Toxoplasmosis

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii and, if acquired prenatally, can cause SNHL. T gondii is the second leading cause of death from foodborne illness in the United States and has recently been named by the Centers for Disease Control and Prevention (CDC) as 1 of the 5 “neglected parasitic infections.” Humans acquire toxoplasmosis by ingesting the oocysts of the parasite. This can occur by eating contaminated undercooked meat or by handling and then accidentally ingesting oocysts from cat feces, soil, or water containing the parasite. (Members of the family Felidae [domestic cats] are the only known definitive hosts for T gondii .) Rarely, transmission may be from a contaminated blood transfusion or an organ transplant. The overall prevalence and incidence of congenital toxoplasmosis varies by region and country. In the United States, it is estimated that 22.5% of the population 12 years and older have been infected with T gondii , whereas in some parts of the world up to 95% of the population has been infected. Reporting is hampered by the fact that primary infection in most adults (including pregnant mothers) is asymptomatic. The incidence of congenital toxoplasmosis is estimated to be 1/1000 to 1/10,000. In 2000, the CDC reported that there were an estimated 400 to 4000 cases of congenital toxoplasmosis in the United States, based on the seroconversion rate of pregnant mothers. Massachusetts began screening newborns for toxoplasmosis in 1986, and in 1994 a study from the New England Regional Newborn Screening Program found the incidence of toxoplasmosis in newborns to be 1/10,000. The incidence of congenital toxoplasmosis varies outside the United States, with an estimate of 6/1000 births in France, 2/1000 births in Poland, 7 to 10/1000 births in Colombia, and 2/1000 births in Slovenia. Although recently the incidence of congenital toxoplasmosis has been reported to be decreasing, the rates of positive antibody titers remain high among pregnant women, especially outside the United States. Mothers who become primarily infected with T gondii have approximately a 30% to 50% chance of transmitting the infection to their fetus. Although the most severe disease is experienced by fetuses becoming infected during the first trimester, transmission of infection (transplacental) is much more common later in pregnancy, especially during the third trimester, or during delivery. Eighty-five percent of infants with congenital toxoplasmosis are asymptomatic at birth, with those infected later in pregnancy most likely to be asymptomatic. Although vertical transmission of infection is most likely to occur with primary maternal infection, immunocompromised women with chronic infection may also pass on the disease. If new infection is detected in the mother in early pregnancy, treatment with oral spiramycin, which does not cross the placenta, can prevent transmission to the fetus. If infection occurs later in pregnancy, and/or if the fetus is also infected, treatment with pyrimethamine, sulfadiazine, and folinic acid (pyrimethamine is a folic acid antagonist) may prevent transmission to the infant by treating the mother and may also treat the fetus.

The classic symptoms of congenital toxoplasmosis are chorioretinitis, hydrocephalus, and intracranial calcifications. Other symptoms can be seen in other congenital infections, including CMV, rubella, and herpes, and may include hepatosplenomegaly, jaundice, anemia, microcephaly, and lymphadenopathy. Although a 2009 systematic review by Brown and colleagues did not find any cases of hearing loss in infants with appropriately treated congenital toxoplasmosis, others have reported an incidence of hearing loss from 0% to 20%. Earlier studies with a higher incidence of SNHL often included untreated infants, whereas most infants in recent studies had been treated, suggesting that adequate treatment decreases the occurrence of SNHL. Treatment of congenitally infected infants with pyrimethamine and sulfadiazine is generally effective, although infants who present without neurologic disease have somewhat better outcomes than those who present with neurologic impairment. In addition, babies asymptomatic at birth may develop signs later in life, including chorioretinitis.

Toxoplasmosis is diagnosed using serologic testing. Measuring toxoplasma-specific IgG antibodies can determine if a person has been infected, whereas IgM is used to estimate when infection occurred. The lack of specificity of the IgG and IgM antibody test can make testing somewhat difficult to interpret. If the mother is both IgG and IgM positive, then further IgG avidity testing should be performed at a reference laboratory experienced in toxoplasmosis testing. Newborns suspected of having congenital toxoplasmosis should be tested for both IgM- and IgA-capture enzyme immunoassay. Diagnosis can also be made by direct observation of the parasite in stained tissue sections or cerebrospinal fluid. Polymerase chain reaction (PCR) can also be used to detect parasite genetic material and is especially useful if in utero infection is suspected.

Rubella

Rubella is caused by a togavirus of the genus Rubivirus . Until the introduction of the rubella vaccine, rubella was the most common viral cause of congenital SNHL. The rate of congenital rubella syndrome (CRS) for infants born to women infected during their first 11 weeks of pregnancy is 90%; if infected during the first 20 weeks of pregnancy it is 20%. The most common features of CRS are cataracts, heart defects, hearing impairment, and developmental delay. After the licensure of live attenuated rubella vaccines in the United States in 1969, the number of reported cases of CRS declined 99%, from 77 cases in 1970 to 4 total cases from 2005 to 2011. Although no longer endemic in the United States, rubella continues to be endemic in many other countries, where vaccination rates may also not be uniformly high in postpubertal girls. Therefore, babies with congenital hearing loss born outside the United States in areas where rubella remains endemic, or born to mothers who may not have been vaccinated, may be more likely to have CRS as a cause of their hearing loss. According to the WHO, the number of countries that have incorporated rubella vaccine into their immunization programs increased from 83 countries (12% of the birth cohort) in 1996 to 134 countries (44% of birth cohort) in 2012. In addition, the development of CRS is a theoretic risk in infants of mothers vaccinated during pregnancy.

Rubella virus can be cultured from nasal, throat, urine, blood, and cerebrospinal fluid specimens in infants with CRS. The serologic tests for rubella in babies with suspected CRS include IgG and IgM antibodies to rubella, with the enzyme immunoassays the most widely used and available. Infants with CRS may have detectable IgM antibody for 6 to 12 months after birth, and IgM can also be detected in cord blood or serum. Reverse transcription–PCR for detection of rubella virus RNA can also be used to detect the virus in clinical specimens, including blood, serum, and tissues.

Cytomegalovirus

Prenatal exposure CMV, a β-herpesvirus, is the most common congenital viral infection and currently the most common viral cause of congenital SNHL. The prevalence of congenital CMV infection is approximately 0.4% to 2.3% of all newborns. A 2008 study in Dallas, Texas, by Stehel and colleagues documented a 6% incidence of congenital CMV in babies with confirmed hearing loss. If the mother has a primary CMV infection during pregnancy, there is a 40% chance that the infant will become infected; and if she has a reactivation infection, there is an approximately 2% chance. The possibility of transmission of primary infection from mother to child is 25% in the first trimester, 50% in the second, and 75% in the third. Infants exposed to the virus during the first trimester, however, are the most likely to develop serious neurologic sequelae. Although 90% of infants with congenital CMV are asymptomatic at birth, 10% to 15% develop hearing loss, whereas 65% to 70% of infants with symptomatic CMV infection at birth also develop hearing loss. In the study by Stehel and colleagues, 75% of the infants with congenital CMV were only diagnosed because they had hearing loss. Because CMV-related hearing loss may not develop until later in infancy/childhood, however, the diagnosis can easily be missed. Infants with symptomatic CMV may present at birth with microcephaly, intrauterine growth restriction, developmental delay, hepatosplenomegaly, chorioretinitis, jaundice, petechiae, thrombocytopenia, hyperbilirubinemia, anemia, and hearing loss. The diagnosis of congenital CMV is made in the first 2 to 3 weeks of life by viral culture or PCR of saliva, urine, blood, or other bodily tissues. Positive PCR using dried blood spots can confirm a diagnosis of congenital CMV outside the newborn period when viral culture or CMV IgG cannot differentiate between congenital and postnatally acquired infection. In addition, PCR technology may become a basis for large-scale screening. In the United States, Utah (2013) and Connecticut (2015) have passed laws mandating the testing of newborns who fail their newborn hearing screen for CMV.

Initially, treatment of symptomatic congenital CMV involved 6 weeks of intravenous ganciclovir; more recently, oral valganciclovir, a prodrug of ganciclovir, has been used. Although the optimal duration of therapy remains unclear, a recent study looking at 6 weeks versus 6 months of valganciclovir showed modestly improved hearing and developmental outcomes at 24 months in babies with symptomatic congenital CMV in the infants who received 6 months of valganciclovir. Although several studies support improved hearing in infants receiving antiviral therapy, the numbers of treated patients remain small, the follow-up is variable, and progression of the hearing loss may occur after the drugs are stopped. Side effects of ganciclovir and valganciclovir include bone marrow suppression (neutropenia, thrombocytopenia, and anemia), and kidney and liver toxicity. Teratogenesis, mutagenesis, inhibition of spermatogenesis, and impaired fertility have been reported, primarily in animal studies, as a result of exposure to these agents. Once a baby is out of the newborn period, making a definite diagnosis of congenital CMV is difficult. It can be suspected, however, based on findings of developmental delay, microcephaly, and hearing loss; some infants have a history of intrauterine growth retardation, prematurity, hepatosplenomegaly, petechiae, and neurologic impairment in the perinatal period. Visual impairment may be present in 10% to 20% of symptomatic babies and includes strabismus, optic atrophy, macular scarring, pigmentary retinitis, and visual loss. Boppana and colleagues have reported late-onset or reactivation chorioretinitis in 7/31 (23%) children after 1 to 10 years of age. Imaging findings can help narrow the diagnosis in older children or confirm the diagnosis in newborns. Intracranial calcifications, migrational abnormalities (eg, polymicrogyria), cerebral and cerebellar volume loss, ventriculomegaly, and white matter disease are commonly seen on a combination of ultrasound, MR imaging, and CT. Characteristic imaging findings in association with neurodevelopmental delay and hearing loss suggest a diagnosis of congenital CMV. Treatment of older children with progressive hearing loss due to congenital CMV has not been studied.

Herpes simplex

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are double-stranded DNA viruses of the Herpesviridae family that commonly infect humans. Neonatal HSV infections occur in approximately 1/3200 births in the United States, with a majority HSV-2. Kimberlin reported that 85% of transmission is peripartum, 10% is postnatal, and 5% is in utero, with primary maternal infection resulting in a higher transmission rate than reactivation disease. Approximately 50% of neonatal HSV infections have CNS involvement. HSV-1 infections have also been associated with hearing loss after infection or reactivation of infection after infancy. Some are associated with HSV meningitis or encephalitis. The incidence of hearing loss in children with neonatal HSV is unclear, with hearing loss secondary to HSV-1 more common than in HSV-2. A recent systematic review of the incidence of SNHL in neonates exposed to HSV found that SNHL occurs rarely in infants with exposure to HSV, and there was no evidence of delayed onset of SNHL in infants with asymptomatic perinatal HSV infection. The few articles that reported audiometric data found a prevalence rate of 0% to 33% for hearing loss associated with intrauterine HSV-2 infection, with all infants also having severe CNS disease; however, all studies were small and audiometric techniques varied. Based on the limited information available, Westerberg and colleagues did not find that routine serologic screening for HSV infection in otherwise asymptomatic neonates with SNHL was justified. If congenital or perinatally acquired HSV infection is suspected, testing using direct viral culture of lesions or blood, or serologic testing, is recommended; if HSV infection is confirmed, audiometric evaluation is recommended.

Syphilis

Transplacental mother-to-child transmission of syphilis has been recognized since the fifteenth century. Congenital syphilis (CS) and syphilis acquired after birth are caused by Treponema pallidum , a gram-negative spirochete bacterium. Worldwide, 2 million mothers test positive for T pallidum infection during pregnancy, comprising 1.5% of all pregnancies. Prenatal T pallidum infection can lead to stillbirths and neonatal death. In the United States, however, CS is uncommon, with the result that hearing loss due to CS may be missed. In a systematic review of CS cases and articles contained in multiple databases published in 2009, Chau and colleagues did not find any reported cases of SNHL in infants with CS born to mothers with syphilis acquired during pregnancy. The number of CS cases reported annually in the United States was 10.6/100,000 live births in 2003, 8.2/100,000 in 2005, 10.1/100,000 in 2008, and 8.7/100,000 in 2013. These rates parallel the primary and secondary syphilis rates among US girls and women from 2005 to 2008 of 1.5/100,000 but with a subsequent decrease in 2013 to 0.9/100,000. Therefore, CS remains uncommon in the United States and, therefore, any associated hearing loss may not be readily recognized or even sought. Although late CS may present as the classic Hutchinson triad of interstitial keratitis, notched incisors, and SNHL, it can present as hearing loss alone. Clutton joint (symmetric hydrarthrosis, especially of the knees) and mulberry molars (malformed first molar resembling a mulberry) were added as additional features of CS by Fiumara and Lessell. Prenatal diagnosis involves testing pregnant mothers, generally at the first prenatal visit and then toward the beginning of the third trimester, with nearly complete elimination of any serious complications in the baby if the mother is treated before 24 weeks’ gestation. For babies with CS identified after birth, appropriate treatment with penicillin usually results in a cure. Because syphilis acquired after birth may present as progressive and/or sudden hearing loss or vertigo, the diagnosis should be considered in any sexually active patient who presents with recent-onset hearing loss and/or vertigo.

Human immunodeficiency virus

Audiologic and vestibular symptoms can occur in children infected with Human immunodeficiency virus (HIV)-1. These include conductive hearing loss (often due to otitis media [OM]), SNHL, tinnitus, vertigo, and ataxia. Hearing loss may occur due to direct infection of the inner ear with HIV or secondary to opportunistic infections (eg, CMV, syphilis, tuberculosis, and cryptococcal meningitis) or ototoxic drug therapy. In several studies, children with perinatally acquired HIV seem to have a higher incidence of hearing loss than normal children, with both SNHL and conductive hearing loss, due mainly to otitis media. A recent study in HIV+ adults compared with HIV− adults showed a higher incidence of both low-frequency and high-frequency hearing loss. In 1 pediatric study, there was a suggestion that lower CD4 counts, longer time with HIV, and higher viral load were associated with an increased prevalence of audiologic or vestibular symptoms. Therefore, children who are HIV+ should have audiometric examinations incorporated into their routine care.

Measles (rubeola)

Measles is a paramyxovirus spread via the respiratory route and in the prevaccine era was an identified cause of acquired hearing loss. Although measles was reported to have been eradicated in the United States in 2000, hundreds of cases have been reported since then, including several large outbreaks in 2008, 2011, 2013, 2014, and 2015 These outbreaks occur mainly in unvaccinated children, including those born outside the United States, children too young to vaccinate, and children whose parents have chosen not to vaccinate them. Live attenuated measles virus is included in the standard measles vaccine. Information from the Vaccine Adverse Event Reporting System in the United States estimated the reporting rate of SNHL possibly related to mumps/measles vaccine to be 1 case in 6 to 8 million doses. Measles virus has also been possibly implicated in the development of otosclerosis, although whether this is an association or causation remains unclear.

Lyme disease

Lyme disease is caused by the bacterium Borrelia burgdorferi and is transmitted to humans by the bite of an infected blacklegged tick. It is the most commonly reported vector-borne illness in the United States. In 2013, 95% of cases occurred in 14 states; in the United States, the incidence is highest in the northeast and upper midwest states but has been reported in all 50 states. Although people of any age and both genders are susceptible to tick bites, from 2001 to 2010 Lyme disease was most common among boys aged 5 to 9 years and persons older than 30 years. The CDC reported a 9% incidence of facial palsy among 154,405 patients with Lyme disease between 2001 and 2010. Hearing loss in association with Lyme disease, however, is infrequently reported. A 2010 retrospective review by Wilson and colleagues of patients 18 years of age and older presenting with asymmetric SNHL of uncertain etiology showed that of the 88 who were tested for Lyme disease, 3 were positive. Although the endemic nature of Lyme disease in many parts of the country can make confirming a relationship between Lyme disease and hearing loss challenging, Wilson and colleagues thought that of the many tests ordered in their study, Lyme titers and tests for syphilis were potentially the most useful, potentially treatable, and cost-effective.

Mumps

Mumps is a paramyxovirus that results in an acute viral illness characterized by unilateral or bilateral parotitis, and complications, including SNHL, aseptic meningitis, encephalitis, and, in postpubertal age groups, orchitis, oophoritis, and mastitis. Approximately 20% to 40% of infections are asymptomatic, and many symptomatic patients only have respiratory symptoms. Mumps is endemic in most of the world and by the end of 2013 was included in the vaccine programs of 120 countries. Live mumps vaccine was licensed for use in the United States in 1967, with a drop in incidence of mumps cases to 0.1/100,000 persons (314 cases total) in the United States by 2005, a 99% decrease compared with the prevaccine era. There have been several large outbreaks of mumps since then, however, in 2006, 2009, and 2010, often seen on college campuses. The incidence of SNHL after mumps is unclear, but a 2009 study from Japan suggested an incidence of 0.1%, with the hearing loss unilateral and in the moderate to profound range; the CDC states recently the incidence has been less than 1%. Hearing loss associated with mumps may occur before or after the parotitis and in otherwise asymptomatic cases. The vaccines against rubella, measles, and mumps contain live attenuated virus, and hearing loss in association with measles, mumps, and rubella vaccination has also been reported, although rarely. A 2008 article using data from the US Vaccine Adverse Event Reporting System for the period 1990 to 2003 estimated the reporting rate of SNHL related to vaccine use to be 1 case in 6 to 8 million doses. Because of the rarity of these reports, a causal relationship between mumps, rubella, and measles vaccination and SNHL requires further study.

Other viruses

Other viral infections have been potentially associated with either congenitally acquired or postnatally acquired hearing loss, including sudden hearing loss. These include lymphocytic choriomeningitis virus, varicella zoster virus, West Nile virus, and human parvovirus B19. Varicella zoster virus causes Ramsay Hunt syndrome, also called herpes zoster oticus (HZO), and involves reactivation of the virus in the geniculate ganglion. In addition to facial paresis, hearing loss and vertigo are 2 of the often multiple presenting symptoms of HZO, which can affect multiple cranial nerves. Up to 5% of patients with HZO will have some degree of permanent hearing loss.

Bacterial meningitis

Hearing loss is a well-documented sequela of bacterial meningitis. A 2010 systematic review and meta-analysis of 132 articles from around the world published between 1980 and 2008 reported a 33.6% incidence of hearing loss due to bacterial meningitis from all causes (Streptococcus pneumoniae , Haemophilus influenzae type B, Neisseria meningitidis , and others). Although H influenzae type B meningitis was the most common type of meningitis, hearing loss occurred most often after pneumococcal meningitis. The use of systemic steroids in the management of meningitis remains controversial. A 2013 Cochrane Database review looked at 25 randomized controlled trials of corticosteroid use (4121 subjects) in acute bacterial meningitis. For the group as a whole, they found a significantly reduced rate of hearing loss and neurologic sequelae, although overall mortality was not reduced. The data supported beneficial effects of steroids, including decreased hearing loss and neurologic sequelae, in high-income, but not low-income, countries. Therefore, the benefits of dexamethasone or other steroids in the prevention of hearing loss or other neurologic sequelae due to bacterial meningitis continue to remain unclear.

Bacterial meningitis–related hearing loss generally has its onset early in the course of the disease, and the incidence has not been decreased by any specific antibiotic regimen. Although otitis media with direct spread through labyrinthine windows may precede onset of the disease in some cases, a more likely route is penetration of bacteria and bacterial toxins via the cochlear aqueduct or internal auditory canal contents, resulting in perineuritis or neuritis of the cochleovestibular nerve and/or suppurative labyrinthitis. Other pathophysiologic mechanisms operative in producing hearing loss may include serous or toxic labyrinthitis, thrombophlebitis or embolization of labyrinthine vessels, and hypoxia or anoxia of the eighth nerve and central auditory pathways.

If a child with meningitis has normal audiometric studies after the first few days of antibiotic therapy, it is unlikely that significant SNHL will develop later, and some children with initially abnormal hearing may improve, suggesting a resolving serous labyrinthitis. Well-documented late progression of postmeningitic SNHL after years of stability has been reported, however, in a few patients, along with some fluctuation of the hearing for up to a year after the initial episode of meningitis. In addition, Worsøe and colleagues found that many patients who were not suspected of having hearing loss at the time of discharge were later found to have SNHL, supporting the need for close follow-up.

For those children with profound bilateral SNHL after bacterial meningitis, cochlear implantation has been a successful means of auditory rehabilitation. Surgery for cochlear implantation must be expedited, because labyrinthine ossification as a sequela of meningitis may make implantation of the electrode array into the cochlea difficult if not impossible.

Otitis media

Although OM is common, permanent SNHL in the pediatric population as a result of uncomplicated OM is not. SNHL can, however, occur in association with acute suppurative labyrinthitis and with longstanding chronic suppurative otitis media, with or without cholesteatoma. Therefore, the hearing in children with both of these forms of OM must be carefully monitored.