OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation

Abstract

Hearing impairment is the second most prevalent clinical feature after optic atrophy in dominant optic atrophy associated with mutations in the OPA1 gene. In this study we characterized the hearing dysfunction in OPA1-linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (seven males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (three males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harbouring OPA1 missense mutations and were compared to recordings obtained from 20 control subjects with normal hearing and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after 1 year of cochlear implant use. Nine of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harbouring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and subjects with cochlear hearing loss was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all but one patient. Brainstem potentials were recorded in response to electrical stimulation in five of six subjects, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fibre activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by bypassing the site of lesion.

Keywords: OPA1-related hearing impairment; auditory neuropathy; cochlear implants; electrocochleography; speech perception.

Figure 1

Articulation gain curves from patients with DOA. Articulation curves obtained from OPA1-H and OPA1-M groups have been superimposed on the mean articulation functions (dashed lines) with 95% confidence limits (shadowed areas) calculated for controls at corresponding PTA values. These were defined by minimum and maximum (10–14 dB) PTA values in the OPA1-H group, whereas the OPA1-M subjects were pooled into three classes characterized by increasing PTA values (15–28 dB, 35–50 dB, 58–73 dB). Mean function is displayed for the OPA1-H group, whereas articulation curves from individual ears have been considered for the OPA1-M patients due to the high variability of scores. Speech intelligibility was within normal limits in OPA1-H patients, whereas a remarkable decrease in reception scores compared to controls was found for all but one of the OPA1-M subjects. R = right, L = left.

Figure 2

ABRs recorded at 90 dB nHL from one control with normal hearing and three subjects with DOA, one included in the OPA1-H and two in the OPA1-M group. ABRs were normal in the OPA1-H subject, whereas OPA1-M patients had no brainstem responses (#4-L) or showed a delayed wave V (#1-L). For each subject the thick line results from the average of individual recordings (thin lines). Vertical dashed black lines indicate wave I, III and V peaks in the control, while the vertical red line refers to wave V peak in OPA1-M Subject 1. L = left.

Figure 3

Cochlear microphonic potentials. Left: Cochlear microphonic potentials recorded at 120 dB SPL from one control with normal hearing, one hearing-impaired subject with cochlear hearing loss and one representative OPA1-M patient (Subject 7, left ear). Right: Mean cochlear microphonic amplitudes are reported as a function of stimulus intensity for the OPA1-M patients and for both normally-hearing and hearing-impaired subjects. Cochlear microphonic potentials recorded from OPA1-M patients are significantly larger compared to controls with normal hearing and hearing-impaired subjects with cochlear hearing loss (Cochlear HL).

Figure 4

Cochlear potentials recorded from OPA1-M patients. Left: ECochG waveforms obtained after cochlear microphonic cancellation from two representative OPA1-M patients are superimposed on the corresponding responses recorded from one control with normal hearing and from one hearing-impaired child with cochlear hearing loss (Cochlear HL) at decreasing stimulus intensity. Right: Means and standard errors of summating potential (SP) peak latency and amplitude obtained from OPA1-M patients are superimposed on mean compound action potential (CAP) and summating potential amplitude and peak latency calculated for controls with normal hearing and hearing-impaired subjects with cochlear hearing loss. Mean amplitude and latency of the prolonged potentials (OPA1-Prolonged) are also reported. Mean response duration as calculated from onset to return to baseline (SP-CAP) is shown for OPA1-M subjects and for both normally-hearing and hearing impaired groups in the lower right corner. Time ‘0’ refers to cochlear microphonic onset. In each recording the horizontal dashed line refers to baseline.

Figure 5

Adaptation of ECochG potentials in OPA1-M patients. ECochG recordings obtained at 100 dB SPL from one control with normal hearing and two OPA1-M patients in response to the stimulus sequence reported at the bottom are illustrated in the left panel. In the right panel the means and standard errors of normalized summating potential–compound action potential (SP-CAP) amplitudes are reported as a function of click position in the stimulus sequence for normally-hearing controls and OPA1-M patients superimposed on mean summating potential amplitudes calculated for controls. In OPA1-M patients the size of attenuation of cochlear potentials during adaptation was within the range of compound action potential attenuation calculated for controls. The vertical dashed lines indicate the summating potential and compound action potential peak in the control and the peak of the prolonged response in OPA1-M patients. Time ‘0’ refers to cochlear microphonic onset. In each recording the horizontal dashed line refers to baseline.

Figure 6

Speech perception scores obtained from OPA1-M patients using a cochlear implant. Individual and mean scores on open-set disyllable recognition test measured in quiet and in the presence of competing noise at two signal-to-noise (S/N) ratios (+10, +5) are reported for the pre-implant condition and within 1 year of cochlear implant (CI) experience. Speech perception improved in all OPA1-M patients after cochlear implantation except for Subject 9 (not shown).

Figure 7

Electrically-evoked compound action potentials and ABRs from OPA1-M implanted patients. Electrically-evoked potentials from two representative subjects are displayed. In Subject 7 (bottom) both electrically-evoked compound action potentials (left) and electrically-evoked ABRs (middle and right) were recorded at all electrode locations; wave II was also identified in electrically-evoked ABR recordings in addition to wave V. No electrically-evoked compound action potentials were obtained from Subject 4, whereas electrically-evoked ABR wave V was recorded at all electrode locations. In both patients wave V was recorded with increasing latency from apical to basal electrodes (vertical dashed lines, middle). For a given electrode location, decreasing current levels resulted in increased latencies and attenuated wave V amplitudes (vertical dashed lines, right).