CHAPTER 152 Infections of the Labyrinth
Infectious agents, particularly viruses and bacteria, are thought to play a direct or indirect role in causing several inner ear disorders.1 Each year, several thousand infants are born deaf or with impaired hearing. At least 18% of these cases are proven to be caused by congenital viral infection, and a greater percentage are suspected to have an infectious cause.2 Each year, about 10 out of every 100,000 individuals are stricken by so-called sudden deafness, which occurs as unilateral or bilateral sensorineural hearing loss (SNHL) of varying degrees.3 Infectious agents are often suspected as the cause. Bacterial labyrinthitis with profound hearing loss occurs in 10% of patients with bacterial meningitis.4 Thousands of individuals each year have vestibular neuritis, which many authors think has an infectious origin.5
Although many infectious agents are thought to play important etiologic roles in labyrinthine disorders, there are many difficulties in proving that a given infectious agent infects the human labyrinth.1
Establishing whether a given virus is the cause of the patient’s deafness or vertigo is difficult. The criteria in Box 152-1 are proposed for determining causality.
Box 152-1 Optimal Proof for Infectious Cause of Inner Ear Infection
Modified from Davis LE. Neurovirology of deafness, labyrinthitis and Bell’s palsy. In: Johnson RT, ed. Neurovirology. Minneapolis: American Academy of Neurology; 2002.
PCR has become a powerful tool in the detection of nucleic acid from infectious agents in human tissues. PCR is difficult to use, however, when tissues, such as temporal bones, have been fixed in formalin and decalcified for weeks with nitric acid. Formalin fixation cross-links DNA and RNA, and nitric acid harms nucleic acids. PCR has been helpful in analyzing small amounts of fresh perilymph removed during surgery and detecting cytomegalovirus (CMV).8–10
At present, an unresolved controversy exists regarding the significance of detection of latent herpesvirus DNA in human tissue. Several PCR studies have detected HSV DNA in neurons at autopsy from previously healthy patients from several sites, including the brainstem and cerebral cortex11 and spiral and vestibular ganglia.12–14 To date, culture of neuronal explants from these sites has not yielded isolation of HSV similar to culture of trigeminal or sacral ganglia.15 Clear evidence for the breaking of viral latency and subsequent viral replication currently is lacking. It is unclear whether vestibular and cochlear neurons are dead-end cells, capable of developing latency, but incapable or poorly capable of breaking latency. The latter possibility might allow for occasional patients developing a solitary episode of vestibular neuritis or sudden hearing loss, whereas many patients develop repeated episodes of lip or genital HSV blisters from repeated breakage of latency in the trigeminal and sacral ganglia.
To date, only a few infectious agents have been recovered from or identified within human labyrinthine tissues. CMV8,9,16 and mumps virus17 have been isolated from perilymph. CMV antigen has been detected by immunohistochemistry within inner ear tissues.16,18 Morphologic identification of infectious agents within the labyrinth has been accomplished for several bacteria,19,20 fungi,20,21 and Treponema pallidum.22 A multinucleated giant cell, typical of rubeola (measles) virus infection, has been seen within the scala vestibuli.22 HSV DNA10,12,23 has been identified within vestibular and cochlear ganglia neurons by PCR assay. One study reported detection of HSV DNA by PCR in vestibular labyrinth tissue.24 To date, intranuclear inclusion bodies or viral antigens have not been identified within inner ear tissues.
It is assumed that infectious agents are not normally present in the membranous labyrinth or adjacent ganglia; isolation of an infectious agent from the inner ear carries considerable etiologic significance. This assumption is not based on comprehensive bacteriologic or virologic studies, however. Healthy guinea pigs may harbor herpeslike viruses in the spiral ganglia neurons.25,26
Many infectious agents have been reported to be associated with deafness or vertigo. For some infectious agents, the association has been based on case reports that describe acute deafness or vertigo that developed during a systemic infection. For other infectious agents (e.g., rubella), the epidemiologic association has been strong between systemic infection of the individual or mother, and subsequent deafness or vertigo. Box 152-2 lists infectious agents that have been associated with deafness or vertigo, but have yet to fulfill the criteria for optimal proof of causality.
Box 152-2 Infectious Agents Associated with Acquired Sudden Sensorineural Hearing Loss or Vertigo*
Congenital Hearing Loss
Cytomegalovirus
Clinical Features
CMV is the most common infectious cause of congenital hearing loss in the United States, accounting for 2600 to 4000 cases of SNHL each year.27,28 The incidence of congenital CMV infection is about 0.3 to 1 case/100 live births.29–31 Less than 5% of all congenital CMV infections result in the severe infection termed cytomegalic inclusion disease. In this multiorgan infection, the incidence of SNHL is 50% in infants who survive the neonatal period.32 Hearing loss when measured years later is bilateral, symmetric, and often severe.33 High-frequency hearing loss is usually greater than lower frequency hearing loss.
Most (>95%) congenital CMV infections are silent, and the newborn appears normal at birth. When 12,371 newborns were screened for the presence of CMV in urine that would indicate a congenital infection, the incidence of SNHL was found to be 1.1/1000 live births.30 Another study of 307 infants with asymptomatic congenital CMV infection reported 7.2% had SNHL that ranged from mild to profound.28 Fifty percent had bilateral hearing loss, and 20% had late-onset hearing loss. Other studies have reported that 5% to 15% of children born with silent congenital CMV infection and normal hearing in the neonatal period subsequently developed mild to moderate bilateral SNHL that may be progressive.31,34–36 Occasionally, these children progress to profound hearing loss in one or both ears. Studies estimate the prevalence of moderate or worse SNHL caused by congenital CMV to be 0.2 to 0.6 case/1000 live births.29
Diagnosis
Congenital CMV is diagnosed in symptomatic and asymptomatic infants by isolation of CMV from fresh urine during the first 1 to 2 weeks of life. CMV DNA can also be detected by PCR from urine, blood, cerebrospinal fluid (CSF), and infected tissues.37 Of congenitally infected infants, 60% to 75% have detectable IgM antibodies to CMV in the umbilical cord or infant serum. Antibodies of the IgM class imply fetal synthesis because maternal IgM antibody normally does not cross the placenta. This serologic test is difficult to perform and should be done only in qualified laboratories. CMV has been isolated from the amniotic fluid of mothers with a congenitally infected fetus.38,39 After 1 year of age, diagnosis of congenital CMV infection is very difficult. Healthy infants may acquire the virus infection asymptomatically, shedding the virus in their urine and developing antibody titers. Because most maternal infections are asymptomatic, no reliable history can be obtained retrospectively from the mother.
Temporal Bone Pathology
Limited histologic studies of infants dying with cytomegalic inclusion disease show labyrinthitis of the endolymphatic system.18,40–43 Inclusion-bearing cells have been identified in the auditory and vestibular portions of the inner ear (Fig. 152-1). Within the cochlea, damage is most severe along the basal turn. Evaluating the condition of the organ of Corti has been difficult because of postmortem autolysis, but it seems that the major hair cell degeneration seldom occurs, and that the tectorial membrane remains normal. There is little histologic damage to the auditory and vestibular nerves along with the spiral and vestibular ganglia. Hydrops of the cochlea and saccule and collapse of Reissner’s membrane have been observed. In one patient with cytomegalic inclusion disease, a thick layer of these inclusion-bearing cells was found inside the membranous walls of the utricle in the regions where dark cells are located.41
The temporal bones of an infant with severe cytomegalic inclusion disease and bilateral deafness who survived 14 years were studied.44 Chronic pathologic changes were seen in the cochlear and vestibular and nonsensory tissues. Reissner’s membrane was collapsed in the more apical turns. Strial atrophy and a loss of cochlear hair cells were observed along the entire length of the basilar membrane. Vestibular neuroepithelial regions were degenerated, and fibrosis was seen within the vestibular perilymphatic tissue spaces. In cochlear and vestibular spaces, isolated regions of calcifications were present. The fibrosis and calcifications suggest that late pathologic changes developed months to years after the acute viral damage had subsided.
In infants dying of cytomegalic inclusion disease, CMV antigen has been identified within cells lining the membranous labyrinth by immunofluorescent antibody staining.41 Virus particles belonging to the herpesvirus family have been seen within cells of the membranous labyrinth by electron microscopy.40,41
CMV has been isolated from perilymph obtained at autopsy from an infant with cytomegalic inclusion disease.41 CMV also has been isolated from the perilymph of a 5-month-old infant who died with asymptomatic congenital CMV infection whose inner ear morphology was normal by light microscopy.42 CMV has been detected by PCR in perilymph removed during placement of cochlear implants in children 
years old with congenital CMV,8 but CMV was not isolated from perilymph, or cytomegalic inclusion body–containing cells were not seen in a child with cytomegalic inclusion disease and bilateral deafness who survived 14 years.44 It seems that CMV can persist for years in children with congenital viral infections. What role CMV persistence plays in the delayed hearing loss of asymptomatically infected children is unclear.
Management and Prevention
Four approaches have had limited success in preventing or treating SNHL in congenital CMV. Toward prevention of primary CMV infection in a CMV-seronegative woman of childbearing age, several experimental CMV vaccines have been developed and are in clinical testing. These include protein subunit vaccines, DNA vaccines, vectored vaccines using viral vectors, peptide vaccines, and live attenuated vaccines.45,46
Treatment of pregnant women with primary CMV infection has been tried by passive immunization using hyperimmune CMV gamma globulin. A nonrandomized study of pregnant women with primary CMV infections showed a significant reduction in symptomatic infected newborn infants at 2 years of age.47 Valacyclovir at 8 g/day given to pregnant women with primary CMV infection has been shown to achieve therapeutic levels in maternal and fetal blood with a reduction in fetal viral load.39 Mixed clinical outcomes occurred in the 21 fetuses treated at 28 weeks of gestation, however.
The antiviral drugs, ganciclovir and valganciclovir, have had some success in treating infants with cytomegalic inclusion disease.48–52 Ganciclovir requires phosphorylation to ganciclovir triphosphate in part by enzymes from CMV. The triphosphate molecule inhibits viral DNA polymerase with inhibition of CMV replication.48 In a randomized controlled trial, intravenous ganciclovir begun in the neonatal period of symptomatically infected infants was effective in preventing hearing deterioration at 6 months, and may prevent hearing deterioration past 1 year.49
Ganciclovir can be delivered only by the intravenous route, and so creates a major problem for extended delivery of the agent. Valganciclovir, a monovalyl ester of ganciclovir, is an oral prodrug of ganciclovir, and in small studies seems to have similar efficacy in treating congenital CMV infections.50,51 Both drugs reduce CMV viral load in blood and urine, but rarely eliminate the virus from the host. Both drugs also frequently cause neutropenia, so dosages must be carefully monitored.
There is increasing evidence that deafness from congenital CMV is not a contraindication for cochlear implantation. Studies of these children have shown hearing improvement results similar to other congenitally deaf children, and no unusual complications have developed.53,54
Experimental Cytomegalovirus Inner Ear Infections
The human strain of CMV has not been shown to infect the labyrinth of small animals. The mouse and guinea pig strains of CMV have been shown to infect primarily perilymphatic structures of the cochlea and vestibule with variable secondary degeneration of the organ of Corti.55 In guinea pigs, guinea pig CMV has been inoculated directly into the basal turn of the cochlea, resulting in inflammation and cytomegalic cells within the perilymphatic duct along with variable secondary degeneration of the organ of Corti.56,57 These strains are also capable of infecting neurons in the spiral and vestibular ganglia. Guinea pig CMV has been shown to reach the cochlea by the intravenous route, and to cross the placenta to infect the fetal cochlea.58 Electrophysiologic recordings of cochlea microphonic and eighth cranial nerve have shown objective hearing loss in N1 compound action potential thresholds of infected guinea pigs.59–61 To date, all experimental models differ from human inner ear infection in that the animal viruses have primarily infected cells of the perilymphatic system, whereas human CMV primarily infects cells of the endolymphatic system.
Congenital Rubella Deafness
Clinical Features
Rubella infection of the pregnant mother as a cause of neonatal deafness was first recognized during the 1939 Australian rubella epidemic.62 From 1964 to 1965 during the U.S. rubella epidemic, more than 12,000 infants were found with hearing loss and congenital rubella.63 Since the introduction of rubella vaccine, the number of cases in developed countries has dramatically decreased, but not disappeared. The World Health Organization estimates that more than 100,000 infants are born each year with congenital rubella syndrome with 50% having hearing impairment.64 In many developed countries, it is estimated that 15% to 20% of women in childbearing years are susceptible to rubella infection, a number that is similar to that in industrialized countries in the prevaccination era.65 Since 2001 in the United States, there have been less than 25 cases of rubella each year, and no reported cases of congenital rubella syndrome.66
Maternal rubella infection during the first trimester of pregnancy places the fetus at the highest risk of congenital infection and subsequent hearing loss. In addition to the hearing loss, infants are often born with cardiac malformations, vision loss, and mental retardation.67 Approximately 50% of infants born with symptomatic congenital rubella have hearing loss. Infants infected with rubella during the second and third trimesters often are born with silent rubella infection and appear healthy at birth. Ten percent to 20% of these children are subsequently identified as hearing impaired.68
Hearing Loss
Congenital rubella infection involving the inner ear usually results in bilateral, often asymmetric, hearing loss. In a series of 8168 children with hearing loss from congenital rubella, 55% had profound hearing loss (≥91 dB ISO [International Standards Organization]), 30% had severe hearing loss (71 to 90 dB), and 15% had mild to moderate hearing loss (<70 dB).63 The audiograms of most children were usually flat, with hearing deficits occurring in all frequencies, but some had the greatest hearing loss in the midfrequency range of 500 to 2000 Hz, which is the range of voice.69 Children with rubella deafness may have poor speech discrimination, and a few may experience progressive hearing loss. Some children have had delayed or impaired speech development, but still have healthy pure tone hearing, which suggests a central auditory imperception.70 Adults who experience rubella infection rarely develop hearing loss.71
The vestibular system seems to be involved to a lesser extent than the auditory system.72 Caloric stimulation with 1 mL of ice water has suggested that some children have reduced caloric responses in one or both ears.73
Temporal Bone Pathology
Histopathologic changes seen in the temporal bones of congenital rubella deafness show characteristic changes, but the histopathologic findings are not specific for a rubella infection. The predominant abnormality is cochleosaccular degeneration and strial atrophy of varying degrees.74,75 Reissner’s membrane and the wall of the saccule may sag and even collapse (Fig. 152-2). The tectorial membrane is frequently abnormal, often displaced from the organ of Corti toward the limbus. The stria vascularis shows varying degrees of atrophy. Inflammatory cells in the cochlea are seldom seen. Cells with inclusion bodies do not occur. The vestibular neuroepithelia and their nerves usually appear healthy. There are no animal models for congenital rubella or rubella deafness.
Acquired Sensorineural Hearing Loss
Sudden Sensorineural Hearing Loss
Clinical Features
Many causes of SNHL have been described in children76,77 and adults.78 Although several definitions exist, most require a loss of greater than 30 dB in three contiguous frequencies that occurs in less than 3 days in the absence of a skull fracture.79 The incidence of severe SNHL is about 10/100,000 persons per year.3,80 The incidence of mild cases is unknown because many individuals do not seek medical attention. Most patients awaken with the hearing loss, or the loss develops within minutes to several hours. The hearing loss is unilateral in more than 90% of cases. Approximately half of the patients note accompanying vertigo or imbalance. Recovery of hearing ranges from 45% to 60%.3,81 The usual recovery period is days to weeks. After 1 month, little recovery occurs.3 The extent of recovery is related to age and severity of initial hearing loss. Untreated patients younger than 40 years of age have a better recovery rate. For individuals older than 40 years, the recovery rate may be only 30%.79
Temporal Bone Pathology
The mechanisms involved in the sudden hearing loss have not been fully clarified because there are few available temporal bone studies from patients during the acute period. A viral infection of the cochlear endolymphatic structures or spiral ganglia is one of several theories that has been postulated as the cause. Schuknecht82,83 examined the temporal bones of 12 patients with idiopathic sudden SNHL in his series and reviewed 9 additional published cases. Vertigo was noted in 47% of cases. Histologic abnormalities were identified in the organ of Corti (76%), tectorial membrane (53%), stria vascularis (62%), cochlear neurons (48%), saccule (43%), fibrosis with ectopic bone formation (10%), and tears in Reissner’s membrane or oval or round windows (10%). Schuknecht82,83 concluded that a viral infection of the endolymphatic labyrinth was the most tenable pathogenesis. Another study of 15 temporal bones from patients with SNHL reported the most prominent histologic findings to be loss of hair cells and supporting cells of the organ of Corti (with or without atrophy of the tectorial membrane), stria vascularis, spiral limbus, and cochlear neurons.84 This study reported examination of one temporal bone from a patient who died 9 days after unilateral sudden hearing loss and failed to find evidence of cochlear inflammation.
Several studies have attempted to define the infectious causes of idiopathic SNHL. Two viruses, mumps and measles (rubeola), have been recognized for centuries as a cause of acquired hearing loss in children. For other viruses, associations generally have been made on the basis of fourfold elevations in viral antibody titers in convalescence or case reports with isolation of the candidate virus from the nasopharynx or mouth. In addition to viruses, syphilis is recognized to cause acute hearing loss85; Lyme disease may also be a cause.86 Box 152-2 lists these candidate infectious agents. To date, associations of infectious agents have represented only a small fraction of the total SNHL cases.
Management
Administration of high-dose corticosteroids shortly after the onset of SNHL has been shown to have a significant benefit in recovery of hearing.87–89 More recently, nonrandomized studies of repeat treatment with intratympanic dexamethasone in patients who failed systemic corticosteroids reported that occasionally additional hearing recovery ensued.90–92 Because of the possibility that SNHL might be due to reactivation of HSV, a prospective, randomized, double-blind clinical trial of systemic prednisolone versus corticosteroids and acyclovir was performed on 91 patients.93 The investigators reported no additional benefit of the acyclovir over prednisolone only. If the sudden severe hearing loss permanently involved both ears, these patients may be candidates for cochlear implants.
Major Causes of Acquired Deafness from Viruses
Mumps Deafness
Clinical Features
Mumps was first recognized to cause deafness in 1860. Since then, it is estimated that 5 of every 10,000 patients with mumps have hearing loss develop.94 The widespread use of the mumps vaccine in developed countries has dramatically reduced the incidence. Mumps deafness continues to occur, however, in developing countries that do not have major vaccination programs. A study of 115 children with profound bilateral deafness reported that mumps was responsible for 7% of the cases.95 There has been a more recent increase in mumps in college-aged individuals in the United States (>2600 cases) and United Kingdom.96 Many of these individuals had previously received two doses of the mumps vaccine. It is unclear how often the mumps caused hearing loss in these patients.
Deafness associated with mumps usually develops in children toward the end of the parotitis, but can occur from a subclinical infection in the absence of parotitis.97–100 The onset of the deafness is usually rapid and unilateral in 80%. Hearing loss is maximal at high frequencies. Tinnitus and fullness in the involved ear are common. In two patients with acute mumps deafness, MRI showed enhancement of the labyrinth and CN VIII101 and the cochlea and vestibule.102
The hearing loss is often profound and usually permanent. A prospective study by Vuori and colleagues103 found the hearing loss to be transient in some patients, however. Some patients have vertigo develop that usually resolves over several weeks, but the patient may be left with permanent diminished or absent caloric responses in that ear. Absent caloric responses have also been found in patients with deafness associated with mumps, but without a history of vertigo.
Diagnosis
Mumps is diagnosed by (1) isolation of mumps virus from the saliva or CSF, or detection of mumps virus RNA, or (2) a fourfold or greater serologic increase in mumps antibodies between acute and convalescent serum samples. Sensitive real-time reverse transcriptase PCR assays are available for rapid detection of mumps virus from saliva.104 Mumps virus has been isolated from the perilymphatic fluid in one patient with acute unilateral deafness associated with parotitis.17 Currently, no specific antiviral drugs for mumps deafness exists, and it is unclear whether administration of corticosteroids improves hearing recovery. Administration of mumps vaccine in infancy effectively prevents subsequent mumps infections in childhood and adulthood.
Temporal Bone Pathology
Temporal bones from two patients with mumps-associated deafness have been examined.105,106 The cochlea showed severe atrophy of the organ of Corti and the stria vascularis, with partial collapse of Reissner’s membrane in the basal turn (Fig. 152-3). The tectorial membrane in one case was folded, thickened, and displaced from the organ of Corti. The upper turns of the cochlea showed less damage with occasional loss of hair cells. Cochlear ganglion neurons may be decreased in the area of the basal turn. Minimal vestibular abnormalities were seen.
Experimental Mumps Viral Labyrinthitis
Mumps virus inoculated into the inner ear of hamsters, guinea pigs, and monkeys principally infected non-neuroepithelial cells of the membranous labyrinth, which included cells of Reissner’s membrane, stria vascularis, and supporting cells of the organ of Corti.73,107,108 In the cochlear basal turn, degeneration of the organ of Corti and damage to the stria vascularis developed. Cells of the inner ear could be infected if the virus was inoculated directly into the inner ear, or if the virus entered the perilymphatic fluid of the scala tympani by way of the cochlear aqueduct after intracerebral inoculation.
Because the virus could reach the perilymph from the CSF in the model, the question arises as to whether this route of infection could occur in humans. Support for this hypothesis is severalfold. Mumps viral meningitis occurs in one third of infected children.109 The cochlear aqueduct is more often patent in children than adults, and dilated cochlear aqueducts have been recognized by CT in 6% of children with SNHL.76,110 Finally, deafness often develops toward the end of the first week of parotitis, a time consistent with spread of mumps virus from the infected CSF because of the meningitis from the cochlear aqueduct to the scala tympani. Spread of virus from CSF to the inner ear could also occur by way of the CN VIII pathway through the internal auditory canal to the spiral ganglion. Against both hypotheses is one study that did not find a correlation between mumps meningitis and deafness.103
Measles Deafness
Clinical Features
Measles virus involvement of the labyrinth usually is seen with the abrupt onset of bilateral hearing loss at the time of the rash, but occasional children have only unilateral hearing loss develop. In one large study, 45% of the children were left with severe bilateral hearing loss, and 55% had mild to moderate hearing loss.111 The typical audiogram shows bilateral loss that is often asymmetric and maximal at higher frequencies. The hearing loss is usually permanent and acutely may be accompanied by vertigo and tinnitus. Seventy percent of patients are left with absent or diminished caloric responses in one or both ears even though the vertigo has subsided.111
Conductive hearing loss from otosclerosis is becoming highly associated with persistent rubeola virus infection of the stapes footplate. Rubeola virus RNA has been detected by PCR in the stapes footplate removed at stapedectomy from patients with otosclerosis, but not stapes footplates of other diseases.104,112,113 Tissue culture explants of the stapes footplates also showed rubeola virus RNA.114 In addition, filamentous structures in osteoblast-like cells resembling nucleocapsids of rubeola virus were seen by electron microscopy.115 One laboratory was unable, however, to detect by PCR or immunofluorescence rubeola RNA or antigen in stapes footplates or their explants.116 Epidemiology studies in Denmark and Germany have shown a significant reduction in stapedectomies, particularly in younger patients, since the rubeola vaccination campaign began.117 The pathogenesis of how measles virus can persistently infect the stapes footplate in healthy individuals and cause otosclerosis is still unclear.
