Nodoka Adachi

Etiology and one-year follow-up results of hearing loss identified by screening of newborn hearing in Japan

Objective: To evaluate the incidence of newborn hearing loss in a Japanese population and to elucidate etiological factors and one-year prognosis. Study Design: Screening of newborn hearing. Setting: Childrens tertiary referral center. Subjects and Methods: Between 1999 and 2008, 101,912 newborn infants were screened, with 693 infants (0.68%) referred. Etiology investigation included CT, detection of cytomegalovirus (CMV) DNA, and connexin 26 mutation. Results: Abnormal results (auditory brainstem response [ABR] threshold ≥ 35 normal hearing level [dB nHL] in either side) were observed in 312 infants (0.31%), and 133 subjects (0.13%) with ABR thresholds ≥ 50 dB nHL on both sides were classified into the habilitation group. In this group, inner ear/internal auditory meatus anomalies were detected in 20 of 121 subjects (17%) tested, middle/external ear anomalies in 14 of 121 subjects (12%), CMV DNA in 13 of 77 subjects (17%), and connexin 26 mutation in 28 of 89 subjects (31%). In 68 subjects undergoing all three investigations (CT, CMV, and connexin 26), 41 (60%) had positive results in at least one test. With inclusion of otitis media with effusion and perinatal problems, this rate amounted to 78% (53 subjects). Of the 97 infants in the habilitation group successfully followed up to one year, 36 (37%) showed a threshold change of 20 dB or more in either ear: 11 (11%) progression and 25 (26%) improvement, and 15 infants (15%) were reclassified into a less severe classification. Conclusion: Considering that 26 percent of infants with bilateral moderate to severe hearing loss showed improvement in one year, habilitation protocols, especially very early cochlear implantation within one year of birth, should be reconsidered.

Cholesteatoma of the petrous bone: the crucial role of diffusion-weighted MRI

It is not easy to identify the nature of various mass lesions, e.g., cholesteatomas, cholesterol granulomas, mucoceles, neurinomas, etc., in the pyramidal portion of the temporal bone. Difficulty in direct access to the petrous apex makes diagnostic biopsy practically impossible. However, correct diagnosis is very important for treatment planning. While simple drainage is sufficient for lesions such as mucoceles and cholesterol granulomas, total removal should be performed for lesions such as cholesteatomas and schwannomas. Although diagnostic biopsy should be followed immediately by removal (one-stage operation) for such lesions, this is not always possible because of the limited number of experienced surgeons (sometimes also neurosurgeons), availability of operation rooms and medical support teams, and other reasons. Since delayed removal increases the risks of dissemination and infection, one-stage surgery should be properly planned with a correct diagnosis of lesions that necessitate total excision. Therefore, the imaging study plays an important role in diagnosing mass lesions in the petrous bone. Here, we present a demonstrative case of imaging diagnosis. High resolution CT (Fig. 1) demonstrated an expansive and destructive lesion, which offered few clues to its nature, since bone destruction may also occur with mucoceles and granulomas. On MRI, the standard imaging properties (comparison with adjacent brain) of four representative lesions of the petrous apex are: (1) T1 high intensity and T2 high intensity with cholesterol granulomas, (2) T1 low intensity without contrast enhancement and T2 high intensity with mucoceles, (3) T1 low intensity without contrast enhancement and T2 high intensity with cholesteatomas and (4) T1 low intensity with contrast enhancement and T2 high intensity with schwannomas [1]. Thus, MRI in our case (Fig. 2) did not exclude either cystic lesions or cholesteatomas. Diffusionweighted MRI (DWI) [2] was found useful to detect epidermoids and brain ischemia in the 1980s, and its clinical application started in the late 1990s [3]. Generally, on DWI, granulomas, cystic lesions, cholesteatomas (epidermoids) and schwannomas show low, isoto low, markedly high and isoto low intensity, respectively [4, 5], facilitating differential diagnoses. DWI in our case (Fig. 3) established the final diagnosis: large cholestatoma of the petrous bone, involving the cochlea, posterior semicircular canal and facial nerve. The cholesteatoma was successfully removed using a one-stage combined (middle fossa and mastoid) approach surgery, and the facial nerve was reconstructed using the sural nerve. Our case demonstrated and confirmed the crucial role of DWI in the diagnosis and treatment-planning of petrous apex lesions. We would like to stress that DWI is the imaging method of choice for diagnosing petrous lesions.

GJB2-associated hearing loss undetected by hearing screening of newborns.

The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.

Cisplatin-induced Hearing Loss: The Need for a Long- term Evaluating System

Cisplatin is an effective chemotherapeutic agent against pediatric cancers; however, ototoxicity is a concern. This study describes the frequency, severity, and clinical course of hearing loss in Japanese pediatric patients treated with cisplatin-based multimodal therapy. A total of 55 children who received cisplatin-based therapy from 1983 to 2012 underwent audiologic evaluations. Data were analyzed to determine the onset, time-to-progression, and severity of hearing loss. Thirty-five patients, 12 of 16 older patients (4 y or older), and 23 of 39 younger patients (under 4 y), including 7 of 8 patients treated with cisplatin, carboplatin, and radiotherapy, developed hearing loss. Ten of 18 patients who received a cumulative cisplatin dose of <360 mg/m2 developed hearing loss at a minimum dose of 200 mg/m2. Median time to onset after the last cisplatin dose was 71 days; 6 patients developed hearing loss after ≥2 years. Four patients required hearing aids, 6 patients developed progressive hearing loss with time, and 4 patients exhibited persistent hearing failure at low frequencies. Risk factors for acquired hearing loss and its severity may be associated with a combination of factors such as cisplatin and carboplatin therapy, radiotherapy, age at diagnosis, and genetic background. Our results suggested that all pediatric patients treated with cisplatin would have their hearing evaluated regularly, irrespective of the cumulative cisplatin dose as a suggestion, and that further prospective studies regarding ototoxicity including genetic polymorphisms analysis were required.

Risk factors for hearing loss after pediatric meningitis in Japan.

Objectives We sought to identify predictors for hearing loss in Japanese children with meningitis. Methods We analyzed 155 cases of pediatric meningitis without other entities causing hearing loss in children admitted to Saitama Childrens Medical Center between 1990 and 2005 for potential risk factors for hearing loss, using multiple logistic regression. Auditory brain stem response tests were performed to evaluate hearing loss. Results Of 155 children, 35 (23%) developed hearing loss (21 unilaterally and 14 bilaterally). Profound hearing loss (greater than 90 dB normal hearing level) occurred in 15 patients (9.7%; 4 unilaterally and 11 bilaterally). Of 112 patients with positive cerebrospinal fluid cultures, 27 (24%) developed hearing loss and 13 (12%) showed profound loss. Of 22 patients with Streptococcus pneumoniae meningitis, 11 (50%) developed hearing loss and 7 (32%) showed profound loss. Of 54 patients with Haemophilus influenzae meningitis, 11 (20%) developed hearing loss and 4 (7.4%) showed profound loss. High serum C-reactive protein levels and cerebrospinal fluid cultures positive for Streptococcus pneumoniae were identified as significant risk factors for hearing loss. Conclusions A high serum C-reactive protein level was first identified as a risk factor for hearing impairment after pediatric meningitis.

Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study

Objective Approximately 8–10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. Study design The study included 23 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5 days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. Results The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). Conclusions We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders.