TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

[Nonorganic (functional) hearing loss in children]. / Nichtorganische (funktionelle) Hörstörungen bei Kindern.

Nonorganic (functional) hearing loss in children is characterized by hearing loss without a detectable corresponding pathology in the auditory system. It is not an uncommon disease in childhood. Typically, there is a discrepancy between elevated pure tone thresholds and normal speech discrimination in everyday life. We evaluated 85 original publications, 27 reviews and 4 textbook articles. Mean age at diagnosis was 11.3 years. Girls were affected twice as often as boys. Patient histories showed a high prevalence of emotional and school problems. Pre-existing organic hearing loss can be worsened by nonorganic causes. A brainstem audiometry should confirm the diagnosis. The differential diagnosis includes auditory processing disorder, elevated thresholds in mental retardation and auditory neuropathy. We recommend taking a personal history including biographical factors, a psychological assessment including intelligence testing and referral to a child psychiatrist. Prognosis seems to be dependent on the severity of the patient's school and/or personal problems. Categorization following the Austen-Lynch model can be a valuable prognostic factor.

[Pedaudiological diagnostics in the first year of life . Clinical follow-up, risk factors, and middle ear function]. / Pädaudiologische Diagnostik im ersten Lebensjahr. Klinische Verläufe, Risikofaktoren und Mittelohrfunktion.

The universal neonatal hearing screening (UNHS) program demands detection of hearing loss within the first 3 months of life. Practicability and different screening methods should be evaluated. Thus, 617 patients (329 m., 288 w.) were analyzed; 246 children were referred in the UNHS, 389 with risk factors. In 459 children (74%), automated auditory brainstem response (ABR) screening in our department excluded hearing loss, thereof 129 (21%) underwent diagnostic auditory brainstem-evoked audiometry responses: 20 (16%) showed normal and 109 (84%) elevated ABR thresholds. A total of 91 children (83%) received hearing aids and 11 children (10%) treatment of middle ear effusion. Hearing loss was diagnosed in 18% of all children, 24% with UNHS referral and 34% with both referral and risk factors. Craniofacial anomalies, premature birth < 32 weeks of pregnancy, and syndromes were the most frequent risk factors. Reevaluation by ABR showed an improvement to normal hearing in 3 (of 14) children. The 226 Hz compared to 1,000 Hz-tympanometry showed different specificity (95.5 vs. 85.5%) and sensitivity (32.5 vs. 57.1%). Diagnosis within 3 months is possible, but very challenging in children with risk factors.

[Identifying language and communication disorders as part of the medical curriculum]. / Erkennen von Sprach- und Sprechstörungen als Lerninhalt des Medizinstudiums.

BACKGROUND: Like hearing loss, language and speech disorders can also lead to impaired communication. Speech and language disorders can occur at any age, for example as a specific language impairment, stuttering, dysarthria, and aphasia. Hence, irrespective of their speciality, there is a high probability that physicians will at some point encounter communication-impaired patients, be required to classify their disorder and refer them for appropriate therapy. METHODS: A new module entitled 'communication disorders' consisting of two teaching units was integrated in the practical course 'ENT--phoniatrics--pedaudiology' for undergraduate clinical students in 2008. The learning objective of the first unit was to identify and classify communication disorders, presented using sound and video data, by means of simple criteria. The module was evaluated on the basis of questionnaires completed by 164 students. RESULTS: On a scale of 1-7, the evaluation showed overall positive results with 6.54 (highest score) for professional competence and 5.32 (lowest score) for discussion. The overall score was 12.28 out of a possible maximum of 15 points. CONCLUSION: The ability to identify communication impairments is an important medical skill. Since communication disorders are common diseases we suggest that this skill be incorporated in the medical curriculum. Thus we have introduced a module for communication disorders; its evaluation by students shows a high level of satisfaction in each category. After developing specific diagnostic indicators students were able to independently describe and identify communication disorders.

Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.

Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear - tissues, which accumulate high levels of platinum-DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro- and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (chi(2)=5.83, P<0.02; odds ratio: 3.45; 95% confidence interval: 1.11-11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.

Melatonin is a useful alternative to sedation in children undergoing brainstem audiometry with an age dependent success rate--a field report of 250 investigations.

Though brainstem audiometry is one of the most important investigations in pediatric audiology, it often necessitates sedation or general anaesthetics, especially in newborns and infants. Melatonin, inducing natural sleep without the risks of sedation, has been successfully used to induce sleep prior to EEG investigations. 250 children (142 male, 108 female) with suspected hearing loss underwent ABR (auditory brainstem responses) tests in melatonin-induced sleep. Click-induced and notched-noise ABR tests were performed. Click tests were successfully performed in 216 of 249 children or 86.7% (123 male, 93 female), notched-noise tests in 115 of 155 children or 74.2%. Failure rates showed an age dependence increasing from 4% in children <1 year to 25%>3 years, but no gender difference. In conclusion, melatonin-induced sleep is a good alternative to sedation, especially in children younger than 3 years. This method is widely accepted by parents and permits earlier diagnosis of hearing impairment in a routine clinical setting. The number of children undergoing general anaesthesia for ABR investigation was reduced from over 60 per year in 2000-2002 to 12 in 2005, which means >80% less general anaesthesia.

[The "Muenster classification" of high frequency hearing loss following cisplatin chemotherapy]. / Die "Münsteraner Klassifikation": Eine neue Einteilung der Hochtonschwerhörigkeit nach Cisplatingabe.

BACKGROUND: Slight high frequency hearing loss following cisplatin chemotherapy can be proof of an ototoxic effect even when hearing ability is not yet clinically affected. To answer scientific questions, such as the relationship between cisplatin ototoxicity and drug regime or individual tolerance, early detection of ototoxicity and a classification relating to intensity and the affected frequencies are required. A search for relevant literature resulted the WHO-classification (1991) describing clinically relevant hearing loss and two high frequency hearing loss classifications published by Khan et al. (1982) and Brock et al. (1991). Their application is compared to a new, proprietary classification. PATIENTS AND METHODS: 55 patients (32 boys, 23 girls) undergoing cisplatin chemotherapy at Muenster University Hospital from 1999 to 2004 underwent audiometric tests in our department. From this data we developed a grading system, that was based on the WHO classification, but paid special attention to early ototoxic effects, to intensity of hearing loss and to the frequencies affected: Grade 0 (normal hearing) includes hearing loss of not more than 10 dB in all frequencies. Grade 1 (beginning hearing loss) encompasses > 10 dB up to 20 dB in at least one frequency or tinnitus. Grade 2 (moderate impairment) describes hearing loss > or = 4 kHz and differentiates 2a (> 20 to 40 dB), 2b (> 40 to 60 dB) and 2c (> 60 dB). Hearing loss < 4 kHz > 20 dB in grade 3 (severe impairment, hearing aids needed) is further classified according to grade 2 in a, b and c. Grade 4 (loss of function) finally describes average hearing loss < 4 kHz of at least 80 dB. This classification is compared to the two high frequency hearing loss classifications (Khan et al. and Brock et al.). RESULTS: The Muenster classification, compared to Khan et al. and Brock et al., demonstrated the best results in the early detection of hearing loss: All children with hearing loss of at least 20 dB after therapy had already shown pathological audiograms during treatment, when those audiograms were assessed by our classification. All children whose audiograms were flagged as pathological by our classification finally developed hearing loss. In terms of the prediction of hearing loss, our classification evaluated processing audiograms with a sensitivity, specificity and efficiency of 1.0. Progressive hearing loss was detected in 45 patients (Khan et al. 30, Brock et al. 38). Therefore our classification showed a better suitability for monitoring hearing loss than the other classifications. CONCLUSION: The Muenster classification is a suitable new basis for scientific questions concerning cisplatin ototoxicity. It detects hearing loss earlier and maps progression of hearing loss more precisely than the existing high frequency classifications (Khan et al. and Brock et al.).

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters.

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

[The use of melatonin as an alternative to sedation in children undergoing brainstem audiometry]. / Melatonin als Alternative zur Sedierung bei Durchführung einer Hirnstammaudiometrie bei Kindern.

BACKGROUND: Though one of the most important investigations in paediatric audiology, brainstem evoked response audiometry (BERA) often necessitates sedation or general anaesthetics, especially in newborn and infants. In paediatric neurology, melatonin has been successfully used for some years to induce sleep prior to EEG investigations. Melatonin as a hormone regulating the circadian rhythm induces natural sleep without the risks of sedation. Side effects are not known. METHODS: Click-induced BERA was first performed in 10 adults with normal hearing with and without previous melatonin administration, and click thresholds and latencies of evoked potentials were compared. 50 children then underwent BERA in melatonin-induced sleep. RESULTS: Click thresholds in adults were mostly identical (r = 0,88), while the mean latencies of evoked potentials seemed to be minimally prolonged (r from 0,82 to 0,95). Click-induced BERA was successful in 45 of the 50 children, and notched-noise BERA in at least 2 frequencies in 38 of 43 children. CONCLUSIONS: Offering a high success rate with no side effects, melatonin-induced sleep seems to be a good alternative to sedation. This method is widely accepted by parents and permits earlier diagnosis of hearing impairment in the routine clinical setting.