cCMV infection is the most common non-genetic cause of SNHL, whereas the term SNHL classically defines a hearing loss possibly due to both cochlear and/or auditory nerve damage.
Two recent consensus statements on cCMV infection have recently highlighted the uncertainty surrounding the therapeutic management of isolated SNHL at birth [4, 5]. In fact, despite some experts believe that affected children should be treated with antiviral drugs [5, 6], no definitive evidence about the potential benefit of antivirals is currently available [4].
The aim of our study was to investigate the auditory evolution of children with cCMV asymptomatic infection, not receiving antiviral treatment, who had a diagnosis of isolated SNHL at birth due to AN (i.e., abnormal/absent ABR response in combination with a bilateral “pass” OAE). In order to emphasize any change in the auditory threshold over time, we choose to rely on the worst ear for severity grading of SNHL, rather than on a functional evaluation based on best-ear assessment [2].
Our study demonstrates that a mild/moderate isolated AN at birth (particularly in the range ≤ 50 dB-HL), is a not negligible event in infants with asymptomatic cCMV infection. Of interest, a normal hearing threshold was always recovered over time, in absence of antiviral treatment, in these cases.
Our data suggest that a delayed maturation of the auditory pathways, rather than a “true” SNHL, may affect the auditory outcome of the infants diagnosed with AN. This hypothesis is supported by the existence of a difference in the mean age at first ABR between the two study groups, whereas AN infants underwent first ABR significantly earlier (p = 0.007) than not affected ones. In this light, also the distribution of AN cases along all trimesters of maternal infection (Table 1) suggests that a different pathogenesis is involved in these cases if compared to SNHL cases reported in medical literature, where a primary maternal infection of the first trimester of pregnancy is demonstrated to be a major risk factor [15, 16].
The presence of a physiological delay of maturation of the auditory pathways in newborns and children has already been highlighted in previous studies, with consequences on the results of ABR and cortical auditory evoked potential [17, 18]. Studies performed in neonates and infants at risk of hearing loss have shown the possibility of complete or partial recovery of auditory thresholds over time, even in severe cases [9, 10]. Interestingly, in a large group of infants at risk of hearing loss with abnormal ABR at initial hearing evaluation, a normal OAE at first evaluation and a very young age at initial hearing screening were associated with a normal ABR threshold restoration on reexamination, and a delayed myelination of the acoustic pathway was deemed the main reason for this to occur [9]. Oligodendrocyte maturation - and then myelin production - depends on a variety of growth factors, hormones, cytokines, surface receptors, and secreted ligands [19]; in this light, the proinflammatory state which follows in utero CMV infection might affect, to some extent, the maturation of the auditory pathway [20]. However, due to the lack of a control group of term, not-infected infants, we were not able to establish the real contribution of cCMV infection to the incidence of isolated AN in our population.
Several studies have investigated the auditory evolution of isolated SNHL at birth in cCMV infection [21,22,23]. Dahle et al [21], have demonstrated that an improvement in hearing thresholds may occur in up to 47.9% of infants with cCMV asymptomatic infection. Foulon et al [22], have reported a complete normalization of the auditory thresholds in 35.0% of the infants with cCMV asymptomatic infection. Recently, Pasternak et al [23], in a retrospective study on 59 infants with cCMV infection and isolated SNHL who received prolonged antiviral treatment, reported an improvement of 68.6% of affected ears with hearing deficit at baseline during follow-up (96.3% returning to normal hearing). In the studies mentioned above [21,22,23], the hearing thresholds were investigated by means of ABR and no relationship with OAE results was established; then, what part of SNHL burden was attributable to AN is unknown in these studies.
Our results are in accordance with Foulon et al [24], that among 18 hearing-impaired children out of a cohort of 206 cCMV infected infants, could not detect OAE in any of the SNHL cases; the authors concluded that AN does not appear to be a feature of cCMV infection. Royackers et al [25], describe only one case (in seventy cCMV infected children) of AN in a symptomatic infection that spontaneously resolved over time.
When the cognitive, language, and motor areas were investigated by means of BSID-III composite scores, no significant differences were detected between the two groups (Table 3), suggesting that a delay of the auditory pathway maturation does not seem to affect the child development. The validity of these results could be partially flawed by significantly different lenghts of Bayley III follow up between the two groups (Table 3); a greater concern for parents of children diagnosed with SNHL may explain the greater compliance with the scheduled Bayley III assessment in this group.
Although based on a small number of cases, the strength of our work is represented by the highly selected population included, avoiding biases due to prematurity and additional diseases/therapies known to affect the audiologic outcome.
However, several limitations should be noted. This is a retrospective study, thus dealing with possible biases (mostly related to information and/or selection bias) relevant to the nature of the study itself. Further, though our population was scheduled for ABR within 3 months of life, the resulting mean age at first ABR was substantially higher (5.00 ± 2.79 months). Frequent postponements of audiological appointments by parents and busy waiting lists were the main reasons for this to occur. Finally, the lack of a systematic ABR assessment in the first month of life prevented us an accurate estimate of the burden of AN at birth and, most important, some applicability of these data in the restricted time window available to decide if therapy has to be performed (within 28 days of life) [2, 3]. Nonetheless, the sixteen AN cases were diagnosed at a mean age of 3 months in our study, thus suggesting a congenital AN form be involved in most, if not all of these cases.
Despite the above limitations, we believe that this study could raise some important cues worthy of being further verified in prospective, possibly controlled, trials.
Infants with mild/moderate SNHL on first ABR and a bilateral pass OAE should be suspected for a maturation delay of the auditory thresholds and, in our opinion, these infants should be possibly retested before any possible therapeutic decision. Severe/profound AN cases were almost absent in our cohort (only 1 ear with severe AN) and this prevented us any meaningful consideration about the possible management of AN of higher degree.
OAE, together with ABR, should be part of the initial hearing evaluation of SNHL in cCMV infected infants in order to assess if a cochlear damage, or an auditory neuropathy, is responsible for a hearing loss. In fact, if the clinician relies exclusively on ABR testing to assess the burden of SNHL at birth, this might include, according to our experience, a variable amount of mild/moderate “maturative” AN cases possibly leading to antiviral overtreatment in this population.
Besides, testing cCMV infected infants with both OAE and ABR could allow a separate evaluation of both audithory outcome (SNHL due to cochlear damage vs. SNHL due to AN), thus enabling to draw data about a possible, different management between the two types of hearing loss.
