Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: A prospective cohort study.

OBJECTIVE: To determine the benefit of sequential cochlear implantation after a long inter-implantation interval in children with bilateral deafness receiving their second implant between 5 and 18 years of age. STUDY
DESIGN: Prospective cohort-study.
SETTING: Tertiary multicenter. PATIENTS: 85 children with bilateral deafness and unilateral implantation receiving a contralateral cochlear implant at the age of 5 to 18 years.
METHOD: The primary outcomes were speech recognition in quiet and noise (CVC) scores. The secondary outcomes were language outcomes and subjective hearing abilities, all measured before and 12 months after sequential bilateral cochlear implantation. Medians of the paired data were compared using the Wilcoxon signed-rank test. Univariable linear regression analyses was used to analyze associations between variables and performance outcomes.
RESULTS: A significant benefit was found for speech recognition in quiet (96% [89-98] vs 91% [85-96]; p < 0.01) and noise (65% [57-75] vs 54% [47-71]; p = 0.01) in the bilateral CI condition compared to unilateral (n = 75, excluded 10 non-users). No benefit was seen for language outcomes. The subjective sound quality score was statistically significant higher in bilateral compared to the unilateral CI condition. Pre-operative residual hearing level in the ear of the second implant, the inter-implant interval and age at time of second implantation was not significantly associated with performance scores.
CONCLUSION: After 12 months of use, sequential bilateral cochlear implantation showed improved speech perception in quiet and noise and improved subjective sound quality outcomes in children despite a great inter-implantation interval (median of 8 years [range 1-16 years]).

Introduction

In recent years, literature demonstrating that bilateral cochlear implantation in children results in superior hearing outcomes compared to unilateral implantation steadily increases [1]. Despite the fact that unilateral cochlear implantation (UCI) gives generally rise to good speech perception performance in quiet conditions, bilaterally implanted children perform better in noisy environments (i.e. classrooms) and more challenging hearing conditions [2-4]. Moreover, children with bilateral cochlear implantation (BICI) achieve better sound localization [5,6], speech and language development [7-10], and self-rating outcomes [11] when the second implant is provided simultaneously (within a single surgery) or sequentially within a short inter-implant interval [12,13]. As a result, in numerous countries bilateral cochlear implantation has become the standard of care as treatment for young children with bilateral severe to profound sensorineural hearing loss (SNHL). In the Netherlands from 2013 onwards, bilateral cochlear implants became available for all children with bilateral sensorineural hearing loss up to the age of five years. Shortly after this milestone, a conditional reimbursement was granted for all children aged five to eighteen years for a second cochlear implant. For this, outcome evaluation on a national level was requested by the Dutch health care institute as a necessity for this refund.

The timing of auditory stimulation in relation to the process of cortical development is considered as a major factor of importance to explain variations in outcomes of children receiving their second cochlear implant in later childhood [14]. If the stimulation by the second CI is out of the sensitive period, which is described to be approximately around 7 years of age, this could limit functional outcome [15]. Therefore, simultaneous BICI or sequential implantation within a short interval is advised for children with bilateral deafness [16,17]. Nonetheless, there is still a cohort of children with bilateral hearing loss who were implanted unilaterally early in life, comprised of children with prelingual deafness and children with progressive hearing loss. These children either experience unilateral stimulation by the cochlear implant, or bimodal input by wearing a contralateral hearing aid before being implanted with their second implant. Children from this cohort with demonstrated effectiveness of the first implant are thought to qualify for a second (contralateral) cochlear implant. This is substantiated by earlier evidence showing the advantage of sequential bilateral implantation for speech recognition in quiet and noise and the receptive vocabulary [18-19]. In the long term, the improvement in the more basic language skills, like receptive vocabulary, may also lead to an improvement in more complex linguistic skills.

In case of sequential implantation, it is demonstrated that not only a short inter-implant interval but also younger age, better residual hearing and bimodal stimulation favors functional outcomes [20,21]. So far, most studies analyzing outcome of sequentially implanted children included populations with a mean age between 5 to 10 years at the time of the second cochlear implantation [3,17,20,21]. Only a few studies reported outcomes even in cases receiving their second implant during adolescence [14,22]. For this group of children, receiving their second cochlear implant many years after their first implant, the association between these factors and hearing performance is unclear. Following the conditional reimbursement for the second implant for the children aged five to eighteen years in the Netherlands, a Dutch national multicenter prospective trial was initiated to assess the benefit of the second cochlear implant in terms of speech perception, subjective performance of hearing abilities and speech and language development after one year.

Materials and methods

Study objective, design and participants

In this study we aim to assess hearing outcomes in children receiving their second cochlear implant in the age of 5–18 years after being previously unilaterally implanted at a younger age. Secondly, we aim to analyze the influence of patient related characteristics on speech reception and speech and language development scores with their second implant.

The data in this multicenter prospective cohort study were collected from January 2014 to December 2016, in which five cochlear implantation centers (CI-centers) in the Netherlands participated: Radboud University Medical Center Nijmegen (Radboudumc), the University Medical Center of Utrecht (UMCU), Leiden University Medical Center (LUMC), Erasmus Medical Center (EMC) and Maastricht University Medical Center (MUMC). Patients eligible to participate in this study were previously unilaterally implanted with a cochlear implant, where some of these children wore a hearing aid in addition (bimodal stimulation) to their cochlear implant. To be eligible to receive a second, contralateral implant and to be included in the study, the following criteria were handled; patients with bilateral severe-to-profound hearing loss (≥85dB at 2 and 4 kHz) aged between 5 and 18 years, previously implanted on one side. Patients with cochleovestibular malformations or with signs of intracochlear obliteration on CT-scan that might prevent full insertion of electrode array were excluded. Patients with a high suspicion of having an aplasia of the auditory nerve diagnosed by previous Magnetic Resonance Imaging and with no detectable hearing thresholds were excluded. Otherwise, no limitations were made for any type of etiology of hearing loss. Cases with limited expectations of a second cochlear implant in terms of speech perception results were not qualified for conditional reimbursement of the contralateral implant and therefore not included in this study. These expectations were not based on the distinction of pre- or post-lingual deafness or factors of comorbidity (i.e. developmental delay), but on factors such as limited benefit of the first cochlear implant, sign language as preferred communication mode at home, and minimal abilities to develop speech and language skills.

A full diagnostic evaluation was performed by a multidisciplinary cochlear implantation team (CI-team) embedded within the participating University Medical Centres to assess eligibility. These multidisciplinary CI-teams consisted of an otorhinolaryngologist, audiologist, speech and language pathologist and a psychologist. Every case underwent an additional, independent review from a second CI-team of another University Medical Centre (based on the patients’ file) to make a well-advised decision before giving consent for a second cochlear implant. Parents of patients were counselled about the possible risks of surgery including bilateral vestibular areflexia. The surgical procedure for cochlear implantation was performed according to the standard of care of each cochlear implant team. Cochlear implants from the same manufacturer as the first cochlear implant (Cochlear, Med-El or Advanced Bionics (AB)) were implanted in each individual at the contralateral side.

The study was performed in accordance with the Declaration of Helsinki. Exemption for a full review from the Local Research Ethics Committee (UMCU, Utrecht, The Netherlands) was approved considering the prospective design with the use of pseudo-anonymized data extracted from the regular performance evaluations (local ethics committee No 15–336). Written form of consent was obtained before evaluation. The outcome measurements were included in a coded way in the database during the evaluation moments before and after the second cochlear implant of the individual patients.

Demographic data collection

Demographic data were collected prior to the implantation of the second cochlear implant (CI2). General characteristics comprised of sex, age at onset of deafness in months, duration of deafness before the first cochlear implantation in months, age of the first and second cochlear implantation in years, level of residual hearing (hearing threshold, in the ear to be implanted with second CI at 250 Hz and 500 Hz) and the pre-implantation use of a hearing aid in the ear to be implanted with CI2 (contralateral of the first cochlear implant (CI1)). Medical characteristics about etiology of hearing loss and comorbidity were collected. Etiology was divided in subgroups of congenital hearing loss with unknown cause (including genetic non-syndromic hearing loss), meningitis, intrauterine infection (including congenital Cytomegalovirus [CMV] infection), inner ear malformations (including Enlarged Vestibular Aqueduct [EVA]), syndromic hearing loss and auditory neuropathy. Syndromic hearing loss includes mutations in DFNA/DFNB or DFNX genes. Comorbidity was categorized in somatic comorbidity, a subgroup of psychiatric and behavioral problems and a subgroup of developmental delay including mild cognitive impairment. Implantation related data were registered; implantation related complications, status of electrode insertion in the cochlea, and the brand of CI device implanted (Cochlear, Med-El or Advanced Bionics (AB)). Education characteristics reported included: type of secondary education of the patient, divided into preparatory vocational or senior general / university preparatory education; type of primary education, classified in special or mainstream education; use of speech therapy; number of spoken languages by patient; maternal education level, divided in secondary (vocational) education level or university (of applied sciences); domestic communication, divided into spoken language either with or without sign language. Frequency of use of the second CI was recorded in the subdivision of daily use, frequent use or non-use, as self-reported by the CI users or parents.

Outcome assessment

Data of 85 Dutch-speaking children were collected on primary outcomes of speech recognition in quiet and noise, and secondary outcomes of subjective performance of hearing abilities in daily life and speech and language development scores. In all participants these measurements (including residual hearing level assessment) were taken within three months before the second cochlear implantation (baseline measurement) and at 12 months after the second cochlear implant (postoperative measurement). Comparisons were made between the bilateral CI condition 12 months after implantation compared to ‘best aided condition’ in unilateral CI1 condition meaning with or without an additional contralateral hearing aid, as chosen by the patient as best condition.

Outcome measurement

Speech recognition was measured by a speech and language pathologist with the stimulus-repetition task, designed by Bosman and Smoorenburg [23]. During this task the patient had to repeat recorded Dutch monosyllabic words (consonant-vowel-consonant [CVC]), provided by the computer without visual support. These open-set meaningful words were presented in a quiet room at a level of 65dB SPL, first in quiet and subsequently in the presence of steady state noise (with a Signal-to-Noise Ratio [SNR] of 0dB presented at S0°N0°). The measurement of speech recognition was performed with two randomly selected CVC word lists, taken from the available pediatric (patients < 12 years of age) or adult (patients ≥ 12 years of age) word list of the NVA (Dutch Audiology Society). Each assessment consists of a list of 11 recorded words (accordingly 33 phonemes), obtained by three conditions: with the first CI, with the second CI and with both CI’s. For each condition, the mean percentage correct phoneme score was calculated over the two lists of words. In case of unilateral implantation (before implantation of the second CI) the speech recognition measurements were performed in the ‘best aided condition’ which means either with only the unilateral cochlear implant or with an additional contralateral hearing aid, as chosen by the patient as best condition. The speech recognition of this unilateral condition was recorded separately in quiet and noise and compared to the speech recognition in quiet or noise measured in the post-implant bilateral condition.

To quantify the receptive vocabulary, the Dutch version of the Peabody Picture Vocabulary Test (PPVT-III-NL) was used, applicable from an age of 2 years and 3 months. The PPVT-III-NL consists of 204 test parts with each 4 pictures, as a multiple-choice test, carried out by a speech and language therapist. The patients had to match the correct picture for each offered spoken word. Subsequently raw scores were recalculated as a standard score, with a population mean of 100 and an +/-1SD of 15, corrected for chronological age in the standard score. The PPVT-III-NL is validated with intelligence tests and other vocabulary tests [24].

The subset “recalling sentences” of the Dutch version of the Clinical Evaluation of Language Fundamentals (CELF-4-NL) [25] was used. The CELF-4-NL is designed to represent the language proficiency in young children of 5 to 18 years old. In this subtest the patient had to listen to spoken phrases uttered by a speech and language therapist, concerning sentences of sequential increasing length and complexity. Thereafter, the patient had to repeat the phrases in the same order and in the correct sentence structure. Outcomes were reported in norm scores, calculated with a reference score, according to age [26]. This subtest of the CELF-4-NL requires higher order complex linguistic skills. The CELF-4-NL is validated with other vocabulary tests, including the PPVT-III-NL and secondly corrected for learning effect [32]. Both tests (PPVT-III-NL and CELF-4-NL) were performed in the preferred or best aided condition as explained above in the unilateral cochlear implant condition.

Information about subjective perceived speech perception, localization abilities and quality of sound was collected with the parent-reported Speech, Spatial and Qualities of Hearing Scale (SSQ) [12]. This questionnaire consists of 30 questions distributed in 3 domains: speech, spatial and qualities of hearing. The questionnaire is adjusted for children by Galvin et al [27] and was translated in Dutch. A scale ranging from 0 (not at all) to 10 (perfectly) is applied to answer the questions about the several aspects of hearing performance of the child. Total score of each domain is divided by 10 to provide comparable outcomes. The questions were mainly answered by parents of the implanted children or in exceptional cases by the children themselves when they were old enough to rate their own hearing experience.

Non-user characteristics

In case of perceived non-use of the second cochlear implant one year after surgery, the 12 months outcome measurements of speech recognition with the second cochlear implant and language skills tests were not executed by the inexperience with the second implant. This led to data not at random missing. Though, the patient characteristics (i.e. etiology of deafness) were collected to study this population in more detail and assess the reasons for non-use. The CVC scores and scores in language skills of the unilateral pre-surgery situation were also registered.

Data analysis

The data of the five participating CI-centers were collected and merged into a uniform database. Medians and quartile percentiles (25th and 75th) or means and standard deviations of the data of users and non-users were reported, depending on normality of the variable. Differences between performance in the unilateral CI and bilateral CI conditions were tested using Wilcoxon signed rank test (for related samples) in case of not normally distributed outcomes, Student’s t-tests in case of normally distributed outcomes. Univariable linear regression analyses were performed of the users of the second CI to determine the effect of individual variables on performance outcomes. No multivariable regression will be performed by the expected limited sample size. In each analysis, the level of statistical significance was set at a p-value of < .05. Details for non-users will be descriptively described because of the low number of non-users. Statistical analyses were performed using SPSS 21.0 for Windows and R [28].

Results

Study population

In Fig 1 the number of available data, categorized by outcome, is shown of the 85 patients receiving their second, contralateral cochlear implant between January 2014 and December 2016. This figure displayed the available data excluded the number of missing data. Data did not comply with the assumptions for missing data at random, therefore multiple imputation was not possible. In the study population, 75 (88%) had used their second implant at least 12 months following its implantation. The remainder of the children were non-users of the second device at 12 months post implantation evaluation.

Fig 1

Flow chart of available test scores.

Flow chart of study population and numbers of participants in analysis per outcome measure (in brackets missings per outcome). Note: CVC = consonant-vowel-consonant; SSQ = Speech, Spatial and Qualities of Hearing Scale; PPVT = Peabody Picture Vocabulary Test; CELF = Clinical Evaluation of Language Fundamentals. *For the non-users no postoperative performance outcomes were measured by the non-use of CI2 in daily life.

Implantations were performed in five different University Medical Centers: 32 (40%) implantations in Radboud University Nijmegen Medical Center, 22 (28%) implantations in the University Medical Center of Utrecht (UMCU), 14 (16%) in Leiden University Medical Center (LUMC), 11 (13%) in Erasmus Medical Center (EMC) and 6 (7%) in Maastricht University Medical Center (MUMC). In Table 1, the subject characteristics are described.

Table 1

Baseline characteristics.

Demographic data	User n (%)1	Non-user n (%)1
Number of patients	75	10
General characteristics
Sex    Male	34 (45%)	2 (20%)
Medical characteristics
Etiology         Congenital with unknown cause2     Syndromic hearing loss         Meningitis     Intrauterine infection     Inner ear malformation         Auditory neuropathy         Unknown	41 (55%)12 (16%)3 (4%)2 (3%)2 (3%)1 (1%)14 (19%)	3 (30%) 6 (60%) 1 (10%) - - - -
Comorbidity         Somatic comorbidity         Psychiatric and behavioural problems         Developmental delay	10 (13%)7 (9%)2 (3%)	3 (30%)--
Age at onset of deafness (median in months)3	0 (0–30)	0 (0–6)
Time of preimplantation deafness CI1 (median in months)	46 (5–165)	35 (19–68)
Implantation characteristics
Age of CI1 implantation (median in years)	3 (0–13)	2 (1–9)
Age of CI2 implantation (median in years)	12 (5–18)	15 (9–17)
Inter-implant interval (median in years)	8 (1–16)	12 (11–15)
Residual hearing 250 Hz (median in dB)	85 (35–110)	85 (55–95)
Residual hearing 500 Hz (median in dB)	95 (55–120)	95 (65–105)
Hearing aid use pre-CI2	35 (41%)	1 (10%)
Frequency of use CI2         Daily use         Frequent use	55 (73%)20 (27%)
Brand of CI device Cochlear         AB         Med-EL	58 (77%)15 (20%)2 (3%)	10 (100%)--
Education characteristics
Type of primary education         Mainstream education         Special education         Unknown	30 (40%)16 (21%)29 (39%)	6 (60%)2 (20%)2 (20%)
Type of secondary education         Preparatory vocational         Senior general / University preparatory         Unknown	15 (20%)8 (11%)52 (69%)	3 (30%)1 (10%)6 (60%)
Speech therapy     Unknown	11 (15%) 64 (85%) 52 (69%) 9 (12%) 14 (19%)	2 (20%) - 10 (100%) - -
Spoken languages by patient     Native language         Multiple languages         Unknown
Domestic communication     Spoken language without sign language     Spoken language with sign language         Single sign language         Unknown	44 (59%) 13 (17%) 3 (4%) 15 (20%)	6 (60%) 4 (40%) - -
Maternal education level     Secondary (vocational) education University (of applied sciences) Unknown	26 (35%)11 (15%)38 (51%)	6 (60%)4 (40%)-

Note: CI2 = second cochlear implant.

1 Reported in median (range) when noted.

2 Including genetic non-syndromic hearing loss.

3 Based on the available data (missing excluded data).

Table 1 shows the baseline characteristics of the study population. Median age in months at onset of deafness was 0 [range 0–30 months] based on n = 65 (76%) patients (n = 10 with no strict definition of onset of deafness regarded as missing data). Median age at time of the first cochlear implantation was 3 years [range 0–13 years] compared to 12 years [range 5–18 years] at time of the second CI implantation. 35 out of 85 patients (41%) made use of an additional hearing aid at the contralateral side of the first CI before receiving their second implant and therefore regarded as patients with bimodal stimulation. CI2 was implanted in the left ear in 62% (n = 53). Congenital hearing loss with unknown cause, including genetic non-syndromic hearing loss was the main cause (62%, n = 44) of bilateral deafness in the total cohort of implanted children. In two patients an inner ear malformation was present and considered as the etiology of the hearing loss, consisting of an enlarged vestibular aqueduct without malformation of the cochlear duct or modiolus. Implantation related complications occurred in 8 out of 85 cases consisting of 6 patients (8.5%). This required revision surgery to drill-out the implant receiver-site because of receiver migration (n = 4) or an incomplete insertion of the electrode array (n = 2). Remaining complications included fever the day after surgery without the need of antibiotics (n = 1), and a defect of the external ear canal that occurred during drilling of the mastoid which was repaired during the same surgical procedure with a bonechip (n = 1). Fig 1 shows the numbers of available data for the different outcomes.

Speech recognition and speech and language outcomes

Table 2 contains the results of speech recognition outcomes in quiet and noise and language outcomes before (baseline) and 12 months after second cochlear implantation (postoperative measurement). With bilateral CI, the median phoneme score in quiet at the 12 months evaluation showed a significantly higher score compared to the unilateral implanted situation for the total group of recipients (postoperative CI2 bilateral condition 96% [90-98] vs baseline best aided CI1 condition 91% [85-96]; p = 0.02) and for the subgroup of recipients with unilateral stimulation before CI2 (postoperative CI2 bilateral CI 96% [89-98] vs unilateral stimulated baseline CI1 condition 90% [84-96]; p < 0.01). Also, the phoneme score in noise [SNR 0dB] 12 months after the second implantation showed a significant higher result in comparison to the best aided unilateral implanted situation for the total group as well for the group of bimodal stimulation recipients (respectively median score of 66% [57-75] vs 54% [47-71]; p = 0.01 and median score of 66% [58-75] vs 51% [47-74]; p = 0.03). Receptive vocabulary and recalling sentences, showed no statistical differences when comparing unilateral to bilateral implantation.

Table 2

Results of speech recognition and speech and language development outcome.

ConditionOutcome	Baseline CI1 condition		Baseline CI2 unilateral condition 4		Postoperative CI2 unilateral condition		Postoperative CI2 bilateral condition		Z-statisticp-value 5
	n	Median (IQR)	n	Median (IQR)	n	Median (IQR)	n	Median (IQR)
Total	85		85		75		75
CVC score in quiet (daily life) 1Missing	850	91(85–96)	3055	45(20–69)	3639	65(43–80)	6114	96(90–98)	Z = 3.01 0.02
Bimodal	35	96(86–98)	23	52(21–68)	13	77(65–83)	29	96(90–99)	Z = 1.100.27
Unilateral	44	90(84–96)	NA	NA	17	44(16–63)	28	96(89–98)	Z = 2.70 <0.01
Missing 2	6		6		6		4
CVC score in noise (daily life) 3Missing	5728	54(47–71)			966	36(28–50)	3936	66(57–75)	Z = 2.80 0.01
Bimodal	29	51(47–74)			6	38(26–47)	22	66(58–75)	Z = 2.18 0.03
Unilateral	28	55(46–68)			3	30(*)	17	63(54–76)	Z = 1.370.17
Missing 2	0				0		0
PPVT standardscoreMissing	5431	89(79–99)					2550	92(79–105)	Z = 1.610.16
Bimodal	27	96(85–104)					12	96(88–104)	Z = 1.070.29
Unilateral	27	80(63–96)					13	85(65–109)	Z = 1.120.26
Missing 2	0						0
CELF normscoreMissing	2263	4.5(1.0–8.0)					2253	6.0(2.0–8.0)	Z = 1.140.32
Bimodal	7	8.0(5.0–9.0)					10	7.0(4.0–9.0)	Z = 0.650.52
Unilateral	15	3.0(1.0–5.0)					12	4.0(1.0–7.0)	Z = 0.960.34
Missing 2	0						0

Results of speech recognition and speech and language development outcome of the baseline situation with first CI (CI1) without (unilateral stimulation) or with contralateral hearing aid (bimodal stimulation)(‘baseline CI1 condition’), the baseline perception of the ear of second CI (‘baseline CI2 unilateral condition’), the post-operative perception of the ear with second CI (‘Postoperative CI2 unilateral condition’), and the post-operative perception measured with both implants (‘Postoperative CI2 bilateral condition’). Outcomes were scored for all participants at baseline (n = 85). Postoperative scores depict the outcomes of participants registered as users of CI2 (n = 75).

Note: CI = Cochlear Implant; Scores displayed by the medians and 25th and 75th percentiles (IQR, in parentheses).

* IQR not applicable by low numbers of participants. The exact number of data used for analysis is specified with n.

1 In ‘best aided’ hearing situation: With (bimodal stimulation) or without (unilateral stimulation) a contralateral hearing aid to the CI, as used in daily life situation by the patient.

2 Missing data of use of hearing aid pre-operative in the ear of the second CI.

3 Measured with [SNR 0dB].

4 Speech perception in quiet, of the bimodal stimulated children, was measured at baseline with hearing aid in the ear of the second CI.

5 p-value of the Wilcoxon signed-ranks test, calculated by comparison of outcomes of participants ‘postoperative CI2 bilateral condition’ and ‘Baseline CI1 condition’.

SSQ perceived hearing abilities in daily life

Table 3 presents the outcomes for the three separate domains of the SSQ (speech, spatial, qualities). The speech and spatial domains and the total SSQ score (total mean score of the 3 domains) did not significantly improve comparing the results of the daily situation of the unilateral implanted condition versus the post-operative measurement 12 months post second cochlear implantation. The sound quality domain showed a statistically significant higher rating for the bilateral CI situation (6.6 [5.0–7.1]) in comparison to the unilateral CI scores (5.0 [3.4–6.7]; p = 0.041).

Table 3

Results of Speech, Spatial and Qualities of Hearing Scale (SSQ).

Outcome	Baselinen = 9		Post-operativen = 19		Z-statisticp-value
	Median		Median
Speech domain	5.5	(3.7–5.8)	6.0	(5.4–6.3)	Z = 1.190.24
Spatial domain	3.4	(0.7–6.7)	4.9	(3.0–6.4)	Z = -1.010.31
Qualities domain	5.0	(3.4–6.7)	6.6	(5.0–7.1)	Z = 2.040.04
Total SSQ score	4.9	(2.7–6.4)	5.9	(5.0–6.6)	Z = 1.520.13

Note: Scores displayed by the medians and 25th and 75th percentiles (in parentheses).

Ten out of 85 (12%) second cochlear implant recipients were registered as non-user at the 12 months evaluation assessment (Table 1). These patients either did not experience added value of the second device (n = 4, 40%), were not motivated for revalidation for unknown reasons (n = 3, 30%), suffered from incoherent hearing performance with both CI’s during simultaneously use (n = 2, 20%) or suffered from pain complaints wearing the second CI (n = 1, 10%). 6 patients (60%) of this non-user group had etiology of syndromic hearing loss (i.e. Pendred syndrome), 1 patient (10%) had meningitis and 3 patients (30%) had congenital hearing loss with unknown cause. Secondly, 3 patients (30%) had somatic comorbidity (Usher syndrome (2), vitamin deficiency (1)). In two (20%) patients (one with ossification (meningitis) and one with cochlear anomaly (Pendred syndrome)) full insertion of the electrode array was not achieved. After revision surgery (full insertion achieved) there was no increase in (bilateral) subjective speech perception compared to the situation with CI1 only, which resulted in non-use of CI2 by all 3 patients. The level of residual hearing before implantation of CI2 was similar with the user group. The median age of the first cochlear implantation in the non-user group was 2 years and of the CI2 implant 15 years (user group respectively 3 years and 12 years). The differences between the non-users group and the group of users were: a median inter-implant interval of 147 months (range 133–178 months) versus 96 months (range 13–192 months), median best-aided preoperative CVC score in quiet of 90% (range 36–100) versus 91% (range 85–96), median best-aided preoperative CVC score in noise of 48% (range 18–76) versus 54% (range 47–71), median preoperative PPVT WBQ score of 85 (range 55–96) versus 89 (range 79–99) and a median preoperative CELF norm score of 4.0 (range 1.0–11.0) versus 4.5 (1.0–8.0) respectively. The 12 months evaluation scores were not available, since this group did not use the second cochlear device.

Linear regression analysis

The results of the univariable linear regression analysis are presented in Table 4. Frequent use was significantly negatively associated with the postoperative CVC outcome in noise (β = -12.05; 95% CI -22.17- -1.94; p = 0.02) compared to daily use of the second CI. Special education as type of primary school was significantly associated with lower PPVT (age corrected) scores 12 months after CI2 (β = -21.30, 95% CI -37.36- -5.25; p = 0.01). A higher secondary education level (β = 4.30; p = 0.02) was significantly positively associated with the CELF outcome in the bilateral CI condition. Residual hearing level in the ear to be implanted with the second implant, and age at the time of the second implantation were not significantly associated with the performance outcomes (Table 4). Similar results were seen for the inter-implant interval which was not significantly related to the performance outcomes after CI2 for the studied cohort in total, or for the individual groups of unimodal and bimodal stimulated recipients. In the Supporting information the results are visualized for the CVC outcomes in relation to the inter-implant interval for the bimodal and unilateral users separately.

Table 4

Univariable linear regression analysis of outcomes of CI2 users 12 months after the second cochlear implant (CI2).

Variable		CVC in quiet					CVC in noise				PPVT1				CELF1
	n	Mean (SD)	β(95% CI)	p	n	Mean (SD)	β(95% CI)	p	n	Mean (SD)	β(95% CI)	p 2	n	Mean (SD)	β(95% CI)	p 2
Sex    Male (ref)Missing    Female Missing	26 8 35 6	94.4 (6.0)91.3 (11.9)	-3.12(-8.22–2.00)	0.23	17 17 22 19	61.2 (22.3)65.8 (9.6)	4.64(-6.04–15.32)	0.38	13 21 12 29	95.2 (15.5)89.3 (25.0)	-5.98(-23.06–11.10)	0.48	13 21 9 32	7.0 (3.7)3.6 (2.4)	-3.44(-6.39- -0.50)	0.02
Age at CI2 (years) Missing	61 14	92.6 (9.9)	-0.39(-1.01–0.23)	0.21	39 36	64.2 (16.3)	-0.98(-2.30–0.34)	0.14	25 50	93.5 (20.0)	-0.16(-2.77–2.46)	0.90	22 53	5.8 (3.6)	0.43(-0.03–0.90)	0.06
Residual hearing level3Missing	53 22	92.6 (10.5)	0.11(-0.09–0.31)	0.28	30 45	64.0 (15.7)	-0.03(-0.51–0.44)	0.89	17 58	96.9 (19.2)	-0.34(-1.46–0.79)	0.54	14 61	6.6 (3.6)	0.12(-0.13–0.37)	0.32
Inter-implant interval (years)     Unilateral         Missing     Bimodal         Missing	53 28 7 29 5	92.6 (10.5)93.9 (4.8)93.6(6.9)	0.40(-0.25–1.06)-0.23(-0.75–0.28)0.22(-0.79–1.22)	0.220.360.66	39 17 18 22 12	63.8 (16.3)64.9 (13.3)63.0 (18.5)	0.98(-0.68–2.63)0.62(-1.45–2.68)1.49(-1.68–4.65)	0.240.530.34	25 13 22 12 22	92.4 (20.4)88.2(26.2)96.8(11.0)	-1.37(-3.86–1.12)-1.29(-5.87–3.29)-0.48(-3.42–2.47)	0.660.550.73	22 11 24 11 23	5.6 (3.6)4.2(3.1)7.0(3.6)	-0.13(-0.64–0.39)-0.07(-0.74–0.60)0.19(-0.81–1.18)	0.610.820.68
Hearing aid before CI2     Bimodal         Missing     Unilateral (ref)         Missing	29 5 28 7	93.5 (6.8)93.8 (4.7)	-0.30(-3.42–2.81)	0.85	22 12 17 18	63.0 (18.5)64.9 (13.3)	-1.93(-12.70–8.85)	0.72	12 22 13 22	96.3 (11.0)88.2 (26.2)	8.60(-8.27–25.47)	0.30	11 23 11 24	7.0 (3.7)4.2 (3.1)	2.82(-0.21–5.85)	0.07
Secondary education level     Sr. general / Univ. prep.         Missing     Prep. Vocational (ref)         Missing	7 1 15 0	93.0 (6.1)91.9 (7.3)	1.13(-5.54–7.81)	0.73	6 2 11 4	58.7 (22.3)64.5 (23.1)	-5.79(-30.52–18.94)	0.63	5 3 8 7	107.8 (12.7)96.5 (8.5)	11.30(-1.53–24.13)	0.08	5 3 8 7	9.8 (3.1)5.5 (2.3)	4.30(1.03–7.57)	0.02
Type of primary school     Special         Missing     Mainstream (ref)         Missing	12 4 49 10	93.3(4.6)92.5 (10.8)	0.76(-5.67–7.19)	0.81	11 5 28 31	64.7 (13.2)63.4 (17.5)	1.30(-10.59–13.19)	0.83	8 8 17 42	77.9 (15.1)99.2 (19.3)	-21.30(-37.36- -5.25)	0.01	7 9 15 44	4.3 (2.8)6.2 (3.9)	-1.91(-5.34–1.51)	0.26
Frequency of CI2 use     Daily use (ref)         Missing Frequent use         Missing	43 0 18 2	92.7 (11.1) 92.6 (6.6)	-0.04(-5.65–5.57)	0.99	23 31 16 4	68.7 (11.9)56.7 (19.2)	-12.05(-22.17- -1.94)	0.02	13 41 12 8	91.3 (25.0)93.5 (15.1)	2.20(-15.05–19.44)	0.80	10 44 12 8	4.1 (3.1)6.8 (3.6)	2.73(-0.33–5.79)	0.08
Maternal education level     Secondary voc. (ref)         Missing     University         Missing	20 6 10 3	89.9 (14.9)96.5 (4.5)	6.60(-3.36–16.56)	0.19	13 13 10 3	67.6 (16.0)66.3 (8.7)	-1.32(-13.00–10.37)	0.82	10 16 2 11	93.6 (28.2)85.0 (12.7)	-8.60(-55.25–38.05)	0.69	7 19 2 11	4.9 (3.4)5.5 (2.1)	0.64(-5.58–6.86)	0.81
Speech therapy     Yes         Missing     No (ref)         Missing	7 4 16 0	81.7 (23.9)93.6 (4.9)	-11.85(-24.51–0.81)	0.07	5 6 12 4	46.4 (28.1)63.8 (18.4)	-17.43(-41.73–6.86)	0.15	5 6 14 2	77.4 (12.4)94.7 (19.6)	-17.31(-37.27–2.64)	0.09	5 6 13 3	3.4 (2.3)6.8 (3.7)	-3.37(-7.19–0.45)	0.08
Spoken languages         Multiple         Missing         Single (ref)         Missing	7 2 43 9	93.6 (4.5) 92.3 (11.4)	1.29 (-7.54–10.12)	0.77	7 2 32 20	62.9 (18.1)64.0 (16.2)	-1.14(-15.08–12.80)	0.87	4 5 21 31	97.3 (25.7) 91.4 (19.9)	5.82(-17.58–29.23)	0.61	4 5 18 34	7.8 (5.4) 5.1 (3.1)	2.64(-1.46–6.74)	0.19

Note: (BI)CI = (Bilateral) Cochlear Implant; n = number of available biographic data; β = standardized regression coefficients; SD = Standard Deviation; p = p-value.

1 Reference (norm) score, according to age.

2 Results marked in bold showed a statistically significant association (p < 0.05).

3 Pre-implantation scores of the ear to be implanted with CI2 (mean threshold of 250-500Hz).

Discussion

Key findings and comparison with other studies

In this multicenter prospective trial, we evaluated the benefit (at 12 months post-surgery) of a second cochlear implant in children at the age of five to eighteen years with severe to profound hearing loss after previous unilateral implantation. We demonstrated a significant and relevant improvement in speech perception in both quiet and noise scores at 12 months post-implantation compared with the (best aided) unilateral CI situation. Generally, speech recognition scores in quiet were considered to be good, even with a unilateral cochlear implant, limiting the maximum improvement in scores especially for those with bimodal sequential stimulation as in accordance with previous literature [29,30]. Though in this study, a significant increase of speech recognition in noise after the second CI was demonstrated, combining the unilateral and bilateral sequential stimulation recipients, even with a mean inter-implant interval of 8 years and a median age of 12 years [SD = 4,0 years] at second implantation. This outcome adds value to existing literature describing benefits in situations with shorter intervals and younger study populations [3,16,21,31].

In our study, no statistical significant difference was seen in receptive vocabulary and sentence recalling between the bilateral CI situation and unilateral CI condition. The median bilateral PPVT and CELF scores yielded a large standard deviation possibly induced by a heterogenic study population or a large variety in verbal intelligence [32,33], which was not tested in our study. Some children performed poorly and therefore received speech therapy to improve and stimulate their language abilities, some children did not need this support and performed better on outcomes, as shown in Table 4. In addition, it has been reported by Hay-McCutcheon et al. [34] that the age of implantation does not have a significant impact on the receptive and expressive language abilities of children aged nine years and older. For this reason, the effects on language performance in our study population aging 5–18 years is expected to be limited, as most of the children were older than 9 years old at time of their second cochlear implantation. In addition, the effect of the bilateral cochlear situation in our study was evaluated at 12 months after implantation of the second cochlear implant. Sparreboom et al. [19] found a significant bilateral benefit on receptive vocabulary after 5 years of bilateral implant experience in older children. One could therefore hypothesize that the duration of bilateral implant use of 12 months in the current study group might be too short to expect a benefit in speech and language development. Besides that, the PPVT scores corrected for age in the unilateral CI situation (median of 89 [79-99]) were already adequate before the second cochlear implantation. As the scores for the subtest recalling sentences was on average below that of their peers with normal hearing, one would therefore expect that the improvement in language skills might be eventually seen in de the more complex linguistic skills.

Overall, no significant benefit was measured on the subjective outcome measured by the SSQ. When analyzing the domains separately a significant increase on the domain of ‘qualities’ in the bilateral CI condition compared to the unilateral CI condition was found. This outcome repletes the improvement of hearing quality with the second cochlear implant in comparison to the unilateral implanted condition.

In our study, no effect was seen by the age of implantation of the second CI or the length of the inter-implant interval on speech perception performance or development by univariable linear regression analysis, even when analyzing unilateral and bimodal stimulated users separately. This could be explained by the eligibility criteria and characteristics of the studied cohort, combining cases with and without progressive hearing loss. Though, longer time of deafness before the first cochlear implant as well as a higher age at time of the second implantation have previously demonstrated to be negatively correlated with these outcomes [31,35,36]. This could be contributed to a specific sensitive period for auditory development on the deprived side [37]. Also, from several studies it seems that limited device use besides a longer inter-implant delay has a detrimental effect on auditory brainstem and subsequent cortical maturation [38-40]. However, in these particular studies, no children with progressive hearing loss were included. As in our study children with progressive hearing loss were included, the negative effect of a longer inter-implant delay might have been less obvious. Recently, Illg et al. demonstrated the impact of the length of the inter-implant interval on the benefit of sequentially implanted bilateral CI. The authors suggested a maximum interval of up to four years for receiving their second implant for children implanted with their first CI under the age of 4 [41]. The older the children were at first implantation, the shorter the inter-implant interval had to be to favor good speech comprehension results. The non-users in our study population showed a greater inter-implant interval in comparison with the user group, which could therefore have a negative effect on outcome. Interesting issue is to discuss the question why the non-users became non-user of the second CI. A possible reason could be the timing of implantation during (early) adolescence which could be related to difficulties with the acceptation of a new (hearing) situation. Additionally, only one out of ten (10%) used a hearing aid prior to CI2 in this non-user group compared to 35 out of 85 (41%) in the user group. As a result, motivation or expectations of outcomes might have been different between these children. Another explanation could be the incoherent hearing performance experienced with both CI’s during simultaneously use or pain complaints [42]. Easwar reported that higher speech perception scores were associated with longer everyday CI use and CI experience (p < 0.05). Secondly, they described that asymmetry in speech perception between both CIs decreased with consistent everyday use of the second CI (p < 0.05) [21]. These results have to be taking in account in the clinical counseling before implantation of a second sequential CI.

Strengths and limitations

Strength of this study is the unique study population of sequentially implanted children with the first implant at a relatively early age (median 3 years) and their second implant between 5–18 years of age, considered the study population also contains children with progressive hearing loss. By the multicenter design and prospective data collection the outcome of this study will strengthen the evidence of the benefit of sequential cochlear implantation with larger implant-intervals in children. In addition, in this study we were able to combine objective and subjective outcomes of hearing abilities. This makes the results applicable for use in a clinical setting and useful for counseling patients and their parents about the benefit of this intervention, even with children at an older age.

A limitation of this study is the number of missing data, i.e. the SSQ scores, since not every participating CI-center was using this type of evaluation. Based on the studied sample size and anticipated missing data we were not able to perform multivariable regression analysis to calculate outcomes whilst controlling for covariates. Moreover, due to the multicenter data collection, small deviations in test setups of speech recognition outcomes can be expected. Thirdly, in this study, the used eligibility criteria were set based on the criteria advocated by the Dutch health care institute for conditional reimbursement at that time. These criteria have impact on the generalizability of the outcome of the study. Another issue is the ‘early’ age of the first CI implantation in our study population. The median age at first implantation was 3 years old but with a range until 13 years old. This can be due to variable reasons, i.e. included patients with progressive hearing loss at older age in the study population, comorbidity or domestic situation. Because of the non-user status of CI2 of 10 out of 85 patients, the overall outcome of the second cochlear implant measured in remaining group could be overestimated. Moreover, in the current study we were not able to analyze the influence of the daily device use by lack of datalogging features in the used cochlear implants. Therefore, the relation between daily CI use and performance outcomes could not be analyzed as potential factor of influence. Lastly, we were not able to test localization skills which could be of importance to analyze benefits in more detail. Only the spatial domain of the SSQ was assessed demonstrating no significant bilateral benefit, possibly caused by the limited number of measurements.

Future recommendation

Because of the lack of objective measures in the postoperative CI2 situation for the non-user group, we were unable to analyze the contributing factors responsible for this result. The non-user group contained children with specific conditions (e.g. Usher syndrome) eligible for a second cochlear implant, notwithstanding a limited expectation of increase of speech perception of the multidisciplinary CI-team, but indicated as eligible by ‘benefit of the doubt’. For future analysis it would be interesting to account for expectations of outcome and prognostic social-emotional factors possible influencing the frequency of CI use [13,43,44]. Secondly, including a larger cohort to compare outcomes in unilateral and bimodal stimulated sequential cochlear implants users and including longer period of follow-up after sequential cochlear implantation could provide knowledge about the long-term outcomes in receptive vocabulary and recalling sentences for these children.

Conclusion

This study demonstrated, statistically significantly and clinical relevant, better speech recognition in quiet and noise, regardless of a greater inter-implant interval in children receiving their first cochlear implant at an relatively early age and then sequentially implanted aged 5 to 18 years. Bilateral cochlear implantation was not associated with positive effects on receptive vocabulary or sentence recalling after 12 months of BICI use. The subjective sound quality was statistically significant higher rated for the bilateral CI situation in comparison to the unilateral CI scores. Out of the participants 12% was found to become non-user within 1 year after CI2, possibly due to limited residual hearing and a larger inter-implant interval compared to the user-group.

Regression line between speech perception scores (CVC) in quiet in the bilateral CI situation and the inter-implant interval.

β unilateral = -0.23 (n = 29); p = 0.22. β bimodal = 0.08 (n = 28); p = 0.66. Note: CI1 = first cochlear implant; CI2 = second cochlear implant CVC = consonant-vowel-consonant (speech perception).

(DOCX)

Click here for additional data file.

Regression line between speech perception scores (CVC) in noise in the bilateral situation and the inter-implant interval.

β unilateral = 0.44 (n = 17); p = 0.63. β bimodal = 1.49 (n = 21); p = 0.34. Note: CI1 = first cochlear implant; CI2 = second cochlear implant CVC = consonant-vowel-consonant (speech perception).

(DOCX)

Click here for additional data file.

5 Jan 2021

Submitted filename: Rebuttal letter PONE-D-19-15922.docx

Click here for additional data file.

24 Feb 2021

PONE-D-20-37958

Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: a prospective cohort study

PLOS ONE

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Reviewer #1: Summary:

The manuscript presents a multi-centre prospective study of the benefit of sequential cochlear implantation on speech, language, and quality of life outcomes. The study examines a group (n=85) or children (5 – 18 yrs old) who have experienced a long delay between receiving their first and second implant.

This is a revised version of a previous manuscript. Whilst the authors have made significant changes to the manuscript, there are several major concerns regarding the analysis that need to be addressed before the main claims of the paper can be fully supported.

What are the main claims of the paper and how significant are they for the discipline?

The manuscript reports significant improvements in speech recognition in quiet and in noise following receipt of the second implant. The authors claim no evidence of a relationship between outcomes and key predictors of interest such as inter-implant delay and age at implantation.

In the current form, these findings are not significant for the discipline due to my concerns outlined below. However, the data are important and would be of value to the field if analysed and presented more appropriately.

Are the claims properly placed in the context of the previous literature? Have the authors treated the literature fairly?

Whilst the authors have made improvements to the introduction, I am surprised to see that key work is still not considered here. The authors state that “so far, studies of sequentially implanted children included populations with a mean age between 5 to 10 years” and that outcomes “in older children and adolescents and the influence of preoperative residual hearing is not clear from the literature so far”. This is not the case and the authors are clearly unaware of the available body of literature. Of particular relevance, please see key studies from Dr Karen Gordon’s lab such as Easwar et al., (2018) and Polonenko et al., (2018). These papers include data from older children and adolescents and demonstrate the bilateral benefits of sequential implantation in quiet and noise. Furthermore, they demonstrate the relationship between inter-implant delay and pre-operative residual hearing (amongst other key factors such as age and daily CI use).

It is not until the methods section that is becomes apparent that some children in the sample used a unilateral CI only and so experienced unilateral deprivation/stimulation prior to receiving the second CI. Whereas others (45% stated in Table 1) wore a contralateral hearing aid and so experienced bimodal input (i.e. bilateral access to sound from a combination of electric and acoustic input). These are two very different groups and this should be highlighted to the reader from the very beginning of the manuscript. Literature on bimodal users should also be reviewed. The definition of inter-implant delay therefore also differs for these groups and should be explicated for the non-expert. I.e. duration of unilateral deprivation/stimulation, vs duration of bimodal stimulation.

Do the data and analyses fully support the claims? If not, what other evidence is required?

No. Given that almost half of the sample were bimodal CI and HA users and the other half were unilateral CI users, this should be treated as a factor in the analyses. Bimodal sequential users are likely to receive more benefit from a second implant as their pathways have received acoustic stimulation vs no stimulation in the unilateral CI users. There is evidence that bimodal sequential users gain similar bilateral advantage to that of simultaneous bilateral CI users. Therefore, data for unilateral sequential and bimodal sequential should be investigated to understand if there are group differences here as this could be driving the main result reported here.

Age at time of speech perception testing should be entered as a covariate as younger children can have worse speech reception thresholds, and any developmental effects should be considered when reporting changes in children’s speech and language outcomes over a 12-month period.

I am concerned that the objective of the manuscript is to determine the benefit of a second sequential CI, yet “limited expectations in terms of speech perception results were an exclusion factor to qualify for this study”. Therefore, the inclusion criteria could bias the results by including only those children who were expected to show improvements in speech perception. It is understandable to exclude children based on non-verbal communication/inability to undergo speech perception outcome measures. However, if they received little benefit from the first implant, is that to say that they would not benefit from bilateral input?

Non-use of the second CI is an important outcome as it suggests that the child gained no benefit from sequential implantation. The outcome data from these children is not missing at random – it is missing because they have low benefit. The authors acknowledge this and provide information about this (lines 330-351). However, rather than repeating summary statistics already listed in Table 1, it would be useful if the authors provided information regarding any significant differences between the non-users and the user groups. Of note, the non-users appear older at CI2, have a longer inter-implant interval, and only 10% compared to 45% of users are bimodal hearing aid users prior to CI2. The implications of this on the current findings and main claims should be considered and unpacked further.

The authors state that there are no significant associations between outcomes and certain predictors of interest. However, they fail to identify and discuss some clear trends that are approaching significance. It is likely that some associations have not been detected due to my aforementioned concerns of the mixed group of bimodal sequential and unilateral sequential users, as well as age at time of testing that should be treated as a covariate. Indeed, Table 4 shows that hearing aid use is a predictive factor of language outcomes. The relationships presented in Table 4 should be examined in these two groups separately. Data should be presented visually in the form of scatterplots with regression lines, for example, so that any trends and their importance can be assessed by the reader.

PLOS ONE encourages authors to publish detailed protocols and algorithms as supporting information online. Do any particular methods used in the manuscript warrant such treatment? If a protocol is already provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred?

No

If the paper is considered unsuitable for publication in its present form, does the study itself show sufficient potential that the authors should be encouraged to resubmit a revised version?

Yes.

Are original data deposited in appropriate repositories and accession/version numbers provided for genes, proteins, mutants, diseases, etc.?

Yes. The data are available without restriction. I cannot comment on whether these are deposited in appropriate repositories as this information is not available.

Are details of the methodology sufficient to allow the experiments to be reproduced?

Yes.

Is the manuscript well organized and written clearly enough to be accessible to non-specialists?

Yes. However, certain key elements should be more clearly outlined to make it accessible to non-specialists such as the difference between bimodal and unilateral CI users.

Specific comments:

Line 65. “contralateral” implant – it is not clear what it is contralateral to (although I assume the first implant). Using “second implant” would be clearer for a naïve reader.

72. ...the secondary outcomes WERE disease...

74 ...were compared USING THE WILCOXEN SIGNED-RANK TEST....

74 statistical association between what? Outcomes and clinical characteristics of the CI user? Please specify.

84. 1-16 years of inter-implant delay is a very large range that includes children with minimal and short duration of delays as well as long delays. However, the authors classify it here as a “great inter-implant interval” with the main claim being that benefit can be obtained despite a great interval. However, it is possible that these benefits observed are being driven by those with minimal and short delays. This is difficult for the reader to assess given the absence of plots for data visualization.

97 – conditional reimbursement – please briefly explain what this means in this context

100 – what does “minor” hearing performance mean? Poorer speech perception/worse outcomes compared to short-delay or simultaneously implanted?

157 – if describing male or female then please refer to “sex” rather than “gender”, unless they were asked what they gender identify with

157 – age at time of speech test should also be reported for pre and post measures

176 – please outline how frequency of CI use was determined. Was this self-report or from datalogging built into the CI device?

184 – 186. Some children wore a unilateral CI only and so experienced unilateral deprivation/stimulation prior to receiving the second CI. Whereas others wore a unilateral CI with a contralateral hearing aid and so experienced bimodal input (i.e. bilateral access to sound from a combination of electric and acoustic input). These are two very different groups and this should be highlighted to the reader from the very beginning of the manuscript. Furthermore, literature on bimodal users should also be reviewed. The definition of inter-implant delay therefore differs for these groups and should be explicated. I.e. duration of unilateral deprivation/stimulation, vs duration of bimodal stimulation.

Table 4: “Gender, Men, Woman” should read “Sex, Male, Female”

References:

Easwar, V., Sanfilippo, J., Papsin, B., & Gordon, K. (2018). Impact of Consistency in Daily Device Use on Speech Perception Abilities in Children with Cochlear Implants: Datalogging Evidence. Journal of the American Academy of Audiology, 29(9), 835–846. https://doi.org/10.3766/jaaa.17051

Polonenko, M. J., Papsin, B. C., & Gordon, K. A. (2018). Limiting asymmetric hearing improves benefits of bilateral hearing in children using cochlear implants. Scientific Reports, 8(1), 13201. https://doi.org/10.1038/s41598-018-31546-8

Reviewer #2: The presented paper presents the results of a prospective study of a multi-centre study in sequential bilateral cochlear implantation in children between 5 to 18 years. This revised version is good to read, but there are still some things that are misleading for the uninitiated reader.

So far, I am still missing a clear research question as far as the main message is concerned. The paper contains a collection of speech comprehension data for the patient group. These have also been presented in dependence of predictors in other papers (e.g. Illg et al. 2019, which was also cited). Page 4, line 110 et seq. is described: "The speech perception outcome of

sequential BICI in older children and adolescents and the influence of preoperative residual hearing is not clear from the literature so far" What do you mean with this sentence? What is the point?

In the evaluation, the 10 non-users are listed separately to describe the group. However, their speech perception results are not included in the calculations. When conducting a prospective study, these data would also have to be calculated, or did these patients no longer appear at the 12-month deadline? It is not clear which result in speech understanding is achieved by a non-user, because there are different reasons for this. However, these data also belong to the total group and must not be eliminated, according to my understanding.

I also find it very difficult that patients with hypoplasia of the cochlea and the like were included in the total group, because they have different preconditions than children and adolescents with regular anatomy. From my point of view, these two groups should be separated and considered separately.

Furthermore, I do not understand in table 2 the CVC score in quiet (no HA) values for the bilateral CI condition and likewise the CVC scores in noise (no HA) in bilateral condition. Why do the have the same values like in daily life? If these are the results of a measurement without HA, then unilateral measurements must have been taken, or? Why is this listed under bilateral condition?

The description of tabel 1 (page 12 line 279 et seq.) is partly redundant because of adding the table.

Please correct the following sentencs page 18, line 400 "language skills might be eventually seen in de the ....."

My request for the further revision is that a clear question emerges on which the discussion can also be guided and that the data evaluation takes place in clearly defined groups.

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Reviewer #2: No

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21 Jun 2021

Dear editor,

We would like to thank the editor for the opportunity to resubmit the manuscript entitled ‘Benefit of sequential bilateral cochlear implantation in children between between 5 to 18 years old: a prospective cohort study’.

We submitted this paper last year and received valuable comments of the reviewers of PLOS ONE with the advice to revise the paper thoroughly before publication could be considered. Based on these comments we revised the paper carefully to improve the quality of the text including the statistical analysis and conscientiously revised the discussion. This resulted in an improved manuscript which we would like to offer to PLOS ONE for reconsideration of publication. Our detailed responses to the reviewers’ comments of the previous submission can be found in the attached file 'Response to Reviewers'.

Thank you for considering our manuscript for publication.

Sincerely,

On behalf of the author-team,

Drs. W.J. Kleijbergen

For journal use only: [PONE-D-20-37958] - [EMID:c008340100aa58f8]

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

3 Nov 2021

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We look forward to receiving your revised manuscript.

Kind regards,

Andreas Buechner

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Dear authors,

Thank you for the revision of your submission. For me, there are now still a few small things that should be revised:

Please revise the references in the text. In the chapter Discussion, for example, the references do not have associated numbers, so that one can then find them.

P. 13 line 357 The dot from the end of the sentence belongs after the bracket (Table 1).

The last two sentences in the Conlcusion section are slightly misleading, please adjust them. First you write that the inter-implant distance has no significant influence on the results and then you conclude in the last sentence that a larger inter-implant distance could have an influence.

Reviewer #3: The manuscript presents a multi-centre prospective study of the benefit of sequential cochlear implantation on speech, language, and quality of life outcomes. The study examines a group (n=85) or children (5 – 18 yrs old) who have experienced variable durations of delay between receiving their first and second implant.

This is a revised version of a previously revised manuscript. The authors have made improvements to the clarity of the research objectives and have improved the framing on these within the context of existing research. However, my previous suggestions for how to address some key problems and improve the manuscript have not been addressed, particularly regarding the level of transparency and technical standards of the methods and statistical analyses. I reiterate these recommendations below and include further comments that I hope the authors will find useful. The conclusions are not supported by the data and do not make a valid contribution to the field, nor enable parents or clinicians to make more informed decisions.

General comments:

1. The authors’ main claim is that children showed significant improvements in speech recognition in quiet and in noise despite a great inter-implant interval. However, this is not explored in the manuscript: changes in children’s outcomes over time are not reported (e.g. what percentage showed improvements, no improvement, or got worse?) and whether this level of improvement was impacted by inter-implant interval has not been explored. The statistical effects of inter-implant interval have not been reported for the two subgroups separately (‘bimodal’ children who wore a hearing aid during this inter-implant interval and ‘unilateral’ children who did not). If the level of benefit and predictive factors of the benefit of sequential implantation is to be truly understood, then the effect of inter-implant interval must be explored, and also reported for each group separately rather than collapsing the effect across the two groups and (potentially erroneously) claiming it is irrelevant to speech outcomes.

2. Developmental effects have not been examined or controlled for in analyses. The sample is heterogenous in terms of age and so confounding factors such as linguistic maturation over time must be reported. Likewise, the effect of age at CI1 on bilateral outcomes has not been reported. Again, this is highly variable in the sample, and is a key factor to consider when evaluating the level of benefit of sequential implantation and predictive factors.

3. This is a prospective cohort study that, at first look, appears to employ a longitudinal, repeated-measures design to compare pre- and post-CI2 outcomes to address the main objective of determining the benefit of sequential implantation. However, it is unclear for which participants repeated measurements were collected, or whether different groups were in fact assessed at each time point. This confusion is further compound by the author’s contradictory statement in line 264-265: ‘Between group differences were tested using Wilcoxon signed rank test (for related samples)’. Were two separate cohorts assessed at each time point, or were the same children assessed at pre- and post-CI2? The manuscript should be more transparent about what participants were tested and when, and therefore whether between-group or within-subject statistical analyses methods were employed.

4. Further to the above point, there appears to be much missing follow-up (and/or baseline) data. The authors state that missing data has been handled using multiple imputation. This could mean that missing data has been replaced with the mean or a predicted value. However, the authors provide no information about the methods involved and how the missing data was imputed. For repeated measures analyses, only participants with both baseline and follow-up data should be included.

5. The total number of participants and the number of data sets analysed is inconsistent throughout the manuscript and difficult to navigate. For example, Figure 1 reports that for CVC in silence post-CI2 n=63, but in Table 4 this is n=61 for the first 4 variables. Furthermore, in Table 4 reports that for CVC in silence post-CI2 use of hearing aid (yes/bimodal = 29, no/unilateral = 13) total n = 42. But in Table 2 CVC in silence outcomes use of hearing aid (bimodal = 33, unilateral = 30) total n = 63.

Specific comments:

1. Table 2 – Effects of sequential implantation on CVC speech perception (comparison of ‘bilateral CI’ to ‘CI1’) have been helpfully presented separately for bimodal and unilateral subgroups as well as together. Please do the same for the language outcomes presented in this table (even if the n is small for each subgroup, it is still useful for the reader to see this information).

2. Table 2 – Why are the 12-month unilateral CI2 outcomes not reported? Baseline Pre-CI2 is reported but post-CI2 are not, only bilateral outcomes are reported. It seems central to the main objective of the manuscript to understand if implantation of the second ear improved outcomes for this ear, especially for those who wore a hearing aid before implantation.

3. Table 2 – condition labels used in column headings are unclear and footnotes are confusing. For improved clarity, please consider using more descriptive labels such as ‘baseline CI1/best-aided’, ‘baseline CI2’, ‘postoperative bilateral’, (and also include ‘postoperative CI2’ as mentioned above) and remove footnotes where possible. These labels should be defined in ‘Outcome assessment’ (line 200) or similar.

4. Table 2 – CVC score in quiet ‘Baseline Pre-CI2’: Bimodal (n=13) and unilateral (n=17) gives a total n=30, not n=36 as reported here. What is the discrepancy in the reported numbers?

5. Table 4 – those with support of speech therapy (‘yes’) had lower outcomes than those without (‘no’). Does this mean that children received speech therapy because they were performing poorly and therefore needed it, whereas ‘good’ performers did not need speech therapy? Without context or interpretation, there is a risk that parents may see this result and think that speech therapy is detrimental to outcomes.

6. Table 4 – CELF, use of hearing aid, p value is reported as ‘>0.05’. Please report exact p value consistent with all other reporting of p values in this table.

7. I understand why separate regression analyses were conducted for each outcome measure (e.g. CVC, PPVT, CELF). However, for each of these separate outcomes, there are multiple predictors that are analysed separately. Therefore, all results reported in Table 4 have not been corrected for multiple comparisons and have not been estimated whilst controlling for covariates. This should be clearly stated.

8. Why were the effects of predictors on CVC scores in noise not analysed, especially given that this outcome was seen to improve post-CI2?

9. Line 383 – 387 No sig effect of inter-implant delay on CVC words across whole group, but was there an interaction? See next comment.

10. S1 Fig 2a/b – Please report the associated statistics (i.e., effect size, p value, and/or regression line equation) and n = for each regression line shown.

11. I am not familiar with the terms ‘Univariable’ and ‘Multivariable’. When talking about assessing the effect of a single predictor variable on a single outcome variable, the standard term is ‘univariate’ or ‘simple linear regression’. Likewise, the standard term for assessing the effect of several predictor variables on one outcome variable is ‘multivariate’ or ‘multiple linear regression’. Please clarify the analysis method used and use standard terminology throughout.

12. Line 387 ‘Multivariable regression analysis was not performed as no significant associations were tested in univariable regression analysis’. Please be aware that if a predictor is not significant in a univariate analysis, it could still be significant in a multivariate relationship once other effects have been incorporated in the model’s estimates. Consider rephrasing or expanding on why a multivariate regression was not performed on those factors with predictive effects (even if they did not reach significance threshold, e.g. moderate effects of age at CI2 and inter-implant delay).

13. SSQ ‘quality’ domain significantly improved from baseline to post-CI2. This is important and should be reported in the conclusion and abstract. Subsequently, please correct in abstract ‘No significant effect was seen on language outcomes and SSQ’ as the findings reported do not support this statement.

14. Line 430 – when discussing improvements in the SSQ ‘qualities’ domain, the authors state that ‘This outcome repletes the objective measurements of the speech perception scores in quiet and noise as descripted above’. In fact, the qualities domain most closely reflects/represents quality and effort of listening, rather than speech understanding ability. The ‘speech’ domain is the scale that most closely reflects speech understanding ability.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Jan 2022

Dear editor and reviewers,

We first would like to thank the editor for the opportunity to resubmit the manuscript entitled ‘Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: a prospective cohort study’. We would like to thank also the reviewers for the valuable comments, in this way we were encouraged to made a major revision. Based on these comments we revised the paper carefully to improve the quality of the text including the statistical analysis and reconstructed Table 2 and 4 in detail. This resulted in a strongly improved manuscript which we would like to offer to PLOS ONE for reconsideration of publication.

Thank you very much for considering our manuscript for publication.

Sincerely,

On behalf of the author-team,

Drs. W.J. Kleijbergen

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

4 Apr 2022

25 Apr 2022

Dear editor,

We would like to thank you again for the opportunity to resubmit the manuscript entitled ‘Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: a prospective cohort study’. We added or changed the specific parts, mentioned in the valuable comments of the reviewers and re-submitted our paper again. Our detailed responses to the reviewers’ comments of the previous submission can be found in the document 'Response to Reviewers'.

Dear reviewer 2,

We would like to thank the reviewer for the valuable comment to explain the methodological choice of the selected test procedures for the outcome of speech perception and secondly for the encouragement to add an additional part to the discussion about the critical time of period of speech perception.

Firstly, we want to underline that we tested speech perception with meaningful words. These words were monosyllabic and had a CVC-structure. In the Netherlands, this is a standardized test that is used for measuring speech recognition. We feel that the reason that the outcomes were not correlated with age of the second cochlear implantation or inter-implant interval was rather related to the time of onset of severe hearing loss rather than the use of our speech recognition task. To clarify this to the reader that these CVC words were meaningful, we added this to methods section.

Secondly, we added a part to the discussion were we discuss the fundamental issue of the critical time period of the inter-implant delay and limited device use on auditory brainstem and subsequent cortical maturation to explain our results in more detail.

Dear Reviewer 3,

We would like to thank the reviewer for the feedback. We changed the text accordingly. We also added the Wilcoxon signed ranks Z test statistic in Table 2 and 3 accordingly.

Sincerely,

On behalf of the author-team,

Drs. W.J. Kleijbergen

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

5 Jul 2022

Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: a prospective cohort study

PONE-D-20-37958R3

Dear Dr. Kleijbergen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Andreas Buechner

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Good work! Thank you for revising and resubmitting the manuscript. By adding the new statistical values ​​and revising the discussion, the article has gained significantly for the reader.

Reviewer #3: The authors addressed all my comments adequately and I can fully recommend the manuscript for publication in your journal.

**********

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Reviewer #2: No

Reviewer #3: No

**********

8 Jul 2022

PONE-D-20-37958R3

Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: a prospective cohort study

Dear Dr. Kleijbergen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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