Short- and Long-Term Effect of Cochlear Implantation on Disabling Tinnitus in Single-Sided Deafness Patients: A Systematic Review

Patients with single-sided deafness can experience an ipsilateral disabling tinnitus that has a major impact on individuals’ social communication and quality of life. Cochlear implants appear to be superior to conventional treatments to alleviate tinnitus in single-sided deafness. We conducted a systematic review to evaluate the effectiveness of cochlear implants in single-sided deafness with disabling tinnitus when conventional treatments fail to alleviate tinnitus (PROSPERO ID: CRD42022353292). All published studies in PubMed/MEDLINE and SCOPUS databases until December 2021 were included. A total of 474 records were retrieved, 31 studies were included and were divided into two categories according to whether tinnitus was assessed as a primary complaint or not. In all studies, cochlear implantation, evaluated using subjective validated tools, succeeded in reducing tinnitus significantly. Objective evaluation tools were less likely to be used but showed similar results. A short-(3 months) and long-(up to 72 months) term tinnitus suppression was reported. When the cochlear implant is disactivated, complete residual tinnitus inhibition was reported to persist up to 24 h. The results followed a similar pattern in studies where tinnitus was assesed as a primary complaint or not. In conclusion, the present review confirmed the effectiveness of cochlear implantation in sustainably reducing disabling tinnitus in single-sided deafness patients.


Introduction
Single-sided deafness (SSD), also known as unilateral profound hearing loss [1], is associated with a hearing impairment with higher perception of hearing handicap and visual annalog scores [2]. Despite normal or near-normal contralateral hearing status, monaural stimulation can lead to a wide range of audiological disabilities such as poor speech perception in noise and sound localization [3,4]. In addition, patients with SSD can deafness [Title/Abstract] AND Cochlear implant) and the different combinations (tinnitus AND single-sided deafness), (tinnitus AND cochlear implant), and (cochlear implant AND single-sided deafness). The search was conducted in December 2021. All published studies available at this time were included in the review process. The search terms included combined expressions and synonyms of tinnitus, single-sided deafness, and CI. These include ear ringing, buzzing, unilateral hearing loss, and intracochlear electrical stimulation.

Study Selection
All studies on cochlear implantation in adult patients with SSD and disabling tinnitus, in which tinnitus was evaluated as a primary or non-primary complaint, were selected. Studies where tinnitus was evaluated pre-and post-operatively, using subjective and/or objective tools, in the short-or long-term, were eligible. During screening, duplicates, systematic reviews, and articles written in languages other than English were excluded. Case reports and studies with overlapping study population were not excluded. Lack of previous therapeutic trials was not an exclusion criterion. Two reviewers, S.A.I. and P.R., screened each study (title/abstract) independently. Disagreements were resolved by a third reviewer. Studies were divided into two groups according to whether the primary complaint was tinnitus.

Quality Assessment
Two authors, S.A.I and K.K.S.A., independently assessed the risk of bias (RoB). We used the ROBINS-I tool (Risk Of Bias In Non-randomized Studies-of Interventions) to evaluate risk of bias [53]. The tool consists of seven domains: confounding, selection of participants, classification of interventions, deviation from intended intervention, missing data, measurement of outcomes, and selection of reported results. The criteria were defined and adapted to our research question about cochlear implantation for SSD with disabling tinnitus. Items were scored as low risk of bias, moderate risk of bias, serious risk of bias, or unclear based on the guidelines of the ROBINS-I tool. Consensus was obtained after discussion between the two reviewers.

Data Extraction
All study characteristics and outcomes were extracted by S.A.I. and P.R. independently. The primary outcome was the difference between pre-and post-operative evaluation of tinnitus on validated multi-item tinnitus distress questionnaires and/or objective evaluation measurements. Additional outcomes were also extracted including hyperacusis, sound hypersensitivity, speech perception, sound localisation, word recognition, quality of life, work performance, and psychosocial comorbidities.

Search Strategy and Study Selection
A total of 474 records were retrieved, and 31 studies were included in the systematic review ( Figure 1). Post-implantation tinnitus suppression was analysed in 479 patients using various assessment methods. These studies were divided into two groups; 14 studies in which the primary complaint was tinnitus, and 17 studies in which tinnitus was not the primary complaint. Some studies had an overlap in their population samples [54][55][56][57].

Search Strategy and Study Selection
A total of 474 records were retrieved, and 31 studies were included in the systematic review ( Figure 1). Post-implantation tinnitus suppression was analysed in 479 patients using various assessment methods. These studies were divided into two groups; 14 studies in which the primary complaint was tinnitus, and 17 studies in which tinnitus was not the primary complaint. Some studies had an overlap in their population samples [54][55][56][57].

Quality Assessment of Included Studies
The critical appraisal can be found in Tables 1 and 2 for studies where tinnitus was the primary complaint and those where tinnitus was not the primary complaint, respectively.
In studies where tinnitus was the primary complaint, only one study [58] defined appropriately its inclusion criteria. The remaining studies either did not provide information on contralateral ear [59] or included moderate hearing loss thresholds for inclusion criteria [54,55,[60][61][62]. In addition, in several studies, the efficacy of conventional treatments was not tested before CI [56,[63][64][65][66][67][68]. When selecting participants, inclusion and exclusion criteria were not well defined [55]. Two out of fourteen studies were retrospective [55,64]. Blinding was applied in only one study [62]. The population samples of two

Quality Assessment of Included Studies
The critical appraisal can be found in Tables 1 and 2 for studies where tinnitus was the primary complaint and those where tinnitus was not the primary complaint, respectively.
In studies where tinnitus was the primary complaint, only one study [58] defined appropriately its inclusion criteria. The remaining studies either did not provide information on contralateral ear [59] or included moderate hearing loss thresholds for inclusion criteria [54,55,[60][61][62]. In addition, in several studies, the efficacy of conventional treatments was not tested before CI [56,[63][64][65][66][67][68]. When selecting participants, inclusion and exclusion criteria were not well defined [55]. Two out of fourteen studies were retrospective [55,64]. Blinding was applied in only one study [62]. The population samples of two studies overlapped and the criteria for recruiting additional participants were not well defined [54,56]. The process of cochlear implantation and rehabilitation was not clear in all studies [60,64,67]. The intervention protocol was either unreported [55,58,59,63,64] or did not respect standard process [56,59,61,62,65,67]. Missing data, participant dropouts and withdrawal exceeding 10% [54,58,65] were justified in only one study [58].  In studies where tinnitus was not the primary complaint, five studies defined appropriately its inclusion criteria [44,[69][70][71][72]. When selecting participants, inclusion and exclusion criteria were not clearly provided [73,74], and blinding was not applied. Several studies were retrospective [71,72,[74][75][76]. The CI intervention was not constantly described [57,77], and the majority of studies did not clarify if the standard CI protocol was adopted [44,69,71,72,[74][75][76][78][79][80][81]. Missing data, participant dropouts and withdrawals exceeding 10% [71,[74][75][76] were not constantly justified [75].  Missing data: O = < 10% missing data, • = ≥10% missing data, Ø = no information. Measurement of outcomes: O = similar measurement of outcomes between intervention groups AND blinding of the outcome assessors for intervention received by study participants, = similar measurement of outcomes between intervention groups AND no blinding of the outcome assessors for intervention received by study participants, • = difference of measurement between groups AND no blinding of the outcome assessors for intervention received by study participants, NA: not applicable. Selection of reported results: O = primary outcomes reported according to the protocol, = primary outcomes reported for all groups (no subset) and explanation if missing data, • = missing outcomes/data reported for a subset of measures, Ø: no information.

Tinnitus Evaluated as a Primary Complaint
In studies in which tinnitus was the primary complaint, pre-and post-operative tinnitus was evaluated, using numerous tools including validated questionnaires and scales, and objectives tests (Table 3). Validated self-reported instruments were used in all such studies, namely the Tinnitus Questionnaire (TQ) [10,11], THI [12], Tinnitus Reaction Questionnaire (TRQ) [13], VAS [14], Tinnitus Rating Score (TRS) [15], Subjective Tinnitus Severity Scale (STSS) [16], and/or Numeric Rating Scale (NRS) [17]. Objective measurements including electroencephalogram (EEG) along with functional imaging [58], and/or evoked and spontaneous cortical activities [67] were less frequently used. The follow-up period was variable studies and ranged between 12 min [67] to 36 months [55].    In all studies in which tinnitus was the primary complaint, early after implant activation, electrical stimulation succeeded to significantly reduce, sometimes completely, tinnitus loudness and distress [60,68]. VAS, THI, and TQ were used in the majority of studies, but also similar results were obtained with other tools such as TRQ, TRS, and STSS [63,65]. No tinnitus aggravation was noted in any of the included studies. Long-term (>12 months) tinnitus suppression was reported in several studies [54,55,65]. Tinnitus suppression was less likely to persist when CI was turned off [54,59,60,68]; persistence of suppression after CI deactivation was only reported in one study [61]. While some studies reported complete residual inhibition of tinnitus that ranged between a minute to 30 min [55,62,66], others reported that residual inhibition persisted for 12 [54] and 24 h [59,68]. Taken together, these results confirm the effectiveness of CI as a treatment in disabling tinnitus (Table 3).
Zeng et al. [67] assessed tinnitus presence objectively by recording cortical potentials and tinnitus loudness subjectively using a VAS. Evoked and spontaneous cortical activity was recorded in "tinnitus-presence" and "tinnitus-suppressed" conditions. Complete suppression of tinnitus was obtained after a low-rate low-level electrical intracochlear stimulation and was associated re-established brain activities. These results were coherent with a reduction of tinnitus loudness (VAS). In another study, Song et al. [58] explored EEG waves and activated Auditory Cortex (AC) areas by brain electromagnetic tomography among patients with tinnitus and SSD pre-and post-cochlear implantation; those with pre-operative enhanced activity in different regions of the AC, higher delta and gamma bands, and an increased connectivity between different area of the AC, were less likely to improve after CI. These results matched with NRS and TQ scores (Table 3).

Tinnitus Evaluated as an Additional Complaint
In studies in which tinnitus was not the primary complaint, tinnitus was also investigated via validated questionnaires and scales including VAS, THI, TRQ, TQ, and/or tinnitus handicap questionnaire (THQ) ( Table 4). No objective measurements were used.
All studies in which tinnitus was not the primary complaint reported tinnitus suppression. Among the 296 patients included in these studies, tinnitus was not suppressed in only one patient [75]. Tinnitus suppression remained stable over time [57,70,76,77]. When CI patients were compared to a control group, THI scores were significantly lower [83]. No objective measurements were applied for tinnitus in any of these studies (Table 4).

Effect of Cochlear Implant on Other Factors
Along with tinnitus suppression, other criteria were assessed including speech comprehension in quiet and in noise, spatial hearing, hearing quality, speech perception and localization, sound quality, hyperacusis, work performance, psychological comorbidities, and QoL. Most studies reported improvement of sound localization and speech perception. The improvement of speech perception remained inconstant and oscillated during the first 6 months after implantation [81]. Speech recognition threshold (SRT) was improved [57]. No deterioration of speech performance was noted in the better hearing side with electric and acoustic signals integration [71]. Communication leading to less fatigue after a long workday and better work performance was also reported [80]. In addition, hyperacusis, evaluated using sound hypersensitivity questionnaire (SHQ) [55,66], as well as sound intolerance [78] were decreased among patients with CI. Furthermore, intracochlear electric stimulation improved QoL indexes and psychological comorbidities [44,72,75,80,83]. Taken together, these findings suggest that CI reduced tinnitus, restored hearing aspects, and improved QoL in SSD patients (Tables 3 and 4).

Discussion
The present systematic review describes the effect of cochlear implantation on tinnitus in patients with SSD and disabling tinnitus. Reduction of tinnitus was reported in a relatively high number of studies (31 studies, 479 patients). No aggravation of tinnitus was reported in any patient. When compared to no treatment, CI was associated with better tinnitus suppression scores. These findings are encouraging in considering CI for SSD patients with disabling tinnitus, more specifically when conventional treatments fail to relieve the tinnitus. Although results are promising so far, the indication of CI for these patients is not yet widespread.
Most studies included in the present review assessed tinnitus using subjective tools; these are available in different languages, are not time consuming, and provide validated scores. VAS and THI were the most frequently used, followed by TQ. Although it could seem advantageous to not to be limited to a single tool, particularly since not all tools are validated for all languages, and some are more difficult to use than others, the heterogeneity of tools employed hampers comparison between studies. It is of note that objective tools were less likely to be used, which is possibly related to the difficulty of access to equipment required for electrophysiological and radiological assessments but also to the lack of available personnel with the skills to perform the assessments and interpret the results. These tools are, however, interesting in further understanding the mechanism of tinnitus reduction as well as the anatomical areas intervening in this process. It may also be helpful in identifying parameters that can predict prognosis. More generally, further research is needed to objectively assess treatment related physiological processes.
All SSD patients included in this review had disabling tinnitus, but the characteristics of their deafness were variable in terms of interval between onset and cochlear implantation, aetiology, and type of CI device. This makes it difficult to compare studies, but suggests treatment is successful independent of these factors. The risk of bias assessment showed a lack of precise inclusion criteria as well as a definition of the intervention in many studies. This emphasizes the need for a randomized clinical trial with clearly defined inclusion criteria and standard and clear intervention and rehabilitation protocols.
Whether tinnitus was evaluated as a primary complaint or not, CI succeeded to alleviate tinnitus. Studies in which tinnitus was evaluated as a primary complaint discussed several tinnitus characteristics including residual inhibition and recurrence of tinnitus after deactivation of implant. These studies were less likely to discuss hearing aspects or psychosocial benefits compared to studies where tinnitus was not the primary complaint.
Our review included all studies until December 2021. The present systematic review differs from previous published reviews in several ways. First, and to the best of our knowledge, this is the only review in which the listed studies have been divided into two groups depending on whether or not tinnitus was the primary complaint. The latter division permits reducing the risk of false-positive and false-negative errors. Second, the present review is not limited by the type of questionnaires used to assess tinnitus [50]: all validated multi-item questionnaires have been considered. In addition, studies using subjective assessment tools and studies using objective assessment tools were included. Audiological and neurophysiological levels of evidence were simultaneously considered when available. Last but not least, data on short-and long-term tinnitus suppression were analysed. The improvement of tinnitus, reflected by a significant reduction in various validated multi-item questionnaire scores, should strengthen considering CI in SSD with disabling tinnitus when conventional treatments are insufficient.
The present study has certain limitations; similar to the previously published systematic reviews, studies were mostly observational, and there was wide heterogeneity of tools used and a small sample size. This may preclude generalization of the results to a wider more heterogeneous population. Further studies with larger samples are needed to develop prediction models of tinnitus outcomes after cochlear implantation, where objective methods of tinnitus could be of interest.

Conclusions
In conclusion, this review included a large number of studies reporting the effectiveness of CI in suppressing disabling tinnitus in SSD patients when conventional treatment is insufficient. Tinnitus improvement is maintained in the long-term (>12 months). Considering the positive effect observed in all the studies, CI indication deserves to be more widely considered in such patients.
Author Contributions: H.T.-V. designed the plan of the article, contributed to the manuscript draft, and closely reviewed and revised the whole article critically for important intellectual content. S.A.I. made the literature review and data collection, wrote the manuscript draft, conceived and designed the tables and figures, and interpreted the data. M.M. and A.M. participated in the conception of the work, contributed to the article plan, and reviewed the article. P.R. participated in drafting the work and data collection. C.-A.J. contributed to data collection and analysis. K.K.S.A. participated in the quality assessment and reviewed the whole article. E.C.I. reviewed the whole article. All authors have made substantial contributions to this manuscript. They gave their final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.