Aim: The goal was to compare temporal resolution of children with normal hearing, with those bearing conductive hearing loss and auditory processing disorders. Materials and methods: The sample had 31 children, between 7 and 10 years of age, broken down into three groups: G1: 12 subjects with normal hearing; G2: 7 with conductive hearing loss and G3: 12 subjects with auditory processing disorders. This study was clinical and experimental. Selection procedures were: a questionnaire to be answered by the parents/guardians, audiologic and hearing processing evaluation. The study procedure was the test to detect breaks in silence at 50 dB HL above the mean values of 500, 1000 and 2000 Hz in both ears in 500, 1000, 2000 and 4000 Hz. To analyze the data we used the Wilcoxon Test with a 1% significance level. Results: We noticed a difference between G1 and G2 and between G1 and G3 in all the frequencies. On the other hand, this difference was not seen between G2 and G3. Conclusion: conductive hearing loss and auditory processing disorders can impact break detection thresholds.Temporal resolution is essential to speech acoustic perception. It may be altered in subjects with auditory disorders, thus impairing the development of spoken and written language.  In order for the communication process to be effective among individuals, the speaker must express him/herself properly and make it so that the listener can understand the message.In listening and decoding what is being said, we can observe the relationship between the peripheral auditory system integrity with the central auditory system. Therefore, in order to have an effective communication, auditory processing effectiveness is paramountAuditory processing is associated with what happens when the brain recognizes and interprets soundsAuditory processing plays a fundamental role in speech and language development, and a deficit in some of these hearing skills can cause severe speech, reading and writing learning problems to the individualIndividuals with hearing loss and even those with normal hearing may complain of difficulties understanding speech. This is explained by the auditory processing being incomplete in the periphery of the auditory system; it is not enough to detect sounds, it is necessary to assign some meaning to them. In this context, areas from the central auditory pathway and other systems such as attention, memory, language and thought are involvedBecause of the number of skills being analyzed, it is necessary to have a battery of tests to assess central auditory processing, and each test assesses, mainly, some auditory skill. This test battery must have, at least, dichotic, monaural, low redundancy tests of binaural interaction and temporal processingTemporal processing is associated with the perception of the sounds that vary with time, especially in relation to the thresholds of the capacity to detect changes in timeNumerous researchers say that children’s performance in temporal resolution improves with ageTemporal resolution has been investigated in psychoacoustic paradigms since the 70’s; nonetheless, temporal resolution tests were only commercially available in the late 90’s. In Brazil, temporal resolution protocol studies are still very recent and, clinically, are not yet procedures used in the routine evaluation of central auditory processing by all professionals.Among the temporal resolution evaluation procedures there is the auditory fusion revised test (auditory fusion test-revised - AFT-R) which measures the auditory fusion threshold by the listener’s perception in identifying one stimulus or two, since stimuli duration vary between 0 and 300ms. This threshold is measured for frequencies between 500 and 400Hz15. AFT-R was used in a study with children with reading and writing disorders (RWD) stressing that auditory fusion thresholds are higher in these children when compared to children without RWDAnother, more recent, clinical assessment procedure for temporal resolution is an AFT-R revision called Random Gap detection test - RGDT. Such procedure also uses tones, clicks, and the interval presentation is randomized. The task the individual has to perform in these procedures is to identify whether he/she heard one or two sounds. These are tones or clicks with silence intervals which vary from 0 to 300ms in between the tonesThe original RGDT study was carried out in the United States, with children between 5 and 11 years of age without hearing or school complaints, showed that the mean threshold found in children from five to seven years was 7.3ms (sd = 4.8ms); in 8 year-old children the average threshold was 6.0ms (sd = 2.5ms); in nine year-olds 7.2ms (sd = 5.3ms) and in 10 and 11 year-old children it was 7.8ms (sd = 3.9ms)In Brazil, a study with children from private schools in Recife showed a significant difference between the frequencies in which the RGDT was studied; however, there was no difference in relation to gender, age and educationThe influence of hearing loss caused by a sensorineural problem was broadly investigated in psychoacoustic paradigms of temporal resolution assessment and showed that it does impact temporal resolution, in such a way that individuals with hearing loss have longer duration thresholds when compared to individuals without itThere are few literature reports about conductive hearing loss influences, as well as which are the temporal resolution test characteristics in children with central auditory processing disorders, considering that the RGDT is still not used in the clinical assessment routine. In this context, the need to study these populations in an attempt to characterize whether its response pattern is clear, in order to guide diagnostic processes which aim at classifying the type of hearing processing disorder present. On the other hand, it helps identify which areas of the central auditory system have dysfunctions and it also helps plan strategies for its rehabilitationIn the clinical setting, there is also the need to carry out research that show the pros and cons of each temporal resolution protocol, in order to help one chose which would be the most efficient and adequate protocol to use with children. This concern has been the focus of a study carried out in the United States, which aimed at comparing the performance of children with normal development in four temporal resolution tests - auditory fusion test-revised - AFTR; random gap detection test - RGDT; Gaps-in-noise - GIN and the binaural fusion test - BFT. The authors showed that there is a performance difference associated with the task, type of stimulus, presentation and response, and the RGDT and GIN seem to be more advantageous in terms of results and application. Nonetheless, the authors stress that other studies are necessary in order to confirm these findingsBased on the aforementioned information, this studied aimed at checking the temporal resolution in children with conductive hearing loss (CHL) and with central auditory processing disorders (CAPD).The sample in this paper was made up of 43 children from the 1st to the 4th grades of a Municipal school, as well as children seen in the Audiology Department of the Universidade do Vale do Itajaí, Santa Catarina. These children were invited to participate in this study, and before carrying out the procedures, their parents or guardians were informed about the goals of the study and how it would be done and, after they accepted to participate, they signed an informed consent form, according to the instructions from the Ethics in Research Committee of the Institution, under protocol 145/2006.This study’s sample had 31 subjects in the age range between 07 and 10 years and 10 months of age, 18 males and 13 females. This population was broken down in three groups: Group 1 (G1): 12 subjects with normal hearing , group 2 (G2): seven subjects with conductive hearing loss  and Group 3 (G3): 12 subjects with auditory processing disorder  . Twelve subjects were taken off the study because they did not have the inclusion criteria in the groups or because they did not return in the appointed date to conclude their evaluation.In order to select the children, the parents and guardians filled out a questionnaire on current and past information about the children, who also underwent audiological and central auditory processing testing. For the audiological assessment, the following procedures were carried out: external ear canal inspection, audiometric screening, tympanometry, and investigation of ipsi and contralateral acoustic reflexes. The children with alterations in the latter were submitted to complete audiological evaluation with: air conduction, bone conduction, speech reception threshold and speech recognition percentage index.Aiming at diagnosing the central auditory processing disorder, the following procedures were carried out: digit dichotic tests, filtered speech test and Staggered Spondaic Word - SSW. They were all carried out at 50 dB SL above the average of 500, 1000 and 2000Hz-no otologic and/or audiologic past problem;-no school complaints;-no known neurologic, psychiatric and psychological disorders;-auditory thresholds within normal values, with type A tympanometric curve and ipsi and contralateral acoustic reflexes, confirmed by audiometric screening through the scanning technique in the frequencies of 500 to 4,000Hz in both ears and auditory thresholds equal to or better than 15 dB;-uttering of all sounds in Portuguese;-having read Portuguese as the first and only language;-no auditory processing disorder, having normal results at the digits dichotic test, alternate dissyllable test and filtered speech test-no hyperactive behavior, lack of attention and/ or impulsiveness.Starting from these assessments, the group 1 children had the following characteristics:-Mild and/or moderate hearing loss by the mean values of frequencies 500, 1000 and 2000Hz with types B or C tympanometric curves in at least one of the ears, as well as no contra or ipsilateral acoustic reflex;G2 children, with conductive hearing loss, had the following characteristics:G3 children, with central auditory processing disorder, had low results in at least two tests from the central auditory processing battery, as well as complaints and a history of signs and symptoms indicating the disorderAfter the selection procedures, we assessed the temporal resolution - Random gap detection - RGDT. This was carried out through a Compact Disc Player coupled to the Interacoustic AC-33 or AC-40 audiometer. The RGDT had pairs of pure tones in the frequencies of 500, 1,000, 2,000 and 4,000Hz, with intervals between pure tones that varied from 0 to 40ms (RGDT) and from 40 to 300ms (expanded RGDT). The child was instructed to respond with a hand movement if she/he heard one or two tones. The test was carried out at 50 dB SL in binaural tested frequencies. Initially, we carried out the training track 2, if the child detected intervals equal to or below 40ms, we continued in order to measure the frequencies of 500, 1,000, 2,000 and 4,000Hz. If the child did not identify any of the intervals as two tones, the test continued as Expanded RGDT. RGDT result is measured by means of the shortest interval from which the subject started to identify the presence of two stimuli. The result was calculated for each frequency, from 500 to 4,000Hz, and we also calculated the mean result from the four frequencies. The normal value used for comparison was of 6.0 to 7.8ms with 2.5 to 5.3ms of standard deviation in North-American ChildrenIn analyzing the RGDT, we first checked the number of children who underwent RGDT and the expanded RGDT. Later on we calculated the duration mean and standard deviation at 500, 1,00, 2,000 and 4,000Hz, as well as the duration threshold mean value of all the subjects in each group assessed. For the statistical analysis of the results we applied the Wilcoxon Test, establishing a 0.1 (1%) significance level, because of the small size of the sample in three groups.Following, we describe the results attained from all the groups separately and, later on, we present the comparison between both groups.On On RGDT results from G3, children with central auditory processing disorders, can be seen on As we analyze Thus, we see in this study that the RGDT test is influenced by the conductive hearing loss and the central auditory processing disorder, being a test that differentiates children with normal hearing from those with hearing disorders. On the other hand, the test can not differentiate between the types of hearing disorder: conductive hearing loss and central auditory processing disorder.The analysis of the results obtained from the RGDT varied according to the group in which the children were classified, there were evidences that the conductive alterations and the central auditory processing disorder generated silence interval detection thresholds above those from the normal group.We notice that G1 had RGDT mean values similar to that of a Brazilian studyAnother question regarding temporal resolution skills is the very hypothesis raised by the authorsChildren from G3 also had interval detection threshold mean values higher than those children from G1 and lower than the G2 ones. Thus, there is evidence about the RGDT validity to diagnose children with central auditory processing disorders. We stress the study on children with reading and writing disordersTemporal processing, especially temporal resolution, has been described as the basis for specific language disordersWhen we analyzed threshold mean values by frequency in the RGDT from 500 to 4000Hz in all the groups, we did not see significant differences, showing that both in normal development as well as in the presence of conductive hearing loss and CAPD, the findings are homogeneous among the frequenciesWe stress that the RGDT test showed great performance variability in all the groups studied, and such variability was higher than the one observed in studies with adultsWe stress that if the conductive hearing loss is present at the time of the central auditory processing clinical evaluation, the child can present temporal resolution alterations which can not be differentiated from the signs of central auditory processing alterations. Thus, we call the attention of health care professionals and families that the children who are referred for central auditory processing evaluation must present normal bilateral tympanometry at the time of the evaluation.We need more studies with this protocol as well as a larger study sample in order to further our knowledge about its application and also to characterize it in different populations. It is also necessary to more carefully investigate whether there is or there isn’t influence of the individual’s otologic background besides the momentaneous presence of conductive hearing loss at the time of the temporal resolution development.•Children with conductive hearing loss have silence interval thresholds, measured by the RGDT test, above those of normal children. Thus, there is an impact of conductive hearing loss in obtaining silence interval thresholds.•Children with auditory processing disorder  show a different performance than normal children, showing that the RGDT test is sensitive to detect these alterations and, therefore, must be included in the battery of tests to assess auditory processing.•There is no statistically significant difference between silence thresholds of children with central auditory processing disorder and conductive hearing loss. In this case, one must associate the auditory processing assessment  at least through tympanometry in order to clear up the diagnosis.Based on the results we can conclude that:


Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder of the peripheral nerves which can lead to gradually increasing motor and sensory loss. It can be a difficult entity to diagnose, particularly in elderly patients with a history of Diabetes Mellitus due to their overlapping neuropathic syndromes. Reported is a case of CIDP in an elderly female who manifested multiple sensory, motor, and autonomic complaints. A compilation of clinical features, neuroimaging, lumbar puncture, electromyography, nerve conduction studies, and nerve biopsy were used to reach the diagnosis. Highlighted is a clinical approach to identifying CIDP that can cause neuropathy in the setting of other potential confounding disorders namely Diabetes Mellitus.  Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare form of acquired peripheral neuropathy that can present with a wide variety of sensory and motor deficits. In the most typical form, there is gradually progressive, symmetric loss of distal and proximal motor function as well as sensory involvement that is less prominent in comparison . We repoA 74-year-old female with Insulin-dependent Type II Diabetes Mellitus (DM) and a history of gastric bypass surgery presented due to progressive motor decline over a four-month period. Her history was notable for a neurogenic bladder diagnosed two years prior and chronic pain of the neck, shoulders, hips, and lower back. Her weakness progressed in an ascending pattern, initially involving the lower extremities with associated foot drop, and recurrent falls followed by involvement of the arms and bulbar weakness causing severe oropharyngeal dysphagia. On presentation, she was found to have marked atrophy and weakness involving the thigh and calve musculature. Deep tendon reflexes were globally diminished. Babinski's reflex was negative. Sensory testing revealed allodynia, decreased vibratory sense, normal light touch sense, and decreased proprioception in the lower extremities.Serologic testing including vitamin and trace mineral levels, creatinine kinase, aldolase, paraproteins, antinuclear antibodies (ANA), thyroid function, and acetylcholine receptor antibodies were all unremarkable. Her hemoglobin A1c was 5.9%. Magnetic resonance imaging (MRI) of the cervical, thoracic, and lumbosacral spine showed multilevel disc disease with mild-moderate neuroforaminal narrowing affecting the C5, C6, and L2 nerve roots and hyperintense short TI inversion recovery (STIR) signals within the paraspinal musculature Figure , 1B. MRI2O (6-2 cmH2O), protein of 187 mg/dL (15-45 mg/dL), glucose of 39 mg/dL (60-80 mg/dL), and white blood cell count of 3 x 106/L. Electromyography (EMG) and Nerve conduction studies (NCS) are depicted in Tables A lumbar puncture (LP) resulted in an opening pressure of 15 cmHmg/dL 15-5 mg/dL, The patient underwent quadriceps muscle and sural nerve biopsy which showed marked muscle atrophy and extensive loss of large and small myelinated nerve fibers with features of active axonal and demyelinating neuropathy. There were rare endoneurial T-Lymphocytes and a macrophage attached to relatively intact myelin of one nerve fiber. There was no onion bulb formation. Also noted were arteriosclerotic changes without evidence of vasculitis. A history of progressive weakness coupled with findings of cytoalbuminologic dissociation on LP and evidence for demyelination on biopsy was most consistent with a diagnosis of CIDP. The patient was initiated on intravenous (IV) solumedrol 250 mg daily for three days then transitioned to 1 mg/kg daily. She was then treated with intravenous immunoglobulin (IVIG) 2 g/kg evenly distributed over a period of five days. She experienced an overall improvement in her upper extremity and bulbar weakness. Steroids were tapered over a two-month period. Her lower extremity weakness had mild improvement, but she remained wheelchair dependent. She was arranged for outpatient IVIG 1 g/kg daily over two days every three weeks as maintenance.CIDP is a type of immune-mediated neuropathy that can lead to progressive weakness, abnormal sensation, and autonomic dysfunction. The diagnosis of CIDP can be challenging to ascertain given its rarity and similarities with other common neuropathic diseases. History of DM is especially problematic when considering CIDP given that diabetic polyneuropathy and diabetic amyotrophy can also lead to elevated protein in the cerebrospinal fluid (CSF) and axonal damage as seen in nerve conduction studies and nerve biopsy. Nutritional deficiency and insulin neuritis were also considered but difficult to prove in retrospect. A normal hemoglobin A1c and response to treatment favors CIDP over diabetic neuropathy in our case but does not effectively rule it out. Interpretation of electromyography (EMG) and nerve conduction studies in the presence of multilevel intervertebral disc disease also poses a challenge. Despite the multifactorial nature of her disease, a diagnosis of CIDP can still be made based on clinical characteristics, electrophysiological criteria, biopsy, and CSF findings.No gold-standard set of diagnostic criteria exists, however, the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria seem to be one of the most useful in identifying CIDP with a reported sensitivity and specificity of 81 and 97% respectively . The EFNTypical CIDP is defined by chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least two months. There are also absent or reduced tendon reflexes in all extremities. Other causes of demyelinating neuropathy must be ruled out such as POEMS syndrome, Lyme infection, or lumbosacral radiculoplexus neuropathy. Other supportive criteria are defined including cytoalbuminologic dissociation on CSF, characteristic neuroimaging findings, abnormal sensory electrophysiology, objective improvement following immunomodulatory treatment, and nerve biopsy showing evidence of demyelination . Other fMRI with gadolinium is the imaging modality of choice and should be performed to exclude other forms of neuropathy that can mimic CIDP. Features that are suggestive of CIDP are thickening and enhancement of peripheral nerves, brachial or lumbosacral plexus, and nerve roots .Electrodiagnostic testing is an essential component of diagnosing CIDP as most patients will show evidence of primary demyelination. Features that are suggestive of demyelination on nerve conduction and electromyography testing include partial conduction block, conduction velocity slowing, temporal dispersion, and distance-dependent reduction of CMAP . It is hSome studies even suggest a potential association between CIDP and DM. In some cohort analyses, diabetics were observed to meet electrophysiologic criteria for CIDP 12-17% of the time ,7. The pThere are no laboratory findings that are specific to CIDP, however, certain tests should be done to exclude other disorders. In general laboratory testing should include complete blood count, liver function tests, thyroid function studies, serum and urine protein electrophoresis with immunofixation, serum-free light chain assay, fasting serum glucose, glycated hemoglobin, and serum calcium and creatinine. CSF analysis revealing an elevated protein level is a nonspecific finding but tends to be higher in CIDP compared to diabetic neuropathy.This case highlights the complexity of diagnosing CIDP, particularly in the presence of multiple comorbid conditions which can confound clinical, imaging, and electrophysiologic studies. It is important to remember that CIDP is a treatable form of neuropathy in diabetics. Clinicians should have a low index of suspicion for CIDP in diabetics with progressive motor neuropathy that is unproportionate to that of diabetic neuropathy alone and to weigh the potential benefit of treating these patients with immunotherapy. Though a primarily motor neuropathy, it is also important to recognize the wide heterogeneity of CIDP types and to not discount this diagnosis based on atypical features of dysautonomia and sensory dysfunction.


In recent years, there has been an intense debate in literature regarding the definition of the individual variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), their possible pathogenetic mechanisms, and impact in the diagnosis of CIDP.The 2021 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines revised the definition of the individual CIDP variants and implemented their diagnostic criteria. Diagnosis of atypical CIDP is challenging and misdiagnosis is frequent, leading to diagnostic delay and consequent greater accumulation of disability and treatment dependency. Recent studies suggest that patients with typical CIDP have an antibody-mediated mechanism of neuropathy whereas in those with Lewis--Sumner syndrome (LSS) neuropathy is preferentially mediated by macrophages and T cells.Although the validity of the 2021 EFNS/PNS diagnostic criteria for atypical CIDP is unknown, they will hopefully lead to greater uniformity in the selection of patients to be enrolled in future studies and to a greater diagnostic accuracy. New data are emerging on the possible pathological mechanisms of individual variants and this could result in the discovery of specific diagnostic biomarkers and new therapies. Along with a typical clinical phenotype , defined as symmetric sensorimotor neuropathy involving proximal and distal segments of the four limbs with a relapsing or progressive course of at least 2 months, a few atypical variants have been described  7▪▪,▪▪,9–40. ▪▪]. The application of these criteria in a large cohort of patients with atypical CIDP has surprisingly shown that 53% of the patients with atypical CIDP at onset progressed to typical CIDP during the course of the disease [7▪▪]. Progression to typical CIDP, however, was not absolute and a considerable proportion of patients maintained their atypical CIDP phenotype even after several years from symptoms onset [7▪▪]. Transition from atypical to typical CIDP has been questioned by some authors . According to some studies, DADS is the most common variant of CIDP, with a frequency that ranges from 2 to 15%  in DADS was lower compared with typical CIDP [7▪▪]. Most studies report DADS as a mild form of CIDP . These figures are interesting as they show that the asymmetric form of CIDP is much more frequent than expected from a clinical entity that is considered ‘atypical’. It cannot, however, be excluded that, as in vasculitic neuropathies, a certain number of patients with multineuropathic CIDP evolve over time towards an asymmetrical form. Finally, the 2021 EFNS/PNS criteria has defined LSS as a sensory or sensorimotor multineuropathy specifying that its clinical presentation is usually asymmetric [▪▪].LSS was initially defined as a sensory or sensorimotor multineuropathy with persistent motor nerve conduction blocks –13. Acco8ymmetric ▪▪.et al.[et al.[▪▪]. The reported response to therapy and particularly to high-dose IVIg in LSS vary among studies, although in most of them is reported to be unsatisfactory .Pure motor CIDP was initially defined as a pure motor symmetric polyneuropathy ,31. Subs49▪▪,7▪▪], whereas another study reported a response of 80% [7▪▪]. This finding, which was later confirmed by others [▪▪].Some of the initial reports of this clinical entity reported unresponsiveness or worsening with steroids while having an excellent response to IVIg ,31,32 T. This ea7e of 80% . It has y others , suggesty others ▪▪.▪▪]. In this study, patients with sensory DADS but not those with pure sensory CIDP had a lower response to treatment compared with typical CIDP [7▪▪]. This figure has not yet been confirmed by other studies.The clinical boundaries between pure sensory CIDP and sensory DADS are not well clear, and this may possibly explain why in some studies, patients with a pure sensory neuropathy with a ‘stocking-and-glove distribution’ are included under DADS while in others under pure sensory CIDP ,34,50. T7▪▪]. No studies have yet compared the clinical and immunological characteristics of these two CIDP subforms.Although defined as a pure sensory neuropathy, most of the pure sensory CIDP cases so far described had subclinical electrophysiological involvement of the motor fibers but this is likely to be explained by the fact that signs of demyelination in the motor nerves were required by the 2010 EFNS/PNS diagnostic criteria for the diagnosis of CIDP . Some de49▪▪,7▪▪,8▪▪].Response to treatment in pure sensory CIDP is reported to be similar to that of typical CIDP 7▪▪,,36,39, w▪▪]. In the first description of 15 patients, all the patients had ataxia, nine had frequent falls, and six were severely disabled [▪▪].CISP is generally considered pure sensory CIDP because of its similar clinical presentation characterized by only sensory symptoms without weakness . Its pec7disabled . All of disabled . CISP-pldisabled ▪. Its sydisabled ▪. CIMP idisabled . Imagingdisabled . To our disabled ,45▪. Eledisabled ,45▪. Altdisabled ▪▪.▪▪]. Validity of these diagnostic criteria remains, however, to be established. Furthermore, these criteria still leave some areas of uncertainty. For instance, it is not clear how to classify patients with asymmetric but not multineuropathic CIDP or patients with a sensorimotor polyneuropathic CIDP only involving the proximal and distal segments of the lower limbs.As for typical CIDP, no diagnostic biomarker exist for atypical CIDP making clinical and electrophysiological criteria essential for diagnosis. The 2021 EFNS/PNS criteria refined the diagnostic criteria for the CIDP variants and expanded the 2010 EFNS/PNS criteria by including sensory nerve conduction studies as a mandatory diagnostic criterion and by defining specific clinical and electrophysiological criteria for each CIDP variant ▪▪. Valid▪▪].Atypical CIDP is a challenging diagnosis and its diagnostic workflow and differential diagnosis may differ compared with typical CIDP ▪. In one49Although the cause of CIDP and its pathogenesis are still unknown, in the last years some progress has been made in deciphering the pathogenetic mechanisms underlying the disease. Several recent lines of evidence suggest that typical CIDP and its variants potentially have heterogeneous pathogenetic mechanisms.▪▪,8▪▪,8▪▪,8▪▪]. The hypothesis, raised by some authors on the basis of these findings, is that in typical CIDP, the damage occurs in the proximal and distal portions of the nerve where the blood--nerve barrier is most deficient, and therefore, is likely mediated mainly by antibodies and humoral factors [8▪▪,8▪▪,8▪▪,8▪▪,Electrophysiological studies have shown that the distribution of lesions in the peripheral nervous system is different among the individual CIDP forms ▪▪,10,56▪ 8▪▪,8▪▪,▪. DADS aAlthough the validity of the 2021 EFNS/PNS criteria for CIDP has not yet been assessed, they will lead to greater uniformity in the selection of patients to be enrolled in future studies and this, hopefully, will result in greater comparability of studies. Their implementation should also lead to an improvement in diagnostic accuracy. There are still, however, areas of uncertainty in the definition of the individual variants. Recent studies are starting to bring to light the pathogenetic mechanisms of the individual CIDP variants and this could result in the discovery of specific diagnostic biomarkers and new therapies.None.None.E.N.-O. reports personal fees for Advisory or Scientific Board from Argenx, Belgium, Baxter/Takeda, Italy and USA, CSL-Behring, Italy and Switzerland Janssen, USA, Kedrion, Italy, Novartis, Switzerland, Roche, Switzeland, Sanofi, USA, outside the submitted work and travel grants to attend Scientific Meeting from Baxter, Grifols, Kedrion, and Novartis, Italy. P.E.D. has received travel grants to attend scientific meetings from CSL Behring and Kedrion. M.D. declared no conflicts of interest.


Among the investigated equations, our proposed equation showed the best adequacy and lowest overestimation. The predictive formulae that consider WC improve RMR prediction, thus preventing overestimation in older women.Resting metabolic rate (RMR) depends on body fat-free mass (FFM) and fat mass (FM), whereas abdominal fat distribution is an aspect that has yet to be adequately studied. The objective of the present study was to analyze the influence of waist circumference (WC) in predicting RMR and propose a specific estimation equation for older Chilean women. This is an analytical cross-sectional study with a sample of 45 women between the ages of 60 and 85 years. Weight, height, body mass index (BMI), and WC were evaluated. RMR was measured by indirect calorimetry (IC) and %FM using the Siri equation. Adequacy (90% to 110%), overestimation (>110%), and underestimation (<90%) of the FAO/WHO/UNU, Harris–Benedict, Mifflin-St Jeor, and Carrasco equations, as well as those of the proposed equation, were evaluated in relation to RMR as measured by IC. Normal distribution was determined according to the Shapiro–Wilk test. The relationship of body composition and WC with RMR IC was analyzed by multiple linear regression analysis. The RMR IC was 1083.6 ± 171.9 kcal/day, which was significantly and positively correlated with FFM, body weight, WC, and FM and inversely correlated with age ( Underestimating or overestimating the energy requirements of an individual leads to inadequate diet prescription and nutritional food management. Energy balance determines body weight based on body mass and the relationship between energy intake and expenditure .The main components of total energy expenditure include dietary thermogenesis, physical activity, and basal metabolic rate (BMR). BMR is defined as the minimum energy expenditure rate that is compatible with life, representing 50% to 75% of the total daily energy expenditure based on the level of physical activity, and it decreases with age at a rate of 1% to 2%, on average, per decade from the second to the seventh decade of life [The difference between resting metabolic rate (RMR) and BMR is <10% . The priIt is also important to note that the metabolic activity of body adipose tissue shows regional variation. Body fat located in the abdominal region  has higher metabolic activity than fat located in the gluteal-femoral region . RegardiFurthermore, aging decreases all components of total energy expenditure , in addiThe gold standard to determine RMR is indirect calorimetry (IC). Indirect calorimetry calculates RMR by measuring the oxygen and carbon dioxide concentrations found in exhaled air . The IC Routine clinical practice requires RMR measurement to provide a correct energy prescription. To this end, predictive equations derived from regression models are used, which usually include variables such as sex, age, weight, and height. Such predictive equations are easy to use, cost-free, and always available. Among the most used equations are the Harris–Benedict , FAO/WHOA high error rate has been observed when applying predictive equations, mainly associated with overestimates of RMR . It is pTherefore, the objective of the present study was to analyze the influence of waist circumference in predicting resting metabolic rate and propose a specific estimation equation for older Chilean women.This was an analytical cross-sectional study.The sample was non-probabilistic and consisted of 45 older women between the ages of 60 and 85 years, who were recruited at a primary healthcare center in south-central Chile. All participants met the following selection criteria: general good health, absence of hypermetabolic disease, stable body weight (±3 kg) in the last 6 months, and absence of medication consumption that modifies RMR prior to its measurement.The present study was reviewed and approved by the Ethics and Biosecurity Committee of the Universidad del Bío-Bío, and all participants provided informed consent. The procedures were conducted according to the ethical norms of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS).Weight and height were categorized using cutoff points established by the WHO in 1998 . Body we%FM was calculated according to the Siri equation , expressBody density (D) was obtained with the equation proposed by Durnin and Womersley and expressed as:omersley . %FFM waThe IC method was used to obtain RMR. Participants were asked not to consume caffeine, smoke, or exercise for 24 h and to fast for 10 to 12 h prior to the measurement. We verified that the subjects had no previous history of thyroid disease or anemia. Vital signs were monitored during the procedure: axillary body temperature < 37 °C and respiratory rate between 12 and 18 breaths per minute. Measurements were taken early in the morning.2 concentration <5% and an ambient temperature between 20 and 24 °C were provided in the environment. Following a 30 min rest, a canopy was placed over the participant’s head, and expired air was measured with a respiratory analyzer . A metabolic chart reading was taken once the stable period was reached, which included VO2 consumption, VCO2 production, and the respiratory quotient (RQ). Test validity was confirmed by the RQ value obtained from the eliminated VCO2 and consumed VO2, with a normal physiological range from 0.7 to 1.0, and by verifying the fluctuation in the VCO2 (mL/min) and VO2 (mL/min) exchange [2 and VCO2 [Prior to measurement, the equipment was calibrated according to the technical manufacturing specifications and using standard gases. A COexchange . Steady and VCO2 .estimated − RMR IC)/RMR IC × 100.The adequacy of the FAO/WHO/UNU 1985 , Mifflinadjusted = RMR ICmean + RMR ICindividual − RMRpredicted. The predicted metabolic rate is the calculated rate obtained by using FFM in the linear equation generated in the studied sample.The quantitative variables were described with central tendency and dispersion measurements, and their normal distribution was verified by the Shapiro–Wilk test. Pearson’s correlation analysis was used to evaluate the correlation between RMR IC, anthropometric measurements, and age. Pearson’s correlation analysis was also used for the adjusted RMR IC to control its variability due to body composition of FFM, which was based on a study by Ravussin and Bogardus  and exprThe prediction of RMR IC according to body composition, age, and WC was modeled by multiple linear regression analysis. Assumptions of collinearity through the variance inflation factor (VIF), error normality (Shapiro–Wilk), and homogeneity of variance (Breusch–Pagan) were verified.t-test. Regression equations with probability value (p), multiple coefficient of determination (R2), and standard error of estimate (SEE) were obtained.The mean estimated RMR of the sample derived from the analyzed predictive equations was compared with the mean RMR IC of the sample according to Student’s We analyzed the consistency between the RMR estimated by the proposed equation and the RMR IC according to the Bland and Altman method , as wellThe normal distribution was verified by the Shapiro–Wilk test. RMR values obtained using the investigated equations were compared using ANOVA and Tukey’s test. The analyses were performed with the STATA 14.0 software  at α = 0.05 level of significance.r = 0.70), weight (r = 0.64), WC (r = 0.56), FM (r = 0.51), and BMI (r = 0.40) and inversely correlated with age (r = −0.48). However, RMR IC adjusted for FFM only showed a statistically significant and inverse correlation with age (r = −0.42) (p < 0.0001) (data not shown).RMR IC was significantly and positively correlated with FFM (R2 = 0.59). WC explained an additional 6% of the variance in the estimated RMR (R2 = 0.65). Stepwise multiple linear regression analysis showed that age, FFM, FM, and WC were significant predictive variables explaining RMR in the group under study. The predictive equation was RMR = 1012 − 17.6 AGE (year) − 11.8 FM (kg) + 23 FFM (kg) + 8.1 WC (cm).p < 0.01). However, there were no statistically significant differences in the measurement of RMR IC as related to estimation with the Mifflin-St Jeor equation and the equation proposed in the present study (p > 0.05).The main determinant of the RMR IC in the studied women was FFM, which is consistent with findings reported in other studies ,5. Otherr = 0.64), which was explained by the observed proportionality of the FM and FFM components, as well as their influence on each other. However, as aging progresses, RMR/kg of body weight decreases, which is not only explained by changes in body composition [There was a positive and significant correlation between body weight and RMR IC , which is similar to findings reported in other studies [We observed a statistically significant and positive correlation between WC and RMR IC  with RMR IC, it was to a lesser degree than WC (r = 0.56) and did not influence the variation in the estimated RMR according to multiple regression analysis. This contrasts with findings of another study in which body fat accounted for between 1% and 10% of the variance in RMR in young and middle-aged women [Although body FM was also positively correlated (ed women .p < 0.0001). This phenomenon is attributed to decreased FFM and the associated increased body FM that occurs with age, as well as to body fluid content, alterations in body temperature and hormones, total body area, physical inactivity, and genetic factors [Aging entails reduced total energy expenditure associated with a decrease in each of its components, that is, RMR, thermogenic effect, and physical activity . In our  factors .p > 0.05), which is in agreement with previously reported findings [The estimation of BMR with predictive equations derived from studies conducted in populations with racial/ethnic characteristics different from those found in Chile, such as the FAO/WHO 1985 and Harris–Benedict equations, showed statistically significant differences with the mean RMR IC of the group under study (findings . In addiThe equation proposed by Carrasco  includesp > 0.05). The Mifflin-St Jeor equation is recommended by the ADA because it has good adequacy in subjects with normal weight and obesity. However, it has also been described as producing a substantial clinical error of approximately 20% overestimation and underestimation of RMR; in addition, the racial origin of the population from which it was derived is unknown [Unlike the aforementioned equations, use of the Mifflin-St Jeor equation and our proposed equation to estimate the RMR of women showed no statistically significant differences with the RMR IC (The strength of our study is that we carefully controlled for the effect of several potentially important confounding factors, such as the absence of medical conditions that affect the RMR of the older women and the possible thermogenic effects of food, caffeine, and nicotine.Estimation of RMR using traditional predictive equations is not error-free and can lead to inaccurate estimation when calculating the energy requirements of a subject, especially if they differ in terms of ethnic/racial characteristics from the population from which they are derived.The proposed equation showed that considering body composition data, especially WC, improved the prediction of RMR, which is consistent with previously reported results . TherefoIn conclusion, including body composition, especially waist circumference, as an indicator of abdominal fat distribution improves the prediction of RMR with the proposed equation for the group of older women under study. This reduces errors, mainly due to overestimation of energy requirements and their implications on body weight.


Hearing, listening, communication and participation in the context of hearing loss are complex constructs to measure. This is because those constructs are intertwined with other complex constructs including language, cognition, social engagement, and fatigue. Hearing loss (passive) impacts listening (active) which, for many adults who live with hearing loss, impacts communication  and participation (everyday life). A plethora of hearing-based interventions are available to support the needs of adults with hearing loss. This includes a range of hearing aid and hearing implant technologies, personal sound amplification products, assistive-listening devices, communication strategies, and auditory/cognitive training. To evaluate the benefits of these interventions, we require valid, relevant and reliable outcome measures before and after the interventions.A valid outcome measure means that it measures what it intends to measure, a relevant measure is that which taps into the intended mechanism of benefit or outcome domain, while a reliable measure means that the same result would be found if that measure was repeated in the same circumstances (high test-retest reliability). Because of their simplicity and reliability, hearing thresholds and speech recognition tests, typically conducted at a fixed volume in a quiet environment, have dominated clinical practice and research in audiology  version of the Spatial Speech-in-Noise (SSiN) test, the SSiN-VA, for the purpose of evaluating hearing abilities with bilateral hearing aids. This approach can enhance clinical efficiency because testing can be conducted at home. In a similar vein, van Wieringen et al. investigated three different speech perception assessments in the same 40 cochlear implant users in their home environment. Their study showed that home-based speech perception testing is reliable and can be used to complement care in the clinic.To assess outcomes that better reflect real-life situations, the complexity and realism of the stimuli and tasks can also be varied . Historically, the main problem with these types of measures is that they have required larger spaces and more complex and expensive equipment. These measures also need to be designed and evaluated carefully to ensure adequate reliability  have been developed, as described in the article by Laplante-Lévesque et al. Modern PROMs are therefore expected to include the rich perspective of people with the lived experience of the construct being measured, and follow good practice guidelines . Using the Cochlear Implant Quality of Life (CIQOL) instruments as an example, these authors provide useful context and guidance for research groups interested in using existing, or developing new self-reported outcome measures. In terms of new patient-reported measures, Humes' contribution describes the development of a new scale to measure the Subjective Wellbeing of older adults with hearing loss. Tapping into the domains of Life Satisfaction, Acceptance of Hearing Loss, and Social Support, the psychometric analysis of this new scale showed very good reliability and good criterion validity. Another new self-reported measure in this Research Topic and presented by Markodimitraki et al. is the COMPASS PROM that aims to quantify the consciousness of wearing a cochlear implant and how this impacts the daily life of cochlear implant users. This includes sleep disturbances due to the physical sensation of the implant on the head or problems with wearing headgear.Outcome measures relevant for adults with hearing loss can be categorized in terms of the type of responses collected from participants . In this Research Topic, however, no articles investigating physiological measures were submitted. In contrast, several submissions included self-reported measures, which are easy to conceptualize in terms of validity and relevance. While Acknowledging the progress made, as well as the need to select outcome measures that are aligned with specific research questions, more work is required before we can agree on an integrated set of outcome measures that are valid, relevant and reliable to support the everyday communication of adults with hearing loss. Study results based on such sets of outcome measures are critical when policy makers approve and fund new products and services. Therefore, with the inclusion of hearing benefit claims within the advertising of everyday technologies such as earphones, the development of alternative services delivery models , the proliferation of hearing-related training programs, and the development of drugs that aim to improve hearing, the need for valid, relevant and reliable outcomes measured cannot be understated, and their selection cannot be overlooked.IB wrote the initial draft of this article and all authors listed made a substantial, direct, and intellectual contribution to the work and approved it for publication.AW was supported by the KU Leuven grant no. C3/21/046.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The correction for extended high frequency average  hearing threshold was significant for performance (p = 0.009) but not perceived exertion on the visual office-like task. Overall, the results showed extended high frequency hearing, but not tinnitus, was associated with every-day cognitive performance. This indicates clinical testing of hearing thresholds above 8 kHz could support clinicians’ identification and management of cognitive difficulties. One management method suggested by the current findings would include provision of auditory stimulation at frequencies exceeding the frequency response of many current hearing aids.Research into the potential associations between tinnitus and cognition has investigated specific cognitive domains in laboratory settings despite adults with tinnitus reporting broad cognitive difficulties in every-day life. To address this limitation, the present study compared performance and perceived exertion on a visual office-like task in 38 adults with tinnitus  and 38 adults without tinnitus  matched for age, sex and educational background. All participants were also assessed for hearing, anxiety and depression, and participants with tinnitus were also assessed for tinnitus handicap. No associations were found between presence of tinnitus and cognitive performance (mean total rate correct score on the visual office-like task being 2.9 for the tinnitus group, 2.8 for the control group,  A common complaint among adults with tinnitus is that tinnitus reduces their ability to concentrate in every-day life . Such coRecently, research associating tinnitus and cognition has been challenged by its failure to control for hearing and hearing impairment . The comA further issue clouding the association between tinnitus and cognition is the lack ecological validity resulting from patient reports of tinnitus affecting concentration in every-day life compared to researchers who assess tinnitus effects using isolated cognitive tasks in the laboratory. The need for future studies to investigate whether tinnitus is associated with cognitive difficulties in an everyday life context has been highlighted by several research groups . In everUsing more ecologically valid measures of cognitive performance could provide better understanding of how tinnitus affects cognition in daily life, particular if the cognitive tasks used more closely resemble tasks performed in real-life. An example of such a task was reported by The ecological validity of measures of cognition could also be improved by adding measures of exertion  to the commonly used measures of performance. Previous studies exploring tinnitus and cognitive performance have focused solely on cognitive performance, typically by measuring accuracy and reaction time on specific cognitive tasks . Such peThe present study aimed to provide a more ecologically valid investigation of tinnitus and cognition in adults with and without hearing impairment by examining behavioral performances and perceived exertion on a visual office-like task VOLT; . Two resSeventy-six adult volunteers were purposely sampled through audiological clinics and public advertising in southern Sweden. Thirty-eight adults, School of Health and Rehabilitation Sciences, were recruited into the tinnitus group (TG) on the basis of subjectively reporting constant or fluctuating tinnitus in the last 6 months or longer prior to their participating in the study. Thirty-eight adults, 19 with and 19 without hearing impairment, were recruited into the control group (CG) on the basis of not experiencing tinnitus and being matched to TG participants for education , age (matched participants differed in age by 24 months or less) and sex. While hearing status was not included as a matching criterion, the TG and CG showed similar audiograms and did not differ significantly in terms of hearing thresholds at frequencies 0.5 to 4 kHz or 10 to 16 kHz. For all participants, normal hearing was defined as worse ear hearing thresholds of 20 dB HL or better at all tested frequencies from 0.125 to 8 kHz (see specifications below), and hearing impairment was defined as having at least one hearing threshold worse than 20 dB HL in the better ear at the mentioned frequencies. All participants reported normal or corrected to normal vision and were fluent in Swedish but not necessarily native Swedish speakers. The present study was approved by the Regional Ethical Review Board in Lund, Sweden . All participants were informed about the purpose and conditions of the study prior to participating and gave written consent to participate.Pure tone audiometry was performed using a Madsen Astera2 (GN Otometrics) audiometer with HDA 200 (Sennheiser) earphones. A Brüel & Kjær type 2209 sound level meter and type 4153 artificial ear were used to calibrate the audiometer in accordance with Pure tone hearing thresholds were measured in each ear at frequencies of 0.125, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12.5, 14 and 16 kHz according to The visual office-like task (VOLT) presented by The Borg CR10-scale  was usedThe Hospital Anxiety and Depression Scale (HADS)  is a scrThe Tinnitus Handicap Inventory THI:  is a queAll but two participants completed the testing in the following order in a sound treated room complying with the maximum permissible ambient sound levels stated in (1)Otoscopy, and pure tone audiometry at 0.125-16 kHz in each ear;(2)cognitive testing (reported in (3)ratings of PE pre-VOLT (baseline rating of PE prior to the VOLT). Specifically, participants were asked to “Please indicate the level of exertion you are experiencing right now”;(4)the VOLT;(5)ratings of PE due to the VOLT. Specifically, participants were asked to “Please indicate the level of exertion experienced due to the visual office-like task”;(6)the HADS; and(7)the THI and a short interview about the participant’s tinnitus (participants in the TG only).Note that it was emphasized to the participants that they should rate their degree of exertion, not their degree of performance or their perception of task difficulty. Two participants underwent the test battery in a slightly different order (completing audiometry last instead of first in the procedure) due to administrative difficulties.As both accuracy and response time were needed for successful completion of VOLT, and analyzing those factors separately could lead to incorrect conclusions regarding task performance, these two measures were combined into a single factor. This factor was obtained by calculating the Rate Correct Score RCS: ;where c = number of correct responses, and RT = response time in seconds of all responses. Hereafter, the RCS will be referred to as task performance.Data were analyzed descriptively by calculating skewness and kurtosis and inspecting frequency histograms and normal Q–Q plots. The equality of covariance matrices in the MANCOVA models were tested using the Box test, and the standardized residuals in these models were examined for normality of distribution and association with predicted standardized residuals. No observed findings threatened the assumptions for MANCOVA analyses.The task performance results were analyzed using a one-way MANCOVA with the dependent variables being simple task-, complex task-, and total task-performance, the independent variable being presence of tinnitus, and the co-variables being HADSA score, HADSD score, S-PTA and EHF-PTA. The task performance results were re-analyzed first using worst ear hearing thresholds, and second using best hearing thresholds, instead of mean thresholds for both ears. As these analyses yielded similar results and thus did not change the interpretation of the findings, only the mean ear hearing threshold data and analysis are reported here. Similar results were expected when using mean, worst, and best hearing thresholds, as the vast majority of included participants had symmetrical hearing.The ratings of PE results were analyzed using a one-way ANCOVA with the dependent variable being absolute PE due to VOLT, the independent variable being presence of tinnitus, and the co-variables being HADSA score, HADSD score, S-PTA and EHF-PTA. The PE results were also analyzed using a using a one-way ANCOVA with the dependent variable being added PE due to VOLT , the independent variable being presence of tinnitus, and the co-variables being HADSA score, HADSD score, S-PTA and EHF-PTA. The reason for analyzing added PE due to VOLT, in addition to absolute PE due to VOLT, was to control for baseline exertion. As the two analyses of PE yielded similar between-group (TG versus CG) results and thus did not change the interpretation of the findings, only the first PE data and analysis are reported here.Pearson’s correlation between absolute PE and task performance were performed to analyze possible correlations between subjective degree of exertion and behavioral task performance.In order to explore potential associations between tinnitus severity and VOLT performance or PE, four further Pearson’s correlations were performed, three between THI score and simple, complex and total VOLT performance, respectively, and one between THI score and PE.The MANCOVA results motivated further exploration between EHF-PTA and VOLT performances. Partial correlations between EHF-PTA and simple, complex and total VOLT performances were performed controlling for age. The choice to control for age was done as it may be a confounding factor in the relationship between high frequency hearing and cognitive performance, indicated by researchers having reported age to be significantly associated with both poorer cognitive performance  and poorAll statistical analyses were performed using IBM SPSS Statistics version 24.0.0.0, 64-bit edition for Windows . An alphp = 0.612] when corrected for S-PTA, EHF-PTA, anxiety, and depression. The correction for EHF-PTA was significant . p < 0.05 for simple , complex , and total task  score], indicating an association between better high-frequency hearing thresholds and higher task scores. The null hypothesis of equal covariance matrices was not rejected for the MANCOVA, with the Box’s M p-value being.416. p = 0.063) when corrected for S-PTA, EHF-PTA, anxiety, and depression. In this model, none of the corrections reached significance. r(75) = –0.129, p = 0.267]. This was also found when analyzing data from the TG  and CG  separately.Pearson’s correlation indicated no significant association between absolute PE due to the VOLT and total task performance , or between THI score and PE .When analyzing data from individuals with tinnitus, Pearson’s correlation indicated no significant association between THI score and VOLT performance for any task condition  when controlling for age.Significant negative partial correlations were found between EHF-PTA and VOLT performance for all task conditions [simple: The results of the present study indicated: (1) no significant association between tinnitus and VOLT performance (regardless of task complexity) when controlling for anxiety, depression and hearing thresholds, with the correction for EHF-PTA being significant for all task conditions; and (2) no significant association between tinnitus and PE on the VOLT when controlling for anxiety, depression and hearing thresholds. In addition, significant but weak correlations were found between EHF-PTA and VOLT performance (regardless of task complexity), when controlling for age. When analyzing data from individuals with tinnitus only, tinnitus severity was not significantly correlated with VOLT performance (regardless of task complexity) or PE.Given the common complaints among adults with tinnitus regarding cognitive difficulties in every day-life, it was somewhat surprising to find no association between tinnitus and VOLT performance or PE in the present study. One interpretation of this finding is tinnitus does not relate to performance or perceived exertion in office-like tasks. Such an interpretation would be partly consistent with An alternative explanation for the present study’s findings could be the VOLT not being sufficiently complex to trigger any cognitive difficulties or induce any fatigue in the participants with tinnitus. Such a possibility was supported by While anxiety, depression, S-PTA and EHF-PTA were all used as covariates in the present study, the finding that only the corrections for EHF-PTA were significant when analyzing tinnitus and VOLT performance (regardless of task complexity) warrants further discussion see , 2021 whThere are several current hypotheses regarding the driving factor explaining associations between hearing and cognitive performance , all of Out of these hypotheses we postulate that the observed associations between high frequency hearing and cognitive performance could be better explained by the common cause hypothesis or the cascade hypothesis. The cognitive load hypothesis (suggesting greater cognitive resources are required to understand speech in the presence of hearing impairment) would initially seem less likely given the importance of hearing in the mid-frequencies (0.8 to 4 kHz) for speech intelligibility and the corrections for S-PTA not being significant in the present study. The potential for hearing loss in the EHFs (above 8 kHz) to contribute to cognitive load should not be rejected outright, however, given recent suggestions that EHF hearing could be needed for optimal speech intelligibility in challenging listening situations  and the The findings of correlations between hearing thresholds above 8 kHz and VOLT performance regardless of task complexity when controlling for age may spark speculations regarding a range of possible implications for clinic, research and future development of hearing aids. Future studies are needed to determine which of the above mentioned hypotheses are at play and to what degree they explain the relationship between auditory and cognitive function. These studies could include longitudinal measures of the relationship between high frequency hearing and cognitive performance, while controlling for aspects such as simultaneous auditory event related potentials and cerebral atrophy (to give an indication whether the cascade hypothesis may be at play), and/or cardiovascular function  and markWhile the correction for EHF-PTA was significant in the analysis of task performance, it was not significant for the analysis of perceived exertion. In line with this finding was the absence of significant correlations between performance on the VOLT and subjective ratings of exertion during the VOLT in all participants or in participants by group (TG or CG). This was consistent with Future research investigating potential associations between tinnitus and performance and exertion in office-like tasks should consider at least two factors. The first factor is the inclusion of more objective measures of cognitive exertion (such as pupillometry: f2 = 0.15) and setting the α-level to 0.05. 80% power is the typical power researchers accept when calculating required sample size, why we conclude that the present study was sufficiently powered to detect medium sized effects between the TG and the CG. As for the number of covariates used, we adopted the formula for limit of covariates suggested by An important aspect to consider when expected significant findings are absent is the statistical power of the analysis. Without information regarding the statistical power it is difficult to interpret whether a meaningful difference is not present or whether it is just not detected. In order to address this issue, we performed a post-hoc power analysis using the G*Power 3.1.9.7 software , 2009 toC is the maximum number of covariates for stable estimation of adjusted, N is total sample size, and J is number of groups. For our study design, where It should also be noted that the included set of participants is not entirely representative of the general tinnitus population. In terms of tinnitus severity, all categories  were represented and with fairly even distribution, though no or moderate handicap were more common than mild or severe handicap among the included participants. This could be compared to the distribution reported by the developers of the THI , reportiThe included tinnitus participants do, however, differ from the general tinnitus population in terms of educational background. Educational level was high among the included tinnitus participants in the present study, all were either current or former university students. In the general population, however, lower educational background may be a risk factor for tinnitus, as individuals with lower educational level are more likely to work in environments where there is a risk of being exposed to excessive noise , which mIt is also unclear whether the finding of significant association between hearing above, but not below, 8 kHz and cognitive performance could be due to sampling bias. Most of the included participants had no, or mild to moderate, hearing impairment at standard frequencies (0.125–8 kHz). EHF thresholds were poorer than at standard audiometric frequencies, implying that it may be the case that hearing impairment was associated with cognitive performance were sufficient hearing impairment was present, rather than EHF thresholds being more important for cognitive function than hearing thresholds at standard audiometric frequencies.Furthermore, we did not control for possible impact of received interventions in the present study. Recent studies have reported that hearing aids may be able to slow down e.g., , or evenNo associations were found between tinnitus and performance and perceived exertion on the VOLT in adults when corrected for hearing thresholds, anxiety, and depression. The correction for extended high frequency average  hearing threshold was significant for performance but not perceived exertion on the VOLT. Overall, the results showed extended high frequency hearing, but not tinnitus, was associated with every-day cognitive performance.sebastian.waechter@med.lu.se.The datasets presented in this article are not readily available because the Regional Ethical Review Board in Lund, Sweden has not granted the researchers to share the dataset with others than those directly involved in the research project. Requests to access the datasets should be directed to SW, The studies involving human participants were reviewed and approved by Regional Ethical Review Board in Lund, Sweden. The patients/participants provided their written informed consent to participate in this study.SW and JB designed the experiments. SW collected the data and wrote the manuscript with input from WW, MM, and JB. SW, WW, and JB performed the data analysis. SW, WW, MM, and JB interpreted the results. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 8 variants reported as causative for DFNA36. Here, we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss, with the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort being 0.17% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. Based on the audiometric data from the probands, family members and previously reported cases, we evaluated hearing deterioration for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.Asp543Asn. The results clearly indicated that the same haplotype was present despite the families being unrelated, supporting the contention that this variant occurred by founder mutation.The online version contains supplementary material available at 10.1007/s00439-021-02364-2. TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL) as first reported by Kurima et al . ma et al . The encma et al .TMC1 variants are a relatively common genetic cause of non-syndromic hearing loss, and accounts for 3.4% (19/557) of Pakistani ARNSHL patients . Among the 125 pathogenic variants, only 8 variants were reported as causative for ADNSHL (DFNA36). The TMC1 gene variants associated with ADNSHL are p.Ile266Thr , generated by ENU mutagenesis, showed autosomal dominant inherited progressive hearing loss  were reported  analyze the rate of HL deterioration in TMC1-associated ADNSHL patients, and (3) carry out haplotype analysis of the TMC1: NM_138691:c.1627G > A:p.Asp543Asn variant identified from 11 unrelated ADNSHL families to confirm whether the mutation occurred by founder mutation or in a mutational hotspot.In this study, we sought to (1) elucidate the prevalence of hearing loss (HL) caused by We performed target re-sequencing analysis for 12,139 Japanese non-syndromic sensorineural hearing loss patients and controls  from 90 otorhinolaryngology departments spread across Japan enrolled in this study. In addition, we also analyzed 187 cochlear implant patients or electric acoustic stimulation patients enrolled from 10 cochlear implantation centers listed below: Antwerp University Hospital, Belgium (Prof. Paul Van de Heyning); Hospital Universitario La Paz, Spain (Prof. Javier Gavilán); Klinikum der Universität München, German (Prof. Joachim Müller); Karolinska University Hospital, Sweden (Prof. Eva Karltorp); Institute of Physiology and Pathology of Hearing, Poland (Dr. Henryk Skarzynski and Dr. Piotr Skarzynski); King Abdulaziz University Hospital, Saudi Arabia (Prof. Abdulrahman Hagr), ENT Super Speciality Institute and Research Center, India (Dr. Manikoth Manoj); University of Western Australia, Australia (Prof. Gunesh Rajan); Kansas University, USA (Prof. Hinrich Staecker); and Allende Sanatorio, Argentina (Dr. Mario Zernotti).Informed written consent was obtained from all subjects (or guardians in the case of minors) prior to participation. This study was approved by the Shinshu University Ethics Committee  and the respective ethics committees of all other participating institutions.Next-generation sequencing was performed for the 63 genes reported to cause non-syndromic hearing loss as described in a previous report , the 6500 exome variants (http://evs.gs.washington.edu/EVS/), The Genome Aggregation Database (https://gnomad.broadinstitute.org), the human genetic variation database (dataset for 1208 Japanese exome variants) (http://www.genome.med.kyoti-u.ac.jp/SnpDB/index.html), the 8300 Japanese genome variation database (https://jmorp.megabank.tohoku.ac.jp/202102/) and the 333 in-house Japanese normal hearing controls. All filtering procedures were performed using original database software described previously (Nishio and Usami http://www.bioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi).The effects of the variants were analyzed using ANNOVAR software  (21 sites for upstream and 26 sites for downstream). For this analysis, we selected 15 individuals (including 11 affected and 4 un-affected family members) from 5 families. Haplotype analysis was performed by Sanger sequencing. The mutation-linked haplotype was determined by family member segregation analysis with multiple family member samples, and compared among unrelated families with the same mutations.The haplotype pattern within the 3 Mbp region surrounding the frequent Japanese variation TMC1-associated hearing loss  for all patients, 0.61% (15/2462) for ADNSHL and 0.07% (5/6912) for ARNSHL or sporadic hearing loss cases.As a result of the large cohort next-generation sequencing analysis, we identified 26 probands with TMC1 variants, 7 of which were novel variants and 10 were previously reported. Based on ACMG guidelines and ClinGen HLCDWG expert specifications, 5 were classified as “pathogenic” variants and 2 were classified as of “uncertain significance”. Interestingly, TMC1:c.1627G > A:p.Asp543Asn variants and TMC1:c.1714G > A:p.Asp572Asn variants were identified from 11 and 4 unrelated families with ADNSHL, respectively. Both variants were only identified from ADNSHL patients and were not identified from 6912 autosomal recessive inheritance or sporadic cases, or 2220 unknown family history cases. In addition, these variants were not identified in the gnomAD database or 8.3KJPN (Japanese 8380 genomic variant database). Taken together, the above results strongly supported the pathogenicity of these variants as causative for TMC1-associated ADNSHL.The variants identified in this study are summarized in Table TMC1-associated ARNSHL patients showed congenital onset severe-to-profound hearing loss, whereas the TMC1-associated ADNSHL patients showed late-onset progressive hearing loss . Most of the ADNSHL cases complained of the progression of hearing loss and tinnitus; however, only two patients suffered episodes of vertigo.In terms of clinical features, TMC1-associated ARNSHL patients showed congenital severe-to-profound hearing loss. On the other hand, TMC1-associated ADNSHL patients showed late-onset progressive hearing loss  identified in this study and shown in Supplemental Fig. 1. In addition, we also included all available hearing threshold data (34 hearing threshold data) for 24 affected individuals with TMC1-associated ADNSHL from previous reports . We, therefore, carried out haplotype analysis to confirm whether this mutation occurred by founder mutation or in a mutational hotspot. Figure TMC1: NM_138691:c.1627G > A variant. As a result, the four unrelated families were found to carry the same haplotype in the 1.3 Mbp region surrounding this mutation (the preserved region ranged from 0.7 Mbp upstream to 0.6 Mbp downstream), suggesting that this mutation occurred and spread as a founder mutation in Japanese populations.Interestingly, 11 unrelated Japanese ADNSHL families carried the same variant , supporting the late-onset nature of their hearing loss. In addition, we also clarified the progression of hearing loss for DFNA36 using the hearing threshold data obtained in this study and previous reports, and revealed the hearing deterioration in terms of pure-tone average was 1.0 dB per year. Most of the TMC1-associated HL patients identified in this study did not have vestibular symptoms and only two patients had episodes of vertigo. Thus, vestibular symptoms may not be associated with TMC1-associated HL cases.Similar to previous studies, TMC1-associated ADNSHL is believed to be a good candidate, as the late-onset and progressive hearing loss phenotype can be stopped or slowed down by gene therapy prior to hearing deterioration. In addition, ENU-induced model mice with the orthologous mutation identified in human ADNSHL patients are widely used for translational research for gene therapy . Haplotype analysis of TMC1: NM_138691:c.1627G > A:p.Asp543Asn showed the same haplotype among the families with the same mutation. This result suggested that this mutation occurred in one common ancestor and was subsequently spread by founder mutation rather than in a mutational hot spot (a mutation which frequently occurs in a specific DNA position). This hypothesis was supported by the fact that this mutation was only identified from Japanese hearing loss patients. This is the first report of a founder mutation identified in DFNA36. Based on the higher prevalence , this mutation will be a good candidate for the clinical study of gene therapy for DFNA36. On the other hand, the c.1714G > A:p.Asp572Asn variant observed in this study may be caused by a mutational hotspot. The p.Asp572Asn variant was identified from four Japanese ADNSHL patients in this study, but this variant was also identified from North American, Chinese and Saudi patients Below is the link to the electronic supplementary material.


Background: Since both surgery and more conservative treatments show long-term outcomes in patients with VS, the current challenge in its therapeutic strategy is to offer a cure with lower functional morbidity in terms of facial and hearing preservation or the possibility of hearing rehabilitation with a cochlear implant. Methods: PubMed and Scopus databases were searched from 2017 to November 2022. Fifteen articles met our selection criteria: (1) patients with a diagnosis of VS, either sporadic or NF2-related; (2) simultaneous or sequential cochlear implantation; (3) specified audiological test results and follow-up timing. Conclusions: Although the level of evidence for the presently included studies is low due to either the study design or the lack of treatment consensus, CI rehabilitation is a promising option, especially in small VS with compromised hearing and as a salvage option after a failed attempt at hearing preservation surgery. Vestibular schwannoma (VS) is a benign tumor arising from the nerve sheath of the VIII cranial nerve. In the last decades, the global incidence has increased from the historical “1 per 100.000” to 3.0–5.2 per 100.000 person-years, with a lifetime prevalence of 1 in 100 persons ..26].Sporadic VS occurs mostly unilaterally with a common symptom of hearing loss that may be sudden or may progress slowly over time. The prevalence of VS in patients with sudden sensorineural hearing loss (SSNHL) who undergo MRI is 3.0%, which is 150 times greater than the prevalence of incidental VS . CommonlThe hearing results  showed a significant increase in postoperative PTA and SDS in all groups and specifically proved the better performance of bimodal hearing stimulation compared to only CI use . In thesThe first prospective study that explored the audiological outcomes of CI after translabyrinthine resection of sporadic VS was conducted by Rooth et al. Seven patients met the inclusion criteria  and underwent CI simultaneously; the main determinant for cochlear implantation was the surgeon’s perception of an intact cochlear nerve after schwannoma resection . Five pap > 0.05). Likewise, PTA, disyllabic word recognition, sentence recognition, and common phrase comprehension improved in the second control, but this improvement was not statistically significant (p > 0.05). Ninety percent of the patients reported using the CI between 5 and 7 days per week. The median satisfaction score on a 10-point scale was 8. The limitations of this study were the small, albeit the only existing, series of patients, short follow-up (13 months), and lack of intraoperative tests to assess cochlear nerve functionality [Sanna et al. conducted a prospective study with the largest series of patients and analyzed the hearing results and subjective benefits of cochlear implantation concurrent to tumor resection in sporadic VS when contralateral hearing is normal . A totalionality .Conway et al. showed similar outcomes in their most recent prospective study in terms of improved hearing performance in background noise, better spatial discrimination, and a decrease in tinnitus . Given tTadokoro et al. reviewed 16 articles from 1995 to 2017, including 45 patients. The postoperative auditory outcomes were SDS 56.4 +/− 27.6% (vs. pre-op SDS 30.0 +/− 40.0%), PTA 28.8 +/− 8.3 dB (vs. pre-op PTA 79.8 +/− 32.7 dB), and AzBio 75.0 +/− 14.3%. A higher preoperative ipsilateral SDS speech discrimination score predicted a lower postoperative SDS, while tumor resection status, tumor location, the duration of deafness, ipsilateral PTA, and the timing of CI placement had a significant effect on patient outcomes. Additionally, among seven patients complaining of tinnitus, five noticed an improvement in symptoms .In Thompson et al.’s systematic review on concurrent CI during VS exeresis, approximately 85% of subjects had auditory perception with their CI. A total of 75% of subjects were high to intermediate performers in terms of audibility, while most of the low performers still noted the subjective benefit of their implants and improvement from their preoperative condition .3 were implanted after MRI surveillance for 2 months up to 7 years. All patients improved monosyllabic word recognition (from 6% to 55%) with a stable performance at the 12-month follow-up [Noteworthy are the preliminary results about IC in small non-growing VS without surgical resection. Seven patients with VS volumes from 0.11 to 1.02 cmollow-up . To summollow-up .Four to six of all diagnoses of VS are associated with neurofibromatosis type 2 (NF2), an autosomal dominant condition caused by pathogenic variants in the NF2 gene on chromosome 22q . This coThe resulting bilateral hearing loss, the tendency toward larger VS, and the higher recurrence rate represent a challenge in terms of hearing rehabilitation. Traditionally, the only option for patients with NF2 and severe to profound sensorineural hearing loss has been an auditory brainstem implant (ABI) .Borsetto et al. evaluated hearing rehabilitation outcomes in CI recipients whose VSs were either observed or treated with radiotherapy. CI for hearing restoration in patients with stable VS is possible, regardless of whether tumor stability has been reached because of radiosurgery or because the tumor has stopped growing. Thus, radiotherapy seems not to influence CI outcomes, even though the follow-up in the majority of the studies was 12 months or shorter .West et al. investigated the results of simultaneous tumor removal and cochlear implantation and compared NF2 to sporadic VS. Mean extrameatal tumors (0–40 mm) were not significantly different between the groups, but almost all NF2 tumors were in the CPA. Speech detection scores (SDS) were 65% for monosyllables, 58% for bisyllables, and 57% for sentences. The higher performers were those patients with preoperative hearing class A or B. There were no significant differences in SDS outcomes between NF2-associated and sporadic VS. Some tinnitus improvement and vertigo reduction were reported. Additionally, no association was found between the use of cochlear nerve testing and postoperative results, possibly due to the existence of time windows of 6–8 weeks for the cochlear nerve to recover after surgery manipulation . SimilarIn conclusion, CI seems to be effective even without the removal of the tumor, with reasonable hearing outcomes. The main requirement is a documented non-growing tumor. There is little consensus on the length of observation for untreated tumors before CI. A recent review encompassed these variables: the observation time extended from 1 to 3 years . ReportiSorrentino et al. analyzed and correlated CI outcomes after VS surgery within a 24-month follow-up. Favorable CI outcomes at the 24-month follow-up with a high rate of daily users (77.8%) were in line with the literature. The NF2 group showed progressive improvement within 6–24 months after activation, underlining the importance of consistent audiological and speech rehabilitation over time. No correlation was found between good preoperative hearing and postimplant performance, while good preoperative contralateral hearing was revealed to be a negative prognostic factor for CI outcomes. In addition, patients with good contralateral hearing improved more gradually than patients with impaired contralateral hearing. This aspect highlighted the importance of preoperative patient selection, appropriate audiological counseling, and a well-structured rehabilitation plan, which should be tailored to patients’ needs and conditions. Therefore, similarly to what was proposed by other authors, CI after VS surgery is preferred when the preoperative hearing class is C worse. The option of HPS is preferred in good-hearing patients (A–B classes), setting aside CI when this attempt fails .CI may affect the imaging surveillance of tumor progression or other disease-specific conditions. MRI is the gold standard for the imaging of VS. The main issues in performing MRI are distortional artifacts, safety, magnet displacement, and pain. Walton et al.  reportedIntralabyrinthine schwannomas (ILSs) are very rare, with fewer than one thousand cases described in the literature. They usually arise in the modiolus and then seem to spread through three different patterns: the invasion of the cochlear basal turn, the erosion of the cribriform area, or intravestibular diffusion . ILSs arFor purely intracochlear schwannomas, Carlson et al. describe leaving the intracochlear tumor in situ to preserve the cochlear anatomy and physiological function while using a styleted electrode with the late deployment of the off-stylet electrode to aid in its advancement. A total of 80% of the affected ears achieved good open-set word recognition .Laborai et al. report a small case series of patients with ILSs undergoing CI with a standard round window approach without tumor removal, showing it is a feasible option for binaural hearing restoration in these patients. The issue is debated regarding the long-term outcome with the possible growth of the residual VS and the issue of MRI monitoring of VS schwannoma growth .Plontke et al. reported the audiological outcomes of four patients who underwent subtotal cochleoectomy for IVS removal and concurrent CI with a new, perimodiolar malleable electrode array; this surgical technique allows a more radical and safe removal of the tumor compared to other techniques (“double cochleostomy” with “pull-through” or “push-through” of the tumor), with a minor risk of residual tumor growth. Additionally, the pre-shaped malleable array allows the maximum approximation of electrode contacts with the spiral ganglion cells in Rosenthal’s canal with probable better long-term audiological outcomes .Jia et al. retrospectively evaluated the audiological outcomes in a small case series of NF2 patients with ILSs. This study demonstrates that the removal of IVS with concomitant CI implantation provides a long-term benefit from CI, although it could be altered by the occurrence of other intracanalicular and/or CPA NF2-related tumors, the treatment of which might restore the initial CI benefit .In Zanoletti et al. 2019, the transmeatal approach to remove small intrameatal VS with intralabyrinthine–intracochlear extension preferably excluded the possibility of hearing rehabilitation with CI, with the potential exception of intravestibular VS or small VS of the basal turn of the cochlea, where it seemed possible to remove the tumor and apply CI .Cochlear implantation is an effective hearing rehabilitation option when good patient selection is conducted, and realistic expectations are foreseen. From many of the studies mentioned above, the best preoperative condition is indicative of the best postoperative results. Radiosurgery is effective in tumor control for selected patients, but the potential delayed effect of radiation on long-term hearing outcomes is unknown, mostly due to cochlear damage. Large VSs often need to be surgically removed with worse facial and cochlear nerve outcomes, and consequently, hearing rehabilitation with CI is not feasible since the cochlear nerve is rarely preserved. Early surgery seems to be preferable to delayed surgery when hearing preservation/rehabilitation is the goal. Natural hearing preservation with HPS is a preferable option to CI rehabilitation, but when the best conditions are not preoperatively maintained, CI rehabilitation is a promising option. Sequential CI may also be a choice in HPS failures. Our in-home recommendations that reflect these statements are shown in CI after translabyrinthine resection should be considered in small growing tumors when the cochlear nerve has been macroscopically conserved, even in the case of a negative intraoperative response, possibly due to sensory neuropraxia.CI in NF2 patients with bilateral hearing loss should be considered after either surgical VS resection or radiotherapy. In the likelihood of worsened hearing or tumor recurrence in the implanted ear, Bevacizumab could be an option.Lastly, patients with symptomatic intracochlear schwannomas who undergo surgical removal of the tumor may benefit from simultaneous CI when no radicality doubts exist, while sequential CI could be preferred after the placement of a dummy electrode to mitigate the risk of fibrosis.To date, most of the existing studies are based on growing VSs that have already impaired cochlear nerve integrity or function. In our opinion, a paradigm shift should be undertaken considering the natural history and the long-term outcome of surgery; when a small VS is affected by a medium-severe degree of hearing loss, it should be treated earlier in order to obtain the best preconditions for simultaneous CI.