Can positron emission tomography support the characterization of immune-mediated inner ear disease? / ¿Puede la tomografía por emisión de positrones ayudar en la caracterización de la enfermedad inmunomediada del oído interno?

INTRODUCTION: To evaluate the utility of 18F-FDG PET/TC as an imaging tool for the characterization of immune-mediated inner ear disease (IMIED), providing measurements of the inner ear region activity as well as detecting possible involvement of other organs. MATERIAL AND METHODS: The study included 28 patients with IMIED and 4 sex-matched and age-matched control subjects with no history of ear disease. Eighteen patients were considered to be suffering from primary IMIED and 10 patients from secondary. PET/CT scans with 18F-FDG were performed to assess systemic involvement as well as inner ear region activity. Interpretation of PET/CT scans was performed independently by 2nuclear medicine physicians blinded to clinical history. In order to assess inter-rater agreement before performing the analysis of the inner ear, different Bland & Altman plots and the intraclass correlation coefficients were estimated. RESULTS: Different metabolically active foci findings were reported in 13 patients. Four patients diagnosed as primary IMIED showed thyroid and aorta activity. Regarding the inner-ear semiquantitative analysis, the inter-rater agreement was not sufficiently high. Comparisons between groups, performed using Mann-Whitney test or Kruskal-Wallis tests, showed no differences. CONCLUSIONS: The study showed 18F-FDG PET/TC could be an important tool in the evaluation of IMIED as it can support the characterization of this entity providing the diagnosis of unknown or underestimated secondary IMIED. Nevertheless, we consider PET is not an adequate tool to approach the inner ear because of the small size and volume of the cochlea which makes the assessment very difficult.

Eosinophilic esophagitis: an underdiagnosed cause of dysphagia and food impaction to be recognized by otolaryngologists.

Eosinophilic esophagitis (EoE) is a recently recognised pathologic entity whose prevalence has risen significantly since first being described in 1993. Defined as a chronic, local immune-mediated disease with predominant eosinophil infiltration, it is nowadays the leading cause of dysphagia and food bolus impaction in children and young adults. Genetic and environmental risk factors, and especially food antigens, trigger the disease and are in the focus of investigation as avoidance can cure three quarters of patients. The most common antigen involved is milk, followed by egg and gluten. These patients frequently come undiagnosed to the otolaryngologist with complaints of dysphagia and recurrent non-sharp food impactions, although pharyngolaryngeal reflux symptoms and other airway complaints could also be a first sign. Delayed diagnosis and treatment can produce fibrostenosis of the esophagus that greatly impairs patients' quality of life.In-office transnasal esophagoscopy with esophageal biopsy offers a unique opportunity to promptly diagnose and follow-up these patients, without causing the morbidity of repeated sedations and reducing exploration overload in gastroenterology departments. The search for food-antigen triggers, response evaluation to swallowed steroids, or proton pump inhibitors (PPIs) make multiple endoscopies and biopsies necessary every 6 to 8 weeks.There are three first-line interchangeable treatments with the same recommendation: PPIs, dietary allergen elimination and topical swallowed steroids. The choice should be discussed with the patient on an individual basis.The objective of this article is to raise awareness of this condition, update otolaryngologists with the new EoE consensus, and highlight the need for biopsy in patients with dysphagia to rule out EoE.

Intratympanic gadolinium magnetic resonance imaging supports the role of endolymphatic hydrops in the pathogenesis of immune-mediated inner-ear disease.

OBJECTIVE: To evaluate the presence of endolymphatic hydrops in patients with immune-mediated inner-ear disease. METHODS: The presence of endolymphatic hydrops was prospectively evaluated in 17 patients clinically diagnosed with secondary (n = 5) or primary (n = 12) immune-mediated inner-ear disease, who attended the ENT department of a tertiary care centre for evaluation or treatment over the previous year. All patients underwent magnetic resonance imaging of the temporal bone. RESULTS: Intratympanic gadolinium three-dimensional magnetic resonance imaging diagnosed hydrops in 11 of 12 patients with primary immune-mediated inner-ear disease (92 per cent). Of these, seven patients (64 per cent) presented only cochlear (n = 5) or predominantly cochlear (n = 2) hydrops. A positive magnetic resonance imaging result was observed in only one of five patients with secondary immune-mediated inner-ear disease (20 per cent). CONCLUSION: This study confirms the presence of endolymphatic hydrops in immune-mediated inner-ear disease patients. The virtual absence of hydrops in patients with secondary immune-mediated inner-ear disease is remarkable, although firm conclusions cannot be drawn; this should be explored in a multicentre study with a larger sample of patients. A different immune reaction without development of endolymphatic hydrops should not be ruled out in secondary immune-mediated inner-ear disease patients.

Diagnosis of endolymphatic hydrops by means of 3T magnetic resonance imaging after intratympanic administration of gadolinium. / Diagnóstico del hidrops endolinfático mediante resonancia magnética de 3T tras administración de gadolinio intratimpánico.

OBJECTIVE: To detect and graduate endolymphatic hydrops or endolymphatic space dilations in patients with suspected Meniere's disease or immune-mediated inner ear disease by magnetic resonance imaging. MATERIAL AND METHODS: A prospective study was performed including all the patients with clinical suspicion of Meniere's disease or immune-mediated inner ear disease treated at the Otolaryngology department during a one year period. In all cases, magnetic resonance imaging (MRI) was performed in a 3T scanner. IR sequence was performed after 24 to 28h prior intratimpanic injection of gadolinium on both ears. Two neurorradiologist graduated endolymphatic space volume as agreed on normal, moderate and significant in the obtained images. RESULTS: The presence of hydrops was documented by MRI in six patients with definite or probable Meniere's disease. In two of the four cases without vertigo hydrops was not demonstrated. In the other two cases with a high clinical suspicion of immune-mediated disease but with negative autoimmune tests hydrops was proved. There was only disagreement on cochlear hydrops presence on two patients. CONCLUSION: The detection of endolymphatic hydrops in patients with definite or probable Meniere's disease served to confirm the final diagnosis. Moreover, hydrops was detected in patients with suspected immune-mediated inner ear disease, which could have an impact on the diagnosis and treatment of these patients. Therefore, we suggest that this test could be included for the diagnosis of these inner ear diseases.

In vitro and in vivo effects of lutein against cisplatin-induced ototoxicity.

INTRODUCTION: Cisplatin is a commonly prescribed drug that produces ototoxicity as a side effect. Lutein is a carotenoid with antioxidant and anti-inflammatory properties previously tested for eye, heart and skin diseases but not evaluated to date in ear diseases. AIM: To evaluate the protective effects of lutein on HEI-OC1 auditory cell line and in a Wistar rat model of cisplatin ototoxicity. MATERIALS AND METHODS: In vitro study: Culture HEI-OC1 cells were exposed to lutein (2.5-100 µM) and to 25 µM cisplatin for 24h. In vivo study: Twenty eight female Wistar rats were randomized into three groups. Group A (n=8) received intratympanic lutein (0.03 mL) (1mg/mL) in the right ear and saline solution in the left one to determine the toxicity of lutein. Group B (n=8) received also intraperitoneal cisplatin (10mg/kg) to test the efficacy of lutein against cisplatin ototoxicity. Group C (n=12) received intratympanic lutein (0.03 mL) (1mg/mL) to quantify lutein in cochlear fluids (30 min, 1h and 5 days after treatment). Hearing function was evaluated by means of Auditory Steady-State Responses before the procedure and 5 days after (groups A and B). Morphological changes were studied by confocal laser scanning microscopy. RESULTS: In vitro study: Lutein significantly reduced the cisplatin-induced cytotoxicity in the HEI-OC1 cells when they were pre-treated with lutein concentrations of 60 and 80 µM. In vivo study: Intratympanic lutein (1mg/mL) application showed no ototoxic effects. However it did not achieve protective effect against cisplatin-induced ototoxicity in Wistar rats. CONCLUSIONS: Although lutein has shown beneficial effects in other pathologies, the present study only obtained protection against cisplatin ototoxicity in culture cells, but not in the in vivo model. The large molecule size, the low dose administered, and restriction to diffusion in the inner ear could account for this negative result.

Hearing threshold levels for an otologically screened population in Spain.

OBJECTIVE: The aim of the present study was to provide thresholds data as a function of age for an otologically normal population in Spain, compared to the current ISO 7029 (2000) standard. DESIGN: A prospective study in an otologically screened population. STUDY SAMPLE: Data was collected from 1175 otologically-normal persons aged between 5 and 90 years. Inclusion criteria involved those listed in ISO 389-1 (1998) and the 8253-1 (2010). Suitability for inclusion was evaluated through interview, based on a questionnaire, and physical examination. RESULTS: The hearing thresholds decreased slightly from 125 to 2000 Hz. From 2000 Hz onwards the thresholds increased; this increase being more pronounced with increasing frequency and age. No statistically significant sex differences were found. The hearing threshold levels in the present study were higher (poorer) than the ones provided by ISO 7029 (2000). CONCLUSIONS: Results from this study suggest that the thresholds listed in ISO 7029 (2000) may be too restrictive, and could be useful in formulating the ISO 7029 update.

Earphones in extended high-frequency audiometry and ISO 389-5.

OBJECTIVE: To determine common reference equivalent threshold sound pressure levels (RETSPL) for the earphones used in the extended high-frequency (EHF) range, as different earphones are commercially available, but there are not RETSPLs for each model. DESIGN: Hearing threshold sound pressure levels were measured up to 20 kHz for the Sennheiser HDA 200 audiometric earphone, and were compared to the ISO 389-5 (2006) norm and other investigations using that earphone and different ones. STUDY SAMPLE: A total of 223 otologically-normal subjects (aged 5-25 years old) participated in the hearing determination. RESULTS: The results are in good agreement with previous studies of hearing thresholds using the same and other earphones. CONCLUSIONS: The results of the present investigation are relevant for the international standard for the calibration of audiometric equipment in the 8 to 16 kHz frequency range, ISO 389-5. The data may be used for a future update of the RETSPL for circumaural and insert audiometric earphones.

Extended high-frequency (9-20 kHz) audiometry reference thresholds in 645 healthy subjects.

OBJECTIVE: The aim of the present study was to study patterns in the extended spectrum of the human hearing (0.125 to 20 kHz) in order to obtain reference thresholds. Then, we compare our values with existing results at extended high-frequencies (8 to 20 kHz) in an attempt to establish new standards for potential international adoption. DESIGN: A prospective study in a group of otologically healthy subjects. STUDY SAMPLE: A total of 645 subjects aged between 5 and 90 years were recruited. Pure-tone thresholds were determined for conventional and extended high-frequencies. RESULTS: There was an increase in the hearing thresholds as a function of frequency and age. For the 20 to 69 years old group, thresholds were lower in females than in males, especially at 12.5 and 16 kHz. Our threshold values are comparable to those presented in previous studies that used different instrumentation and populations. CONCLUSIONS: When comparing different studies the hearing thresholds were found to be similar. Therefore, it would be possible to establish international standard thresholds.

Effect of intratympanic dimethyl sulphoxide (DMSO) in an in vivo model of cisplatin-related ototoxicity.

Although dimethyl sulfoxide (DMSO) is one of the most common solvents employed in otoprotection studies, its effect on the inner ear remains unknown. Only a few in vitro studies have addressed the effect of DMSO in cochlear cells. Up to the date, no in vivo functional studies have been reported. To determine the effect of intratympanic DMSO application in the inner ear, and to evaluate its effect in combination with cisplatin in Wistar rats, twelve Wistar rats were randomly assigned into two groups. Group A received intratympanic 1 % DMSO in both ears. Group B received intraperitoneal cisplatin (10 mg/kg) and intratympanic 0.5 % DMSO in the right ear and saline solution in the left ear. Functional changes were evaluated with Auditory Steady-State Responses before and 5 days after the procedure. Morphological changes were studied by means of confocal laser scanning microscopy following the removal of the temporal bones and cochlear dissection. Hearing threshold levels in group A did not show any statistically significant changes after the treatment. In group B, significant differences between pre- and post-treatment were found, with no statistically significant variations between right (DMSO) and left ear (saline solution). We suggest that DMSO could be safely used to dissolve hydrophobic compounds in otoprotection studies without interfering with the cochlear damage produced by cisplatin.

Young systemic lupus erythematosus patients with no hearing involvement: 10-year follow up.

OBJECTIVE: To evaluate patients with systemic lupus erythematosus and normal hearing over 10 years, compared with healthy controls. METHODS: Thirty patients diagnosed with systemic lupus erythematosus were evaluated in a prospective, descriptive study. Eight patients fulfilled the inclusion criteria, i.e. normal otoscopy, normal hearing, normal imaging and disease duration of less than one year. Eleven healthy companions of ENT patients were recruited as controls. RESULTS: At study commencement, the mean patient age was 32.75 years (range, 15-49 years) and there were no statistically significant audiometric differences between patients and controls. No statistically significant audiometric changes were found either within or between the patient and control groups at 10-year follow up. CONCLUSION: These results supply no evidence for progressive hearing loss in systemic lupus erythematosus patients with no hearing involvement at study commencement. Therefore, we recommend audiometric tests only for systemic lupus erythematosus patients complaining of hearing loss, or for other clinical purposes. It is conceivable that asymptomatic hearing loss could be observed over a more extended follow-up period (i.e. more than 10 years).

Clinical-scintigraphy discordance in a case of malignant external otitis.

We report the case of an immunocompromised female patient with external otitis, who developed a picture of external otitis with poor response to conventional treatment and subsequent isolation of Pseudomona Aeruginosa in the ear secretion culture. The final diagnosis was malignant external otitis. Our objective is to describe the scintigraphic findings as well as to analyze their correlation with the clinical pattern and to evaluate the possible causes of the discordance found.

Biofilm colonisation in nasolacrimal stents.

PROBLEM/OBJECTIVE: Nasolacrimal duct obstruction is a common problem. A Song stent is a useful and simple treatment with low morbidity. However, the success rate is limited, especially in long-term follow-up. The aim of the present study is to determine the presence of biofilms in failing nasolacrimal stents. METHODOLOGY: Thirty-three polyurethane nasolacrimal stents were implanted between January 2006 and December 2007 using Song's technique. Patients were followed for a mean of 21.5 months (range 11-30 months). Removed nasolacrimal stents were preserved in saline and examined using environmental scanning electron microscopy (ESEM). RESULTS: Eighteen nasolacrimal stents were removed because of the failure of the device (follow-up range 11-30 months). Seven stents were recovered for this study. Biofilms were identified in all the specimens studied. Five prostheses showed occlusion caused by mucus or granulation tissue. CONCLUSIONS: Biofilm colonisation of nasolacrimal stents could play a major role in prosthetic failure leading to stent occlusion. Mucus, granulation tissue and irregularities of the biomaterial are factors that facilitate biofilm colonisation. Non-stick material for newly developed stents or drugs capable of destroying the polysaccharide matrix should be considered as future therapeutic options.

Cisplatin-induced hearing loss does not correlate with intracellular platinum concentration.

CONCLUSION: Inductively coupled plasma mass spectrometry (ICP-MS) can be applied to organic tissues obtained from experimental animals. Hearing loss does not correlate with the platinum (Pt) concentration found in the inner ear. Drug structure and affinity to inner ear proteins could explain ototoxicity caused by cisplatin. OBJECTIVES: To analyse Pt affinity for brain and ear tissues (of similar embryologic origin) in the Wistar rat and clearance gradient after a single dose, and to correlate these findings with hearing changes. MATERIALS AND METHODS: Thirty-two Wistar rats were intraperitoneally injected with cisplatin at a dose of 5 mg/kg. Animals were sacrificed after obtaining auditory brain responses (ABRs) at 3, 7, 30 and 90 days (nine, seven, seven and nine animals, respectively). Brain and both temporal bones were extracted from each animal and analysed by ICP-MS to determine the absolute concentrations of the metal. Eight non-treated animals were employed as a control group. RESULTS: The ABR thresholds were significantly elevated in animals from all groups after cisplatin treatment. A maximum accumulation of Pt for inner ear and brain was revealed around the first week: 3.175 (57%) and 0.342 (72%), respectively. Pt significantly accumulated in greater quantities in ear than in brain (p<0.01) and was cleared at a higher rate in brain than in ear (p<0.01) following cochlea/brain ratio analysis. No statistically significant correlation was found between amounts of Pt and hearing loss in the study animals.

Blebs in inner and outer hair cells: a pathophysiological hypothesis.

INTRODUCTION: The ototoxic effects of cisplatin include loss of outer hair cells, degeneration of the stria vascularis and a decrease in the number of spiral ganglion cells. Scanning microscopy has shown balloon-like protrusions (blebs) of the plasma membrane of inner hair cells following cisplatin administration. The present study was undertaken to identify the possible role of inner and outer hair cell blebs in the pathogenesis of cisplatin-induced ototoxicity. MATERIALS AND METHODS: Twenty-five guinea pigs were injected with cisplatin and their hearing tested at different time-points, before sacrifice and examination with scanning electron microscopy. RESULTS AND ANALYSIS: Seven animals showed blebs in the inner hair cells at different stages. Hearing thresholds were lower in animals showing blebs. DISCUSSION: Cisplatin seems to be able to induce changes in inner hair cells as well as in other structures in the organ of Corti. Blebbing observed in animals following cisplatin administration could play a specific role in the regulation of intracellular pressure.

Diagnostic tests for immunomediated hearing loss: a systematic review.

OBJECTIVE: To quantitatively evaluate the diagnostic accuracy of diagnostic tests for immunomediated hearing loss. DATA SOURCES: We searched Medline and the Cochrane Database of Systematic Reviews for potentially relevant studies. STUDY SELECTION: Twenty-five studies met the inclusion criteria of this systematic review. The diagnosis of immunomediated hearing loss was based on the clinical presentation and the response to corticosteroid administration. DATA EXTRACTION: The following data were extracted from the selected studies and entered into a standardised database: population demographics; exclusion and inclusion criteria; diagnostic tests; sensitivity; specificity; the number of true positive, true negative, false positive and false negative values; therapy used, including dose and duration; and delay between symptom onset and therapy commencement. DATA SYNTHESIS: This systematic review combined data from 679 patients with immunomediated hearing loss, reported by 22 research teams. Substantial heterogeneity was found among the included studies; for this reason, summary sensitivity and specificity values were not computed. CONCLUSIONS: The results of diagnostic tests for immunomediated hearing loss depend on many factors, and there is a risk of potential bias. This is the first time that such a systematic review has been presented; such a review is a more rigorous method of demonstrating the utility of the available diagnostic tests.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear.

BACKGROUND AND PURPOSE: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg(-1) body weight). EXPERIMENTAL APPROACH: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. KEY RESULTS: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. CONCLUSIONS AND IMPLICATIONS: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.

HSP-70 as a nonspecific early marker in cisplatin ototoxicity.

CONCLUSION: The great variety of pathological entities related to the presence of circulating HSP-70 suggests a nonspecific cellular damage. As the present study shows, positive results decrease with respect to the time elapsed after the injection of the ototoxic agent. HSP-70 appears as an early and transient marker that could permit early detection of inner ear damage. OBJECTIVES: The aim of this study was to determine the presence of HSP-70 at different time points by means of Western blot immunoassay in the sera of rats treated with cisplatin. MATERIALS AND METHODS: Thirty-six Wistar rats were intraperitoneally injected with cisplatin at a dose of 5 mg/kg and blood samples were collected at 7 and 90 days. Determination of HSP-70 was made by means of a modified Western blot immunoassay kit originally used for human HSP-70 antigen detection. A control group of 18 animals was used for comparison. RESULTS: Western blot was positive in 77.8% of the animals in the 7 days group, decreasing to a 44.4% in the 90 days group. In the control group, Western blot was positive in 5.5%.

Endonasal endoscopic management of a large meningocephalocele in a patient with concomitant middle skull base defect.

The presence of a skull base defect can lead to major complications such as cerebrospinal fluid leak, meningocele, encephalocele and meningitis. It is exceptional to find the existence of two concomitant defects in the skull base. We present the case of a patient with concomitant spontaneous defects of the anterior and middle skull base that were surgically repaired. After 18 years of right rhinorrhea the patient was referred after being diagnosed with a large right nasal fossa meningoencephalocele, which was surgically removed by functional endoscopic sinus surgery. Following the surgery the patient complained about unilateral ear fullness. A paracentesis revealed a highly suspicious cerebrospinal fluid collection. High resolution scans revealed a defect in the mastoid tegmen; subsequently a transmastoid approach was carried out. Greater defects or those lying around the internal auditory canal, are best treated via the middle fossa approach. In the anterior cranial fossa the treatment of choice is provided by endoscopic procedures, but frontal bone craniotomy should be considered if the defect is in the frontal sinus or greater than 5 cm in size.

[External auditory canal cholesteatoma as a complication of ear surgery]. / Colesteatoma de conducto auditivo externo secundario a cirugía previa.

External auditory canal cholesteatomas are a rare disease. Their usual clinical appearance is a mass eroding the bony external auditory canal, normally in the inferior or anterior parts, with an intact tympanic membrane and a normal middle ear. A case of this uncommon disease with a review of the scientific literature is presented. Guidelines for the prevention, diagnosis and management are examined.

Central role of supporting cells in cochlear homeostasis and pathology.

HYPOTHESIS: Supporting cells have a crucial role in degenerative and regenerative events of primary sensorial hair cells of the organ of Corti. This new role should determine future studies about pathophysiology of hearing loss and its regenerative treatment. SUPPORTING EVIDENCE: Recent findings suggest an active role of supporting cells in the maintenance of hair cell function and structure. Evidences of high energy consumption and close proximity to auditory nervous fibers suggesting K+ active exchange, preferential expression of specific proteins and antigens, presence of glucocorticoids receptors, affinity for cisplatin and regenerative potential give the supporting cells an important role in homeostasis of the organ of Corti and in some specific diseases affecting this structure. CONCLUSION: As well as glial cells provide protection and regeneration to neural tissues, supporting cells may provide the necessary metabolic and electrolitic conditions for hair cells mechanical and bioelectrical function. This opens new possibilities for the treatment of apparently "irreversible" destruction of the inner ear.