CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Auditory and audio-visual processing in patients with cochlear, auditory brainstem, and auditory midbrain implants: An EEG study.

There is substantial variability in speech recognition ability across patients with cochlear implants (CIs), auditory brainstem implants (ABIs), and auditory midbrain implants (AMIs). To better understand how this variability is related to central processing differences, the current electroencephalography (EEG) study compared hearing abilities and auditory-cortex activation in patients with electrical stimulation at different sites of the auditory pathway. Three different groups of patients with auditory implants (Hannover Medical School; ABI: n = 6, CI: n = 6; AMI: n = 2) performed a speeded response task and a speech recognition test with auditory, visual, and audio-visual stimuli. Behavioral performance and cortical processing of auditory and audio-visual stimuli were compared between groups. ABI and AMI patients showed prolonged response times on auditory and audio-visual stimuli compared with NH listeners and CI patients. This was confirmed by prolonged N1 latencies and reduced N1 amplitudes in ABI and AMI patients. However, patients with central auditory implants showed a remarkable gain in performance when visual and auditory input was combined, in both speech and non-speech conditions, which was reflected by a strong visual modulation of auditory-cortex activation in these individuals. In sum, the results suggest that the behavioral improvement for audio-visual conditions in central auditory implant patients is based on enhanced audio-visual interactions in the auditory cortex. Their findings may provide important implications for the optimization of electrical stimulation and rehabilitation strategies in patients with central auditory prostheses. Hum Brain Mapp 38:2206-2225, 2017. © 2017 Wiley Periodicals, Inc.

[Multi-channel cochlear implant in cochlear ossification]. / L'impianto cocleare multicanale nelle ossificazioni cocleari.

Cochlear ossification, considered until only a few years ago as a contraindication for cochlear implants (C.I.), may now be managed by means of a wide variety of surgical techniques. In cases with massive ossification, the drill-out circummodiolar technique described by Gantz et al. in 1988 and successively modified by Balkany et al. in 1997 may be adopted. The technique of electrode insertion in the scala vestibuli, perfected by Steenerson et al. in 1990, may be used when cochlear ossification has spread no further than the scala tympani. Other methods call for a groove to be drilled along the proximal tip of the basal turn of the cochlea (Cohen and Waltzman, 1993), the insertion of electrodes through the middle cranial fossa (Colletti et al., 2000), or the utilization of a double electrode array (Bredberg et al., 1997, Lenarz et al., 2001). This study reports the experience conducted at the Cochlear Implants Centre of the Otorhinolaryngoiatrics, Otological and Otoneurological Microsurgery Section of the University of Parma in a group of 15 patients who underwent C.I. in the presence of varying degrees of ossification. In 3 cases the ossification was limited to the region of the round window and a few millimetres of the scala tympani; cochleostomy was performed anteriorly and inferiorly to the anterior niche of the round window. In 11 cases (of which 3 of pediatric age), the ossification had spread to the horizontal portion of the scala tympani; in these cases, the electrodes were inserted in the scala vestibuli. The scala vestibuli was opened by drilling anteriorly to the round window and superiorly to the spiral ligament. In the only case of massively ossified cochlea, it was possible to partially insert the electrodes in a circum-modiolar tunnel. In the 12-month follow-up hearing test, the 3 patients with ossification of the round window region and the first millimetres of the scala tympani respectively averaged 61.6% in recognizing 2-syllable words and 59% in recognizing words embedded in phrases. The averages on the 12-month follow-up hearing test in the 8 adult patients who received the implant in the scala vestibuli were 80.6% in recognizing 2-syllable words and 89.1% in recognizing words in phrases. The 3 pediatric patients were classified on the Geers and Moog scale, which situated 2 of them in the 6th category of perception and 1 of them in the 4th category of perception. As regards the only case of massive cochlear ossification, the patient underwent surgery recently, and the sole follow-up available is the one conducted after only 3 months; the vowel identification average was 55%; the average on the VCV test was 31%; and the 2-syllable word recognition average was 20%.

Accuracy of high-resolution computed tomography in cochlear implantation.

Multichannel cochlear implants are a proven method for the auditory rehabilitation of individuals who have severe-to-profound sensorineural hearing loss. These devices typically require insertion into the scala tympani of the cochlea to provide auditory stimulations. A patent scala provides the best chance for an adequate insertion of the electrode array. Preoperative high-resolution computed tomography imaging has traditionally been used to determine the patency of the scala tympani. Its ability to accurately predict the patency of the cochlea has been questioned in several retrospective studies. A prospective study was undertaken in 28 consecutive individuals undergoing cochlear implant surgery to compare the findings on high-resolution computed tomography with the surgical findings in an attempt to determine high-resolution computed tomography's accuracy. Cochlear obstruction caused by ossification was accurately predicted in six of six individuals but overestimated in the round window region in three individuals. High-resolution computed tomography accurately predicted patent cochleas in 19 individuals. No false-negative results were encountered. In this study sensitivity of high-resolution computed tomography was 100%, and specificity was 86%. High-resolution computed tomography appears to be more helpful than previously reported for determining cochlear patency.