 103:443–450, 1990.
www.cdc.gov/niosh/docs/2001-103. Accessed September 3, 2013. 30. Cotanche DA, Lee KH, Stone JS, et al: Hair cell regeneration in
2. United States Government Accountability Office, 2011. GAO the bird cochlea following noise damage or ototoxic drug damage:
Report No. 11-114. Hearing loss prevention: improvements to a review. Anat Embryol (Berl) 198:1–18, 1994.
DOD hearing conservation programs could lead to better 31. Zheng JL, Gao WQ: Overexpression of Math1 induces robust
outcomes. production of extra hair cells in postnatal rat inner ears. Nat
3. Occupational Safety and Health Administration, Department of Neurosci 3:480–586, 2000.
Labor: Occupational noise exposure: hearing conservation 32. Bermingham-McDonogh O, Rubel EW: Hair cell regeneration:
amendment. Fed Reg 46:4078–4179, 1981. winging our way towards a sound future. Curr Opin Neurobiol 13:
4. Nordmann AS, Bohne BA, Harding GW: Histopathological differ- 119–126, 2003.
ences between temporary and permanent threshold shift. Hear Res 33. Kawamoto K, Ishimoto S, Minoda R, et al: Math1 gene transfer
139:13–30, 2000. generates new cochlear hair cells in mature guinea pigs in vivo.
5. Helfer TM: Noise-induced hearing injuries, active component, J Neurosci 23:4395–4440, 2003.
U.S. Armed Forces, 2007-2010. MSMR 18:7–10, 2011. 34. Yang SM, Chen W, Guo WW, et al: Regeneration of stereocilia of
6. Helfer TM, Jordan NN, Lee RB, et al: Noise-induced hearing hair cells by forced Atoh1 expression in the adult mammalian
injury and comorbidities among postdeployment U.S. Army sol- cochlea. PLoS One 7:e46355, 2012.
diers: April 2003-2009. Am J Audiol 20:33–41, 2011. 35. Canlon B, Borg E, Flock A: Protection against noise trauma by
7. Dobie RA: Medical-Legal Evaluation of Hearing Loss. ed 2, Toronto, preexposure to a low level acoustic stimulus. Hear Res 34:197–200,
2001, Cengage Delmar Learning. 1988.
8. Taylor W, Lempert B, Pelmear P, et al: Noise levels and hearing 36. Franklin DJ, Lonsbury-Martin BL, Stagner BB, et al: Altered
thresholds in the drop forging industry. J Acoust Soc Am 76:807– susceptibility of 2f1-f2 acoustic-distortion products to the effects of
819, 1984. repeated noise exposure in rabbits. Hear Res 53:185–208, 1991.
9. Johnsson LG, Hawkins JE: Degeneration patterns in human ears 37. Miyakita T, Hellström PA, Frimanson E, et al: Effect of low level
exposed to noise. Ann Otol Rhinol Laryngol 85:725–739, 1976. acoustic stimulation on temporary threshold shift in young
10. McGill TJI, Schuknecht HF: Human cochlear changes in noise- humans. Hear Res 60:149–155, 1992.
induced hearing loss. Laryngoscope 86:1293–1302, 1976. 38. Kemp DT: Stimulated acoustic emissions from within the human
11. Ou HC, Harding GW, Bohne BA: An anatomically based auditory system. J Acoust Soc Am 64:1386–1391, 1978.
frequency-place map for the mouse cochlea. Hear Res 145:123– 39. Brownell WE: Outer hair cell electromotility and otoacoustic emis-
129, 2000. sions. Ear Hear 11:82–92, 1990.
12. Morest DK, Bohne BA: Noise-induced degeneration in the brain 40. Collet L, Kemp DT, Veuillet E, et al: Effect of contralateral audi-
and representation of inner and outer hair cells. Hear Res 9:145– tory stimuli on active cochlear micro-mechanical properties in
151, 1983. human subjects. Hear Res 43:251–261, 1990.
13. Caiazzo AJ, Tonndorf J: Ear canal resonance and temporary 41. Kim DO, Dorn PA, Neely ST, et al: Adaptation of distortion
threshold shift. Otolaryngology 86:820, 1978. product otoacoustic emission in human. J Assoc Res Otolaryngol 2:
14. Schuknecht HF: Pathology of the Ear, Cambridge, MA, 1974, 31–40, 2001.
Harvard University Press. 42. Maison SF, Liberman MC: Predicting vulnerability to acoustic
15. Wang Y, Hirose K, Liberman MC: Dynamics of noise-induced cel- injury with a noninvasive assay of olivocochlear reflex strength.
lular injury and repair in the mouse cochlea. J Assoc Res Otolaryngol J Neurosci 20:4701–4707, 2000.
3:248–268, 2002. 43. Luebke AE, Stagner BB, Martin GK, et al: Adaptation of distortion
16. Clark JA, Pickles JO: The effects of moderate and low levels of product otoacoustic emissions predicts susceptibility to acoustic
acoustic overstimulation on stereocilia and their tip links in the over-exposure in alert rabbits. J Acoust Soc Am 135:1941–1949, 2014.
guinea pig. Hear Res 99:119–128, 1996. 44. Desai A, Reed D, Cheyne A, et al: Absence of otoacoustic emis-
17. Liberman MC: Chronic ultrastructural changes in acoustic sions in subjects with normal audiometric thresholds implies
trauma: serial-section reconstruction of stereocilia and cuticular exposure to noise. Noise Health 1:58–65, 1999.
plates. Hear Res 26:65–88, 1987. 45. Canlon B, Agerman K, Dauman R, et al: Pharmacological strate-
18. Liberman MC, Dodds LW: Acute ultrastructural changes in acous- gies for preventing cochlear damage induced by noise trauma.
tic trauma: serial-section reconstruction of stereocilia and cuticu- Noise Health 1:13–23, 1998.
lar plates. Hear Res 26:45–64, 1987. 46. Kopke RD, Coleman JK, Liu J, et al: Candidate’s thesis: enhancing
19. Rzadzinska AK, Schneider ME, Davies C, et al: An actin molecular intrinsic cochlear stress defenses to reduce noise-induced hearing
treadmill and myosins maintain stereocilia functional architecture loss. Laryngoscope 112:1515–1532, 2002.
and self-renewal. J Cell Biol 164:887–897, 2004. 47. Kopke RD, Jackson RL, Coleman JK, et al: NAC for noise: from
20. Manor U, Kachar B: Dynamic length regulation of sensory stereo- the bench top to the clinic. Hear Res 226:114–125, 2007.
cilia. Semin Cell Dev Biol 19:502–510, 2008. 48. Bielefeld EC, Kopke RD, Jackson RL, et al: Noise protection with
21. Ahmad M, Bohne BA, Harding GW: An in vivo tracer study of N-acetyl-l-cysteine (NAC) using a variety of exposures, NAC doses,
noise-induced damage to the reticular lamina. Hear Res 175:82– and routes of administration. Acta Otolaryngol 127:914–919, 2007.
100, 2003. 49. Kramer S, Dreisbach L, Lockwood J, et al: Efficacy of the antioxi-
22. Bohne BA, Harding GW, Lee SC: Death pathways in noise- dant N-acetylcysteine (NAC) in protecting ears exposed to loud
damaged outer hair cells. Hear Res 223:61–70, 2007. music. J Am Acad Audiol 17:265–278, 2006.
23. Kujawa SG, Liberman MC: Adding insult to injury: cochlear nerve 50. Campbell K, Claussen A, Meech R, et al: D-methione (D-met)
degeneration after ‘temporary’ noise-induced hearing loss. J Neu- significantly rescues noise-induced hearing loss: timing studies.
rosci 29:14077–14085, 2009. Hear Res 282:138–144, 2011.
24. Lin HW, Furman AC, Kujawa SG, et al: Primary neural degenera- 51. D-Methione to Reduce Noise-Induced Hearing Loss (NIHL),
tion in the Guinea pig cochlea after reversible noise-induced NCT01345474. Available at ClinicalTrials.gov/ct2/show/
threshold shift. J Assoc Res Otolaryngol 12:605–616, 2011. NCT01345474. Accessed May 26, 2014.
25. Corwin JT, Cotanche DA: Regeneration of sensory hair cells after 52. Le Prell CG, Gagnon PM, Bennett DC, et al: Nutrient-enhanced
acoustic trauma. Science 240:1772–1774, 1988. diet reduces noise-induced damage to the inner ear and hearing
26. Ryals BM, Rubel EW: Hair cell regeneration after acoustic trauma loss. Transl Res 158:38–53, 2011.
in adult Coturnix quail. Science 240:1774–1776, 1988. 53. Le Prell CG, Dolan DF, Bennett DC, et al: Nutrient plasma levels
27. Cruz RM, Lambert PR, Rubel EW: Light microscopic evidence of achieved during treatment that reduces noise-induced hearing
hair cell regeneration after gentamicin toxicity in chick cochlea. loss. Transl Res 158:54–70, 2011.
Arch Otolaryngol Head Neck Surg 13:1058–1062, 1987. 54. Ward WD: General auditory effects of noise. Otolaryngol Clin North
28. McFadden EA, Saunders JC: Recovery of auditory function follow- Am 12:473–491, 1979.
ing intense sound exposure in the neonatal chick. Hear Res 41: 55. Barrenas ML, Lindgren F: The influence of eye colour on suscep-
205–215, 1989. tibility to TTS in humans. Br J Audiol 25:303–307, 1991.
56. Bies DA, Hansen CH: An alternative mathematical description of 82. Shupak A, Bar-El E, Podoshin L, et al: Vestibular findings associ-

the relationship between noise exposure and hearing loss. J Acoust ated with chronic noise induced hearing impairment. Acta Otolar-
Soc Am 88:2743–2754, 1990. yngol 114:579–585, 1994.
57. Macrae JH: Presbycusis and noise-induced permanent threshold 83. Wang YP, Young YH: Vestibular-evoked myogenic potentials in
shift. J Acoust Soc Am 90:2513–2516, 1991. chronic noise-induced hearing loss. Otolaryngol Head Neck Surg
58. McFadden D, Wightman FL: Audition: some relations between 137:607–611, 2007.
normal and pathological hearing. Ann Rev Psychol 34:95–128, 84. Golz A, Westerman ST, Westerman LM, et al: The effects of
1983. noise on the vestibular system. Am J Otolaryngol 22:190–196,
59. Jimenez AM, Stagner BB, Martin GK, et al: Susceptibility of 2001.
DPOAEs to sound overexposure in inbred mice with AHL. J Assoc 85. Zhu S, Sakakibara H, Yamada S: Combined effects of hand-arm
Res Otolaryngol 2:233–245, 2001. vibration and noise on temporary threshold shifts in healthy sub-
60. Vázquez AE, Jimenez AM, Martin GK, et al: Evaluating cochlear jects. Int Arch Occup Environ Health 69:433–436, 1997.
function and the effects of noise exposure in the B6.CAST+ahl 86. Harding GW, Bohne BA, Lee SC, et al: Effect of infrasound on
mouse with distortion product otoacoustic emissions. Hear Res cochlear damage from exposure to a 4 Hz octave band of noise.
194:87–96, 2004. Hear Res 225:128–138, 2007.
61. Candreia C, Martin GK, Stagner BB, et al: Distortion product 87. Chou CK, Guy AW, Galambos R: Auditory perception of radio-
otoacoustic emissions show exceptional resistance to noise expo- frequency electromagnetic fields. J Acoust Soc Am 71:1321–1334,
sure in MOLF/Ei mice. Hear Res 194:109–117, 2004. 1982.
62. Konings A, Van Laer L, Pawelczyk M, et al: Association between 88. Rosowski JJ: The effects of external- and middle-ear filtering on
variations in CAT and noise-induced hearing loss in two indepen- auditory threshold and noise-induced hearing loss. J Acoust Soc Am
dent noise-exposed populations. Hum Mol Genet 16:1872–1883, 90:124–135, 1991.
2007. 89. Foster JR, Hall DA, Summerfield AQ, et al: Sound-level measure-
63. Pawelczyk M, Van Laer L, Fransen E, et al: Analysis of gene poly- ments and calculations of safe noise dosage during EPI at 3 T.
morphisms associated with K+ ion circulation in the inner ear of J Magn Reson Imaging 12:157–163, 2000.
patients susceptible and resistant to noise-induced hearing loss. 90. Brummett RE, Talbot JM, Charuhas P: Potential hearing loss
Ann Hum Genet 73:411–421, 2009. resulting from MR imaging. Radiology 169:539–540, 1988.
64. Konings A, Van Laer L, Michel S, et al: Variations in HSP70 genes 91. Ravicz ME, Melcher JR: Isolating the auditory system from acous-
associated with noise-induced hearing loss in two independent tic noise during functional magnetic resonance imaging: exami-
populations. Eur J Hum Genet 17:329–335, 2009. nation of noise conduction through the ear canal, head, and
65. Konings A, Van Laer L, Wiktorek-Smagur A, et al: Candidate gene body. J Acoust Soc Am 109:216–231, 2001.
association study for noise-induced hearing loss in two indepen- 92. Perron S, Tetreault LF, King N, et al: Review of the effect of air-
dent noise-exposed populations. Ann Hum Genet 73:215–224, craft noise on sleep disturbance in adults. Noise Health 14:58–67,
2009. 2012.
66. Lonsbury-Martin BL, Martin GK: Otoacoustic emissions. In 93. Doring HJ, Hauf G, Seiberling M: Effects of high-intensity sound
Celeste G, editor: Clinical Tests in Auditory Neurophysiology, New on the contractile function of the isolated ileum of guinea pigs
York, 2013, Thieme. and rabbits. In Tobias JV, Jansen G, Ward WD, editors: Noise as a
67. Lapsley Miller JA, Marshall L, Heller LM, et al: Low-level otoacous- Public Health Problem: Proceedings of the Third International Congress,
tic emissions may predict susceptibility to noise-induced hearing Rockville, MD, 1980, American Speech-Language-Hearing Asso-
loss. J Acoust Soc Am 120:280–296, 2006. ciation, pp 288–293.
68. Seixas NS, Neitzel R, Stover B, et al: 10-year prospective study of 94. Narlawar UW, Surjuse BG, Thakre SS: Hypertension and hearing
noise exposure and hearing damage among construction workers. impairment in workers of iron and steel industry. Indian J Physiol
Occup Environ Med 69:643–650, 2012. Pharmacol 50:60–66, 2006.
69. Neitzel RL, Stover B, Seixas NS: Longitudinal assessment of noise 95. Passchier-Vermeer W, Passchier WF: Noise exposure and public
exposure in a cohort of construction workers. Ann Occup Hyg health. Environ Health Perspect 108:123–131, 2000.
55:906–916, 2011. 96. Larsby B, Hällgren M, Lyxell B, et al: Cognitive performance and
70. Brummett RE, Fox KE, Kempton JB: Quantitative relationships of perceived effort in speech processing tasks: effects of different
the interaction between sound and kanamycin. Arch Otolaryngol noise backgrounds in normal-hearing and hearing-impaired sub-
Head Neck Surg 118:498–500, 1992. jects. Int J Audiol 44:131–143, 2005.
71. Tan CT, Hsu CJ, Lee SY, et al: Potentiation of noise-induced 97. Ward WD, Nelson DA: On the equal-energy hypothesis relative
hearing loss by amikacin in guinea pigs. Hear Res 161:72–80, 2001. to damage-risk criteria in the chinchilla. In Robinson DW,
72. Ryan AF, Bone RC: Non-simultaneous interaction of exposure to editor: Occupational Hearing Loss, London, 1971, Academic Press,
noise and kanamycin intoxication in the chinchilla. Am J Otolar- pp 225–231.
yngol 3:264–272, 1982. 98. Burns W, Robinson DW: Hearing and Noise in Industry, London,
73. McFadden D, Plattsmier HS: Aspirin can potentiate the temporary 1970, Her Majesty’s Stationery Office.
hearing loss induced by intense sounds. Hear Res 9:295–316, 1983. 99. Atherley GRC, Martin AM: Equivalent-continuous noise level as a
74. Carson SS, Prazma J, Pulver SH, et al: Combined effects of aspirin measure of injury from impact and impulse noise. Ann Occup Hyg
and noise in causing permanent hearing loss. Arch Otolaryngol 14:11–28, 1971.
Head Neck Surg 115:1070–1075, 1989. 100. Goldstein J: Fundamental concepts in sound measurement. In
75. Spongr VP, Boettcher FA, Saunders SS, et al: Effects of noise and Lipscomb DM, editor: Noise and Audiology, Baltimore, 1978, Uni-
salicylate on hair cell loss in the chinchilla cochlea. Arch Otolaryn- versity Park Press, pp 3–58.
gol Head Neck Surg 118:157–164, 1992. 101. Occupational Safety and Health Administration. Available at
76. Gratton MA, Salvi RJ, Kamen BA: Interaction of cisplatin and www.osha.gov. Accessed September 3, 2013.
noise on the peripheral auditory system. Hear Res 50:211–223, 102. Levey S, Levey T, Fligor BJ: Noise exposure estimates of urban
1990. MP3 player users. J Speech Lang Hear Res 54:263–277, 2011.
77. Laurell GF: Combined effects of noise and cisplatin: short- and 103. Sliwinska-Kowalska M, Davis A: Noise-induced hearing loss. Noise
long-term follow-up. Ann Otol Rhinol Laryngol 101:969–976, 1992. Health 14:274–280, 2012.
78. Fechter LD, Chen GD, Rao D: Chemical asphyxiants and noise. 104. Agrawal Y, Platz EA, Niparko JK: Prevalence of hearing loss and
Noise Health 4:49–61, 2002. differences by demographic characteristics among US adults: data
79. Morata TC, Little MB: Suggested guidelines for studying the com- from the National Health and Nutritional Examination Survey,
bined effects of occupational exposure to noise and chemicals on 1999-2004. Arch Intern Med 168:1522–1530, 2008.
hearing. Noise Health 4:73–87, 2002. 105. Hodgetts WE, Rieger JM, Szarko RA: The effects of listening envi-
80. Raghunatch G, Suting LB, Maruthy S: Vestibular symptoms in ronment and earphone style on preferred listening levels of
factory workers subjected to noise for a long period. Int J Occup normal hearing adults using an MP3 player. Ear Hear 28:290–297,
Environ Med 3:136–144, 2012. 2007.
81. Pyykko I, Aalto H, Ylikoski J: Does impulse noise induce vestibular 106. Lusk SL: Preventing noise-induced hearing loss. Nurs Clin North
disturbances? Acta Otolaryngol Suppl 468:211–216, 1989. Am 37:257–262, 2002.
152 | NOISE-INDUCED HEARING LOSS 2358.e3
107. Neitzel R, Somers S, Seixas N: Variability of real-world hearing 110. Social Security Administration: The Social Security Quick Calcula-
protector attenuation measurements. Ann Occup Hyg 50:679–691, tor page. Available at www.ssa.gov/OACT/quickcalc. Accessed
2006. September 2, 2013.
108. Giardino DA, Durkt G, Jr: Evaluation of muff-type hearing protec- 111. Folmer RL: The importance of hearing conservation instruction.
tors as used in a working environment. Am Ind Hyg Assoc J 57:264– J Sch Nurs 19:140–148, 2003.
271, 1996. 112. Peters RJ: The role of hearing protectors in leisure noise. Noise
109. American Academy of Otolaryngology–Head and Neck Surgery. Health 5:47–55, 2003.
Available at entnet.org. Accessed September 3, 2013.
Infections of the Labyrinth 153
John C. Goddard | William H. Slattery III
Key Points
■ Cytomegalovirus is the most common cause of nongenetic hearing loss in the United States.
■ The use of antiviral medications in the treatment of children with congenital cytomegalovirus
infection may help minimize deterioration in hearing.
■ Congenital rubella remains an important cause of sensorineural hearing loss (SNHL) worldwide.
■ Prevention of congenital rubella through routine vaccination is the best method of avoiding SNHL
and other sequelae.
■ Early identification and treatment of children with congenital syphilis will often help avoid late
complications associated with labyrinthine involvement.
■ Measles and mumps infections remain important causes of childhood hearing loss in countries that
lack routine vaccination programs.
■ Suppurative labyrinthitis may develop as a sequela of bacterial and nonbacterial meningitis as well
as from infectious conditions that affect the middle ear, mastoid, and temporal bone.
■ Routine vaccination against common bacterial pathogens, widespread use of antibiotic therapy, and
early identification of infection have all led to the reduction in the number of meningogenic and
otogenic cases of suppurative labyrinthitis.
■ Idiopathic disorders such as sudden SNHL, vestibular neuritis, and labyrinthitis have not
conclusively been linked to an infectious etiologic agent.
I nfections of the labyrinth may arise from direct invasion by a noninvasive manner that avoids loss of cochlear and/or ves-
bacteria, fungi, parasites, and viruses as well as from toxic sub- tibular function.9 Although sampling of perilymph may be
stances associated with an adjacent infectious process. In the achieved during cochlear implant surgery and from labyrin-
preantibiotic era, suppurative (bacterial) labyrinthitis was a fre- thine tissue collected during surgeries that sacrifice the inner
quent sequela of acute pyogenic otitis media and often increased ear (i.e., labyrinthectomy), patients who undergo these proce-
the likelihood of associated meningitis and subsequent death.1 dures do not always have a history of labyrinthine infection.10
In developed countries, routine use of antibiotic therapy has Moreover, the time interval between a suspected labyrinthine
significantly reduced the rate of otitis media–related complica- infection and subsequent surgical intervention may be signifi-
tions, and suppurative labyrinthitis occurs only rarely.2 Syphi- cantly delayed, which makes meaningful analysis difficult. Alter-
litic (luetic) involvement of the labyrinth has been well natively, postmortem temporal bone histopathologic analysis
documented histopathologically and was a frequently observed
clinical picture during the 1900s.3 As the rates of syphilis have
fallen significantly within the United States, so too have cases
Box 153-1. ELEMENTS NEEDED FOR CONFIRMATION
of luetic-induced sensorineural hearing loss (SNHL) and ves-
OF AN INNER EAR INFECTION
tibular dysfunction.4 Measles, mumps, and rubella (MMR)
infections have been a significant source of morbidity and mor- 1. Clinical association of infectious agent with a specific cochlear or
tality worldwide, with associated hearing loss in certain cases.5-7 vestibular syndrome
The development of MMR vaccines in the 1960s, however, led a. Epidemiologic studies of infectious agent and syndrome
to a dramatic decline in the incidence of these viral diseases, b. Clinical studies of syndrome and isolation of infectious agent at
other sites or serologic antibody titer rise
with a concomitant decrease in the number of cases with
2. Clear evidence of infectious agent presence within inner ear tissue
hearing loss.8 Whereas the United States and other developed a. Isolation of infectious agent vRNA or mRNA, excluding mRNA
countries have seen a decline in the overall number of labyrin- latency-associated transcripts, in inner ear tissue
thine infections associated with the above-named conditions, b. Histologic demonstration in inner ear tissue by electron
the incidence of these conditions in developing countries microscopy of infectious agent or by light microscopy finding of
remains significant. Consequently, it is imperative that otolar- inclusion bodies or characteristic cell morphology plus isolation of
yngologists remain knowledgeable about all of the potential infectious agent at other body sites
causes of labyrinthine infections. 3. In experimental animals, demonstration that suspect infectious agent
Identification and isolation of a specific causative agent in can cause similar auditory or vestibular signs and inner ear pathology
suspected cases of labyrinthine infection remains elusive (Box Modified from Davis LE. Neurovirology of deafness, labyrinthitis and Bell’s
153-1). Much of the difficulty in determining causation stems palsy. In Johnson RT, ed: Neurovirology. Minneapolis: American Academy of
from an inability to obtain tissue samples from the inner ear in Neurology; 2002.
2359
remains an invaluable tool for examining the architecture of chamber filled with sodium-rich perilymph. The membranous
the labyrinth, particularly in patients with known clinical histo- labyrinth is a completely separate system suspended within this
ries. However, the physical and chemical processing of tempo- perilymph-filled chamber and is composed of potassium-rich
ral bone specimens limits the ability to use certain analytic endolymph. The membranous utricular and saccular ducts
techniques, such as the polymerase chain reaction (PCR), to connect their respective end organs with the endolymphatic
identify viral or other infectious agents.9,11 It is hoped that con- duct, which travels within the bony vestibular aqueduct and
tinued refinement of microbiologic, viral, and genetic tech- terminates as the endolymphatic sac along the posterior face
niques along with the development of novel approaches to of the petrous bone.
safely sample the inner ear will allow for more consistent and The vasculature of the inner ear will not be reviewed here,
reliable identification of the sources of labyrinthine infections but its importance as a potential route of (hematogenous)
in the future. spread of infection to the inner ear must be remembered.
Specific anatomic aspects of the labyrinth provide the remain-
ing routes for spread of infection to the inner ear; these include
BACKGROUND ANATOMY the cochlear aqueduct, internal auditory canal (IAC), and oval
and round windows. The cochlear aqueduct is a bony channel that
AND PHYSIOLOGY contains subarachnoid-like tissue known as the periotic duct.12
The inner ear has been dubbed the labyrinth, owing to the Although it is believed that the cochlear aqueduct is not respon-
complexity of its anatomic design. Although it is beyond the sible for the transmission of high pressure levels of cerebrospi-
scope of this chapter to review the anatomy and physiology of nal fluid (CSF) to the inner ear seen in perilymphatic gushers,
the labyrinth in its entirety, a basic understanding is a prereq- it may serve as a conduit for the spread of infection to and from
uisite to a discussion of infections of the labyrinth. Functionally the intracranial cavity.13-15 The cochlear aqueduct traverses the
characterized by six different sensory end organs—the cochlear inferior petrous bone from the subarachnoid space of the pos-
organ of Corti, the three ampullae of the semicircular canals, terior fossa to the basal aspect of the cochlea and opens into
and the utricular and saccular maculae—the labyrinth is more the medial aspect of the scala tympani. Some histologic studies
broadly characterized as a bony outer shell and a membranous of the cochlear aqueduct suggest higher patency in children,
internal compartment (Fig. 153-1). The shell of the labyrinth whereas others demonstrate patency along the entire length of
comprises otic capsule bone, which defines the shape of the the aqueduct in 34% of specimens.13-15 The cribrose area at the
semicircular canals, vestibule, and cochlea and encloses a fundus of the IAC serves as the point of entry of the cochlear
Crus commune Horizontal semicircular duct
Superior Posterior semicircular duct

semicircular duct
Ampulla
Utricle
Endolymphatic
sac
Dura
Ampulla
Stapes in
Endolymphatic oval window
duct
Saccule Vestibular
cecum
Round window
Helicotrema
Cochlear duct
Scala tympani Perilymphatic duct
Scala vestubuli Ductus reuniens

Figure 153-1. The membranous labyrinth.
153 | INFECTIONS OF THE LABYRINTH 2361
nerve fibers into the modiolus. In cases of congenital deficiency likely to have a child with a significant CMV infection than
of the cribrose area, CSF pressure may be transmitted more women infected during pregnancy.21,23 However, reactivation of
completely to the perilymph.16 This location may also serve as a latent CMV infection (i.e., secondary CMV infection) remains
a route for spread of infection between the intracranial cavity a potential means of maternal-fetal transmission.
and the inner ear. The final potential anatomic routes of spread The current gold standard for the diagnosis of congenital
are from the oval and round windows, which provide the most CMV infection is isolation of the virus from urine, saliva, blood,
direct interface between the middle ear and the labyrinth. or other body fluids within the first 2 to 3 weeks of life.21,23 PCR
Although the stapes footplate serves as a bony barrier at the analysis of CMV DNA has now become the preferred technique
level of the oval window, the round window membrane is three for viral isolation and has replaced viral culture methods of
to four cell layers thick and may offer less resistance to the detection.24,25 Although interest has been shown in using the
spread of various molecules.17 dried blood samples routinely obtained for genetic screening
purposes at birth as a means of identifying CMV DNA, the
sensitivity of this method has been poor when compared with
PERINATAL LABYRINTHINE PCR testing of saliva.10,25-27 Peripheral blood antibody detection
is also not useful for diagnosing congenital CMV. Finally, testing
INFECTIONS performed more than 3 weeks after birth is not considered
A number of infections may affect a pregnancy and jeopardize adequate for a diagnosis of congenital CMV because of the high
the health of the developing fetus or newborn baby. These frequency of asymptomatic CMV infection among infants aged
perinatal infections are typically viral and may impact a variety 3 weeks and older.
of organ systems, including the inner ear. The most common The majority of children born with congenital CMV are
perinatal viral infections that affect the labyrinth are cytomega- asymptomatic, and 80% never develop any significant symp-
lovirus (CMV) and rubella, although herpes simplex virus toms or disabilities.21 Occurring rarely, the most severe form of
(HSV) and other viruses may affect the inner ear as well. Non- congenital CMV, termed cytomegalic inclusion disease (CID),
viral perinatal infections may affect the labyrinth and include affects multiple organ systems and is associated with significant,
toxoplasmosis (parasitic) and syphilis (bacterial), among permanent disabilities.21,23 In patients with this severe pheno-
others. type, SNHL, microcephaly, and learning difficulties are seen in
nearly 50% of cases.28 Hepatosplenomegaly, jaundice, blue-
berry muffin rash, and computed tomography (CT) evidence
PERINATAL VIRAL LABYRINTHINE of intracerebral calcifications are also typical of CID.23 Whereas
the implications for those with CID are fairly clear, the prepon-
INFECTIONS derance of newborns with congenital CMV infection are asymp-
Viruses have been implicated in the development of labyrin- tomatic and have an unpredictable course. Early longitudinal
thine infections for decades. However, as mentioned above, the studies that examined the percentage of asymptomatic cases of
ability to identify and isolate a causative organism in cases of congenital CMV with SNHL reported rates that ranged from
labyrinthine infection remains challenging. Although strong 7% to 15%.29-33 Among these patients, SNHL was often bilateral
clinical evidence supports a causative relationship between and ranged from mild to profound, although unilateral, pro-
many viral infections and the development of cochleovestibular gressive, and delayed-onset losses were also noted.29-33 Addition-
symptoms, CMV is the only perinatal viral infection that affects ally, newborn screening was normal in up to 50% of cases.30
the labyrinth that has actually been isolated from perilymph or More recent studies that examined the rates and characteristics
detected within inner ear tissue.18-20 Other congenital viruses— of hearing loss among asymptomatic patients with congenital
such as rubella, HSV, and human immunodeficiency virus CMV infection found rates of SNHL to be as high as 23%.26,34-36
(HIV)—have not yet been identified within similar inner ear Examination of peripheral blood viral load levels suggests the
samples. risk of SNHL may actually be lower in patients with reduced
viral loads.37 However, specific factors that influence the pattern
Congenital CMV and severity of SNHL in asymptomatic cases of congenital CMV
According to the Centers for Disease Control and Prevention remain unclear. The data concerning vestibular abnormalities
(CDC), CMV is the most common congenital viral infection among patients with congenital CMV are more limited, but
and the most common cause of nongenetic hearing loss in the reports do suggest that patients who are symptomatic at birth
United States.21 Approximately 1 in 150 children is born with can develop vestibular deficits over time.38
congenital CMV infection, which translates into 30,000 chil- The clinical evidence that validates congenital CMV-related
dren per year in the United States alone. Clinical symptoms labyrinthine infections has been strengthened by the ability of
and permanent disabilities will occur in up to 15% to 20% of researchers and clinicians to isolate CMV viral particles from
cases of congenital CMV, including the possible development inner ear tissue.18-20,39-42 In the 1970s, Davis and colleagues9,42,43
of SNHL.21-23 The nature of the hearing loss in these children cultured CMV from perilymph at autopsy from an infant with
is quite variable, and it may be delayed, progressive, bilateral, CID and subsequently identified CMV antigen in cells of the
or even fluctuating.23 Because of the potentially delayed pre- membranous labyrinth and intracellular inclusions within the
sentation of CMV-related hearing loss, newborn hearing screen- inner ear (Fig. 153-2). Prior descriptions of temporal bone
ing may be normal.23-25 histopathologic findings observed in infants dying of symptom-
Congenital CMV infections occur primarily via transmission atic congenital CMV suggest significant changes within the
in utero, although they may occur at the time of delivery or entire endolymphatic system but little histologic damage to the
postnatally. Whereas mothers are the source of transmission to auditory and vestibular nerves, along with the spiral and ves-
their offspring, pregnant women often become infected tibular ganglia.41-45 Hydrops of the cochlea and saccule and
through sexual contact with a partner or spouse or through collapse of the Reissner membrane have also been observed.9
contact with the saliva or urine of an infected child.21 Maternal Teissier and colleagues39 more recently examined six CMV-
CMV infection can occur at any time before or during preg- infected fetuses that ranged in age from 19 to 35 weeks post-
nancy and is typically asymptomatic, although mononucleosis- conception. Cytomegalic cells with inclusion bodies were noted
like symptoms may develop.21 Women who are infected 6 within the marginal cells of the stria vascularis and nonsensory
months or more prior to becoming pregnant are much less epithelium of the vestibular apparatus.39 Extensive involvement
minimizing clinical symptoms, in CMV-infected individuals.

Experimental CMV vaccines that use DNA, protein, and viral
vectors have been under development for several years and
have shown promise with early testing.47-50 Treatment of preg-
nant women with primary CMV infection has included passive
immunization with CMV γ-globulin as well as oral antiviral
therapy. Studies have shown that CMV γ-globulin treatment of
pregnant women with primary CMV infection results in a sig-
nificant reduction in the number of symptomatic CMV-infected
infants at 2 years of age, whereas oral valacyclovir can achieve
therapeutic levels in maternal and fetal blood such that fetal
viral loads are reduced.51,52 However, in the trial that examined
oral acyclovir, a less than 50% survival rate was noted among
(severely) affected fetuses of CMV-infected mothers.52 Treat-
ment of newborns with symptomatic congenital CMV has con-
sisted primarily of intravenous (IV) ganciclovir,23,53 which works
by inhibiting viral DNA polymerase with resultant inhibition of
CMV replication.54 Its administration requires a peripherally
inserted indwelling catheter, and the drug itself carries a sig-
nificant risk of neutropenia. In the only randomized controlled
trial to examine outcomes of ganciclovir treatment, infants with
symptomatic congenital CMV treated within the first month of
life had no hearing deterioration at 6 months and after 1 year.53
10 µM
A Presently, ganciclovir efficacy has only been demonstrated in
symptomatic newborns with central nervous system (CNS)
disease and is not recommended for use in asymptomatic cases
or in symptomatic newborns without CNS disease.23 Valganci-
clovir, an oral prodrug of ganciclovir, has been studied over
the last several years as an alternative to ganciclovir. In a ran-
domized study that compared ganciclovir and valganciclovir
treatments among symptomatic neonates, similar outcomes
between the two regimens were found.54 Two recent studies
have also demonstrated improvement in hearing levels with
valganciclovir treatment.55,56 However, a more robust, random-
B ized placebo-controlled study is currently underway that should
help clarify the role of valganciclovir in patients with congenital
Figure 153-2. Congenital cytomegalovirus (CMV) infection in a 1-month-
CMV infection.23
old infant. A, Scanning electron micrograph shows large, osmophilic, CMV
inclusion-bearing cells lining the membranous wall of the utricle. B, Transmis- In terms of SNHL management, the observed variability in
sion electron micrograph shows CMV particles with dense cores forming hearing outcomes among asymptomatic congenital CMV
aggregates in the cytoplasm of utricular epithelium (×34,500). (From Davis patients requires regular hearing assessment, preferably every
LE, Johnsson L-G, Kornfeld M. Cytomegalovirus labyrinthitis in an infant: mor- 3 to 6 months for the first 3 years then annually thereafter.
phological, virological, and immunofluorescent studies. J Neuropathol Exp Neurol Amplification should be instituted as soon as SNHL is identi-
1981;40:9.) fied, and cochlear implantation should be considered for cases
of severe to profound SNHL. Children with severe forms of
congenital CMV may suffer from mental disabilities, offering
of the semicircular canal and otolith epithelia was observed and challenges to cochlear implantation that are encountered
included CMV infection within the endolymph-secreting dark when treating developmentally abnormal patients. However, in
cells. These data, combined with the findings from earlier children with congenital CMV and SNHL who undergo cochlear
studies, suggest that CMV involvement of (potassium-regulating) implantation, outcomes have been similar to children with
endolymphatic structures may be responsible for the SNHL SNHL as a result of other etiologies.57,58
observed in these patients.39-45
In the last several years, CMV has been detected by PCR Congenital Rubella Syndrome
analysis of perilymph obtained at the time of cochlear implant Congenital rubella syndrome, also known as German measles, was
placement in children with known congenital CMV and also in initially described following the Australian epidemic in 1941.59
individuals with SNHL of unknown cause or documented Caused by the rubella virus, congenital rubella syndrome
acquired CMV infection.10,18,40,46 Given that cochlear implant includes such clinical findings as microcephaly, heart defects,
surgery often occurs months to years after birth, these findings hearing loss, and cataracts.60 Additional clinical findings were
demonstrate the ability of CMV viral DNA to persist within the described following the global rubella pandemic of the 1960s,
inner ear. Whether persistent CMV within the inner ear affects when 20,000 infants in the United States were born with con-
hearing outcomes of individuals with congenital CMV remains genital rubella syndrome.61,62 Since the introduction of the
unknown, but the ability to sample the inner ear and isolate rubella vaccine in 1969, the number of cases in developed
viral DNA during cochlear implant surgery has important countries has dramatically decreased; in the United States,
implications. More specifically, as the number of cochlear endemic rubella was eliminated in 2004.63 However, the World
implants performed worldwide increases, future PCR analysis Health Organization estimates that worldwide, more than
of perilymph (or endolymph) samples may prove to be an 100,000 infants are born each year with congenital rubella
important tool for understanding a variety of causes of SNHL. syndrome, and up to 50% have hearing impairment.64,65
Current CMV treatment efforts are focused on minimizing Given the large number of worldwide cases of congenital
seroconversion of women and reducing viral load, and thereby rubella syndrome, it is imperative that otolaryngologists
consider this condition as a source of unexplained SNHL,

particularly among children. Rubella is transmitted in utero NONVIRAL PERINATAL
through a transplacental route. Maternal rubella infection LABYRINTHINE INFECTIONS
during the first trimester, as opposed to the second or third
trimester, places the fetus at the highest risk of congenital Congenital Syphilis
infection and subsequent hearing loss. Infants infected with Congenital syphilis is caused by the spirochete Treponema palli-
rubella during the second and third trimesters are often born dum and results from vertical transmission from mother to fetus
with asymptomatic rubella infection and appear healthy at either in utero, at the time of vaginal delivery, or postnatally.
birth. However, 10% to 20% of these children will likely The CDC estimated the rate of congenital syphilis to be 8 cases
develop SNHL.66 Congenital rubella infection that involves per 100,000 live births in the United States in 2011, a decline
the inner ear often results in bilateral SNHL, which typically from 4 years prior.77 Early, or infantile, congenital syphilis is
affects the mid frequencies more than the low and high fre- often severe and is characterized by hepatosplenomegaly,
quencies.59 The resultant “cookie-bite” deformity may make it papular rash, nasal discharge, and pseudoparalysis of an
difficult to distinguish between this and other genetic etiolo- extremity.12,77 Whereas hearing loss and vestibular symptoms
gies of SNHL. In a large series of children with hearing loss may occur in these infants, these symptoms may be overlooked
secondary to congenital rubella syndrome, 55% had profound because of the severity of other symptoms. Late congenital
hearing loss, 30% had severe hearing loss, and 15% had mild syphilis is also possible and may present in late childhood,
to moderate hearing loss.61 Children with congenital rubella adolescence, or adulthood. Lesions typical of late congenital
syndrome may have poor speech discrimination and may syphilis include saddle nose deformity, saber shins, keratitis,
experience progressive hearing loss. Interestingly, individuals Hutchinson teeth, hearing loss, and vestibular complaints.12,77
who experience rubella infection as an adult rarely develop Hearing loss has been reported to occur in as many as 38% of
hearing loss.67 Studies that have examined vestibular function congenital syphilis cases, although more recent studies are
in children with congenital rubella syndrome demonstrate lacking.78-80 Great variability is reported in the presentation of
caloric hypofunction in up to 20% of cases with a lack of individuals with late congenital syphilis. Hearing loss may be
correlation between the degree of SNHL and vestibular sudden, bilateral, and severe in children. In adults, hearing loss
dysfunction.68,69 may be progressive, asymmetric, and associated with poor dis-
Congenital rubella syndrome may be diagnosed by 1) isola- crimination scores, and symptoms similar to Meniere disease
tion of rubella or detection of rubella-specific ribonucleic acid may occur with fluctuating hearing loss, tinnitus, and vestibular
(RNA) from urine or throat cultures during the first weeks of attacks.12
life, 2) identification of immunoglobulin M (IgM) antibodies The CDC has extensive recommendations in regard to the
against rubella in serum from the neonate, and/or 3) increased diagnostic evaluation of infants with suspected congenital syph-
antibody titer to rubella in an infant during the first few months ilis.77 Infants born to mothers with reactive treponemal tests
of life who did not receive the rubella vaccine. Real-time reverse (FTA-ABS) should undergo a quantitative nontreponemal sero-
transcriptase polymerase chain reaction (RT-PCR) and stan- logic test (RPR or VDRL) and careful physical examination at
dard RT-PCR techniques are used to identify viral RNA, whereas birth. The placenta and umbilical cord should also be exam-
enzyme immunoassays are commonly used for identification of ined with dark-field microscopy if possible.77 Titers of the quan-
IgM and IgG antibodies against rubella.59,62 titative nontreponemal test in neonates with suspected
Histopathologic changes seen in the temporal bones of congenital syphilis are important, because levels more than
patients with congenital rubella syndrome and associated deaf- fourfold higher than the mother’s titer suggests more severe
ness do show characteristic changes; however, these changes disease and requires CSF analysis. The CDC also recommends
are not specific for a rubella infection. The predominant a full evaluation and testing for HIV in cases of known congeni-
abnormality is cochleosaccular degeneration and strial atrophy tal syphilis.77
of varying degrees, and the Reissner membrane and the wall of The pathology in cases of early congenital syphilitic hearing
the saccule may sag and even collapse; the tectorial membrane loss is primarily that of a “meningo-neuro-labyrinthitis” as
is frequently abnormal and is often displaced from the organ described by Schuknecht12 and Goodhill.81 This is character-
of Corti toward the limbus.12,70-72 The stria vascularis shows ized, as are all early syphilitic lesions, by a leukocytic infiltration
varying degrees of atrophy, whereas the vestibular neuroepithe- with endarteritis and fibrosis, and degenerative changes of both
lia and their nerves usually appear healthy. sensory and neural elements within the labyrinth are character-
Treatment of congenital rubella syndrome is currently sup- istic.12 Spirochetes have been demonstrated using a silver stain
portive, because no antiviral medications have been designed in postmortem temporal bone specimens of patients with syphi-
specifically for the rubella virus. As with other causes of SNHL, lis.82 In late congenital syphilis, an osteitis of the otic capsule is
amplification should be initiated as early as possible. Depend- seen along with secondary involvement of the membranous
ing upon the general health of the individual, in cases of severe labyrinth.83 The end result of late congenital syphilis in the
to profound hearing loss, cochlear implantation should be temporal bone is typically endolymphatic hydrops, which is also
considered. seen in tertiary forms of acquired syphilis (Fig. 153-3).12,83
The CDC recommends 10 days of IV aqueous crystalline
Congenital Herpes Simplex Virus penicillin G in neonates with congenital syphilis.77 Therapy is
Neonatal HSV infection is rare and occurs in 1 in 3,000 to aimed at halting disease progression and is thought to be highly
20,000 live births.73 Whereas infection may occur in utero, it is effective if instituted early.84 Data are lacking, however, on the
more commonly transmitted at the time of vaginal delivery. long-term benefit of treatment of congenital syphilis with
Consequently, cesarean section is often used in cases of known, regard to hearing outcomes.84
active genital HSV infections. In neonates, HSV infection often
occurs in a disseminated form, and patients may display HSV Congenital Toxoplasmosis
encephalitis. The incidence of SNHL in congenital HSV is Toxoplasma gondii is a protozoan parasite that typically affects
approximately 10%, although data are limited.74-76 Screening immunocompromised individuals and neonates. It is transmit-
for HSV in cases of idiopathic neonatal SNHL is not currently ted through oral ingestion of material, such as raw or under-
recommended because of the rarity of asymptomatic congeni- cooked meat, that contains infectious parasitic oocysts.
tal HSV infections.76 Domestic cats that eat potential hosts of T. gondii, such as
and histopathologic studies. Rates of hearing loss after menin-
gitis may approach 35%, and severe to profound hearing loss
and labyrinthine ossification occurs in a number of cases.92-97
The spread of bacterial infection from the subarachnoid space
to the labyrinth most likely occurs via the cochlear aqueduct or
the cribrose area of the fundus of the IAC.12,91,92,98-101 However,
vascular routes, abnormal traumatic or congenital bony dehis-
cences between the labyrinth and subarachnoid space, and the
endolymphatic sac may also be involved in transmitting these
infections.92
Diagnosis of meningogenic labyrinthitis relies on clinical
history and supportive audiometric data. Clinical findings in
adults may include lethargy, fever, neck stiffness, photophobia,
and headache. In infants and young children, the initial symp-
toms may be more variable. The onset of hearing loss and/or
vestibular deficits may not be readily identifiable, particularly
in infants with meningitis. However, audiometric documenta-
tion of SNHL in patients with a recent history of meningitis is
suggestive of labyrinthine involvement. Further support for
Figure 153-3. Endolymphatic hydrops as a result of syphilis. Arrows depict meningogenic causes of SNHL are provided in cases where
abnormal position of Reissner membrane (hematoxylin & eosin stain, ×20). normal hearing was documented prior to the meningitic event.
(Courtesy Dr. Fred Linthicum, Eccles Temporal Bone Laboratory, House Research Ototoxicity from IV antibiotic therapy used to treat meningitis
Institute, Los Angeles.) must also be considered as a possible etiology of SNHL, espe-
cially in locales where gentamycin and other aminoglycoside
rodents or birds, will have contaminated feces. Consequently, antibiotics are commonly used. Standard pure tone audiometry
people may transmit the cysts to themselves or others via hand with word-recognition testing should be performed as soon as
to oral contact after the handling of litter box materials. Con- a suspicion of meningogenic labyrinthine involvement is enter-
genital toxoplasmosis is relatively uncommon and occurs in an tained. However, such testing is not always practical, and alter-
estimated 1 in 10,000 newborns.85 The majority of newborns natively, otoacoustic emission and auditory brainstem response
with congenital toxoplasmosis are asymptomatic, although testing, which do not require voluntary participation, may be
involvement of the CNS, visual, and other systems is possible.86 used.90 Whereas normal auditory brainstem response results
In a recent systematic review, the prevalence of toxoplasmosis- early in the course of meningitis may be encouraging, follow-up
associated hearing loss in infected newborns was found to behavioral audiometry is imperative.102 CT imaging of the post-
range from 0% to 26%.87 Determination of antibodies (IgM meningitic patient may also support a diagnosis of meningo-
and IgG) against T. gondii in the hearing-impaired newborn genic labyrinthine involvement when ossification of labyrinthine
should be performed in suspected cases to aid in diagnosis. structures is noted. A lack of middle ear or mastoid infection
Treatment consists of 12 months of antiparasitic medication, at the time of clinical meningitis is also important in distin-
and evidence suggests a reduction in SNHL rates among guishing meningogenic from otogenic labyrinthitis. Timing of
patients with high compliance and early treatment initiation.87 the occurrence of labyrinthine ossification following meningitis
No known reports of temporal bone histopathology in patients is variable, although animal models suggest that ossification
with congenital toxoplasmosis exist in the literature. following S. pneumoniae meningitis occurs as early as 3 days to
3 weeks after inoculation.103,104 The incidence of labyrinthine
ossification following meningitis is also not known, although
ACQUIRED LABYRINTHINE INFECTIONS studies of children with SNHL following meningitis demon-
Acquired labyrinthine infections may be a result of a variety of strate some degree of ossification in up to 70% of cases.105,106
bacterial, viral, or parasitic pathogens. Some of the more Although it does appear that S. pneumoniae meningitis is associ-
common causes of infection are discussed here. ated with a higher incidence of SNHL, there does not appear
to be a significant difference in the development of labyrin-
Meningogenic Labyrinthine Infections thine ossification among S. pneumoniae, N. meningitidis, and
Bacterial Meningogenic Labyrinthine Infections. Meningitis HIB.107
may result from bacterial, viral, fungal, parasitic, or toxic inva- Temporal bone findings in cases of meningogenic labyrin-
sion of the subarachnoid space. In the United States alone, thitis have been fairly well documented.12,92,98-101 Schuknecht12
4100 cases of bacterial meningitis, with nearly 500 associated distinguishes between terminal meningogenic labyrinthitis and
deaths, occur annually.88 Streptococcus pneumoniae, Neisseria men- a more standard form of meningogenic labyrinthitis. In terminal
ingitidis, and Haemophilus influenzae type B (HIB) are the most meningogenic labyrinthitis, suppuration of the labyrinth is thought
common causes of meningitis in children; whereas Escherichia to be a terminal event in a patient who is moribund and in
coli, Group B Streptococcus, and Listeria monocytogenes are often whom cochleovestibular symptoms are not present. In nonter-
implicated in newborns. Adolescents and adults are usually minal meningogenic labyrinthitis, studies of temporal bones
infected by N. meningitides and S. pneumoniae.89 Introduction of reveal fibrosis and ossification within the labyrinth, particularly
the HIB vaccine in the United States pediatric population in within the basal portions of the cochlea.12,98-101 In the most
the 1990s led to a significant reduction in the number of cases recent review of a series of temporal bone specimens with sup-
of HIB meningitis.90 purative labyrinthitis secondary to meningitis, inflammatory
Proper recognition of the link between labyrinthine infec- cells were commonly found within both the vestibular and
tions and meningitis was first recognized in the late 1800s.91 In cochlear perilymphatic spaces.92 Sensory and neural structures
the preantibiotic era, meningitis was suspected to account for were often intact, although loss of spiral ganglion neurons was
as many as 20% of cases of SNHL in children.91 Since that time, seen in 10% to 15% of cases.92
our understanding of meningogenic labyrinthine infections Adherence to childhood and adult vaccination schedules is
has increased greatly through a combination of epidemiologic an important means of meningitis prevention, particularly in
A B
Figure 153-4. Cryptococcal labyrinthine involvement. A, Arrow depicts eighth nerve infiltration by Cryptococcus in the fundus of the internal auditory canal
(hematoxylin & eosin [H&E] stain, ×100). B, High-power view demonstrates cryptococcal spores (H&E stain, ×400). (Courtesy Dr. Fred Linthicum, Eccles
Temporal Bone Laboratory, House Research Institute, Los Angeles.)
regard to HIB, pneumococcal, and meningococcal meningi- cases of various viral forms of meningitis leading to the develop-

tis.89 When bacterial meningitis does occur, initial treatment ment of SNHL have been reported.114 Fungal organisms are an
consists of culture-directed IV antibiotic therapy. Broad- infrequent cause of meningitis, although immunocompro-
spectrum, CSF-penetrating antibiotics are often used initially, mised patients are at higher risk for invasive fungal infections
with tailoring of the regimen following identification of the and account for the majority of such cases. Cryptococcal men-
causative organism through CSF analysis. Early initiation of ingitis, caused by Cryptococcus neoformans, is the most common
treatment is important in the prevention of long-term sequelae cause of fungal meningitis in immunocompromised individuals
associated with meningitis, although the exact effect of treat- and has been associated with SNHL in up to 30% of infected
ment timing on rates of SNHL are not known.108 Recent animal patients.115,116 Histopathologic studies demonstrate cryptococ-
studies suggest free radicals may be responsible for cochlear cal involvement within the IAC and base of the modiolus (Fig.
damage and that antioxidants may play a role in halting menin- 153-4).116 Parasitic meningitis, referred to as primary amebic menin-
gogenic hearing loss, although clinical studies are lacking.109 A goencephalitis, is extremely rare and usually fatal. Finally, nonin-
significant number of studies have examined the role of corti- fectious forms of meningitis may occur as a result of malignancy,
costeroids in treating meningitis-associated SNHL, particularly certain drugs, and head injury. To date, there has been a lack
in children. A meta-analysis of these studies was performed in of data on the incidence of SNHL associated with noninfectious
2006 and concluded that the evidence supporting the use of forms of meningitis.
corticosteroids in preventing SNHL remained unclear.110
However, Hartnick and colleagues111 found that the administra- Otogenic Labyrinthine Infections
tion of steroids at the time of diagnosis was associated with a Suppurative labyrinthitis may occur as a complication of acute
significantly lower rate of labyrinthitis ossificans. These findings or chronic otitis media, chronic tympanomastoiditis, and
highlight the potential benefits of steroid use and require that petrous apicitis.12,100 The majority of cases are bacterial in origin,
further studies be conducted on this subject. although fungal invasion of the labyrinth may occur, particu-
SNHL that results from meningogenic labyrinthitis should larly in immunocompromised hosts. Common bacterial patho-
be treated with early amplification. In cases of severe to pro- gens include S. pneumoniae, nontypable H. influenzae, Moraxella
found deafness, cochlear implantation should be offered. catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, and
Because of the possibility of early labyrinthine ossification, various aerobic and anaerobic organisms.2 In cases of bacterial
cochlear implant evaluations should be performed expedi- infection limited to the middle ear space, suppurative labyrin-
tiously following diagnosis. Bilateral simultaneous implantation thitis occurs via bacterial spread through the oval and round
may be offered to improve the chances of successful implanta- windows.12 In chronic tympanomastoiditis and apicitis, spread
tion in these patients.112 High-resolution computed tomogra- of infection to the labyrinth may occur via the oval and round
phy (HRCT) of the temporal bone is useful for identification windows or via irregular dehiscences in the bony labyrinth.12 In
of ossification within the labyrinth. However, magnetic reso- the preantibiotic era, rates of suppurative labyrinthitis among
nance imaging (MRI) with heavily T2-weighted sequences is patients undergoing mastoidectomy approached 5%.1 Over the
often preferable, because this modality can better identify fibro- last century, the use of antibiotics combined with earlier diag-
sis within the labyrinth, which is not seen on HRCT.113 nosis and treatment and improvement in surgical techniques
has led to rates of suppurative labyrinthitis that approach 0.1%
Nonbacterial Meningogenic Labyrinthine Infections. Viral, in many countries.2,117-119
fungal, parasitic, and toxic forms of meningitis may occur. Viral Otogenic suppurative labyrinthitis is defined by vertigo and
meningitis, often termed aseptic meningitis, has not been strongly SNHL in the setting of acute or chronic middle ear and/or
associated with hearing loss based on early reports.93 However, mastoid disease.2 Hearing loss is typically severe to profound
and permanent. Cholesteatomatous or iatrogenic fistulae of the vertigo is considered uncommon.9,12,124 Mumps virus is one of

inner ear may predispose individuals with chronic tympano- only two viruses that has been isolated from the inner ear.125
mastoiditis and otitis media to suppurative labyrinthitis by pro- Histopathologic changes in the labyrinth in cases of mumps-
viding a direct route for bacterial invasion. HRCT of the related deafness consist of atrophy of the stria vascularis and
temporal bone may provide evidence for labyrinthine erosion, organ of Corti as well as collapse of the Reissner membrane.126
although opacification of the middle ear and/or coalescent The introduction of the mumps vaccine in 1967 led to a
mastoiditis may be the only finding in these cases. Symptoms significant decline in the number of mumps cases within the
of meningitis may occur secondarily, because suppurative laby- United States and other countries with routine vaccination
rinthitis of otogenic origin may continue to spread toward the schedules.123 However, because many countries still do not have
subarachnoid space via the cochlear aqueduct or cribrose area access to routine vaccination, otolaryngologists must include
of the fundus through the modiolus.12 mumps deafness on their differential diagnosis when evaluat-
Temporal bone histopathologic findings of otogenic sup- ing individuals with SNHL. Treatment of mumps-related SNHL
purative labyrinthitis are similar to those seen in meningogenic should include appropriate amplification with devices used in
labyrinthitis.12,100,120-122 The initial stages of suppurative labyrin- single-sided deafness, and cochlear implantation should be
thitis are characterized by infiltration of the perilymphatic considered if bilateral involvement occurs.
spaces by polymorphonuclear leukocytes.12,100,120-122 Subsequent
erosion and necrosis of the membranous labyrinth may ensue, Measles Labyrinthitis. Measles, also known as rubeola, is a viral
with possible spread to the subarachnoid space (Fig. 153-5). illness characterized by fever, cough, coryza, conjunctivitis,
The end stage of suppurative labyrinthitis is characterized by descending rash, and oral lesions known as Koplik spots.127
fibrosis and subsequent new bone formation (labyrinthitis Measles is a paramyxovirus, similar to mumps virus, and is
ossificans).12,100,120-122 extremely contagious, spreading in the air via respiratory drop-
Treatment of otogenic suppurative labyrinthitis often lets. Throughout the world, approximately 20 million cases of
requires early surgical intervention in combination with culture- measles occur each year. However, in the United States and
directed antibiotics. Myringotomy and tympanostomy tube other countries with routine vaccination schedules, endemic
placement may be adequate for cases of acute otitis media measles has become extremely rare. Potential complications of
without involvement of the mastoid or obvious bone or labyrin- measles include pneumonia, middle ear infection, and enceph-
thine erosion. In cases of acute or chronic tympanomastoiditis, alitis. Subacute sclerosing panencephalitis is a rare, progressive
mastoidectomy is often indicated to clear the infection and neurologic disorder that occurs months to years after measles
possibly remove or exteriorize any cholesteatomatous disease. infection and often results in death.127
Prior to the development of the measles vaccine, nearly all
Viral Labyrinthine Infections children were affected before reaching adolescence. SNHL sec-
Mumps Labyrinthitis. Mumps is a viral illness characterized by ondary to measles has accounted for up to 10% of cases of
unilateral or bilateral parotid gland swelling. It is caused by a childhood deafness in selected studies from the early twentieth
paramyxovirus and spread by respiratory droplets. Severe com- century, although the incidence of SNHL in measles is esti-
plications are rare but include encephalitis, orchitis, and SNHL. mated at 0.1%.128,129 SNHL is typically bilateral and severe, with
The estimated incidence of SNHL as a result of mumps is one unilateral and more moderate losses also possible.9,12 Vestibular
in 20,000 cases.123 Mumps is often a clinical diagnosis, although function may be impaired in some individuals.
serologic detection of specific IgM antibodies and viral isola- Although measles virus has not been isolated from the inner
tion (via oral swab) through RT-PCR are needed to confirm the ear, histopathologic changes in the labyrinth have been docu-
diagnosis.123 mented in cases of known measles infection. Severe degenera-
SNHL as a result of mumps virus is often unilateral and may tion of the organ of Corti, stria vascularis, and spiral ganglion
range from mild high-frequency to profound SNHL.9,12 Vestibu- neurons has been noted.130,131 The vestibular end organs also
lar involvement has been reported in the past, although severe demonstrate atrophy of their sensory epithelia.130,131 SNHL sec-
ondary to measles infection should be treated with amplifica-
tion or with cochlear implantation if the loss is severe.
Varicella-Zoster Virus Labyrinthitis (Ramsay Hunt Syndrome).

Varicella-zoster virus (VZV) is a member of the Herpesviridae
family and is responsible for chickenpox.132 VZV is also the
cause of shingles, or herpes zoster, as well as Ramsay Hunt
syndrome, herpes zoster oticus. Shingles occurs mainly in
adults and is characterized by painful vesicular outbreaks, typi-
cally in the distribution of sensory nerves on the face or
thorax.132 It is felt to be a reactivation of VZV, which lies dormant
in the body after the initial (chickenpox) infection.132 Ramsay
Hunt syndrome is similar in this regard, except VZV reactiva-
tion affects sensory and motor cranial nerves, typically causing
a peripheral facial palsy that resembles Bell palsy. The inci-
dence of Ramsay Hunt syndrome is quite variable, and recent
reports suggest a range between 0.3 and 18%.133
Clinical characteristics of Ramsay Hunt syndrome include
pain in and around the ear, vesicular eruption that involves
the pinna and external auditory canal, and facial paralysis.
SNHL, tinnitus, and vestibular symptoms are not infrequent
Figure 153-5. Otogenic suppurative labyrinthitis. Purulent material is seen and occur in up to 50% of patients according to recent
within the cochlea, vestibule, middle ear, and internal auditory canal (hema- reports.134-138 Additional cranial nerve involvement (i.e., cranial
toxylin & eosin stain, ×10). (Courtesy Dr. Fred Linthicum, Eccles Temporal Bone nerves V and IX through XII) may also occur.134 Ramsay Hunt
Laboratory, House Research Institute, Los Angeles.) syndrome is typically a clinical diagnosis, although it can be
confirmed by isolation and culture of VZV from vesicular fluid such as hearing loss or dizziness.12,77 In secondary syphilis, patients

or by detection of viral DNA by PCR analysis.139-141 MRI assess- may have rash, fever, and lymphadenopathy, although menin-
ment of patients with Ramsay Hunt syndrome and facial paraly- gitis and other organ involvement may also occur. Tertiary syphi-
sis often reveals enhancement along the intratemporal portions lis develops many years after the initial infection and includes
of the facial nerve.142 such manifestations as neurosyphilis and cardiovascular
Histopathologic changes in the labyrinth have been observed involvement.
in patients with auditory and vestibular symptoms associated Hearing loss and vestibular symptoms are common in both
with Ramsay Hunt syndrome. Inflammatory cells within the congenital and acquired forms of tertiary syphilis. In symptom-
auditory nerve and modiolus and degeneration of the spiral atic neurosyphilis, rates of hearing loss approach 80%.162
ganglion neurons, stria vascularis, organ of Corti, and semicir- Hearing loss is usually sensorineural in nature, although middle
cular canals have all been observed.12,143 Interestingly, several ear involvement has been reported.163 As with late forms of
pathologic studies have failed to show significant changes congenital syphilis, SNHL is progressive, with fluctuation, asym-
within the geniculate ganglion in these cases, although atrophy metry, bilaterality, and associated vertigo attacks not infre-
and degeneration of the labyrinthine and tympanic segments quently observed.164
have been noted.143,144 Temporal bone findings of late acquired syphilis are charac-
Based on several retrospective studies, treatment of Ramsay terized by a resorptive osteitis with round cell infiltration,
Hunt syndrome has primarily consisted of oral corticosteroids destruction of the bony labyrinth, and associated endolym-
and oral antiviral medication.145-149 Several randomized con- phatic hydrops.12,81 Fibrous proliferation may ensue adjacent to
trolled trials have examined the use of corticosteroids, and a the areas of osteitis, and studies suggest resultant blockage of
recent Cochrane review affirmed their utility in cases of Ramsay the endolymphatic duct may be the cause of the observed
Hunt syndrome.150 However, a similar review of antiviral therapy endolymphatic hydrops (Fig. 153-6).165 Treatment of otosyphilis
suggests adequate data are lacking to recommend routine use consists of intramuscular penicillin G and prednisone, and
of antiviral medications in Ramsay Hunt syndrome.151 In 2006, prior reports suggest that aggressive treatment may slow the
an adult VZV vaccine was introduced to help reduce the risk of progression of SNHL and audiovestibular symptoms.166-168
shingles in adults over age 60. Whereas a significant reduction
in the number of cases of shingles has been observed among
vaccine recipients, the effect of the vaccine on the number of
IDIOPATHIC LABYRINTHINE INFECTIONS
cases of Ramsay Hunt syndrome is as yet unknown.152 For cases Sudden sensorineural hearing loss (SSNHL), vestibular neuri-
in which permanent SNHL occurs, appropriate amplification tis, and labyrinthitis represent a clinical spectrum of inner ear
should be considered. disorders. Whereas SSNHL may have a known cause in some
instances (i.e., trauma, ototoxicity, cerebrovascular accident),
Human Immunodeficiency Virus and Related Labyrinthine in the majority of cases, it is idiopathic. Idiopathic SSNHL
Infections. HIV is a retrovirus that attacks CD4 cells within the (ISSNHL) has been defined as the loss of 30 dB across three
human immune system, and it is responsible for the develop- consecutive frequencies in 72 hours or less in an otherwise
ment of acquired immunodeficiency syndrome (AIDS). Several healthy person. However, this does not consider word-
studies have examined otologic findings in patients with HIV recognition scores, and consequently, alternative definitions
and have found rates of SNHL near 30%, and complaints of are commonly used in clinical practice. Vestibular symptoms
dizziness, tinnitus, and ear fullness were routinely noted.153-155 are not uncommon but are usually minor in cases of ISSNHL.
A recent report suggests that sudden SNHL occurs with a Vestibular neuritis is most often idiopathic and consists of the
twofold greater frequency in HIV patients compared with sudden onset of severe vertigo lasting several days.169 If SNHL
normal controls.156 accompanies an episode similar to that described for vestibular
HIV isolation from inner ear tissue has not been achieved, neuritis, the condition is often termed labyrinthitis.
although HIV-like particles and cytoplasmic inclusions have
been observed in the cochlear and vestibular sensory organs in
temporal bone specimens of patients with HIV.157,158 Other viral
pathogens have been recovered from perilymph at autopsy of
patients with AIDS, but associated inflammatory changes were
not observed within the temporal bones.159 It is possible that
the limited immune response in patients with advanced forms
of AIDS may account for the lack of histopathologic findings
in these cases. Patients with AIDS are susceptible to various
opportunistic infections that include Pneumocystis jiroveci (for-
merly P. carinii), Candida, and other fungal and bacterial patho-
gens that may lead to otologic manifestations.160 HIV treatment
consists of antiretroviral therapy and prophylaxis against oppor-
tunistic infections. Amplification and cochlear implantation
are potential treatment options for patients with HIV and
SNHL.161
ACQUIRED SYPHILITIC
LABYRINTHINE INFECTIONS
As with congenital syphilis, acquired syphilis results from the
spirochete Treponema pallidum. Primary, secondary, and tertiary Figure 153-6. Syphilitic osteitis. Infiltration of the endolymphatic duct (large
forms of syphilis describe the different clinical features of this arrow) with lymphocytic cells and destruction of adjacent bone (small arrow)
multisystem disease.12,77 Primary syphilis is defined by a chancre are shown (hematoxylin & eosin stain, ×100). (Courtesy Dr. Fred Linthicum,
at the site of inoculation, and it lacks inner ear symptomatology Eccles Temporal Bone Laboratory, House Research Institute, Los Angeles.)

Sordera

Uploaded by

Copyright:

Available Formats

Sordera

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sordera

Uploaded by

Copyright:

Available Formats

Genetic Sensorineural 148

I t was famously put by Terry Savage that “A child will hear his loss has mandated a basic understanding of genetics. This

TABLE 148-1. Hearing Loss Classification and Features DIAGNOSIS OF HEARING IMPAIRMENT

HISTORIC BACKGROUND OF GENETICS

75%-80% Autosomal recessive

70% Nonsyndromic 20% Autosomal dominant

FIGURE 148-3. Incidence of different forms of congenital hearing loss.

TABLE 148-3. Autosomal-Recessive Nonsyndromic Hearing Loss

TABLE 148-3. Autosomal-Recessive Nonsyndromic Hearing Loss—Cont’d

TABLE 148-4. Autosomal-Dominant Nonsyndromic Hearing Loss

(DFNA8/12),36 whereas other correlations, such as high- DFNA13 families and were predicted to affect the triple helical

TABLE 148-5. X-Linked Nonsyndromic Hearing Loss

TABLE 148-6. Mitochondrial Nonsyndromic Hearing Loss

TABLE 148-7. Syndromic Forms of Hearing Loss

lenticular opacities/juvenile cortical cataract. The causative

lenticonus and/or macular flecks), and 4) histologic changes involves progressive external ophthalmoplegia, atypical retinal

TREATMENT CULTURAL CONSIDERATIONS

52. Tranebjaerg L, Schwartz C, Eriksen H, et al: A new X linked reces- 79. Ahmad NN, Ala-Kokko L, Knowlton RG, et al: Stop codon in the

massively-parallel sequencing approach. Genet Testing Mol Biomark- 178. Scott HS, Kudoh J, Wattenhofer M, et al: Insertion of beta-satellite

FIGURE 149-4. A higher-powered view of part of the middle ear area

Multiple perforations of the tympanic membrane, exuber-

FIGURE 149-11. Sarcoidosis in a lymph node specimen. Noncaseating

the sarcoid lesion is noncaseating epithelioid granulomas

Hennebert sign, which is the induction of ocular deviation with a specific antibody to B. burgdorferi by enzyme-linked immuno-

Otologic Manifestations 1.0 mm

CYTOMEGALIC INCLUSION DISEASE

FIGURE 149-18. One of several osteolytic lesions of the temporal bone of

FIGURE 149-16. Coronal computed tomography scan shows a large, microscopic level, the marrow spaces of the petrous bone are

FIGURE 149-19. Acute lymphocytic leukemia in a 9-year-old boy. Ten days

FIGURE 149-20. Acute myelogenous leukemia in a 38-year-old man. Leu-

DISEASES OF THE BONE

FIGURE 149-23. Metastatic breast adenocarcinoma in a 75-year-old

disease occur in the temporal bone. Paget disease, osteogenesis decade; greater SNHL, with a descending pattern; enlarged

FIGURE 149-26. Pagetic involvement of the temporal bone in a 70-year-old

FIGURE 149-27. Lateral radiograph of the skull in a patient with osteogen-

FIGURE 149-30. Osteogenesis imperfecta involving the otic capsule of a

deficits. Stenosis of the external canal often requires surgical

FIGURE 149-34. Recessive osteopetrosis of the temporal bone of a

STORAGE AND METABOLIC

COLLAGEN VASCULAR AND IMMUNODEFICIENCY DISORDERS

28. Hybels RL, Rice DH: Neuro-otologic manifestations of sarcoidosis.

61. Levy R, Shvero J, Sandbank J: Granulocytic sarcoma (chloroma) 89. Marie PJ: Cellular and molecular basis of fibrous dysplasia. Histol

121. Stephens SDG, Luxon L, Hinchcliffe R: Immunological disorders 136. Hill HR, Book LS, Hemming VG, et al: Defective neutrophil che-

S ensorineural hearing loss (SNHL) is an extremely common for associated symptoms such as tinnitus, vertigo, dysequilib-

deficits. Three distinct groups have been defined: Type 1

Alport Syndrome. Alport syndrome is characterized by intersti-

Hearing level (dB) (ANSI, 1989)

25 Acquired perilymphatic fistulae can result from barotrau-

consideration in patients with otherwise unexplained SNHL

found between the presence of diabetes and SNHL when

DISORDERS OF UNKNOWN ETIOLOGY

treatment protocol is the so-called shotgun regimen, which uses For a complete list of references, see expertconsult.com.

61. Matz GJ, Naunton RF: Ototoxicity of chloroquine. Arch Otolaryngol 90. Gendeh BS, Gibb AG, Aziz NS, et al: Vancomycin administration

238. Lowry LD, Isaacson SR: Study of 100 patients with bilateral senso- 267. Lindsay JR, Davey PR, Ward PH: Inner ear pathology in deafness

annoying tinnitus was reported in 50% of respondents, and

stimulation of the scalp and auricle, trigger-point treatment, the perceived intensity and intrusiveness of the tinnitus.35 Func-

stimulus, the tinnitus sensation becomes less noticeable. Patients may be fruitful in optimizing sound stimulation parameters

Acoustic Desensitization Protocol. The Acoustic Desensitiza- training, and selective attention distraction to induce habitua-

recent imaging work suggests that at least in people with non- inaudible, transdermal electric current to the mastoid emi-