Sensorineural hearing loss (SNHL) in children is associated with neurocognitive morbidity. The cause of SNHL is a loss of hair cells in the organ of Corti. There are currently no reparative treatments for SNHL. Numerous studies suggest that cord blood mononuclear cells (human umbilical cord blood, hUCB) allow at least partial restoration of SNHL by enabling repair of a damaged organ of Corti. Our objective is to determine if hUCB is a safe treatment for moderate to severe acquired SNHL in children.
Eleven children aged 6 months to 6 years with moderate to severe acquired SNHL were treated with intravenous autologous hUCB. The cell dose ranged from 8 to 30 million cells/kg body weight. Safety was assessed by measuring systemic hemodynamics during hUCB infusion. Infusion-related toxicity was evaluated by measuring neurologic, hepatic, renal and pulmonary function before and after infusion. Auditory function, auditory verbal language assessments and MRI with diffusion tensor imaging (DTI) were obtained before and after treatment.
All patients survived, and there were no adverse events. No infusionrelated changes in hemodynamics occurred. No infusion-related toxicity was recorded. Five subjects experienced a reduction in auditory brainstem response (ABR) thresholds. Four of those 5 subjects also experienced an improvement in cochlear nerve latencies. Comparison of MRI with DTI sequences obtained before and after treatment revealed increased fractional anisotropy in the primary auditory cortex in three of five subjects with reduced ABR thresholds. Statistically significant (
TIntravenous hUCB is feasible and safe in children with SNHL.
Sensorineural hearing loss (SNHL) is a permanent sensory disorder affecting more than 270 million people worldwide. The incidence of SNHL increases from 2/1000 in newborns to 5/1000 in children aged 3-17 years to 33% of adults aged 65-74 years to 50% of those greater than 85 years of age [
Among infants and children with SNHL, 23% to 50% of SNHL is the result of a genetic mutation (Connexin 26 mutation, Waardenburg syndrome, Usher syndrome, mitochondrial disorders, etc.) [
In preclinical and clinical studies, the intravascular delivery of mesenchymal progenitor cells in acute neuro-pathologic insults (stroke, traumatic brain injury, spinal cord injury, etc.) have shown significant promise [
This study presents the results of a phase 1 clinical trial to evaluate the intravenous administration of hUCB mononuclear fraction in infants and children with acquired SNHL. Our protocol was designed to evaluate the feasibility, logistics and safety of autologous hUCB treatment in this patient population. We also sought to acquire limited dose/response data, auditory function, language development and structural [MRI with diffusion tensor imaging (DTI) sequences] outcome data for future trial planning.
This study was conducted under Federal Investigational New Drug (IND) Application #15354 and was approved by the Florida Hospital Committee for the Protection of Human Subjects (IRBnet #434269) and Florida Hospital Office of Research Administration.
Following IND and IRB approval, a recruitment email was sent to families who had banked their children’s cord blood with Cord Blood Registry® (CBR®, San Bruno, CA, USA). The email invited parents of children with SNHL to contact the research team and the Florida Hospital for Children. After contact was initiated, an informed consent form was sent to the subject’s parents/guardians. Once the parents/guardians had reviewed, signed and returned the informed consent, a telephone interview was performed with a member of the research team. Following the interview, parents/guardians who wished to participate forwarded their child’s medical records to Orlando for review. If the subject met the inclusion and exclusion criteria (
Patients could only be enrolled longitudinally after review of their initial post-treatment course by an independent data safety management board. All data were audited by an external clinical monitor.
Parental informed consent was re-obtained in person prior to obtaining a history, conducting a physical exam and performing baseline audiological and neurological assessments. Auditory verbal speech language assessment, audiology testing [auditory brainstem response (ABR), otoacoustic emission testing (OAE), tympanometry and audiogram], screening laboratory and X-ray testing were also performed at the baseline visit.
On the day of infusion, the patient was admitted to the Florida Hospital for Children. Under general anesthesia, a 3 tesla MRI of the brain with DTI sequences was obtained. If the nonsedated ABR was inadequate, an ABR was obtained under anesthesia. The patient was allowed to recover from anesthesia and was then admitted to the bone marrow transplant unit of the Florida Hospital for Children for continued recovery and monitoring.
On the day of the infusion, the hUCB unit was thawed and washed in the Florida Hospital Cell Processing Laboratory. When the cord blood preparation was completed and the cord blood unit was determined to have met laboratory release criteria, it was transported to the bone marrow transplant unit. After baseline vital signs were obtained, the subjects were pre-medicated with diphenhydramine (Benadryl, Johnson & Johnson, New Brunswick, NJ, USA) and methylprednisolone (Solu-Medrol, Pfizer, New York, NY, USA). Thirty minutes after premedication, the hUCB unit was infused intravenously under the supervision of a hematologist (DS) experienced in bone marrow transplantation. Infusion was gravity-based. Vital signs were recorded every 15 minutes during the infusion, as well as for 4 hours following infusion. The patient was monitored overnight in the bone marrow transplant unit, and baseline laboratory values as well as a chest X-ray were rechecked in the morning following infusions. If the repeat lab values and chest films were within expected limits, the patient was discharged from the hospital. The parents/caregivers were provided with a digital thermometer and were contacted daily to follow the patient’s status for 14 days following discharge. The patient’s parents/caregivers were instructed to follow-up with their primary care physician on returning home.
The subjects and their parents returned for follow-up at 1, 6 and 12 months post infusion. At the 1-month, 6-month and 12-month follow-up visits, physical and neurological examinations were performed as well as tympanometry, OAE and ABR testing. Speech-language pathology evaluations were performed during the 6 and 12-month follow-up visits. At the 12-month follow-up visits, an MRI with DTI sequences was obtained.
Pulmonary function was assessed by continuous PaO2 measurement during anesthesia for the MRI/ABR, and while the patient was hospitalized in the bone marrow transplant unit for hUCB infusion. PaO2 was also recorded at each follow-up visit. Standard chest X-rays were obtained on the day of hUCB infusion, the day after hUCB infusion and at each follow-up visit.
Serum creatinine and blood urea nitrogen were obtained as a measure of renal function before hUCB infusion, the day after hUCB and at each follow-up visit.
A complete neurological examination was performed one day prior to and one day following hUCB infusion and at each subsequent follow-up visit.
A complete blood count with differential and platelet count was obtained one day before hUCB infusion, the day after hUCB infusion and at each follow-up visit.
The hepatic transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)] were measured the day before hUCB infusion, the day after hUCB infusion and at each follow-up visit as an index of hepatic injury/toxicity.
ABR, OAE, audiogram and tympanometry were obtained on the day before or if necessary on the day of the hUCB infusion and at each subsequent follow-up visit. Audiologic data were reviewed at the time of collection by a senior audiologist (EM). Changes of greater than a ±5 dB ABR threshold were considered significant. Changes greater than ±0.5 milliseconds in peak 5 of CN VIII conduction latency were considered significant. Age-appropriate speech-language pathology testing was obtained by an experienced auditory verbal speechlanguage pathologist (LB) on the day before hUCB infusion and at the 6- and 12-month follow-up visits, using the Preschool Language Scale, 4th edition [
Statistical analysis was performed by a biostatistician (RN) experienced in analyzing audiologic data. SAS 9.4 (Statistical Analysis System, Cary, NC, USA) was used to perform all the analyses. Statistical significance tests were performed for the effect of hUCB infusion on ABR thresholds and CN VIII peak 5 latencies using the change scores at the three follow-ups after the intervention. To assess the efficacy of the treatment, within-subject analysis of variance (ANOVA) was performed for the change scores at the 1-month, 6- month and 12-month follow-ups. For the ABR thresholds, 5 different measurements at various frequencies [click 2,000 Hz, tone burst (TB) at 500, 1,000, 2,000 and 4,000 Hz] were recorded for each ear, resulting in a total of 10 measurements for each subject at each follow-up time point. For latency, 6 different measurements at various frequencies were recorded for each ear, resulting in a total of 12 measurement for each subject at each follow-up time point. Apart from investigating the overall treatment effect, we also studied the direction of change in the outcome for individual subjects. Due to the very small sample size as well as some missing data within the pool, the overall power is expected to be low. Consequently, statistical significance for treatment may not be achieved for all of the outcomes using ANOVA, even if the treatment is effective. However, even in the absence of statistical significance, if the change in the relevant outcome is in the expected direction in most cases, it can be considered to be an evidence towards efficacy of the treatment. Under the null hypothesis of no treatment effect, there is a 50% chance for the change in each outcome to be in the desired direction. The probability of observing a specific number of change scores in the desired direction can be easily calculated using a binomial distribution with probability 0.5. Let k be the number of observed change scores in the desired direction. If the probability of observing at least k change scores in the desired direction using binomial distribution is less than 0.05 under the null hypothesis, the result will be considered statistically significant and the treatment be deemed effective.
Imaging protocols for brain MRI with DTI were performed using 3.0-T MR (Verio; Siemens Medical, Erlangen, Germany) with a 16-channel head coil. The DTI sequence was as follows: time to echo 84 ms, time to relaxation 10,000 ms, 250×250 mm slice with 4 mm spacing, 0 mm gap, matrix 128×100, 38 directions 25, maximum B value 1,000 s/mm2. Images were obtained on the day of hUCB infusion and at the 12-month follow-up visit. DTI imaging was processed with DynaSuite (In-Vivo; Gainesville, FL, USA). Maximum and mean fractional anisotropy (FA) were recorded for bilateral inferior colliculi, medial geniculate, auditory radiations, and white matter of Heschl’s gyrus for each patient at baseline and 1-year followup MRI using region of interest (ROI) analysis. All images were reviewed in a blinded fashion by an experienced neuroradiologist (SM).
The clinical demographics of the patients enrolled in the study are summarized in
There were no significant hemodynamic changes during or after the hUCB infusion, nor was there a notable change in hemoglobin/hematocrit levels after the procedure.
The total nucleated cells (TNC) administered, age at treatment and response to treatment are summarized in
There were no significant changes in PaO2 between the pre-hUCB infusion, post-hUCB infusion or follow-up PaO2 measurements. No changes were detected on chest X-rays obtained before or after hUCB infusion or at any follow-up visits.
The serum creatinine and blood urea nitrogen levels remained stable and within normal limits before and after hUCB infusion as well as at all follow-up visits.
The ALT and AST transiently and mildly increased following hUCB infusion in 2/11 patients (subjects 5 and 10). Both patients were observed as inpatients for an additional 24 hours post infusion. On repeat lab testing, the ALT and AST had either normalized or were decreasing toward normal. The changes were typical of those observed following stem cell infusion for other conditions. The AST and ALT were within normal limits on all follow-up measurements.
The neurological examinations remained stable for all subjects before and after hUCB infusion and at all follow-up visits.
ABR threshold improvement was observed in five subjects. Four of these five subjects also experienced improvements in CN VIII peak 5 latencies. Representative pre- and post-treatment audiograms, as well as corresponding ABR tracings, are shown in
Regardless of response to hUCB treatment, 10/11 subjects’ standard scores on the Preschool Language Scale 4th edition remained stable or improved (
The overall effect of treatment is statistically significant (
The overall effect of treatment for latencies is not statistically significant for any of the measurements (
FA is a sensitive marker of white matter integrity and myelination [
Our study demonstrates increased mean FA primarily within the white matter of Heschl’s gyrus in some patients who experienced an improvement in audiologic function following hUCB infusion, although this was not statistically significant. The data suggest that hUCB treatment can allow progressive myelination and strengthened integrity of auditory pathways in children with acquired SNHL.
Our data demonstrate that the infusion of autologous hUCB to children with SNHL is safe. There was no evidence of infusion-related toxicity in pulmonary, hepatic, hematologic, renal or neurological organ systems. Further, autologous hUCB is feasible within the context of a children’s hospital with bone marrow transplant expertise. Improvement in ABR threshold, when observed, was evident on testing at one-month post treatment and durable over the 12-month follow-up period.
Our phase 1 study evaluating the potential toxicity of autologous hUCB infusion in children with SNHL followed an uncontrolled design. Because the cochlea is post-mitotic at birth and because spontaneous repair of the cochlea has not been reported, we compared pre-treatment cochlear function to post-treatment cochlear function. Although improved structural, behavioral and functional outcomes were observed, our study is underpowered and not designed to conclude any difference with treatment. However, the observed safety of the protocol and promising pre-clinical research showing a benefit from hUCB-derived cell therapy for SNHL warrants the implementation of controlled phase 2 trials.
Two major classes of progenitor cell-based therapies are commonly utilized: autologous and allogenic. We chose to use autologous hUCB for many reasons: 1) no immune barrier considerations, 2) no
As ours is the first trial to prospectively evaluate the use of autologous hUCB infusion for acquired SNHL, appropriate cell dosing was not defined at the beginning of our study. The cell dose was increased as the study proceeded. We saw no infusion-related toxicities but did note improvement in ABR thresholds and 8th cranial nerve peak V latencies in some subjects receiving greater than 15×106 TNCs/kg. Behavioral testing results (audiograms) correlated with physiologic (ABR) improvement (
We chose to deliver our hUCB intravenously because of the well-established safety of the administration of this cell type using this route in children with hematologic disease. In addition, a treatment effect was observed in pre-clinical trials using the intravenous delivery of hUCB-derived progenitor cell preparations. Further, the risks and potential complications of a direct surgical delivery of progenitor cells to the cochlea were avoided.
Most (5/8) subjects receiving greater than the threshold dose of 15×106 cells/kg experienced a durable reduction in their ABR thresholds following hUCB treatment (
Our study included high-resolution MRI imaging with DTI sequences before and one year after hUCB treatment. We included an analysis of FA at sites along the auditory pathways. FA is a measure of white matter tract integrity, and increased FA suggests white matter tract repair. When FA measures were compared between responding and nonresponding subjects (
Cochlear hair cell regeneration could be caused by direct interaction with hUCB cells, as well as by local or systemic paracrine effects caused by hUCB infusion. The cochlea is known to have resident macrophages, and macrophages can be recruited to the cochlea from circulating monocytes to damaged and dying inner hair cells [
Following intravenous infusion, the majority of hUCB cells do not cross the blood-brain barrier [
Treatments to induce hearing recovery using gene therapy or the direct delivery of stem cells, viruses, or small molecules directly into the cochlea are currently under investigation [
In conclusion, our phase 1 open label study fulfilled the objective of evaluating the safety of intravenous autologous hUCB mononuclear fraction infusion for the treatment of acquired SNHL. We exceeded the minimal 6×106 TNC/kg in all patients, and the per kilo cell dose was increased throughout the trial. Functional and associated structural improvements were observed in several subjects receiving higher perkilogram doses of cord blood cells. The range in age of the responding subjects at treatment (9 months to 3 years 7 months) suggests a long window of opportunity for effective treatment. Because of the limited sample size, our study is underpowered and not designed to make conclusions on differences due to treatment. ABR thresholds would not be expected to spontaneously improve in this patient population. The observed safety of the protocol and promising clinical data suggest a benefit from cord blood-derived cell therapy for acquired SNHL. The data warrant the implementation of larger controlled phase 2/3 trials of this intervention in children with acquired SNHL.
This study was supported by a grant from Cord Blood Registry® (CBR®). Additional support was provided by Wayne Densch Charities.
Graphic representation of the patient enrollment and treatment timeline. CBR: Cord Blood Registry, FHFC: Florida Hospital for Children, FHCPL: Florida Hospital Cell Processing Lab, HLA: human leukocyte antigen, PCP: primary care physician.
Representative audiograms (top) and ABR recordings at 4,000 Hz (below) of subject 5 before (left) and after (right) hUCB treatment. The improvements on the behavioral testing (audiogram) match the changes found on the ABR recordings (physiologic). hUCB: human umbilical cord blood, ABR: auditory brainstem response.
A: Graphic representation of mean FA in the region of interest of Heschl’s gyrus white matter comparing responding and non-responding study subjects before (pre) and after (post) hUCB treatment. B: Graphic representation of maximal FA at selected sites along the auditory pathways comparing responding (R) and non-responding (NR) study subjects following hUCB treatment. FA: fractional anisotropy, hUCB: human umbilical cord blood, SEM: standard error of the mean.
Study inclusion and exclusion criteria
Inclusion criteria for patients with acquired SNHL who were screened for the trial |
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1) Evidence of SNHL: |
a. Moderate to profound in degree (40-90 decibels) |
b. Unilateral or bilateral configuration |
c. Symmetrical or asymmetrical configuration |
d. Sudden or progressive in presentation |
2) Hearing loss must be considered acquired |
a. History of in utero infection or |
b. Negative genetic screening |
3) Fitted for hearing aids no later than 6 months following detection of hearing loss |
4) Aged 6 weeks to 6 years at the time of infusion, with less than 18 months of hearing loss at the time of infusion |
5) Ability of the child and caregiver to travel to Orlando and stay for at least 4 days for infusion |
6) Ability of the child and caregiver to return to Orlando for follow-up visits |
1) Inability to obtain pertinent medical records |
2) Known history of: |
a. Recently treated infection <2 weeks before infusion. |
b. Renal disease (serum creatinine >1.5 mg/dL). |
c. Hepatic disease (SGPT >150 U/L and/or T. bilirubin >1.3 mg/dL). |
d. Malignancy |
e. Immunosuppression (WBC <3000) |
f. HIV |
g. Hepatits B or C |
h. Evidence of an extensive stroke (>100 mL lesion) |
i. Pneumonia or chronic lung disease requiring oxygen |
j. Genetic hearing loss |
3) hUBC sample contamination |
4) Banked cord blood cells totaling <6 million cells per kilogram subject weight. |
5) Participation in a concurrent study |
6) Unwillingness or inability to stay in Orlando for 4 days following cord blood infusion. |
7) Unwillingness or inability to return for scheduled follow-up visits and testing. |
8) Presence of a cochlear implant device |
9) Evidence of active maternal infection during pregnancy |
a. Hepatitis A |
b. Hepatitis B |
c. Hepatitis C |
d. HIV 1 |
e. HIV 2 |
f. Human T-lymphotropic virus (HTLV) 1 |
g. HTLV 2 |
h. Syphilis |
i. CMV is NOT among the exclusion criteria |
10) Conductive hearing loss |
11) Documented recurrent middle ear infections (>5/year) |
12) Otitis media on the pre-infusion physical examination |
13) SNHL that is mild |
14) Greater than 18 months of hearing loss at the time of infusion |
SNHL: sensorineural hearing loss, SGPT: serum glutamate-pyruvic transaminase, WBC: white blood cells, CMV: cytomegalovirus, HIV: human immunodeficiency virus
Study subject demographics
Subject # | Sex/degree of hearing loss | Age at cord blood Rx | Duration of HL prior to infusion | Time from identification to amplification | Failed newborn screening |
---|---|---|---|---|---|
1 | F/mild to moderate | 5 years 7 months | 1 year 3 months | 1 month, hearing aids all waking hours | - |
2 | F/moderate | 12 months 27 days | 11 months | 1 month, hearing aids all waking hours | + |
3 | F/mild to moderate | 6 years 11 months | 1 year 3 months | 1 month, hearing aids all waking hours | - |
4 | F/severe to profound | 9 months | 1 month | 7 months, hearing aids maximum 4 hours/day | + |
5 | M/mild to moderate | 2 years 10 months | 2 years 3 months | 18 months, hearing aids less than all waking hours | - |
6 | F/mixed conductive and mild | 1 year 9 months | 1 year 1 month | 8 months, hearing aids all waking hours | + |
7 | F/moderate to severe right ear | 5 months | 5 months | 4 months | - |
8 | M/unilateral profound | 2 years 10 months | 2 years 7 months | 1 year 11 months (Baha) | + |
9 | F/severe to profound | 3 years 6 months | 3 years 5 months | 8 months | + |
10 | M/moderate right, severe left | 14 months | 10 months | 4 months, hearing aids all waking hours | - |
11 | M/bilateral severe to profound | 11 months | 1 month | 1 month, hearing aids all waking hours | - (33-week preemie) |
Five subjects who passed newborn screening and later developed hearing loss are classified as “acquired SNHL.” The six subjects who failed newborn screening are classified as “congenital SNHL.” Nine subjects’ genetic screenings were negative for genetic SNHL markers. The remaining two subjects experienced CMV infection in utero. SNHL: sensorineural hearing loss, HL: hearing loss
Study subject cell dose and response
Subject # | Age at hUCB treatment | Cell dose/kg | Response: ABR/latency |
---|---|---|---|
1 | 5 years 7 months | 8×106 | -/- |
2 | 1 year 1 month | 8×106 | -/- |
3 | 6 years 11 months | 20×106 | -/- |
4 | 9 months | 21×106 | +/- |
5 | 2 years 8 months | 15×106 | +/+ |
6 | 1 year 9 months | 30×106 | +/+ |
7 | 6 months | 20×106 | -/- |
8 | 1 year 10 months | 28×106 | +/+ |
9 | 3 years 7 months | 28×106 | +/+ |
10 | 1 year 2 months | 20×106 | -/- |
11 | 10 months | 10×106 | -/- |
Changes of greater than ±5 dB ABR threshold were considered significant. Changes greater than ±0.5 milliseconds in CN VIII peak 5 conduction latency were considered significant. Exact treatment responses for responding subjects (ABR threshold and CN VIII peak 5 latencies) at baseline and at each follow-up measurement are summarized in Table 4-7. hUCB: human umbilical cord blood, ABR: auditory brainstem response
ABR and CN VIII wave 5 latencies for responding subject 9
A. ABR sensitivity: ABR AC and ABR TB at 500, 1,000, 2,000, and 4,000 Hz (tympanometry A/A at pre, 1-, 6-, and 12-month follow-up) |
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Test/Ear | Frequency (Hz) | Baseline (dB) | 1 month after Rx (dB) | 6 months after Rx (dB) | 1 year after Rx (dB) | Change from baseline (dB) 1/6/12 months |
ABR/AC/left | 2,000 | 85 | 75 | 80 | 80 | -10/-5/-5 |
ABR/AC/right | 2,000 | 95 | 80 | 70 | 70 | -15/-25/-25 |
ABR/TB/left | 500 | 85 | 85 | 80 | 80 | 0/-5/-5 |
ABR/TB/right | 500 | 90 | 70 | 60 | 60 | -20/-30/-30 |
ABR/TB/left | 1,000 | 85 | 75 | 80 | 70 | -10/-5/-15 |
ABR/TB/right | 1,000 | 80 | 70 | 60 | 65 | -10/-20/-15 |
ABR/TB/left | 2,000 | 90 | 80 | 85 | 85 | -10/-5/-5 |
ABR/TB/right | 2,000 | 80 | 80 | 85 | 80 | 0/5/0 |
ABR/TB/left | 4,000 | 100 | 95 | 100 | 95 | -5/0/-5 |
ABR/TB/right | 4,000 | 90 | 90 | 90 | 90 | 0/0/0 |
ABR/AC/Left | 2,000 at 95 dB | 10.13 | 7.53 | Not collected | Not collected | -0.26/NA/NA |
ABR/AC/Right | 2,000 at 95 dB | 7.47 | 6.47 | 6.53 | Not collected | -1.0/-0.94/NA |
ABR/TB/Left | 500 at 90 dB | 13.33 | 10.00 | 11.33 | 10.00 | -3.3/-2.0/-3.3 |
ABR/TB/Right | 500 at 90 dB | 9.53 | 9.13 | 9.67 | 9.73 | -0.4/+0.14/+0.2 |
ABR/TB/Left | 1,000 at 90 dB | 12.00 | 11.60 | 10.67 | 9.67 | -0.4/-1.33/-2.33 |
ABR/TB/Right | 1,000 at 90 dB | 9.53 | 9.47 | 9.00 | 9.60 | -0.06/-0.53/+0.07 |
ABR/TB/Left | 2,000 at 90 dB | 9.40 | 8.27 | 9.87 | 8.20 | -1.13/+0.47/-1.20 |
ABR/TB/Right | 2,000 at 90 dB | 8.53 | 7.80 | 7.33 | 7.73 | -0.73/-1.20/-0.80 |
ABR/TB/Left | 4,000 at 100 dB | 12.00 | 11.73 | 11.33 | 7.27 | -0.37/-0.67/-4.73 |
ABR/TB/Right | 4,000 at 100 dB | 11.00 | 10.67 | 9.87 | 6.73 | -0.33/-1.33/-4.27 |
ABR: auditory brainstem response, AC: air conduction clicks, TB: tone burst
ABR and CN VIII wave 5 latencies for responding subject 8
A. ABR sensitivity: ABR AC and ABR TB at 500, 1,000, 2,000, and 4,000 Hz (tympanometry C/C pre-Rx and A/A at 1-, 6-, and 12-month follow-up) |
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Test/Ear | Frequency (Hz) | Baseline (dB) | 1 month after Rx (dB) | 6 months after Rx (dB) | 1 year after Rx (dB) | Change from baseline (dB) 1/6/12 months |
ABR/AC/Left | 2,000 | 100 | 85 | 90 | 85 | -15/-10/-15 |
ABR/AC/Right | 2,000 | 20 | 20 | 20 | 20 | 0/0/0 |
ABR/TB/Left | 500 | 95 | 95 | 95 | 90 | 0/0/-5 |
ABR/TB/Right | 500 | 25 | 25 | 25 | 25 | 0/0/0 |
ABR/TB/Left | 1,000 | 95 | 90 | 90 | 90 | -5/-5/-5 |
ABR/TB/Right | 1,000 | 20 | 20 | 20 | 20 | 0/0/0 |
ABR/TB/Left | 2,000 | 90 | 95 | 95 | 95 | 0/5/5 |
ABR/TB/Right | 2,000 | 20 | 20 | 20 | 20 | 0/0/0 |
ABR/TB/Left | 4,000 | 100 | 95 | 100 | 100 | -5/0/0 |
ABR/TB/Right | 4,000 | 20 | 20 | 20 | 20 | 0/0/0 |
ABR/AC/Left | 2,000 at 100 dB | 7.40 | 7.60 | 8.07 | 7.73 | 0.2/0.67/0.33 |
ABR/AC/Right | 2,000 at 20 dB | 7.80 | 7.40 | 7.27 | 8.60 | -0.4/-0.53/0.80 |
ABR/TB/Left | 500 at 95 dB | 8.27 | 7.40 | 7.67 | NA | -0.87/-0.6/NA |
ABR/TB/Right | 500 at 25 dB | 14.53 | 12.73 | 12.20 | 13.73 | -1.8/-2.33/-0.8 |
ABR/TB/Left | 1,000 at 95 dB | 8.93 | 7.60 | 7.07 | NA | -1.33/-1.86/NA |
ABR/TB/Right | 1,000 at 20 dB | 12.67 | 11.87 | 12.07 | 11.20 | -0.8/-0.6/-1.47 |
ABR/TB/Left | 2,000 at 95 dB | 11.47 | 10.73 | 10.07 | 9.33 | -0.74/-1.4/-2.14 |
ABR/TB/Right | 2,000 at 20 dB | 10.00 | 9.40 | 9.13 | 10.07 | -0.6/-0.87/0.07 |
ABR/TB/Left | 4,000 at 100 dB | 8.80 | 8.47 | 9.13 | 8.33 | -0.33/0.33/-0.43 |
ABR/TB/Right | 4,000 at 20 dB | 9.80 | 8.13 | 7.80 | 8.13 | -1.67/-2.0/-1.67 |
ABR: auditory brainstem response, AC: air conduction clicks, TB: tone burst
ABR and CN VIII wave 5 latencies for responding subject 5
A. ABR sensitivity: ABR AC and ABR TB at 500, 1,000, 2,000, and 4,000 Hz (tympanometry: baseline A/B, 1-month f/u A/B, 6-month f/u B/B, 12-month f/u A/B) |
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Test/Ear | Frequency (Hz) | Baseline (dB) | 1 month after Rx (dB) | 6 months after Rx (dB) | 1 year after Rx (dB) | Change from baseline (dB) 1/6/12 months |
ABR/AC/Left | 2,000 | 45 | 40 | 40 | 35 | -5/-5/-10 |
ABR/AC/Right | 2,000 | 55 | 40 | 45 | 45 | -15/-10/-10 |
ABR/TB/Left | 500 | 60 | 50 | 40 | 55 | -5/-20/-5 |
ABR/TB/Right | 50 | 65 | 45 | 60 | 55 | -20/-5/-10 |
ABR/TB/Left | 1,000 | 55 | 45 | 60 | 45 | -10/5/-10 |
ABR/TB/Right | 1,000 | 50 | 45 | 35 | 45 | -5/-15/-5 |
ABR/TB/Left | 2,000 | 45 | 45 | 40 | 45 | 0/-5/0 |
ABR/TB/Right | 2,000 | 55 | 45 | 50 | 45 | -10/-5/-10 |
ABR/TB/Left | 4,000 | 50 | 40 | 35 | 40 | -10/-15/-10 |
ABR/TB/Right | 4,000 | 50 | 40 | 40 | 45 | -10/-10/-5 |
ABR/AC/Left | 2,000 at 80 dB | 6.07 | 5.60 | 5.00 | 5.13 | -0.47/-1.07/-0.94 |
ABR/AC/Right | 2,000 at 80 dB | 6.60 | 5.53 | 6.00 | 5.13 | -1.07/-0.60/-1.47 |
ABR/TB/Left | 500 at 60 dB | 8.60 | 8.13 | 7.87 | 8.00 | -0.47/-0.73/-0.60 |
ABR/TB/Right | 500 at 60 dB | 8.60 | 7.60 | 12.73 | 7.53 | -1.00/+4.13/-1.07 |
ABR/TB/Left | 1,000 at 50 dB | 8.87 | 8.40 | NA | 8.13 | -0.47/NA/-0.74 |
ABR/TB/Right | 1,000 at 60 dB | 8.53 | 7.40 | 8.67 | NA | -1.13/ +0.14/NA |
ABR/TB/Left | 2,000 at 60 dB | 7.07 | 6.73 | 6.60 | 6.53 | -0.34/-0.47/-0.54 |
ABR/TB/Right | 2,000 at 60 dB | 7.60 | 6.67 | 7.87 | 6.60 | -0.93/+0.27/-1.0 |
ABR/TB/Left | 4,000 at 60 dB | 6.67 | 6.20 | 6.07 | NA | -0.47/-0.60/NA |
ABR/TB/Right | 4,000 at 60 dB | 7.13 | 6.27 | 6.87 | NA | -0.86/-0.26/NA |
ABR: auditory brainstem response, AC: air conduction clicks, TB: tone burst
ABR and 7B CN VIII wave 5 latencies for responding subject 6
A. ABR sensitivity: ABR AC and ABR TB at 500, 1,000, 2,000, and 4,000 Hz (tympanometry: baseline A/A, 1-month follow-up A/A, 6-month follow-up C/A, 12-month follow-up C/C) |
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Test/Ear | Frequency (Hz) | Baseline (dB) | 1 month after Rx (dB) | 6 months after Rx (dB) | 1 year after Rx (dB) | Change from baseline (dB) 1/6/12 months |
ABR/AC/Left | 2,000 | 40 | 35 | 40 | 30 | -5/0/-10 |
ABR/AC/Right | 2,000 | 35 | 35 | 35 | 30 | 0/0/-5 |
ABR/TB/Left | 500 | 35 | 40 | 50 | 40 | +5/+15/+5 |
ABR/TB/Right | 500 | 45 | 45 | 50 | 45 | 0/+5/0 |
ABR/TB/Left | 1,000 | 45 | 40 | 40 | 40 | -5/-5/-5 |
ABR/TB/Right | 1,000 | 40 | 30 | 40 | 30 | -10/0/-10 |
ABR/TB/Left | 2,000 | 45 | 35 | 40 | 35 | -10/-5/-10 |
ABR/TB/Right | 2,000 | 35 | 30 | 35 | 40 | -5/0/+5 |
ABR/TB/Left | 4,000 | 55 | 40 | 40 | 40 | -15/-15/-15 |
ABR/TB/Right | 4,000 | 45 | 40 | 40 | 45 | -5/-5/0 |
ABR/AC/Left | 2000 at 80 dB | 6.73 | 6.13 | 6.07 | 6.33 | -0.6/-0.66/-0.40 |
ABR/AC/Right | 2000 at 80 dB | 6.33 | 5.87 | 5.87 | 6.07 | -0.46/-0.46/-0.24 |
ABR/TB/Left | 500 at 70 dB | 8.80 | 8.07 | 8.40 | 8.67 | -0.73/-0.40/-0.13 |
ABR/TB/Right | 500 at 70 dB | 9.13 | 8.00 | 8.27 | 8.27 | -1.13/-0.86/-0.86 |
ABR/TB/Left | 1000 at 50 dB | 9.53 | 9.33 | NA | 9.53 | -0.20/NA/0 |
ABR/TB/Right | 1000 at 50 dB | 9.60 | 9.13 | 9.60 | 9.87 | -0.47/0/+0.27 |
ABR/TB/Left | 2000 at 50 dB | 8.73 | 8.00 | 8.47 | 8.47 | -0.73/-0.26/-0.26 |
ABR/TB/Right | 2000 at 50 dB | 8.33 | 7.73 | 7.80 | 8.60 | -0.60/-0.53/+0.27 |
ABR/TB/Left | 4000 at 50 dB | 7.80 | 7.53 | 7.67 | 8.93 | -0.27/-0.13/+1.13 |
ABR/TB/Right | 4000 at 50 dB | 8.33 | 7.07 | 6.93 | 8.47 | -1.26/-1.40/+0.14 |
ABR: auditory brainstem response, AC: air conduction clicks, TB: tone burst
Statistical analysis of study ABR and cranial nerve 8 wave 5 latencies
A. Within-subject ANOVA results for the change in 5 ABR threshold scores for the left and right ears along with the mean change scores at each of three follow-up times. |
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Test/Ear | Frequency (Hz) | Mean change 1 month after Rx (dB) & |
Mean change 6 months after Rx (dB) & |
Mean change 1 year after Rx (dB) & |
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ABR/AC/Left | 2,000 | -4.5000 (0.0554) | -4.6814 (0.0554) | -3.0759 (0.1103) | 0.2163 |
ABR/AC/Right | 2,000 | -7.7778 (0.0165) | -8.8889 (0.0070) | -5.0000 (0.1103) | 0.0322 |
ABR/TB/Left | 500 | -1.8937 (0.4440) | -2.9642 (0.2562) | -2.3392 (0.3675) | 0.6773 |
ABR/TB/Right | 500 | -5.0000 (0.1955) | -5.0574 (0.2092) | -4.4324 (0.2691) | 0.4983 |
ABR/TB/Left | 1,000 | -3.5000 (0.0516) | -5.1978 (0.0102) | -4.5728 (0.0217) | 0.0404 |
ABR/TB/Right | 1,000 | -3.0000 (0.4769) | -1.2059 (0.7824) | 1.5719 (0.7190) | 0.7495 |
ABR/TB/Left | 2,000 | -1.0000 (0.7039) | -1.4484 (0.6137) | 1.0516 (0.7136) | 0.8226 |
ABR/TB/Right | 2,000 | -1.9279 (0.5318) | 0.2943 (0.9237) | 3.6276 (0.2442) | 0.3493 |
ABR/TB/Left | 4,000 | -6.6667 (0.0021) | -5.4719 (0.0119) | -6.0969 (0.0058) | 0.0081 |
ABR/TB/Right | 4,000 | -4.3750 (0.2584) | -3.7500 (0.3307) | 2.5000 (0.5140) | 0.2481 |
I/Left | 2,000 | 0.05775 (0.7790) | 0.2176 (0.1980) | -0.05711 (0.1715) | 0.3926 |
III/Left | 2,000 | -0.1529 (0.2872) | -0.01496 (0.8894) | -0.1452 (0.2201) | 0.4412 |
V/Left | 500 | -0.3832 (0.0618) | -0.1911 (0.2333) | -0.3991 (0.0299) | 0.0999 |
I-III/Left | 500 | 0.3405 (0.4555) | -0.06258 (0.8655) | -0.3929 (0.3336) | 0.4829 |
III-V/Left | 1,000 | -1.0222 (0.1578) | -0.7122 (0.2195) | -0.2039 (0.7424) | 0.4222 |
I-V/Left | 1,000 | -0.3250 (0.3670) | -0.5089 (0.0890) | -0.3569 (0.2633) | 0.3628 |
I/Right | 2,000 | 0.01866 (0.8069) | 0.09486 (0.1830) | -0.00071 (0.9921) | 0.4923 |
III/Right | 2,000 | -0.2060 (0.0861) | -0.2103 (0.0558) | -0.1967 (0.0796) | 0.1494 |
V/Right | 4,000 | -0.7684 (0.0227) | -0.4232 (0.1575) | -0.3028 (0.3402) | 0.1277 |
I-III/Right | - | -0.1795 (0.0936) | -0.2295 (0.0253) | -0.1489 (0.1602) | 0.1194 |
III-V/Right | - | -0.6369 (0.0489) | -0.2610 (0.3637) | -0.1476 (0.6312) | 0.2350 |
I-V/Right | - | -0.8033 (0.0201) | -0.4910 (0.1109) | -0.3042 (0.3482) | 0.1056 |
ANOVA: analysis of variance, ABR: auditory brainstem response, AC: air conduction clicks, TB, tone burst
Auditory verbal speech-language testing results (Preschool Language Scale, 4th Edition, Pearson, 2002)
Subject | PLS 4, standard score (baseline) | PLS 4, standard score (6 months) | PLS 4, standard score (12 months) | Consistent amplification | Home language |
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1 | 126 | 108 | 115 | + | English |
2 | 86 | 97 | 123 | + | English |
3 | 99 | 97 | 123 | + | English |
4 | 50 | 50 | 50 | - | English |
5 | 61 | 62 | 71 | + | English |
6 | 111 | 113 | 122 | + | English |
7 | 106 | NT | NT | + | English |
8 | 114 | 116 | 115 | + | English/Korean |
9 | 84 | 93 | 108 | + | English/ASL |
10 | 80 | 97 | NT | + | English |
11 | 69 | NT | NT | + | English |
Subject 7 dropped out of the study, and Subject 11 underwent bilateral cochlear implantation after the 1-month follow-up. Subject 10 refused testing at 12-month follow-up. PLS: Preschool Language Score, ASL: American Sign Language