Neurophysiological and brain structural insights into cyclin-dependent kinase-like 5 deficiency disorder: Visual and auditory evoked potentials and MRI analysis.

OBJECTIVE: CDKL5 deficiency disorder (CDD), an epileptic encephalopathy for which novel therapeutics are under development, lacks valid and reliable measures of therapeutic efficacy. We aimed to elucidate the neurophysiological and brain structural features of CDD patients and identify objective indicators reflecting the clinical severity. METHODS: Twelve CDD patients and 12 healthy controls (HCs) participated. The clinical severity of CDD was scored using the CDD severity assessment (CDD-SA). The participants underwent visual evoked potential (VEP), auditory brainstem response (ABR), structural MRI, and diffusion tensor imaging (DTI) analyses. Measurements from each modality were compared with normal values of age-matched cohorts (VEP and ABR) or statistically compared between CDD patients and HCs (MRI). RESULTS: VEP showed a significant correlation between P100 latency and CDD-SA in CDD patients. ABR showed abnormalities in six patients (50%), including prolonged V-wave latency (n = 2), prolonged inter-peak latency between waves I and V (n = 3), and mild hearing loss (n = 4). Structural MRI showed a significant reduction in cortical volume in the left pars triangularis and right cerebellum compared with HCs. DTI showed a widespread decrease in fractional anisotropy and an increase in mean and radial diffusivity compared with HCs. CONCLUSION: CDD patients had reduced cortical volume in the left pars triangularis, a brain region crucial for speech, and one-third of patients had mild hearing loss. These changes may be involved in language impairments in CDD patients. Additionally, P100 latency significantly correlated with the clinical severity. These features can be used to assess the clinical severity of CDD.

Brain structure correlates with auditory function in children diagnosed with auditory neuropathy spectrum disorder.

INTRODUCTION: Auditory neuropathy spectrum disorder (ANSD) is a term for a collection of test results which indicate disruption of the auditory signal at some point along the neural pathway. This results in a spectrum of functional outcomes, ranging from reasonably normal hearing to profound hearing loss. This study assessed brain structure changes and behavioral correlates in children diagnosed with ANSD. METHODS: Seventeen children who had previously been diagnosed with ANSD were recruited to the study and underwent a battery of behavioral measures of hearing, language, and communication, along with structural MR imaging. Analysis of cortical thickness of temporal lobe structures was carried out using FreeSurfer. Tract-based spatial statistics were performed on standard diffusion parameters of fractional anisotropy and diffusivity metrics. The control group comprised imaging data taken from a library of MRI scans from neurologically normal children. Control images were matched as closely as possible to the ANSD group for age and sex. RESULTS: Reductions in right temporal lobe cortical thickness were observed in children with ANSD compared to controls. Increases in medial diffusivity in areas including the corpus callosum and in the right occipital white matter were also seen in the group with ANSD compared to controls. Speech perception abilities, both in quiet and in noise, were correlated with cortical thickness measurements for several temporal lobe structures in children with ANSD, and relationships were also seen between diffusion metrics and measures of auditory function. CONCLUSION: This study shows that children with ANSD have structural brain differences compared to healthy controls. It also demonstrates associations between brain structure and behavioral hearing abilities in children diagnosed with ANSD. These results show that there is a potential for structural imaging to be used as a biomarker in this population with the possibility of predicting functional hearing outcome.

Vestibular and radiological characteristics of children affected by unilateral auditory neuropathy spectrum disorder.

OBJECTIVE: Auditory neuropathy spectrum disorders (ANSD) are defined by the association of a preserved outer hair cell function and an impaired auditory nerve neural response, and present mostly bilaterally. Unilateral ANSD are consequently only seldom described, and most frequently as isolated cases. This study aims to describe the audiological, vestibular and radiological characteristics of a population of children with unilateral ANSD. MATERIAL AND METHODS: We isolated 22 patients with unilateral ANSD, 12 boys and 10 girls from 0 to 95 months, in a database of auditory evoked potentials. We reviewed the audiological, radiological and vestibular assessments. The audiological assessment included tympanometry, otoacoustic emission recording and auditory evoked potential. Otolithic function was assessed by performing cervical vestibular evoked myogenic potential. The canal function was determined by video head impulse test and/or caloric test. The radiological evaluation consisted of an MRI of the internal auditory canal. RESULTS: Many patients with a type A tympanometry had no response to otoacoustic emission (53,8%), in the presence of a cochlear microphonic potential. Vestibular assessment was performed in 9 of the 22 patients. 4 children had impaired otolithic and/or canal function. MRI evaluation of the inner ear was performed in 18 patients. Aplasia or hypoplasia of the cochlear nerve was found in 17 of them. MRI showed additional vestibular or brainstem abnormalities in 7 of the 18 children. All children with impaired vestibular function had vestibular or brainstem radiological alterations in addition to cochlear branch aplasia or hypoplasia. CONCLUSIONS: Radiological and vestibular abnormalities are common in children with unilateral ANSD and suggest that a radiological and vestibular assessment is required.

Retro-labyrinthine Lesion Site Detected by Galvanic Vestibular Stimulation Elicited Vestibular-evoked Myogenic Potentials in Patients with Auditory Neuropathy.

OBJECTIVE: Auditory neuropathy (AN) is a unique pattern of hearing loss with preservation of hair cell function. The condition is characterized by the presence of otoacoustic emissions (OAE) or cochlear microphonic (CM) responses with severe abnormalities of the auditory brainstem response (ABR). The vestibular branches of the VIII cranial nerve and the structures innervated by it can also be affected. However, the precise lesion sites in the vestibular system are not well characterized in patients with AN. METHODS: The air-conducted sound (ACS) vestibular-evoked myogenic potentials (VEMPs) and galvanic vestibular stimuli (GVS)-VEMPs were examined in 14 patients with AN. RESULTS: On examination of VEMPs (n=14, 28 ears), the absent rates of ACS-cervical VEMP (cVEMP), ACS-ocular VEMP (oVEMP), GVS-cVEMP, GVS-oVEMP and caloric test were 92.9% (26/28), 85.7% (24/28), 67.9% (19/28), 53.6% (15/28), and 61.5% (8/13), respectively. Impaired functions of the saccule, inferior vestibular nerve, utricle, superior vestibular nerve, and horizontal semicircular canal were found in 25.0% (7/28), 67.9% (19/28), 32.1% (9/28), 53.6% (15/28) and 61.5% (8/13) patients, respectively. On comparing the elicited VEMPs parameters of AN patients with those of normal controls, both ACS-VEMPs and GVS-VEMPs showed abnormal results in AN patients (such as, lower presence rates, elevated thresholds, prolonged latencies, and decreased amplitudes). CONCLUSION: The study suggested that patients with AN often have concomitant vestibular disorders. Retro-labyrinthine lesions were more frequently observed in this study. GVS-VEMPs combined with ACS-VEMPs may help identify the lesion sites and facilitate detection of areas of vestibular dysfunction in these patients.

Cochlear Nerve Aplasia with Detectable Olivocochlear Efferent Function: A Distinct Presentation of Auditory Neuropathy Spectrum Disorder.

BACKGROUND: Cochlear nerve aplasia (CNA) may present with features of auditory neuropathy spectrum disorder (ANSD), having detectable otoacoustic emissions (OAE) but profound hearing loss. We propose that some children with CNA have a distinct form of afferent ANSD in which efferent cochlear nerve function can be detected using contralateral suppression of OAE. METHODS: Children were prospectively enrolled with MRI and auditory brainstem response evidence of unilateral CNA, a normal contralateral ear, and detectable OAE bilaterally. Distortion product OAE (DPOAE) levels were recorded in real time with default primary tone settings: frequency (f)2 = 4.5 kHz and f2/f1 = 1.22 kHz, with level (L)1 = 65 dB SPL and L2 = 55 dB SPL. Recordings were made over 2 min with simultaneous application of an intermittent contralateral broadband noise (CBBN) stimulus at 60 dB SPL. RESULTS: Three girls, aged 4.5, 7, and 8 years, participated. Suppression of DPOAE of 0.15-1.3 dB was detected in all 3 ears with CNA in response to CBBN stimulation. No response was detected in the normal ears. CONCLUSIONS: Children with unilateral ANSD can have normal efferent cochlear nerve function despite MRI evidence of ipsilateral CNA. The importance of these findings for newborn hearing screening and cochlear implantation is discussed.

Evaluation of cochlear nerve diameter and cross-sectional area in ANSD patients by 3.0-Tesla MRI.

CONCLUSIONS: The size of cochlear nerve (CN) is atrophic in adult auditory neuropathy spectrum disorder (ANSD) patients compared with non-ANSD sensorineural hearing loss (SNHL) patients and normal hearing subjects, and CN deficiency is one of the lesions for ANSD patients. OBJECTIVES: To evaluate the dimensions of CN in adult ANSD patients on magnetic resonance imaging (MRI) and confirm the hypothesis that CN deficiency is one of the lesions for ANSD patients. METHODS: Medical records and MRI of 24 adult ANSD patients reviewed retrospectively and 20 non-ANSD SNHL and 24 volunteers with normal hearing were recruited as control groups. The long diameter (LD), short diameter (SD), and cross-sectional area (CSA) of CN and facial nerve (FN) were measured. RESULTS: Among the 24 ANSD patients, this study was able to reconstruct and measure the CN of 91.7% (22/24, total 43 ears) of patients and FN of 83.3% (20/24, total 38 ears) of patients. The mean values and standard deviations of LD, SD, and CSA of CN in ANSD patients were 0.65 ± 0.20 mm, 0.44 ± 0.15 mm, and 0.30 ± 0.19 mm(2), respectively. They were significantly smaller in ANSD patients than in control groups (p < 0.001).

Auditory neuropathy spectrum disorder: predictive value of radiologic studies and electrophysiologic tests on cochlear implant outcomes and its radiologic classification.

CONCLUSION: The width of the bony cochlear nerve canal (BCNC) and the size of the cochlear nerve are reliable predictors of long-term speech perception abilities for children with auditory neuropathy spectrum disorder (ANSD) after cochlear implantation (CI). In addition, electrical stapedial reflex (ESR) and electrical compound action potential (ECAP) also have considerable value in predicting postoperative speech perception abilities in these children. OBJECTIVES: To assess whether speech perception abilities after CI in children with ANSD can be predicted from the results of radiologic studies and electrophysiologic tests. METHODS: Fifteen children with ANSD underwent CI. The width of the BCNC and the size of the cochlear nerve were measured using preoperative CT and MRI. The results of early postoperative ESR, ECAP, and implant evoked electrical auditory brainstem response were reviewed. The latest speech perception test scores were also reviewed. RESULTS: Radiologic findings of normal BCNC and normal cochlear nerve correlated with excellent speech perception abilities after CI. A narrow or obliterated BCNC and a deficient cochlear nerve correlated with poor speech perception abilities. Children with good speech perception abilities showed robust responses on ESR and ECAP, but there were no responses from any of the children with poor speech perception abilities.

Inner ear dysplasia with agenesis of the corpus callosum.

In this case report we describe a patient with agenesis of the corpus callosum and asymmetric bilateral sensorineural hearing loss, who was found to have a bilateral inner ear dysplasia. Both of these anomalies have been associated with different members of the Pax gene family. However, to our knowledge this is the first report demonstrating the coexistence of these two unusual entities. By uncovering the inner ear malformation, we are able to better counsel this patient with regard to avoidance of high-risk activities such as contact sports and recommend prophylactic vaccination for meningitis prevention.

The morphometry of auditory cortex in the congenitally deaf measured using MRI.

The study of congenitally deaf individuals provides a unique opportunity to understand the organization and potential for reorganization of human auditory cortex. We used magnetic resonance imaging (MRI) to examine the structural organization of two auditory cortical regions, Heschl's gyrus (HG) and the planum temporale (PT), in deaf and hearing subjects. The results show preservation of cortical volume in HG and PT of deaf subjects deprived of auditory input since birth. Measurements of grey and white matter, as well as the location and extent of these regions in the deaf showed complete overlap both with matched controls and with previous samples of hearing subjects. The results of the manual volume measures were supported by findings from voxel-based morphometry analyses that showed increased grey-matter density in the left motor hand area of the deaf, but no differences between the groups in any auditory cortical region. This increased cortical density in motor cortex may be related to more active use of the dominant hand in signed languages. Most importantly, expected interhemispheric asymmetries in HG and PT thought to be related to auditory language processing were preserved in these deaf subjects. These findings suggest a strong genetic component in the development and maintenance of auditory cortical asymmetries that does not depend on auditory language experience. Preservation of cortical volume in the deaf suggests plasticity in the input and output of auditory cortex that could include language-specific or more general-purpose information from other sensory modalities.

Intraosseous dural arteriovenous fistula of the skull base associated with hearing loss. Case report.

The most common clinical presentations of dural arteriovenous fistulas (DAVFs) are bruit, headache, increased intracranial pressure, and intracranial hemorrhage. In particular locations, such as the cavernous sinus or middle cranial fossa, cranial nerve involvement due to dural arterial steal or venous occlusion may develop. A case in which a DAVF is associated with hearing loss, however, has not previously been reported. The authors report a case in which an intraosseous DAVF and associated hearing loss probably resulted from cochlear nerve or vascular compression caused by the draining vein or nidus of the DAVF.

The neural correlates of 'deaf-hearing' in man: conscious sensory awareness enabled by attentional modulation.

Attentional modulation of normal sensory processing has a two-fold impact on human brain activity: activation of a network of localized brain regions is associated with paying attention, and activation of specific sensory regions is enhanced relative to passive stimulation. The mechanisms underlying attentional modulation of perception in patients with lesions of sensory cortices are less well understood. Here we report a unique patient suffering from extensive bilateral destruction of the auditory cortices (including the primary auditory fields) who demonstrated conscious perception of the onset and offset of sounds only when selectively attending to the auditory modality. This is the first description of such an attentively modulated 'deaf-hearing' phenomenon and its neural correlates, using H(2)(15)O-PET. Increases in cerebral blood flow associated with conscious awareness of sound that was achieved by listening attentively (compared with identical auditory stimulation presented when the patient was inattentive) were found bilaterally in the lateral (pre)frontal cortices, the spared middle temporal cortices and the cerebellar hemispheres. We conclude that conscious awareness of sounds may be achieved in the absence of the primary auditory cortex, and that selective, 'top-down' attention, associated with prefrontal systems, exerts a crucial modulatory effect on auditory perception within the remaining auditory system.

[Hearing loss as the leading symptom in anterior inferior cerebellar artery infarction]. / Hörverlust als Leitsymptom von Arteria cerebelli inferior anterior-Infarkten.

Hearing impairment is a rare but characteristic symptom of vertebrobasilar occlusive disease. Two patients with anterior inferior cerebellar artery (AICA) infarction and hearing loss as presenting complaint, are described. In patient 1 progressive bilateral AICA infarction was caused by occlusion of the basilar artery, verified by transcranial Doppler sonography. Initial dizziness and bilateral hearing loss were followed by ataxia, dysarthria, dysphagia and right facial sensory impairment. Hearing loss improved during the second week, parallel to a temporary partial recanalisation of the basilar artery, but the patient subsequently developed further progressive brain stem symptoms and died. A right-sided AICA-infarction was diagnosed in patient 2. Initial symptoms were right-sided deafness and dizziness. Neurological examination revealed nystagmus, ataxia and involvement of th 5th and 6th cranial nerve. A progressive improvement of hearing loss and total recovery of the other brain stem symptoms was evident. In conclusion every patient with sudden hearing loss should be examined for additional brain stem symptoms since this can be the presenting sign of a life-threatening basilar artery thrombosis.

Sensorineural hearing loss in children.

A variety of pathologic conditions cause sensorineural hearing loss in infants and children. Modern imaging techniques such as high-resolution computed tomography (CT) and magnetic resonance (MR) imaging have made it possible to identify a specific cause of pediatric hearing loss in many cases. A classification system has been developed that groups these abnormalities into three anatomic locations along the cochlear nerve: the labyrinth, the internal auditory canal, and the brain stem and cerebrum. Unenhanced high-resolution CT remains the imaging modality of choice in evaluating most cases of pediatric sensorineural hearing loss. In general, CT is the preferred modality in cases of trauma and nonacute congenital otic capsular dysplasias, whereas contrast material-enhanced MR imaging is preferred in cases of inflammatory and neoplastic disorders. Documented acute hearing loss in an older child or adolescent should also be studied with contrast-enhanced MR imaging. Reliable radiologic evaluation requires accurate clinical information as well as knowledge of normal inner ear anatomy and abnormal imaging findings.

'So-called' cortical deafness. Clinical, neurophysiological and radiological observations.

Two patients with severe, persistent hearing loss caused by bilateral cerebral lesions are described. To determine the location of lesions responsible for the severe hearing loss, we examined magnetic resonance images and compared the lesions in these 2 patients with those in another with only mild hearing loss following extensive bilateral temporoparietal lesions. The extent of bilateral damage to the white matter adjacent to the posterior half of the putamen proved crucial in determining the severity of the hearing loss. Hearing loss was more severe when the white matter immediately ventral and lateral to the posterior half of the putamen was involved bilaterally. Based on this observation and from a review of the literature, we infer that the auditory radiations in humans course in a dense tract from the medial geniculate body up to the sublenticular region, and disperse from there to the primary auditory cortex as well as to the other auditory-related areas, partly by coursing through the white matter immediately ventral to the posterior half of the putamen, and partly by penetrating the ventral and lateral portions of the posterior half of the putamen. Accordingly, bilateral lesions in the white matter ventral and lateral to the posterior half of the putamen appear to interrupt all the projection fibres from the medial geniculate bodies to the auditory-related areas, resulting in severe, persistent hearing loss.

Neuroradiologic evaluation of patients with central auditory lesions.

CT and MR imaging have revolutionized diagnostic medical imaging. MR scanning in particular is the method of choice to evaluate the CP angle lesion or other posterior fossa lesion. With CT pneumocisternography, neurovascular structures of the internal auditory canal and lesions can be visualized. Experience indicates that MR scanning will replace CT.

Computed tomography of the anteverted internal auditory canal.

A symmetric variation in the course of the internal auditory canals, visualized best on axial computed tomographic views with thin sections, was observed in three of 75 patients examined mainly for hearing, vestibular, and facial nerve dysfunction. The incidence may be lower in an unselected population. In coronal section, with either pluridirectional or computed tomography, an anteverted internal auditory canal may mimic the normal configuration of "medial narrowing" because of the effect of partial sectioning of an angled cylinder with a thin beam. The pathologic significance of this finding is uncertain. In the three cases reported, it was associated with adult-onset uni- or bilateral hearing loss. Vestibular function may be compromised but may not be symptomatic. Facial nerve function was not impaired.

Hearing loss in skull fractures.

One hundred three cases of skull fractures in or around the temporal bone were reviewed for hearing loss. Of these, 100 patients had skull series, 66 had computed tomographic head scans, and 44 had polytomographic studies of the temporal bone. Hearing loss in head trauma can be grouped into four categories: conductive hearing loss, peripheral sensorineural hearing loss, central sensorineural hearing loss, and combinations of these hearing losses. The cause of conductive hearing loss and peripheral sensorineural hearing loss was usually identified by the type of temporal bone fracture. However, the cause of the central sensorineural hearing loss was more difficult to correlate with the brain lesions shown in the computed tomographic scans.