Kerstin Lamm

The effect of prednisolone and non-steroidal anti-inflammatory agents on the normal and noise-damaged guinea pig inner ear

The effect of anti-inflammatory agents, such as the synthetic glucocorticoid prednisolone, diclofenac sodium, and histamine H1-receptor antagonist, was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1-12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared with the results obtained from no treatment and with isotonic saline (placebo) therapy. The cochlear blood flow (CoBF) and the partial oxygen pressure in the perilymph (PL-pO2) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss paralleled a decrease of PL-pO2. Both were found to occur before evidence of reduced CoBF. PL-pO2 and CoBF progressively declined post-exposure, while CMs, CAPs, and ABRs did not further deteriorate nor showed signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, or after 90 min without manipulation and was then further studied for 120 min. In the unexposed animals, diclofenac sodium and prednisolone induced a significant decline of PL-pO2, while CoBF, CMs, CAPs, and ABRs revealed no change. Isotonic saline did not influence the measured parameters. After infusion of the histamine H1-receptor antagonist, a significant decrease of CoBF together with blood pressure and CMs was observed, while PL-pO2, CAPs, and ABRs showed no change. In the noise-exposed animals, diclofenac sodium induced partial restoration of CM and CAP amplitudes and full restoration of ABRs. Following a high dose of prednisolone (25 mg), partial restoration of CMs and full restoration of CAPs and ABRs were registered. This effect was significantly less pronounced following a low dose of prednisolone (2.5 mg). Restoration of CMs, CAPs, and ABRs was immediate (i.e. 50 min after infusion) and remained stable for another 60 min until the end of the recording period. The histamine H1-receptor antagonist and isotonic saline did not influence CMs, CAPs, and ABRs. None of the applied drugs resulted in relief of progressive noise-induced cochlear hypoxia and post-traumatic ischemia. These findings indicate direct cellular effects of prednisolone and diclofenac sodium in the cochlea taking into account no blood flow and oxygenation. The possible mechanisms involved are discussed.

Noise-Induced Cochlear Hypoxia Is Intensity Dependent, Correlates with Hearing Loss and Precedes Reduction of Cochlear Blood Flow

Anesthetized and artificially ventilated guinea pigs were exposed to broad-band noise of 95, 101, 106 or 115 dB SPL for 30 min and studied for 180 min after cessation of noise. The partial pressure of oxygen (pO2) in the perilymph, the cochlear blood flow (CoBF) and auditory-evoked potentials were continuously recorded. Arterial blood pressure, electrocardiogram, inspiratory and expiratory gas levels, arterial blood gas levels and acid-base status were kept stable to exclude influences of these parameters on cochlear parameters. Exposure to 95 dB SPL did not affect perilymphatic pO2 or CoBF. Cochlear microphonics (CMs) were reduced, but compound action potentials of the auditory nerve (CAPs) and auditory brainstem potentials (ABRs) increased after exposure to this low-level noise. Perilymphatic pO2 decreased during exposure to 101 dB SPL and then further decreased during the subsequent 60 min after cessation of the noise. CoBF did not change significantly during and 30 min after noise but then paralleled the decline of perilymphatic pO2. However, both parameters showed a clear indication of recovery in the second and third hours after noise. At 101 dB SPL, CMs were again reduced immediately, CAPs were unaltered and ABRs again increased. Exposure to 106 and to 115 dB SPL resulted in a decrease in both perilymphatic pO2 and CoBF; this decrease began during the exposure but became progressively worse after the noise. Hearing loss was observed immediately with exposure and showed no signs of further deterioration after cessation. The observed time courses of changes are important. They reveal that hearing loss and cochlear hypoxia precede reduction in CoBF due to noise exposure. The potential mechanisms underlying these effects are discussed.

The effect of blood flow promoting drugs on cochlear blood flow, perilymphatic pO2 and auditory function in the normal and noise-damaged hypoxic and ischemic guinea pig inner ear

The effect of blood flow promoting drugs, such as hydroxyethyl starch (HES) either of low or high molecular weight (HES 70, HES 200), pentoxifylline, ginkgo biloba, naftidrofuryl and betahistine, and various combinations of the drugs was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1-12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared without therapy and placebo (isotonic saline, NaCl). The cochlear blood flow (CoBF) and the partial pressure of oxygen in the perilymph (PL-pO(2)) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs) and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss (NIHL) paralleled a decrease of PL-pO(2). Both were found to occur before evidence of reduced CoBF. PL-pO(2) and CoBF declined progressively post-exposure, while CMs, CAPs and ABRs showed no further deterioration or signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, respectively after 90 min, without manipulation in unexposed animals, and was then studied for a further 120 min. In unexposed animals, CoBF increased significantly during infusion of HES 70, HES 200, pentoxifylline and betahistine. NaCl, ginkgo biloba and naftidrofuryl did not alter CoBF. PL-pO(2) decreased significantly during infusion of all administered drugs and combinations, except for NaCl. CMs, CAPs and ABRs remained constant, with the exception of increased ABRs after infusion of HES 70 and HES 200. In noise-exposed animals, a sustained therapeutic effect on cochlear ischemia was achieved only by HES 200 and pentoxifylline. HES 70, betahistine and ginkgo biloba compensated cochlear ischemia only during infusion; however, 30-60 min after termination of therapy, no significant difference of values for CoBF was observed compared to the untreated noise-exposed groups. NaCl and naftidrofuryl showed no effect on CoBF. None of the applied drugs had a sustained compensatory effect on cochlear hypoxia. CMs, CAPs and ABRs improved significantly after HES 70, HES 200 and betahistine, resulting in partial recovery of CMs, and partial (betahistine) or even full (HES 70 and HES 200) recovery of CAPs and ABRs. In contrast, NaCl, pentoxifylline, ginkgo biloba and naftidrofuryl had no therapeutic effect on NIHL.

Successful Treatment of Noise‐Induced Cochlear Ischemia, Hypoxia, and Hearing Loss

ABSTRACT: Cochlear blood flow (CoBF), perilymphatic partial pressure of oxygen (PL‐pO2), cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brainstem responses (ABRs) were studied in noise‐exposed guinea pigs during and after the following treatments: intravenous infusion of isotonic saline (placebo); blood flow promoting drugs (hydroxyethyl starch = HES, pentoxifylline, betahistine, gingko biloba, naftidrofuryl); antiinflammatory agents (prednisolone, diclofenac sodium, histamine H1‐receptor antagonist); isobaric oxygenation (IBO); and hyperbaric oxygenation (HBO) with and without supplements (simultaneous infusion of isotonic saline, pentoxifylline, prednisolone, or HES). It was found that PL‐pO2 declined simultaneously with deterioration of CM, CAP, and ABR amplitudes after exposure to broad‐band noise (bandwidth 1–12 kHz, 30 min, 106‐dB SPL). CoBF decreased only 30 min after cessation of broad‐band noise and progressed with cochlear hypoxia, while the hearing loss showed no further signs of deterioration and no recovery up to 3 h after exposure. Treatment (60 min) started 60 min after cessation of noise and was studied for a further 60 min. Isotonic saline did not influence the measuring parameters. Noise‐induced cochlear hypoxia was compensated by IBO and more effectively by HBO with and without supplements, while other treatments had no sustained effect. A sustained therapeutic effect on noise‐induced cochlear ischemia was achieved only by HES, HBO+HES, and pentoxifylline. However, the best therapeutic effect on noise‐induced hearing loss was achieved with a combination of HBO and prednisolone, followed by monotherapy with prednisolone or HES with the result that not only did the CAPs and ABRs completely recover, the CMs also showed significant improvement, although full recovery did not occur. All other therapies were significantly less effective or did not improve noise‐induced reduction of auditory evoked potentials.

Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs

Novel drug release microimplants (0.8 × 1.14 mm; custom-made by Leiras, now Schering OY, Finland) of slow- and fast-release types containing either 0.9 mg beclomethasone or no drug at all were placed unilaterally onto the round-window membrane (RWM) of 45 guinea pigs for a maximum duration of 28 days. The following parameters were tested on days 1, 14 and 28 after implantation: threshold levels of beclomethasone in the perilymph of the scala tympani, auditory brain stem responses (ABR thresholds and ABR threshold shifts), RWM morphology and hair cell loss (cytocochleograms). None of the animals in the non-implanted control group (n = 5) or placebo implant group (n = 15), but all animals in the slow-release-type implant group (n = 15) and fast-release-type implant group (n = 15) revealed the presence of beclomethasone on day 1 (34.9 and 64.3 pg/µl, respectively), day 14 (43.8 and 46.9 pg/µl, respectively) and day 28 after implantation (4.7 and 60.5 pg/µl, respectively). Histology of the RWMs appeared normal, and cytocochleograms revealed no inner hair cell loss and outer hair cell loss within normal ranges (from 0.5 ± 0.4 to 0.8 ± 0.2% per cochlea) in both ears in all experimental groups at any time during examination (days 1, 14 and 28). Initial values of ABR thresholds at 3, 6, 9 and 12 kHz did not differ significantly in any of the experimental groups. In non-implanted controls, no significant differences of ABR thresholds were observed in all frequencies tested in either ear on days 1, 14 and 28 compared to initial values, and ABR threshold shifts ranged from –3 ± 5 dB (min.) to +5 ± 7 dB (max.). On day 28 after implantation, there were no significant differences of ABR threshold shifts between this and the implant groups, except for 6 kHz of the slow-release device. Therefore, the placebo implants, the slow-release and the fast-release beclomethasone implants appear suitable for further experiments.

Middle ear and cochlear disorders result in different DPOAE growth behaviour: implications for the differentiation of sound conductive and cochlear hearing loss.

Input/output functions of distortion product otoacoustic emissions (DPOAE I/O-functions) give an insight into the compressive, non-linear sound processing of the cochlea. With an inner ear dysfunction a steeper I/O-function is observed. Due to the linear sound processing of the middle ear, one can assume that the DPOAE growth behaviour remains unaltered with a sound conduction dysfunction. If that is true, a differentiation between middle and inner ear dysfunction will be possible by using the slope of DPOAE I/O-functions as a means for assessing cochlear compression. In order to test that hypothesis, DPOAE I/O-functions were recorded in a wide primary tone level range at up to 8 f2 frequencies between 2.0 and 8.0 kHz (15 dB SPL < L2< 60 dB SPL; L1=0.46 L2 + 41 dB SPL; f2/f1=1.2) in guinea pigs in which middle (saline solution in the bulla) and inner ear (exposure to loud broadband noise) disorders were induced. Middle ear dysfunction resulted in a reduction of the DPOAE amplitude independent of the primary tone level. Consequently, DPOAE growth behaviour was not affected. In contrast to that, during cochlear impairment, steepened DPOAE I/O-functions were observed reflecting loss of compression of the cochlear amplifier. Accordingly, DPOAE I/O-functions allow a differentiation between middle and inner ear dysfunction. Further studies will have to show the usability of this method for clinical diagnostics, e.g. for detecting sound conduction disturbances in newborn hearing screening due to amniotic fluid or Eustachian tube dysfunctions during the early postnatal period.

[Neurofeedback-based EEG alpha and EEG beta training. Effectiveness in patients with chronically decompensated tinnitus].

ZusammenfassungHintergrundChronischer Tinnitus erweist sich bis heute als schwer zu behandelnde Symptomatik, unter der es bei vielen Betroffenen zu einer ernstzunehmenden psychischen Dekompensation kommt.Patienten und MethodeDiese Studie untersucht den Effekt eines neurofeedbackgestützten EEG-α- und EEG-β-Trainings bei 40 Patienten mit einem „chronisch dekompensierten Tinnitus“. In einer 12 Sitzungen umfassenden Kurzzeittherapie trainierten 23 Patienten die Steigerung der EEG-α-Aktivität, 13 Patienten versuchten die Senkung der EEG-β-Aktivität zu erzielen. Eine 3.xa0Gruppe (n=4) trainierte die Steigerung der α- bei gleichzeitiger Senkung der β-Aktivität.ErgebnisseDie Beeinflussung der EEG-Aktivität zeigte sich nicht in allen Gruppen gleichermaßen. Eine deutliche Reduktion der subjektiven Belastung durch den Tinnitus nach Therapieabschluss konnten wir jedoch in allen Gruppen finden.SchlussfolgerungenDie Ergebnisse zeigen, dass sich Neurofeedback als neues, erfolgversprechendes Verfahren in der Therapie des chronisch dekompensierten Tinnitus darstellt. Unbeantwortet bleibt jedoch bislang die Frage, ob die Reduktion der Tinnitusbelastung auf den durch das Neurofeedbacktraining unterstützten Lernprozess zur Beeinflussung der Hirnaktivität zurückzuführen ist.SummaryBackgroundPersisting tinnitus is an often devastating disease condition with restricted and rarely successful therapeutic options.Patients and methodsThe present study investigates the therapeutic effect of short term neurofeedback-based EEG-Alpha- and EEG-Beta-training in 40 patients suffering from “chronic decompensated tinnitus”. Patients were assigned to the Alpha or Beta group according to results of an initial EEG monitored stress-test. Four patients were excluded because they showed abnormal reactions in both EEG patterns.ResultsDuring 12 sessions, 23 patients succeeded to increase EEG Alpha activity by 16% (p≤0.042) while 13 patients achieved no decrease of EEG Beta activity. However, both groups showed a significant reduction of subjective tinnitus annoyance by the end of the therapy (p≤0.001)Conclusions The results indicate that neurofeedback may represent a new promising technique in the therapy of chronic decompensated tinnitus. However, it remains to be established whether the reduction of tinnitus annoyance results from the altered brain activity patterns supported by the neurofeedback learning process.BACKGROUNDnPersisting tinnitus is an often devastating disease condition with restricted and rarely successful therapeutic options.nnnPATIENTS AND METHODSnThe present study investigates the therapeutic effect of short term neurofeedback-based EEG-Alpha- and EEG-Beta-training in 40 patients suffering from chronic decompensated tinnitus. Patients were assigned to the Alpha or Beta group according to results of an initial EEG monitored stress-test. Four patients were excluded because they showed abnormal reactions in both EEG patterns.nnnRESULTSnDuring 12 sessions, 23 patients succeeded to increase EEG Alpha activity by 16% (p< or =0.042) while 13 patients achieved no decrease of EEG Beta activity. However, both groups showed a significant reduction of subjective tinnitus annoyance by the end of the therapy (p< or =0.001)nnnCONCLUSIONSnThe results indicate that neurofeedback may represent a new promising technique in the therapy of chronic decompensated tinnitus. However, it remains to be established whether the reduction of tinnitus annoyance results from the altered brain activity patterns supported by the neurofeedback learning process.

Pharmacological Influence on Inner Ear Endothelial Cells in Relation to the Pathogenesis of Sensorineural Hearing Loss

Despite an increasing incidence of acute sensorineural hearing loss, the pathogenesis of this disease remains uncertain. While viral infection of the stria vascularis, organ of Corti or spiral ganglion cells is discussed in the American literature, a vascular genesis with resulting impaired perfusion of the inner ear is favoured by European investigators. Although both hypotheses are supported by different therapeutic strategies to regain normal hearing, the influence of spontaneous remission remains unclear. This study aims at combining these seemingly opposing concepts with the assumption of an immunologically mediated vasculitis with consequent cochlear hypoperfusion. We already know from other organs that during viral vasculitis circulating immunoglobulins are deposited perivascularly, which leads to a local decrease in perfusion and tissue hypoxia. Also in autoimmune diseases, perivasculitis is common with the endothelium playing a major role at the initial stages of the disease. These endothelial cells promote vasculitis by secreting pro-inflammatory cytokines like IL-1, IL-6 or TNF-alpha in addition to the expression of adhesion molecules. Due to the persistence of these immunopathological mechanisms stenosis or atresia with ischaemic necrosis results. To examine whether this pathomechanism is also important in inner ear dysfunction, the immunological response after stimulation of the cochlear endothelium of guinea pigs was determined. In addition, the influence of corticosteroids on this immune cascade was examined.

How Useful Is Corticosteroid Treatment in Cochlear Disorders

The scientific basis for the administration of corticosteroids classified as glucocorticoids in certain cochlear disorders, such as immune-mediated progressive and idiopathic acute sensorineural hearing loss (SNHL), Ménière’s disease and noise-induced hearing loss (NIHL), was discussed. The current knowledge on the physiological functions of endogenous glucocorticoids and the pharmacological effects of their synthetic analogs was summarized. Emphasis was placed on experimental studies on corticosteroids in the cochleovestibular system and on the therapeutic effects of glucocorticoids on SNHL, Ménière’s disease, NIHL and chronic tinnitus obtained from clinical trials. Glucocorticoids exert numerous profound effects on almost every organ system, including mechanisms involved in anti-inflammatory action and immunosuppression. However, inflammatory tissue alterations are not only elicited by bacterial, viral or other immunopathological processes but also by physically and chemically induced cellular damage, tissue ischemia and hypoxia. Regardless of whether one or more of these insults underlie SNHL, Ménière’s disease and NIHL, glucocorticoids effectively counteract subsequent inflammatory tissue damage in the auditory and vestibular system. This was confirmed in experimental studies on immune-mediated progressive SNHL, and thrombosis-induced and noise-induced cochlear ischemia, hypoxia and hearing loss. Glucocorticoid treatment results of immune-mediated progressive and acute idiopathic SNHL are promising, although placebo-controlled trials on the effect in acute idiopathic SNHL have revealed conflicting data (probably due to the small number of patients). Clinical studies on the effect of systemic glucocorticoid monotherapy on Ménière’s disease and NIHL have not yet been performed. After intratympanic application, relief of vertigo, tinnitus and preservation of hearing in Ménière’s disease was observed in previous studies; however, recently none of these effects have been confirmed in a placebo-controlled trial. Similarly, in contrast to previous reports, chronic tinnitus of various origins did not improve after repetitive glucocorticoid application onto the round window membrane using a micropump connected to an implanted microcatheter.

Ist eine durchblutungsfördernde Therapie bei cochleo-vestibulären Funktionsstörungen wirksam ?

In den “European Archives of Otorhinolaryngology” berichten Doerr et al. von der Wayne State University Detroit (USA) über die Wirkungen von Flunarizin und Pentoxifyllin auf den vestibulären Blutfluß beim Meerschweinchen [1]. Quirk et al. haben die Laser-Doppler-Flowmetrie-Technik für kontinuierliche In-vivo-Blutflußmessungen in der Cochlea für Messungen im peripheren Vestibularorgan adaptiert und erprobt [1–6]. Die Ergebnisse, insbesondere hinsichtlich einer pharmakologischen Beeinflußbarkeit des vestibulären Blutflusses, sind auch für den Kliniker interessant.