Unexpected Hearing Improvement after Treatment with Valganciclovir in a Child with Congenital Cytomegalovirus Infection

A 32-week preterm-born male with symptomatic congenital cytomegalovirus infection was treated with valganciclovir. He was also affected by congenital severe bilateral hearing loss and, unexpectedly, a normalization of the hearing threshold was reached at one year of age. The improvement of hearing level in relationship with both the late development of the auditory system and the administration of antiviral therapy is discussed. This case also highlights the importance of early diagnosis of congenital cytomegalovirus associated with close follow-up.


INTRODUCTION
Cytomegalovirus (CMV) is the most frequent etiologic agent of congenital infection. Approximately 40%-60% of symptomatic infants will develop permanent sequelae of variable severity. 1 Hearing loss is the most common sequelae and it may be present at birth or late onset, mono-or bilateral, fluctuating or progressive. 2,3 Treatment with valganciclovir is an accepted treatment option for children with symptomatic congenital CMV infection involving the central nervous system. 4 Moreover, valganciclovir seems to be effective in improving hearing dysfunction in infants with congenital CMV (cCMV) infection, with the excep-tion of forms of severe hearing loss. 5 We report a case of a preterm newborn with cCMV infection affected by bilateral severe hearing loss with threshold improvement after antiviral therapy.  (Fig. 1A) associated with changes in the signals of the related white matter. At one-year follow-up, cerebral MRI was normal (Fig. 1B), and the research of viral DNA copies at the urine analysis was negative.

CASE REPORT
The first auditory evaluation was performed at two months of age, twelve days after the beginning of antiviral therapy. Transient evoked otoacoustic emissions (TEOAEs) failed bilaterally. Auditory brainstem responses (ABR) showed the presence of a V wave up to an intensity of 80 dB nHL of stimulus in the right ear, while in the left the presence of a wave V was not identified (Fig. 2). All subsequent hearing evaluations are reported in Table 1. Otoscopy and tympanometry were normal at every evaluation. Considering the clinical history of the child and the audiological evaluation, air conduction hearing aids were prescribed at 5 Figure 1. MRI brain scan: a) cystic lesion (arrow) (max. diameter 12 mm) in the right temporal pole, very close to the temporal horn of the right ventricle; b) one year later, the absence of the lesion can be noted. months of age with an initial low gain. At six months of age, the hearing-aids amplification was modified and rehabilitative speech therapy was started. At a further evaluation, the mother reported irregular use of the hearing aids and the child's continued attempts to remove them. The child began babbling and speaking his first words at 11 months of age. At 11 months the hearing aids were discontinued. The speech therapist indicated good comprehension of the Italian language (the child was exposed to bilingualism).
The child is still in follow-up according to guidelines as auditory threshold can fluctuate over time. 3

DISCUSSION
Threshold improvements have been reported in congenitally infected infants even without antiviral treatment [6][7][8] but not often in symptomatic cCMV children or in case of hearing loss of severe entity. In particular, in case series with children treated with antiviral therapy, it was found that the probability of hearing loss was inversely related to the severity of the impairment at birth. 9 Therefore, a normalization of the hearing threshold was not expected as the child presented symptoms and lesions of cCMV infection documented by cerebral MRI. This clinical condition prompted the decision to suggest the very early use of hearing aids, delayed intervention being unjustified. In fact, the second audiological evaluation indicated a possible slight fluctuation of the hearing but the third still indicated a severe bilateral hearing loss. Folia Medica I 2021 I Vol. 63 I No. 2  In the case presented, we should take into consideration a delay in the development of the auditory system, as the auditory nerve is usually completely mature in a term newborn, with the exception of the fibers related to high frequencies which become completely mature during the first post-natal trimester. 10 However, it is not possible to clearly distinguish between the effects of the antiviral treatment and late development of the hearing apparatus.
Given the influence that speech and environment have on the gradual determination of neural connections of the auditory pathway 11 , whose development is characterized by continuous synaptogenesis and myelinization of the nerves, rehabilitative treatment was important to guarantee hearing function.
It might be hypothesized that both auditory rehabilitation and antiviral therapy could have contributed to the good functional result. However, the normalization of cerebral MRI lesions suggests the positive effect of valganciclovir. 9

CONCLUSION
In the case reported a preterm newborn with cCMV infection showed a threshold improvement after antiviral therapy with valganciclovir. We might hypothesize that both antiviral therapy and auditory rehabilitation could have contributed to the good functional result. However, further research is mandatory in order to confirm the positive effect of valganciclovir on hearing function. This case also highlights the importance of early diagnosis of cCMV infection associated with close follow-up.

Funding
None.

Conflicts of interest
None.