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GMS Current Topics in Otorhinolaryngology - Head and Neck Surgery

Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e.V. (DGHNOKHC)

ISSN 1865-1011

Therapy of hearing disorders - conservative procedures

Review Article

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  • corresponding author Stefan Plontke - Department of Otorhinolaryngology - Head and Neck Surgery, Tübingen Hearing Research Center (THRC), University of Tübingen, Germany

GMS Curr Top Otorhinolaryngol Head Neck Surg 2005;4:Doc01

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/journals/cto/2005-4/cto000007.shtml

Veröffentlicht: 28. September 2005

© 2005 Plontke.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Abstract

A wide range of therapeutic strategies are available for the therapy of hearing disorders including pharmaceutical, acoustic, electrical, surgical, radiological, cognitive-behavioural and so-called "alternative" strategies. This review focuses on general conservative strategies and specific therapeutic approaches mainly for inner ear disorders, whereas surgical and device-based therapies including hearing aids and cochlear implants are described in other chapters in this volume.

In addition to the systemic medication-based therapies for the treatment of hearing disorders, the rapidly growing field of local drug delivery to the inner ear as a promising therapeutic strategy is discussed on the background of unresolved issues. After description of non-drug-based therapeutic procedures, the conservative therapy of specific diseases and syndromes is reviewed.

In general, there is a major discrepancy between promising animal studies up to regeneration and stem-cell transplantation, and uncontrolled experimental studies in humans on the one hand and the shortage of randomized controlled clinical trials with a high level of evidence on the other hand. Therefore, the review and comments on published clinical studies should assist the reader in making his/her own decision about the effectiveness of various, especially pharmaceutical treatments. From a critical analysis - particularly of the clinical studies presented - conclusions are drawn for the therapy of hearing disorders in the future.


List of abbreviations

ADANO - Union of German-speaking Audiologists and Neurootologists

AIED - "autoimmune inner ear disease"

AUC - "Area under the curve"

Cmax - Peak concentration

CI - Cochlear implant

dB - Decibel

DGHNO - German Society for Otorhinolaryngology, Head and Neck Surgery

HBO - Hyperbaric oxygen therapy/ hyperbaric oxygenation

ISSNHL - Idiopathic sudden sensorineural hearing loss

ITT - "Intent-to-treat"-analysis

kHz - Kilohertz

MRT - Magnetic resonance tomography

PET - Positron emission tomography

PP - "Per-Protocol" analysis

PTA - Pure tone average

RCT - Randomised controlled trial

RWM - Round window membrane

rTMS - Repetitive transcranial magnetic stimulation

SNHL - Sensorineural hearing loss

(s)AE - (serious) adverse event

TRT - Tinnitus retraining therapy

TDT - Tinnitus desensitization therapy

CNS - Central nervous system


1. Introduction

Worldwide, hearing disorders number amongst the most frequently encountered chronic diseases. Many possibilities are available now to treat hearing disorders and assist in rehabilitation. These include pharmaceutical, acoustic, electrical, surgical, radiological, cognitive-behavioural and so-called "alternative" strategies. Optimal therapeutic results can often only be achieved by combining two or several of the above-mentioned therapeutic modalities. Since therapeutic results often remain unsatisfactory, particularly with chronic hearing disorders, numerous experimental approaches have been taken in addition to the clinically established procedures. The following review focuses on conservative therapies and therapeutic approaches, whereas mainly surgical and device-based therapies using conventional or implantable hearing aids and cochlear implants are described in other chapters in this volume. This review shall also not delve into the therapy of (central) auditory processing disorders. The objective of this review is to describe the current status quo and variety of conservative therapeutic approaches and attempts to treat hearing disorders. The review and comments on clinical studies should assist the reader in making his/her own decision about the efficacy of various, especially pharmaceutical treatments, so that the decision process on choosing a therapy can be facilitated. This review should also enlighten on future therapeutic approaches and provide the impetus to carry out the clinical studies required to assess them. In view of the fact that several thousand publications exist just on the clinical aspects of drug-based hearing disorder therapy, it should be noted that in the present review only a small selection - albeit subjectively influenced - shall be able to be discussed. Firstly, various medication-based therapeutic procedures for treating hearing disorders in general shall be presented together with their mechanism of action and rationale for application. This approach has been chosen since repetition should be avoided as much as possible when discussing the treatment of specific conditions. A separate part has been dedicated to local drug delivery to the inner ear. After description of non-drug-based therapeutic procedures, the conservative therapy of specific diseases shall be dealt with. From a critical analysis - particularly of clinical studies that are already at hand - conclusions shall be drawn for future conservative therapy of hearing disorders.


2. Medication-based procedures I: systemic therapy

2.1 Glucocorticoids and mineralocorticoids

Glucocorticoids exert diverse effects on almost all organs. On the one hand glucocorticoid effects can be explained by a delayed, DNA-mediated induction of protein biosynthesis after transformation of an intracellular glucocorticoid receptor, while on the other they are explained by immediately active effects via mechanisms that have remained unknown until now. In addition to conventional effects at physiological concentrations, the following effects can occur upon increased secretion during stress and upon therapeutic application at higher doses: antiproliferative effect (through suppression of collagen synthesis and fibroblast formation), anti-inflammatory effect (through blockade of proinflammatory mediators), immunosuppressive effect (e.g. through inhibition of the activation of T lymphocytes), improvement of microcirculation in shock (through raised responsiveness of the vessels to catecholamines), increase in thrombocyte numbers in the blood, increased excitability of the brain and a lowering of the seizure threshold, and a psychotropic, euphoric, and sometimes a depressive effect [1].

The blockade of inflammatory processes (anti-inflammatory effect) by glucocorticoids occurs independently of whether these can be attributed to bacterial, viral, immune-pathological, chemical, physical or ischemic-hypoxic causes. Thus a rational basis exists for the universal application of glucocorticoids for various cochlear-vestibular diseases such as acute hearing loss, autoimmune-associated hearing-loss, Menière's disease, tinnitus and acoustic trauma independent of which specific pathological mechanism caused them. An extensive review on the effects of glucocorticoids in the cochlear-vestibular system and relevant studies was published by Lamm and Arnold (1999) [2].

In the inner ear there are receptors both for glucocorticoids and the other group of corticosteroids, the mineralocorticoids [3], [4], [5]. The effects of glucocorticoids are mediated via both receptors. Often used glucocorticoids show relative mineralocorticoid effects of 1.0 (hydrocortisone) or 0.6 (prednisone or prednisolone) compared to cortisol. Others, such as methylprednisolone, dexamethasone or betamethasone show no relevant mineralocorticoid effect with a stronger anti-inflammatory effect compared to cortisol [1]. The fact that cochlear-vestibular structures are affected by mineralocorticoids, in particular the vascular stria, must be considered when evaluating animal-experimental and clinical studies with different glucocorticoids.

The maintenance of the Na/K balance in the inner ear fluids through the regulation of the Na/K-ATPase is of great importance for the normal functioning of the inner ear. This subtle balance can be disrupted with various inner ear disease processes, which via the sodium, calcium and chloride-associated water influx can lead to cell swelling and electrophysiologically detectable functional deficits. The influencing of ion transportation in the stria vascularis is considered to be an important aspect of the therapeutic effect of glucocorticoids and is the subject of much research at this time (see for example the papers of Wangemann et al. [6]). A direct effect of glucocorticoids on the expression of Na/K-ATPase was presumed by Curtis et al. (1993) [7]. However, more recent studies with glucocorticoid-receptor-knockout-mice were not able to find any changes in the distribution pattern of this ion transporter [8].

Of importance to note are experiments demonstrating that Aldosterone (a mineralocorticoid) is equivalent to prednisolone (a glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas1pr autoimmune mice [9], [10], [11] and that "Spironolactone effectively blocked prednisolone from improving hearing in MRL/MpJ-Faslpr autoimmune mice". The authors concluded that "the inner ear mineralocorticoid receptor is the therapeutic target for corticosteroids used to treat autoimmune and sudden sensorineural hearing loss" and that "pharmacologic treatments that selectively target the mineralocorticoid receptor may provide greater clinical benefit with fewer systemic side effects than prednisone in patients with autoimmune sensorineural hearing loss" [12].

Alongside the Na/K-ATPase, aquaporins ("water channels") play an important role in the homoeostasis of the inner ear fluids. The results of more recent animal-experimental studies have revealed an upregulation of aquaporin 1 and 3 -mRNA in the cochlea and endolymphatic sac of the rat after intratympanic or intraperitoneal application of glucocorticoids. This suggests that the mode of action of glucocorticoids in water regulation in the inner ear involves aquaporins, and that the latter may represent a target for the local and systemic therapy of inner ear disorders involving dysregulation of fluid volume (e.g. with Menière's disease) [13], [14].

In addition to animal-experimental studies described here on the effects of glucocorticoids in the inner ear, a number of clinical studies have pointed towards a therapeutic efficacy also in man. The few clinical studies on idiopathic sudden senorineural hearing loss (ISSNHL) that have compared the efficacy of glucocorticoids with placebo or null therapy have produced inconsistent results.

Mattox and Simmons (1977) report that amongst patients who were treated with glucocorticoids, 25 of 45 (56 %) achieved a "good" or full remission, although patients without therapy also showed a similar recovery rate (16 of 28, 57 %) [15]. Wilson et al. in their double-blind, randomised study showed a remission rate of 61 % during therapy with glucocorticoids (dexamethasone or methylprednisolone) compared to placebo (32 %) or null therapy (56 %). The methylprednisolone group showed proportionally many more patients with remissions than the dexamethasone group [16]. Moskowitz et al. achieved a recovery of hearing in 24 of 27 patients (83 %) treated with dexamethasone, a situation observed in only 4 of 9 patients (44 %) without therapy [17]. Veldmann et al. observed a recovery of hearing in half of the 12 patients treated with prednisone as opposed to 6 of 19 patients (32 %) for whom a recovery was observed without therapy [18]. The most extensive study until now on the efficacy of glucocorticoids was published by Alexiou et al. (2001). In a retrospective cohort study (see 5.1.2) the authors found that after therapy with prednisolone as an adjunct to an intravenous rheological therapy, a significantly better hearing-recovery was seen in the frequency range ≤ 2000 Hz or when the hearing-loss was pancochlear [19].

In summary, the observations from previous clinically-controlled studies indicate an efficacy of glucocorticoids in the treatment of idiopathic sudden senorineural hearing loss (ISSNHL). A meta-analysis of the Cochrane-Collaboration on the subject "Steroids for idiopathic sudden sensorineural hearing loss" is currently being prepared. The results, however were not available at the time of printing.

2.2 Rheological therapy

An intact microcirculation is necessary to allow an optimum supply of the inner ear with oxygen and energy substrates and an optimal removal of metabolic products. The improvement in flow-behaviour of the blood is the goal of a therapeutic improvement of the microcirculation with inner ear diseases. The flow-behaviour is determined by the flow conditions and the flow properties of the blood. While the flow properties are defined by rheological parameters, particularly plasma viscosity, but also erythrocyte rigidity amongst other things, the flow conditions of the blood are determined by the angioarchitecture, the perfusion pressure and functional vessel factors. A review and glossary relating to the inner ear was published by Lamm and Arnold in 1993 (also including other references [20]).

2.2.1 Dextran

Dextran preparations (α-glucosidically bonded polysaccharides with glucose as the monomer) exert a marked volume effect, and are therefore contraindicated with cardiac insufficiency. "Low-molecular weight dextran" (Dextran 40) can improve the microcirculation. Erythrocyte and thrombocyte aggregation are decreased. With hypervolemic haemodilution by infusion with dextran and other colloidal solutions (e.g. HES, see below) the haematocrit is reduced, and therefore also the blood viscosity. However, anaphylactic reactions are observed after dextran application at a frequency of 0.03 % that can be avoided by pretreatment with dextran 1 (mean molecular weight of 1000), the so-called Hapten-dextran (Promit®), that blocks dextran-reactive IgG antibodies.

Probst et al. found no difference regarding hearing recovery after acoustic trauma or acute hearing loss when patients were treated with dextran and pentoxifylline, with 0.9 % saline and pentoxifylline, or with 0.9 % saline and placebo [21]. For other clinical studies on the therapy of acute hearing loss with dextran see Table 1 [Tab. 1]. Possible serious side effects that have also been reported therapy of ISSNHL using Dextran must be considered and weighed against it's possible benefits [22], [23].

2.2.2 Hydroxyethyl-starch

Hydroxyethyl-starch solutions (HES) are pharmacologically similar to dextran solutions. The influence on blood coagulation is distinctly reduced and serious anaphylactic reactions occur much more rarely. However, the dose-dependent, continuous and therapeutically resistant itch appearing as a side-effect in a large number of patients treated with HES due to the deposition of HES molecules in the skin must be considered [24], [25], [26], [27], [28]. The risk-benefit scenario of a therapy with HES should therefore be carefully considered. For clinical studies see Table 1 [Tab. 1] and part 5.

2.2.3 Pentoxifylline and naftidrofuryl

With these substances used particularly for the therapy of peripheral circulation disorders, the non vasodilatory effects are of key importance. These include: the reduction of blood viscosity; the improvement of erythrocyte fluidity; a disaggregation of thrombocyte aggregates; a thrombocyte aggregation inhibiting effect. However, Probst et al (1992) found no superiority of therapy with pentoxifylline in 0.9 % saline compared to placebo in 0.9 % saline in a prospective, randomised study on the therapy of ISSNHL and acoustic trauma [21]. For further studies on these medications see Table 1 [Tab. 1].

2.3 Vasodilatory substances

Systemic therapy using substances with a primary vasodilatory effect for acute inner ear diseases is contraindicated according to our current state of knowledge. When using vasodilatory medications in particular the arterial circulation of the inner ear can even be impaired by "vascular steal effects" [29], [30]. The currently used therapeutic doses of calcium channel blockers number amongst these medications, as do higher doses of prostaglandins and other derivatives of arachidonate metabolism.

Calcium channel blockers of the 1,4-dihydropyridine type (e.g. nifedipine, mimodipine), the verapamil type or the diltiazem type lead (in addition to their negatively inotropic effect on heart muscle) to a reduction in tone of the smooth vessel musculature and with that to a vasodilatation. In two prospective, randomised trials, therapy with the calcium channel blockers nimodipine or nifedipine was equivalent to therapy with naftidrofuryl in HES or naftidrofuryl in physiological saline [31], [32].

Prostaglandin (PGE 1 ) and prostacyclin (PGI 2 ) or their analogues were also tested in clinical studies on ISSNHL. While Nakashima et al. (1989, PGE1), Michel and Matthias (1991, prostacyclin analogues) and Ogawa et al. (2002, PGE1) found no benefit of these drugs in placebo controlled or therapy comparison studies, Olszewski et al. (1990) reported a clear superiority for prostacyclin (PGI2) compared to placebo [33], [34], [35], [36]. It must be noted here that PGI2 in particular also exerts a thrombocyte aggregation inhibiting effect.

A meta-analysis of the Cochrane-Collaboration on the topic "Vasodilator-agents for acute hearing loss" is being prepared. The results of this study were still unpublished at the time of printing.

Of special interest are approaches designed to specifically influence intracochlear vessels such as the spiral modiolar artery. Recent in vitro experiments by Scherer and Wangemann et al. (2002) found Rho-Kinase to be a possible target for influencing endothelin-mediated vasospasms in the gerbil spiral modiolar artery [37].

2.4 Ionotropic therapy

The treatment of inner ear disorders and their symptoms with local anaesthetics such as lidocaine was already proposed many decades ago (see for example Bárány 1935, [38]). With tinnitus therapy in particular it has been applied again and again, as it has been for ISSNHL. Although it is particularly effective with tinnitus, its specific mode of action remains unknown. The suggested mechanisms include (a) an inhibitory effect on the Na+ channel, (b) an influencing of Ca2+, Mg2+-ATPase and active Ca2+/Na+ exchange in synaptosomes and (c) an effect on K+ channels [39]. Various animal-experimental and clinical investigations with measurement of cochlear microphonics, sum mating action potentials, inter-peak latencies in brainstem response audiometry, and the activity of tinnitus-associated cortical regions allow us to assume that local anaesthetics bring about effects in several areas of the auditory system: at the outer and inner hair cells, at the auditory nerve and in central areas of the auditory pathway [39], [40]. A placebo-controlled study on the therapy of acute hearing loss with i.v. procaine in dextran solution (albeit with a small patient collective) did not show any benefit of this therapeutic mode [41].

Pharmacological intervention with calcium channel blockers e.g. with acoustic hyperstimulation involving excessive glutamate release and subsequent excitotoxicity is in principle conceivable. One could modulate for example calcium influx through voltage-avtivated calcium channels that induce the exocytosis of glutamate [42]. More than 90 % of these Ca2+ channels belong to the class D L-type Ca2+ (Cav1.3) channels [43], [44]. Since the sensitivity of the Ca2+ channels in the inner hair cell towards known L-type Ca2+ channel blockers (nimodioin, nifedipine, verapamil, diltiazem) is much too low compared to usual therapeutic plasma levels and selective antagonists are not yet known for class D Ca2+ channels, a pharmacological intervention is not currently possible at this level. This is also supported by animal experiments in which nimodipine application conferred no protection against noise damage [45].

2.5 Reduction of endolymph volume

Clinical studies have shown that acute low frequency hearing loss, especially with electrophysiological indicators of a probable endolymphatic hydrops, can be better treated with a dehydration therapy than with a rheologically-based therapy [46]. Mannitol is the main component of the dehydration therapy after Vollrath. This osmodiuretic is filtered by the glomeruli but is not or is only incompletely resorbed by the tubules, so that water is retained in the kidney tubules and diuresis occurs. In addition to intravenous mannitol therapy, the carbonic anhydrase inhibitor acetazolamide is also orally applied. Side effects such as hypokalaemia and displacement of the acid-base balance (metabolic acidosis) must be watched out for.

2.6 Antioxidants

Various factors such as acoustic trauma, hypoxia/ischemia, ototoxic medications and chemicals can lead in the cochlea to a disrupted balance between the formation of reactive oxygen and nitrogen species and endogenous antoxidative systems so that an oxidative stress can result [47], [48], [49], [50]. Cochlear injury induced by oxidative stress in animal experiments can be prevented or at least reduced by the application of antioxidants. Amongst the antioxidants that might feasibly be utilised in the treatment of acute damage to the central nervous system include vitamins (e.g. beta carotene as precursor of vitamin A, vitamin C, E), co-enzyme Q10, melatonin, α-liponic acid, ebselen, superoxide dismutase and superoxide-dismutase like molecules, N-acetylcysteine, glutathione, metal ion chelators, lazaroids, uric acid, creatine, nicaraven and others. Although some of these compounds show potential benefits in animal experiments, most did not meet expectations in clinical trials [51]. Since the absence of evidence for efficacy does not prove ineffectiveness, these substances remain interesting for the therapy of acute inner ear disorders in particular.

In a prospective, randomised study, Joachims et al. (2003) compared the effectiveness of additional application of vitamin E with their standard therapy for ISSNHL (prednisone, magnesium, carbogen). A more than 75% improvement in hearing threshold was achieved in the vitamin E group (26 of 33 patients), while in the standard therapy group only 15 of 33 patients responded. This difference was statistically significant. The number of complete remissions was however almost identical in both groups. A current meta-analysis of randomised studies on the use of vitamin E (total number of 81,788 patients) and beta carotene (total number of 138,113 patients) for the prevention of cardiovascular disease came to the conclusion that the application of beta carotene as a nutritional supplement should be actively discouraged because of the extra risks it entails (slightly increased mortality). The use of vitamin E also brought no benefit regarding cardiovascular end points [52], [53]. Considering the results of these meta-analysis, the application and clinical testing of vitamin A and E as antioxidants for the therapy of acute hearing disorders should therefore be put into question.

α-Liponic acid was earlier considered to be a vitamin, but is no longer so since a disorder associated with its deficiency has not yet been identified. Alpha-liponic acid is reduced intracellularly via various enzymes and in this way influences intracellular processes through its effect as a radical scavenger, its promotion of recycling of other antioxidants, its reinforcement of glutathione synthesis and its modulation of transcription factors including NFκB in particular [54]. A current meta-analysis of randomised studies (1,258 patients) confirmed the clinical experience that a diabetic neuropathy can be favourably influenced by supplementation of high doses of α-liponic acid [55]. Thus an approved efficacious antioxidant is currently available, even though it is not currently reimbursed by legal health insurances in Germany. Animal-experimental studies have verified the effectiveness of α-liponic acid in protecting the cochlea against oxidative stress by ototoxic medications [56], [57]. The therapeutic efficacy against acute inner ear events, such as acute hearing loss or acoustic trauma, should now be investigated in clinical studies.

2.7 Thrombocyte aggregation inhibition

The application of thrombocyte aggregation inhibitors employed for the acute therapy and prevention of cardiovascular diseases (e.g. acetyl salicylate) is also conceivable for the therapy of acute inner ear disorders where a vascular cause is suspected. Other agents such as prostaglandins and related products of arachidonate metabolism also inhibit thrombocyte aggregation. Weinaug (1988) reported on the treatment of 34 acute hearing loss patients with acetyl salicylate and meclofenoxate (a nootropic, see below) and found no benefit of this therapy regarding hearing performance compared to earlier results achieved with a null therapy [58]. With prostaglandins one must also take into account the vasodilatory effect with its possible "stealing effects" (see 2.3).

2.8 Medication-based fibrinogen reduction

Reduction of fibrinogen concentration presents a further possibility to improve the fluid flow properties of the blood by reducing plasma viscosity. The extracorporeal elimination of pathogenic proteins by apheresis confirmed in clinical studies is discussed in part 4.1. With medication-based fibrinogen reduction, protease snake toxins such as batroxobin from the common lancehead Bothrops atrox are used that cleave fibrinopeptide A from fibrinogen. Clinically controlled studies on the therapy of acute hearing loss have produced inconsistent results. While Kubo et al. (1988) in a randomised therapy comparison study showed a superiority for batroxobin therapy compared to therapy with betamethasone, Shiraishi et al. (1991) found no statistically significant difference regarding hearing recovery [59], [60]. Suzuki et al. (2003) even demonstrated a superiority of glucocorticoid therapy (prednisolone) in a retrospective cohort study compared to medication-based fibrinogen reduction [61].

Starting from the idea that particularly severe acute hearing-losses are caused by microthrombi in the labyrinthine artery, therapy of acute hearing loss with fibrinolytics has been proposed. Apart from breaking down the thrombus, this treatment also leads to a reduction in blood viscosity by lowering fibrinogen levels. For pilot studies on this therapeutic strategy see Klemm et al. (1984, streptokinase) and Hagen (1991, tissue plasminogen activator) [62], [63]. Because of the unfavourable benefit risk scenario amongst other things, this drug group was not studied any more with regard to inner ear disorders.

2.9 Hyperbaric oxygen therapy

With hyperbaric oxygen (hyperbaric oxygenation, HBO) the patient breathes in pure oxygen at an increased environmental pressure in a pressure chamber. In this way the oxygen partial pressure climbs in the blood and more oxygen can diffuse into the tissue per unit of time.

In animal experiments it has been shown that oxygen partial pressure after hyperbaric oxygenation also increases in the perilymph compared to initial values by several hundred percent in the healthy inner ear, and after acoustic trauma. Slightly raised values also persist for one hour after a course of hyperbaric oxygenation. With oxidative stress to the cells of the sensory epithelium and the auditory nerve fibres in the cochlea, the increased diffusion pathway due to the raised oxygen partial pressure leads to an increased oxygen supply of these structures and in this way promotes the recovery of different types of damage. In contrast, an isobaric oxygenation (normal environmental pressure) leads to much smaller increases in oxygen partial pressure in the perilymph. Refer to the works of Lamm, C., Lamm, H., Lamm, K. et al. [64], [65], [66] for a discussion on animal-experimental studies related to this topic.

Treatment of acute and chronic inner ear disorders by hyperbaric oxygenation (HBO) has now been administered for almost four decades. An extensive review and analysis of clinical studies involving a total of several thousand patients was published by Lamm et al. 1998 [67]. Only relatively few publications have appeared on the application of hyperbaric oxygen therapy as a primary therapy for inner ear disorders. These studies have produced varying results: Kestler et al. (2001) for example compared the results of a HBO-therapy for ISSNHL with one involving prednisolone, dextran and pentoxifylline. They found that the HBO therapy was inferior [68]. In contrast, Fattori et al. when comparing primary HBO-therapy with an intravenous rheological therapy with buflomedil (medication group as pentoxifylline and naftidrofuryl) found a statistically significantly higher remission rate after HBO-therapy [69]. These results were confirmed by the results of Racic et al. (2003), who showed a statistically-significantly higher absolute hearing-improvement and remission rate with HBO therapy in comparison to rheological therapy with pentoxifylline [70]. Aslan et al. came to the conclusion that adjuvant therapy with HBO is superior to a standard therapy with prednisone, stellate block and betahistin alone [71]. Topuz et al. also found a benefit of HBO-therapy as an adjuvant to prednisone, dextran and diazepam in the treatment of ISSNHL (2004) [72].

The majority of clinical reports refer to cases of secondary HBO-therapy for ISSNHL. These studies imply that hyperbaric oxygen confers benefits as a secondary therapy where other treatments have otherwise proven unsuccessful (see for example: [73], [74], [75], [76]). A meta-analysis by the Cochrane-Collaboration on "Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus" is currently being prepared.

2.10 Antiviral therapy

Various viral infections can lead to hearing loss with or without disturbances in equilibrium and tinnitus. Amongst the viral infections associated with hearing disorders include: german measles, mumps, measles, varicella zoster, herpes simplex, Epstein-Barr, cytomegaly, hepatitis, adeno-, influenza, parainfluenza, coxsackie, and FSME viruses. Inborn and acquired virally-conditioned hearing disorders are distinguished between.

While with most of these virus infections prevention, especially vaccination, is the primary approach, for some infections antiviral medications are available: e.g. with herpes infections (aciclovir, valaciclovir, famciclovir, brivudin), cytomegaly virus (CMV) infections (ganciclovir, cidofovir, foscarnet, note: frequent side effects), influenza (amantadin, zanamivir, oseltamir) and of course the numerous medications available for HIV. The application of interferons as virostatics (and immune modulators) for the therapy of virally-induced hearing disorders is of course conceivable, but has only been described up until now in uncontrolled studies on patients with severe acute hearing loss [77]. See part 5.3 for information on the antiviral therapy of hearing disorders.

2.11 NMDA receptor antagonists

One of the important pathophysiological mechanisms that contribute to hearing loss especially in acoustic trauma and probably also in the origin of tinnitus is excitotoxicity. If the main neurotransmitter glutamate is released excessively at the afferent synapse of the inner hair cell, a neurotoxic effect can arise that has been termed excitotoxicity [78]. For up-to-date reviews on this see Oestreicher et al. (2002) [79] and Puel et al. (2002) [80]. Here, the therapeutic strategy would be to employ N-methyl-D-aspartate-(NMDA) receptor blockers such as memantine and caroverine [81], [82]. In animal experiments in addition to caroverine, MK 801, carbamathione and riluzole have also shown a protective effect against excessive noise exposure. For a review see Plontke and Zenner (2004) [83].

The influencing of NMDA receptors by extracellular magnesium ions also represents an interesting therapeutic approach. The excessive calcium influx should be prevented by these during an excitotoxic episode. In animal experiments, protection could be afforded by pre-, para- or even postexposure magnesium application in acoustic trauma. For this purpose see the experiments of Joachim's as well as Scheibe's research groups [84], [85], [86]. See chapter 5.2 for information about clinical application with acoustic trauma and acute hearing loss.

2.12 Other medications

Anticoagulants like thrombocyte aggregation inhibitors are used for the prophylaxis and therapy of thrombembolic processes. As such, these medications have also been employed in the treatment of acute hearing loss, but have only been examined in a few studies, without any significant superiority having been demonstrated over other therapies [87], [88].

Nootropics such as piracetam are supposed to increase the vigilance and intellectual abilities of demented individuals due to an "improvement in the microcirculation and metabolic processes in the brain", without any mechanism of action having yet been clarified. These medications have also applied for the treatment of acute hearing loss and tinnitus. For none of the mentioned indications was an adequate confirmation of efficacy acquired. In a randomised comparative study with piracetam in 6 % HES, Gutmann and Mees found no difference regarding hearing recovery compared to therapy with naftidrofuryl in 6 % HES [89].

The phytotherapeutic Ginkgo biloba preparations that are also employed as nootropics number amongst the most frequently applied medications for acute hearing loss and tinnitus. Several studies have verified an efficacy in improving cognitive functions amongst patients with dementia. For a meta-analysis see Birks et al. (2002), [90]. A rheological and an antioxidative effect have been assumed to be the primary mechanisms. However, the precise mechanism of action remains unknown [91]. Some randomised, controlled studies on the application of Ginkgo biloba for acute hearing loss and tinnitus exist: for ISSNHL Hoffman et al. (1994) reported a higher full remission rate upon treatment with ginkgo extract and HES compared to therapy with naftidrofuryl and HES [92]. Reisser and Weidauer (2001) found no benefit of treatment with Ginkgo and dextran compared to therapy with pentoxifylline and dextran [93]. Various doses of Ginkgo biloba were compared by Burschka et al. (2001). The authors came to the conclusion that a therapy with high doses of Ginkgo biloba should be preferred in "mild" cases of acute hearing loss without tinnitus because of the minimal side effects associated with this preparation [94]. A current meta-analysis failed to verify an efficacy of Ginkgo biloba against tinnitus as the primary target parameter [95].

The calcium overloading of cells occurring with oxidative stress is thought to be blocked by cinnarizine or its fluorinated analogue flunarizine. An improvement in erythrocyte fluidity has also been described for these substances. However, a clinical effectiveness of these medications in the treatment of inner ear disorders has not yet been verified. Meier et al. (1993) compared the relative hearing recovery after flunarizine application with placebo amongst acute hearing loss patients (as part of another clinical study) and found no statistically significant difference in efficacy [96].

Immunosuppressants have been employed for the treatment of hearing-losses due to autoimmune disorders. Cytotoxic (cyclophosphamide, azathioprin, methotrexate), T lymphocyte activation-inhibiting, non-cytotoxic (e.g. glucocorticoids) as well as antibodies and receptors (e.g. infliximab and etanercept) can be distinguished amongst the immunosuppressants. Whereas therapy with non-organ-specific autoimmune disorders is generally determined by the corresponding organ manifestations, continuous therapy of the primary autoimmune disorder of the inner ear (AIED) e.g. with methotrexate, is not indicated due to its lacking efficacy and the sometimes serious side effects (see chapter 5.4 [97].

Sodium fluoride, calcium, cytokines and bisphosphonate have been proposed as conservative medicinally-based approaches to treat otosclerosis [98]. While fluoride is deposited in the bones, since in the hydroxyapatite F- substitutes OH- and in this way stimulates bone growth at high doses, bisphosphonates specifically inhibit the resorption activity of osteoclasts, whereby the highest efficacy has been ascribed to the third generation bisphosphonates. Proof of efficacy for these medications against otosclerosis has not yet been obtained in clinically controlled studies (see chapter 5.7.2).

Controlled clinical studies have also been performed with regard to hearing disorders on the numerous pharmaceutical and non-pharmaceutical treatments available in traditional Chinese medicine. In a recent paper, the therapeutic effect of the phytotherapeutic puerarin (an extract of Pueraria thomsanii) was compared with that of anisodamine regarding acute hearing loss and was found to be superior [99]. Both medications have been ascribed vasodilating (see 2.3) and thrombocyte aggregation inhibiting properties.

2.13 Pre-clinical experimental therapy forms

2.13.1 Growth factors

Growth factors such as GDNF, BDNF or NT-3 number amongst the substances that until now have only been tested preclinically in animal-experimental studies on the protection and therapy of the inner ear. Animal models have been developed for damage induced by noise or ototoxic medications. Growth factors are involved in development, cell differentiation, cell survival and targeted axonal regeneration (review in [100]). The application of growth factors with cochlear implants represents a particularly interesting approach. Signal transmission to the auditory nerves might be improved by applying neurotrophins either at the same time as or some weeks after implantation. This should be achieved by preventing the degeneration of auditory nerve fibres and spiral ganglion cells and the initiation of a directed growth of afferent nerve fibres to the cochlear implant electrodes. For this purpose either catheter-based application systems (e.g. through a separate channel in the cochlear implant electrode [101]) or biopolymer coated electrodes can be used. An international group of scientists, engineers and doctors as part of the project "EUBioEar" funded by the European Union (http://www.uta.fi/projektit/eubioear/) has set about fulfilling this task.

2.13.2 Apoptosis inhibitors

Oxidative stress, e.g. from ischaemia, noise, ototoxic medications and chemicals, can lead to an initiation of signal cascades resulting in programmed cell death (apoptosis) in the inner ear. Various proteases play a role in this. The inhibition of the activity of these proteases therefore represents a primary approach to intervene so that the apoptotic death of cells in the inner ear can be prevented after a traumatic insult. The following therapeutic strategies are currently being examined: inhibition of caspases, inhibition of calpain, inhibition of the JNK signal cascade and upregulation of antiapoptotic genes (Bcl2). Initial pre-clinical success has been achieved in the protection against acoustic trauma and ototoxicity [102], [103], [104]. In the future it may also be possible to apply apoptosis inhibitors when implanting cochlear implant-electrodes so that apoptotic signal cascades do not become activated upon the trauma induced by insertion [105]. Such inhibitors could be applied to the inner ear via application systems such as those described in chapter 2.13.1 and 3.2.4 so that any undesirable cell death can be prevented.

2.13.3 Gene therapy, regeneration and stem cell therapy

The most frequent hearing disorder is chronic sensorineural hearing loss. A basic problem with this disease is the lacking spontaneous or trauma-induced regeneration capacity of the hair cells and spiral ganglia cells in the mammalian cochlea. Current results of animal-experimental studies in the field of regeneration medicine and stem cell therapy allow opportunities to be recognised for the future application of these procedures in the treatment of inner ear hearing loss. Some aspects of these possible future therapies shall therefore be briefly addressed here.

Gene therapy is an experimental therapeutic form with which a defined foreign gene is introduced into the genetic material of a recipient in order to correct any pathological alterations. Here one can distinguish between somatic gene therapy, i.e. the correction of genetic defects in body cells, and germ-line gene therapy, where cells in the germ-line are corrected so that the modifications carried out can also be inherited by the following generation. This can be carried out in the form of a substitution therapy (correction of missing or defective gene function), a suppression therapy (suppression of pathogenic gene activities) or an additive therapy (reinforcement of already active physiological processes) [106].

The goals of gene therapy with respect to hearing disorders are:

1) to reinforce endogenous protective systems such as inhibitors of apoptotic signal cascades and anti-oxidative systems. Induction of the overexpression of neurotrophins represents another such approach.

2) to specifically correct mutations in dominant alleles or specifically overexpress a gene involved in recessive hereditary hearing impairment, and

3) to influence gene expression so that missing cells are replaced (regenerated) in the inner ear (especially hair cells and spiral ganglia cells).

Its small dimensions and relative isolation make the inner ear a useful object of study for gene therapy. Genes are usually brought to their destination with the help of viral vectors. However, non-viral vectors are of special interest because of the reduced technological challenges, their low toxicity and their low immunogenicity even though they are of relatively low efficiency.

Two impressive examples emphasise the potential of gene therapy in the inner ear and strengthen the hopes that even hereditary hearing loss may be able to be treated one day: in the "shaker2" mouse, an animal model with neuroepithelial inner ear defects, both hearing loss and equilibrium disturbances could be corrected by introduction of the wild-type gene [107]. A similar feat was also made possible with the "Whirler" mouse [108]. For reviews on current aspects of gene therapy see Avraham and Raphael (2003), Lalwani et al. (2002), Minoda et al. (2004), and Pfister and Loewenheim (2002) [109], [110], [111], [112].

Regeneration processes in the inner ear of birds have been known now for almost two decades. For reviews on the cell cycle and in vivo regeneration see Cotanche (1999), Smolders (1999), Loewenheim (2002) and Ryan (2003) [113], [114], [115], [116]. Today, the most promising approaches for in vivo regeneration in mammals are related to the exploitation of Math1 (Atoh1). This gene encodes a basic helix-loop-helix transcription factor and is required for the development of hair cells in the cochlea and the vestibular organ [117]. The Math1 gene introduced into the cochlear endolymph of the guinea pig (via an adenoviral vector) leads to the development of ectopic hair cells in the cochlea (Figure 1 [Fig. 1]) [118]. Also, the use of the human homologue Hath1 shows the clearly increased generation of new hair cells in the macula utriculi of the rat [119] compared to earlier reports [120], [121].

Thus, not only was it possible to generate a significant number of new hair cells in mammalian inner ear with the viral vector-mediated transfer of Math1 and Hath1 [119], but it was also possible to demonstrate for the first time the regeneration of hair cells in mammalian cochlea [118]. In a very recent report it could be demonstrated that Math1 (Atoh1) not only induces regeneration of hair cells but also "…substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal" [122]. Another strategy could be the generation of functional sensory hair cells through mitosis by a targeted delition of the retinoblastoma gene - a regulator of cell cycle exit in hair cells. Acute loss of Rb1 in postnatal hair cells caused cell cycle reentry of these otherwise terminal differentiated hair cells [123].

The replacement of body tissues using stem cells shall prove to be a paradigm shift for medicine in the coming decades. Nevertheless, where human embryonic stem cells are the subject of research, considerable ethical problems are associated with their use. The first successes in the stem-cell-based generation of highly specialised cells for the therapy of degenerative diseases such as Parkinson's disease, heart disease and diabetes mellitus have also extended to research on stem-cells in the region of the inner ear (for reviews see e.g. Li et al. (2004) and Parker and Cotanche (2004), [124], [125]).

Embryonic stem-cells are pluripotent and as such possess the greatest differentiation capacity of all human cells. In recent experiments the group of Stefan Heller in Boston were able to generate precursor cells of hair cells from embryonic stem-cells in the mouse. These precursor cells express a range of marker genes that are also expressed in sensory areas of the inner ear during development. The in vitro generated precursor cells are able to integrate into the developing inner ear of a chicken embryo after implantation. These cells not only express hair cell-typical markers in vivo, but they also form hair bundles (Figure 2 [Fig. 2]) [126]. The same research group also isolated adult stem-cells from the inner ear of the mouse and confirmed their differentiation at least into hair cell-like cells, as verified by their typical marker expression [127].

Regarding regeneration and stem-cell therapy it is being stated more and more that it does not suffice merely to regenerate sensory cells, since both the complex architecture of the Corti organ and the specific neural innervation are fundamental for restoring hearing function. Against this, however, another hypothesis states that it may not in fact be necessary to restore the highly organised form of a Corti organ. Any form of organisation of cells expressing the property of mechanoelectrical transduction may suffice, as long as the sensory cells make contact with the afferent nerve fibres and acoustically produced mechanical oscillations can be effectively transmitted via a tectorial membrane or a similar structure to mechanosensors on the sensory cells [124]. A regenerated inner ear in a mammal may therefore look similar to that observed in a bird or a reptile. Considering the extraordinary plasticity of cerebral portions of the auditory pathway, an adequate hearing capacity might nevertheless arise. Here one is reminded of successes achieved with speech cognition after implantation of cochlear implant electrodes with only a few stimulation channels.

A second argument for attempting to regenerate hair cells even without complete restoration of the architecture of the Corti organ is the production of neurotrophic factors by the newly generated hair cells that might positively influence the retention of afferent nerve fibres. The retention of nerve fibres would in turn increase the effectiveness of a subsequent cochlear implant.


3. Medication-based procedures II: local application of drugs

3.1 Introduction

Over the last years there has been increasing interest in the treatment of inner ear disorders by local rather than systemic application of medicines. Substances are applied intratympanically under the premise that they will diffuse through the round window membrane into the scala tympani and then are distributed from there within the inner ear fluids [128]. The idea of a topical application of medicine to the inner ear is not new. Local anaesthetics and aminoglycosides were applied decades ago through the tympanic membrane into the tympanic cavity to treat inner ear disorders [129], [130].

The most frequently used form of intratympanic therapy is the injection of gentamicin into the middle ear for selective chemical labyrinth ablation in Menière's disease (see the chapter by Walther in this volume). Of major current interest are the increasing number of clinical studies regarding the local application of glucocorticoids for acute hearing loss [131], [132], [133], [134], [135], [136], [137], [138], Menière's disease [139], [140], [141], [142] or tinnitus [143], [144], [145], [146], [147]. Also other substances, such as local anaesthetics and neurotransmitters (-antagonists), have already been tested in humans [148], [149]. A number of different types of medication including growth factors, neurotransmitters, neurotransmitter antagonists, antioxidants, apoptosis inhibitors and antisense-oligonucleotides are the focus of current research. Numerous animal-experimental studies have shown promising results concerning e.g. otoprotection [104], [150], [151], [152], [153], [154], [155], (see also Plontke and Zenner (2004) for a review [83]). Of special interest is also local viral and non-viral gene transfer for the treatment of inner ear disorders [156], [157], [158], [159]. Here, local application to the inner ear represents a particularly useful alternative to systemic therapy. It should be noted, however, that no medicine is as yet approved anywhere in the world for local application in the treatment of inner ear disorders.

Local application is based on the rational approach that despite lower dosing, medications applied topically to the round window membrane can reach higher active levels in the inner ear fluids than would be the case with systemic application. Recent pharmacokinetic studies have confirmed this hypothesis [138], [160], [161], [162], [163], [164]. Potential systemic side effects and complications from a longer lasting higher dose therapy can be avoided through topical application (e.g. a high dose glucocorticoid therapy [165]). Substances applied locally at a low dose can then be administered where there are major restrictions or even contraindications associated with systemic application.

Apart from the selection of a suitable substance, the following additional questions also arise regarding clinical application:

- What are the principles underlying substance distribution in the inner ear fluids, especially after local application and what target structures are reached in the inner ear by the locally applied substances?

- What dose, application procedure and application protocol should be employed?

- What levels of medication are reached in humans within the inner ear fluids?

- What are the main factors that lead to the sometimes very different effects seen after local therapy?

Currently, the applied doses, application protocols and application systems are mainly empirically justified. The varying results from the therapy of Menière's disease by intratympanic gentamicin application serve as current examples of the uncertainty surrounding application strategies. While some authors observed hardly any hearing-losses [166] or deafness as unwanted effects following empirically based titration strategies, others found complete deafness on the treated ear in more than 20 % [167] or even 80 % [168] as a result of intratympanic gentamicin application. It is therefore necessary to acquire an understanding about the quantitative substance distribution in the inner ear fluids after local application of medications.

3.2 Pharmacokinetic aspects of local drug application to the inner ear

3.2.1 General principles of substance distribution in the inner ear

Since unlike circulating blood the inner ear fluids are not actively "stirred", one has to consider that a locally applied substance is not rapidly distributed uniformly over the entire inner ear. As such it is not sufficient to know only the volume of the fluid spaces in the inner ear and the amount of applied medication in order to calculate the concentration of substance in the inner ear. The inner ear represents rather a geometrically complex multicompartmental structure with numerous surfaces between the compartments and between the inner ear and the "outside world", i.e. the systemic blood circulation. Locally applied substances distribute themselves according to physical laws within and between the individual compartments. Diffusion seems to be the main process underlying the distribution of particles in the cochlear fluids [169], [170]. The diffusion coefficient depends on the viscosity of the fluid in which diffusion occurs and on numerous structural characteristics of the diffusing particles/ molecule, with molecular weight playing a dominant role [171].

Transfer of substances through the round window membrane (RWM) to the scala tympani of the inner ear also appears to be a mainly passive process (diffusion). Active transport processes have been assumed particularly for larger molecules and particles, but have not been confirmed so far [128]. The rate at which medications cross the round window membrane to the inner ear depends on the histological property, size and geometry of the RWM. Animal experiments have shown that the round window membrane behaves as a semipermeable membrane despite its three-layered nature. Antibiotics (especially aminoglycosides), arachidonic acid metabolites, local anaesthetics, bacterial endo- and exotoxins, albumin, glucocorticoids, antioxidants, neurotransmitters (and their antagonists), neurotrophins, viruses and other agents have been applied to the RWM and their transition into the scala tympani has been assessed either histomorphologically, quantitatively by measurement of concentrations, or indirectly from the measurement of their physiological effects e.g. on the hearing threshold (reviews in: Goycoolea 2001, Plontke and Salt 2003 [128], [172]). The permeability of the round window membrane might be influenced by simultaneous application of other substances [173], [174]. Although the permeability of the RWM is an important parameter determining the entry of substances into the scala tympani of the cochlea, it is important to consider that (most likely) only the quantity of medication reaching the inner ear is influenced by this, and not its relative distribution in the subsequent compartments of the inner ear (for explanation see below).

The general processes of substance distribution have been termed by Salt as "longitudinal" and "radial" processes (Figure 3 [Fig. 3]) [170], [175], [176]. Amongst the longitudinal processes include the passage of medications from the middle ear into the scala tympani through the RWM, the diffusion of substances along the scalae, the communication between the scala vestibuli and the scala tympani through the helicotrema at the cochlear apex, and the passage of medications from the basal section of the scala vestibuli into the vestibulum. The transportation of substance is also influenced by the flows of endolymph and perilymph. In the normal, unopened cochlea, however, the flow rates of endolymph and perilymph are extremely low, so that their effect on substance distribution can be regarded as negligible in the inner ear compared to diffusion [175], [177].

The most important radial substance distribution process is clearance. Strictly speaking, this refers to the passage of applied substances from the cochlear fluids to the environment via removal by the systemic blood circulation in the lateral wall and the modiolus. Broadly speaking, clearance includes all processes that lead to the reduction of substance levels in the cochlear fluids, i.e. in addition to the above, uptake into the fluid spaces of the modiolus, uptake into intercellular spaces, and inactivation of the applied substance by metabolization or binding. Both clearance from the middle ear and clearance from the various fluid spaces of the inner ear must be considered. The interplay of diffusion within and clearance from the fluid spaces of the inner ear is a key to determining the distribution inner ear of substances applied locally to the round window membrane.

Other "radial" distribution processes include communications between the various compartments (Figure 3A [Fig. 3]). The communication between the scala tympani and the scala vestibuli via the lateral wall appears to be particularly rapid [176], [178], [179].

3.2.2 Pre-clinical studies on pharmacokinetics in the inner ear

The development and approval of medications and drug application systems requires the study of the pharmacokinetics, toxicity and efficacy of medications applied locally to the RWM. Preclinical animal-experimental studies lay the foundations for introducing a therapeutic form into clinical practice. Only a few studies have quantitatively studied concentrations in the inner ear fluids [138], [160], [161], [162], [163], [180], [181], [182]. However, data from two of these studies imply very different perilymph concentrations with similar application modes [138], [160]. However, large deviations in pharmacokinetic profiles in animal experiments considerably restrict their applicability to the human situation (Figure 4 [Fig. 4]). For this reason the problems associated with pre-clinical, pharmacokinetic studies of the inner ear shall now be described in brief.

Because of the extremely small volumes in the fluid spaces of the inner ear, the withdrawal and analysis of samples from the inner ear represents a considerable technical challenge. Just as one example, the entire perilymph volume in the cochlea of the guinea pig is less than 10 µl [183]. In most of the studies sample volumes were withdrawn that correspond to or even exceed the cochlear perilymph volume in order to extract adequate sample volumes for pharmaceutical analysis [138], [160], [161], [162], [163], [180], [182]. Measurement of pharmacokinetic profiles (concentration time curves) in the perilymph based on cochlear samples therefore entails a great risk of misinterpretation. This is also because the sampling process itself strongly influences the substance concentration in the perilymph. When withdrawing large sample volumes, the perilymph is diluted by cerebrospinal fluid that flows through the cochlear aqueduct into the perilymph [172], [184], [185], [186]. Samples obtained this way are therefore fraught with artefacts. It is therefore important to evaluate whether actual perilymph concentrations or merely "perilymph sample concentrations" are dealt with when interpreting published pre-clinical pharmacokinetic studies on the local application of medicine to the inner ear. Such artefacts can be avoided for example by applying ion-selective electrodes [177] or radioactive tracers [181], although such procedures are not necessarily suitable for all medications. Since direct pharmacokinetic studies are not possible in the inner ear of man (as part of a phase I clinical trial), computer simulations may be helpful for human application as part of a phase II clinical trial. Through the quantitative interpretation of published experimental data using a finite-element computer model (http://oto.wustl.edu/cochlea/model.htm) that considers the anatomy of the inner ear, general pharmacokinetic principles and distribution processes as well as sampling techniques, the results can be better interpreted and artefacts produced by sampling can be corrected for. After detailed analysis of the above-mentioned pre-clinical, pharmacokinetic studies it could be shown that the concentration time curves of methylprednisolone in the scala tympani reported by Parnes et el. (1999), which is cited in current clinical publications as a basis for selecting and dosing this medication, appears to underestimate the actual perilymph concentrations considerably (Figure 4 [Fig. 4]). In order to keep the sampling artefacts as small as possible, modern sampling techniques have recently been employed that can not completely suppress the origin of artefacts, but can at least minimise them substantially [162], [187].

3.2.3 Concentration gradients in the inner ear with local application of drugs

Possibly the most important aspect regarding local application of medicine to the inner ear is that the inner ear represents a multi-compartment model with almost stationary fluids. Since administered medications are removed from the cochlea by clearance, two processes act counteractively with regard to substance distribution: i.e. the (longitudinal) diffusion along a compartment (e.g. the scala tympani) and the (radial) clearance from this compartment (Figure 3 [Fig. 3]).

From the results of pre-clinical studies and the interpretation of this data by computer simulations, the following conclusions can be drawn [169], [172], [178]:

1) Substances applied topically to the round window membrane do not distribute uniformly in the inner ear.

2) Substance concentrations show longitudinal gradients along the cochlear scalae. Basal regions of the cochlea are exposed to a far higher dose than apical regions (Figure 5 [Fig. 5]).

3) Concentration differences also exist between the different fluid compartments.

4) Since the substance distribution along the scalae is determined mainly by diffusion and clearance, concentration gradients in the larger cochleae are expected to be larger (Figure 6 [Fig. 6]).

3.2.4 Drug application systems

Single or repeated intratympanic injection with or without visualization of the round window membrane

The most frequently applied and oldest means for intratympanic drug application is transtympanic injection of a drug solution [129], [130], [148], [188], [189]. The disadvantage of this is the fact that the amount of drug and duration of contact with the round window membrane can not be easily controlled. The patient during and after injection usually lies for a certain period of time with the treated ear pointing upwards. The amount and timepoint of drainage of the solution via the eustachian tube or its resorption through the middle ear mucosa is usually uncertain. In order to prevent the uncontrolled loss of drug e.g. via the eustachian tube, means have been sought to stabilise the applied volume in the middle ear. Fibrin glue has been employed in animal experiments [163], while in man hyaluronic acid [133], [190], [191] or resorbable gelatine-sponges [192] have been applied. Despite this, the doses, dosing intervals and therapeutic durations required to achieve a specific therapeutic goal are hard to predict. Amongst the varied influential factors include anatomical obstacles such as plugs of connective or adipose tissue or so-called pseudomembranes of the round window niche, that in approx. every third patient can lead to the obstruction of the round window membrane, as histological studies have shown in more than 200 temporal bone preparations [193]. Therefore, with all transtympanic injection techniques it makes sense to inspect the round window membrane in detail before drug application. In order to avoid the need for a tympanoscopy, a microotoscope (explorent® GmbH, Tuttlingen, BRD) has been developed with which the round window niche can be inspected in a minimally invasive manner (diameter of the endoscope 1.1 mm). If the anatomical status is normal, a defined amount of drug can then be applied in the same session via the working channel of the microendoscope directly into the round window niche [194].

Another mode of transtympanic medicine application is the "microwick" proposed by Silverstein [195]. A "wick" is advanced into the round window niche via a small tube. The external end of the wick is then located in the external auditory canal. In this way the patient can intermittently apply medications him/herself to the external auditory canal so that they can then reach the round window niche via the wick. For physical reasons an application into the external auditory canal would only work if the wick is completely dry. Only in this way can the drug be transported via capillary action of the wick fibre from the exterior to the interior of the round window niche. In the middle ear the wick must have a direct as possible contact to the round window membrane so that a concentration gradient can arise between the wick and the perilymph in the scala tympani via the round window membrane. The capillary effect can then only arise with a completely dry wick. With a wet wick, substance transportation from the external auditory canal would be dependent on diffusion into the middle ear. An effective application of drug to the inner ear would then be rather unlikely given the now very long diffusion pathway.

Discontinuous drug application via partly or fully implantable pump systems

A device that has already been employed in animals, but which has not yet been approved for humans, is the TI-DDS® (Totally Implantable Drug-Delivery-System) [196], [197]. The manually operated pump releases a defined volume of 5 or 10 µl upon push-button activation. A subcutaneously implanted reservoir can then be filled transcutaneously. Such systems are especially suitable for the treatment of hearing disorders that require a chronic drug application over a longer period of time. Using intracochlear catheter-based application systems it shall be possible in future to introduce drugs directly into the inner ear either in a discontinuous or continuous manner. With many outflow points for the drug, intracochlear concentration gradients can be avoided or even deliberately set up, a benefit which is not available with application to the round window membrane. This principle appears to be of particular current interest with cochlear implant treatment, e.g. via a separate channel in the CI electrode [101]).

Biodegradable polymers

Various materials employed for the controlled release of drug represent another approach. Apart from the already-mentioned fibrin glue and hyaluronic acid that probably also cause changes in substance release in addition to their volume stabilization effect, biodegradable polymers are also addressed here [198], [182]. In our own experiments a continuous release of a marker substance from biodegradable polymer spheres (1 µm diameter) was observed over a period of 24 hours (unpublished results). The coating of cochlea implant electrodes with biodegradable carrier substances for drugs is also interesting, where glucocorticoids, antioxidants, apoptosis inhibitors or neurotrophins could be employed to counteract any harmful effects of the insertion trauma, to ensure the survival of the spiral ganglia, or to stimulate the growth of neurites towards the CI electrodes [105].

Continuous drug application

The surest way to achieve a defined level of drug at the round window membrane is to employ a continuous drug application via partially or fully implantable catheter systems and pumps. Although various catheter systems might be employed (mostly not approved for human use), the round window microcatheter from DURECT (RWµCathTM, DURECTTM, Co., Cupertino, USA) represents the best characterised system [136], [137], [149], [167], [199]. Possibly because of its high price, a lack of convincing clinical studies, and the dearth of approved drugs for local drug application to the round window membrane, and probably also because of a lacking interest of the pharmaceutical industry in this area of application, production of the catheter was halted in 2004.

Influence of the application system on pharmacokinetics with round window application

Concerning the influence of various application systems and dosing schemes on medication levels in the inner ear, the following conclusions can be drawn on the basis of a detailed analysis of animal-experimental studies on inner ear pharmacokinetics:

1) The choice of application system is of high importance for determining absolute drug levels in the inner ear.

2) The time that the drug remains in the middle ear and in contact with the round window membrane is decisive.

3) The highest intracochlear drug levels are reached as expected after continuous application to the round window membrane.

4) The relative distribution of the substances in the inner ear seems to depend basically on the relationship between the duration of application and clearance (Figure 7 [Fig. 7]).

3.2.5 Conclusions for clinical application

The above-mentioned aspects that have been described in detail are of great relevance for the clinical application of topical drugs to the inner ear. In order for the same active dose to be reached in the vestibule, higher drug levels are probably required in the basal cochlear turn of man than would be required in (smaller) experimental animals. This is particularly important in the therapy of Menière's disease by intratympanic drug application, where one also has to take into account the relative vestibulocochlear toxicity of a therapeutic form.

It is also important to develop application methods where the amount of substance in the middle ear and the application duration can be controlled as effectively as possible.

The baso-apical concentration gradients in the cochlea are also of clinical interest. The high drug levels in the basal (high frequency) region compared to the lower levels in the apical region of the cochlea (low frequency) can be exploited for the treatment of inner ear disorders. High-frequency tinnitus and high-frequency inner ear disorders are of special interest here, for instance where hearing-loss is due to noise exposure. In contrast, it might not or only barely be possible to treat hearing disorders in the middle and lower frequency range by intratympanic drug application if medications are to be used with only a small therapeutic range. Therapeutic drug levels in the apical turns of the cochlea might then achieve toxicity in the basal sections of the cochlea and in the vestibular organ.

3.3 Clinical studies on local drug application to the inner ear

Over the last years there has been a clear increase in the number of reports on the clinical application of topical drugs to the inner ear for the therapy of acute sensorineural hearing loss. A selection of these studies is listed in Table 2 [Tab. 2]. Mostly glucocorticoids (particularly methylprednisolone and dexamethasone) were applied. From the table it is clear that most of these studies are case reports, i.e. results with a low evidence level. Comparisons of treatment results with control groups are only found in a few studies.

The synopsis of the results of the different studies listed in Table 2 [Tab. 2] allows us to presume that the intratympanic application of glucocorticoids with certain indications, e.g. with non-responsiveness to an initial, guideline-consistent, systemic therapy, represents a reasonable therapeutic alternative. To this end only the results of one randomised comparative study [134] and one retrospective, controlled cohort study [199] are available. Because of pharmacological-pharmacokinetic considerations and earlier experience, such a therapeutic form would also appear to be reasonable as an initial therapy for acute hearing loss. However, one cohort study carried out to answer this (intratympanic glucocorticoid dosing as an adjuvant to systemic treatment) was not able to confirm this hypothesis [200].

In our own studies, a follow-up local therapy (i.e. intratympanic"salvage therapy") was offered to patients with acute, severe to profound, sensorineural hearing loss or acute anacusis and failure of initial, guideline-consitent, systemic therapy. These patients had a very poor prognosis regarding the recovery of their hearing thresholds. If a tympanoscopy was able to exclude a perilymph fistula, a RWµCathTM (see above) was implanted during the same session. Over two to four weeks either methylprednisolone hydrogen succinate (Urbason Solubile®, Aventis Pharma, Bad Soden, Germany) at a concentration of 40 mg/ml and a flow rate of 10 µl/h (corresponding to 9.6 mg/day) or dexamethasone dihydrogen phosphate (Fortecortin Injekt®. Merck, Darmstadt, Germany) at a concentration of 4 mg/ml and a flow rate of 5 µl/h (corresponding to 0.48mg/day) were applied continuously to the round window niche via an external drug pump carried outside on the body (Panomat C5, Disetronic Medical Systems, Burgdorf/Switzerland). The results of the hearing recovery were compared with the results of a historical control group without any "rescue therapy". Using a subgroup analysis to identify suitable patient collectives for prospective randomised clinical studies patients with anacusis, i.e. with a non-measurable hearing threshold in the pure tone audiogram were excluded. In that case, a stronger improvement in the mean hearing threshold (threshold at [0.5+1+2+3 kHz]/4) in the local therapy group (n=14) of on average 19 dB (95 % CI: 6, 32) from 87 dB (95 % CI: 78, 96) to 68 dB (95 % CI: 53, 83) was seen in comparison with that seen in the historical control group (n=14) which increased on average by 5 dB (95 % CI: -2, 11 ) from 86 dB (95 % CI: 76, 95) to 81 dB (95 % CI: 67, 96), (p<0.05). Reports from other authors showed even more marked effects of local glucocorticoid application with a similar indication, although a control group was lacking with these case studies [133], [136], [137]. Noted but not mentioned further here is the fact that the usually employed glucocorticoid preparations (see Table 2 [Tab. 2]) show differing osmolarity and pH-values apart from their very high concentrations. The importance of these pharmaceutical-technical characteristics for local application to te RWM has only been examined inadequately up until now.

Topical inner ear therapy employing glucocorticoids represents a highly promising therapeutic form. However, its efficacy can not yet be regarded as confirmed. As such, the efficacy, safety, indications, dosing and application protocols need to be investigated in higher evidence level studies. For this reason we initiated a placebo-controlled, double-blind, randomised, multicentre clinical trial in 2003 to assess the effectiveness and safety of continuous, intratympanic, dexamethasone application amongst patients who underwent an unsuccessful systemic therapy. Fifteen patients have as yet been included at the time of printing.


4. Non-medication-based therapeutic procedures

4.1 Fibrinogen reduction by apheresis

Apheresis refers to a therapeutic procedure based on the extracorporeal elimination of pathogenic proteins, protein bound pathogenic substances or pathogenic cells from the blood. Non-selective and selective plasma apheresis, whole blood apheresis and cytoapheresis are distinguished.

For treating hearing disorders, the selective plasma apheresis procedures H.E.L.P. ® apheresis (heparin-induced extracorporeal LDL-precipitation, B.Braun, Medizintechnologie GmbH, Germany) and possibly the membrane-differential-filtration (rheopheresis) are relevant. However, the efficacy and safety of apheresis in the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) have been shown up to now only for the H.E.L.P.® apheresis.

Using this procedure, from the plasma of a patient separated by a plasma filter (primary separation), pathogens are removed in a secondary circulation by precipitation (with H.E.L.P.® apheresis) or by another filtration process (rheopheresis). The patient is then supplied with the cleaned plasma again.

The principle of H.E.L.P.® apheresis that is already routinely applied in some hospitals and outpatient clinics is illustrated in Figure 8 [Fig. 8]. The fibrinogen reduction in the plasma lowers the plasma viscosity and reduces the aggregation tendency of the cellular blood components. Unlike hypervolemic haemodilution with dextran or HES, the haematocrit and therefore the oxygen transport capacity of the blood remains constant. The reduction of LDL and cholesterol leads also to an improvement in endothelial function.

Two prospective, randomised studies of a high evidence level by Suckfüll et al. compared therapy with H.E.L.P.® apheresis to a guideline-compliant standard therapy with prednisolone, HES and pentoxifylline [201], [202]. Regarding the recovery of the average hearing threshold, there was an overall tendency for a superiority of the apheresis therapy. In a multicentre study, a statistically significantly greater hearing-recovery was shown after 48 hours but not 6 weeks regarding the 50%-speech comprehensibility for spoken (multisyllable) numbers with H.E.L.P.® apheresis. Patients with high LDL and fibrinogen levels benefited especially from the H.E.L.P.® apheresis [202]. As such Suckfüll et al. were able to demonstrate the equivalence of H.E.L.P.® apheresis to a ten-day standard therapies with glucocorticoids and rheological agents while the apheresis therapy lasted only about two hours. An additional, future differentiation of therapeutic success according to audiological inclusion criteria (e.g. various audiogram types, see also fig. 11) might reveal a patient collective that can benefit especially well from an apheresis therapy.

H.E.L.P.® apheresis requires special equipment. Specific structural, technical and personnel conditions must be met for its application (see the apheresis standard of the German Association of Clinical Nephrologists). However, when considering economic aspects it must be remembered that in the above-mentioned study an approximately two-hour ambulant apheresis is similarly effective to a 10-day hospital-based infusion therapy with prednisolone [202]. Recently Ullrich et al. recommended a modification of H.E.L.P.® apheresis "specific fibrinogen apheresis" that is yet to be tested in controlled studies [203]. The results of a current prospective, randomised, multicentre study on acute hearing loss therapy using rheopheresis are not yet available.

4.2 Magnetic stimulation

Repetitive transcranial magnet stimulation (rTMS) is a procedure for examining and treating central-nervous phenomena and disorders in the area of the cortex. Cortical excitability can be focally measured and modulated non-invasively using rTMS (for a review see Hallett (2000) [204]). Using a coil that is placed on the skull surface, electro-magnetic fields (intensity of 1.5 to 2 T) are induced for short periods (100 to 300 ms). The rapid induction and dissipation of these electro-magnetic fields induces corresponding electrical fields that activate the underlying neurones in the cortex. By applying high stimulation frequencies (> 10Hz), a temporary disruption of cortical function is induced that allows the investigation of the functional role of cortical areas. By applying lower (approx. 1 Hz) stimulus frequencies a decrease in cortical activity can be induced in the stimulated area for a period of up to 30 minutes [205], [206]. Such knowledge forms the basis for testing the therapeutic effects of rTMS on chronic, subjective tinnitus.

Hopes for this procedure are based on the following facts:

1) Both tinnitus and hearing-loss are associated with a reorganisation of specific areas of the central auditory system [207], [208].

2) Perception of tinnitus is associated with a hyperactivity of temporo-parietal cortical regions [209].

3) By applying a targeted transcranial magnetic stimulation of these areas, a suppressant effect on the strength of tinnitus can be achieved in some of the patients that lasts at least for a short time [206].

With the help of imaging procedures, hyperactivity can be detected amongst tinnitus patients in cortical areas that otherwise are involved in the perception and processing of auditory information (Figure 9 [Fig. 9]) [209]. Analogies to modifications in the somatosensory system (e.g. with focal dystonia or phantom pain [210]) have led to the hypothesis that some forms of tinnitus are based on maladaptive neuroplastic modifications, that follow a decrease or other modification of the input of the auditory nerve to higher parts of the auditory pathway. The rTMS is therefore based on the neurophysiological model of disinhibition of the central auditory system that is reflected in an irregular hyperactivity of various sections of the auditory pathway. In a recently published paper, Plewnia et al. used a high-frequency rTMS (10 hertz) to generate a short-lasting functional lesion in the cortex by temporarily disrupting the activity of various brain areas that potentially participate in tinnitus perception [206]. The authors showed that immediately after rTMS the tinnitus had decreased in intensity or disappeared completely in most patients when stimulation was applied to left temporal or left temporo-parietal cortical areas (Brodman regions 42, 22, 21) (Figure 10 [Fig. 10]). Brain areas for which no effect on the cortex was to be expected upon stimulation served as intraindividual controls.

In addition to the temporary effects of high-frequency rTMS, longer-lasting influences on cortical excitability and various longer-lasting central-nervous disorders were described as a result of low-frequency rTMS [205], [211]. Also with tinnitus, longer-lasting suppressive effects on chronic tinnitus can be produced with the aid of low-frequency rTMS [212], [213] (C. Plewnia, personal communication). As such, the potential for a therapeutic use of transcranial magnetic stimulation is not unfounded. Despite this, one should not get too excited about the possibility of a "novel therapeutic procedure" for tinnitus. Clinical studies on the applicability, safety and efficacy amongst patients with chronic tinnitus have been lacking until now.

4.3 Electrical stimulation

Electrical peripheral stimulation with tinnitus: Attempts to treat tinnitus by electrical stimulation date back more than 200 years [214]. Transcutaneous mastoidal tympanic, promontorial and intracochlear methods have been tested with varying success rates. A review on this was published by Okusa (1993) [214]. Controlled studies on this subject are largely lacking however.

Electric stimulation of the auditory cortex with tinnitus: In a recent neurosurgical paper the idea of influencing tinnitus by external stimulation of cortical areas was pursued [215]. The successful implantation of cortical stimulation electrodes for treating phantom pain led to this hypothesis. On the basis of the knowledge that transcranial magnetic stimulation temporarily influences cortical excitability, it was intended to convert this focal and temporary effect to a lasting effect by applying a continuous electrical stimulation. In one patient with chronic tinnitus the auditory cortex in an area of focal reorganisation determined by functional MRT was first stimulated by neuronavigated TMS, an action which temporarily suppressed the tinnitus. Also using the neuronavigation system an electrode was implanted for electrical stimulation of the auditory cortex in a craniotomy operation. The electrostimulation device connected to a cable was implanted in the abdominal wall of the patient. After repeated tuning of the stimulus parameters (current intensity, pulse rate and pulse width), a tinnitus free range was reported by the patient during the follow-up period of one year. The authors concluded from this case that the focal, extradural, electrical stimulation of areas of cortical reorganisation represents a suitable means to completely suppress a contralateral tinnitus. Transcranial magnet stimulation was therefore considered as a suitable means for non-invasively studying and selecting candidate sites for implanting such extradural electrodes.

Irrespective of the scientific importance of this case report, the safety, efficacy and especially the appropriateness of this kind of tinnitus therapy still needs to be assessed critically. Mechanisms of cortical reorganisation and plasticity occurring upon chronic electric stimulation of the cortex must also be considered [208].

4.4 Acoustic stimulation

Noise generators ("noiser") are used for tinnitus retraining therapy (TRT). The "classical" tinnitus retraining therapy is a noise therapy combined with counselling on the basis of the neurophysiological model for tinnitus according to Jastreboff and Hazell (1993) [216], [217] (see below for explanation). Using an emotionally indifferent broad band noise the acoustic background is increased especially at low environmental sound levels. By decreasing the signal-noise ratio (tinnitus vs. acoustic background activity) the perception of tinnitus should be reduced. In the same way as treatment of hearing loss, provision of hearing-aids also plays an important role in the treatment of tinnitus.

According to the model of Jastreboff et al., tinnitus results from an abnormally increased activity in the auditory pathway that is perceived in higher auditory centres as a noise or tone with which emotion and attention-controlling central-nervous structures play a major role. A psychological treatment is not necessarily considered as a component of TRT therapy by Jastreboff. Controlled studies that have documented an efficacy of TRT are still lacking. As such the efficacy of a classical tinnitus retraining therapy can not be regarded yet as proven from our current state of knowledge [218], [219]. In the mean time, several papers have shown that the central component of TRT, i.e noise devices or tinnitus instruments (hearing-aid plus noise device), exert no detectable influence on therapeutic outcome. Goebel et al. compared a cognitive-behavioural oriented therapy consisting of counselling, stress management, attention diversion and cognitive restructuring in the absence and presence of additional noise generators. Both groups found a similar therapeutic outcome that was far superior to treatment with a noise generator device alone, the latter of which was found not to differ from an untreated control group [220]. Also Delb et al. (2002) in their prospective, controlled study on the combined application of TRT and behavioural therapy found an efficacy of the concept based on counselling, multimodal behavioural psychotherapy and hearing-aids in comparison with a control group. Confirmation of an additional benefit from the use of a noiser device could not be obtained here either [221]. McKinney et al. in their studies came to the conclusion that the most important element of the TRT is directive counselling [222]. With habituation training an active, cognitive-behavioural therapeutic approach should therefore be favoured over a passive approach adapted to the use of noise generators (maskers/noisers).

4.5 Cognitive-behavioural therapy for tinnitus

For the treatment of chronic tinnitus, cognitive-behavioural approaches have proven to be more effective than medication-based and mainly acoustic therapeutic procedures. For a meta-analysis on the therapeutic efficacy of medication-based and psychological therapies for chronic subjective tinnitus, see also Schilter et al. (2000) [223]. Other reviews have been published by Dobie (1999), Wedel and Wedel (2000) and Andersson and Lyttkens (1999) [219], [224], [225].

The "re-training group" of the ADANO proposes a combined medical-psychological procedure as an extension and modification to "classical" TRT. According to its definition, the German tinnitus retraining therapy (TRT-ADANO) is " ... a concept for the ambulant therapy of decompensated tinnitus, which on the basis of comprehensive diagnostics by ENT physicians (see "guidelines on tinnitus" of the DGHNO) based on the model of Jastreboff and Hazell [216], introduces an interdisciplinary therapy that then treats the patient using psychological and device-based acoustic procedures. The concept demands the active collaboration of the patient" (quoted after von Wedel and von Wedel 2000 [219]. A permanent habituation to tinnitus is the objective of therapy for chronic tinnitus.

Tinnitus retraining therapy (TRT-ADANO) includes a basic module with comprehensive diagnostics and counselling as well as a follow-up module containing the actual retraining as essential components. Major aspects of the basic module are the "individually-oriented diagnostics" including the "tinnitus questionnaire of Goebel and Hiller 1998 [226] for determining the degree of severity and as a basis for therapeutic control" as well as psychological diagnostics, counselling and the development of individually customised tinnitus models.

The follow-up module includes the "decision-making, introduction and if necessary indication of device-based acoustic measures (hearing aids, noisers) by the ENT physician in close cooperation with an audiologist" and the "continuing, regular counselling by the ENT physician and/or the psychotherapist including the relevant follow-up diagnostics, usually over 18 months" ... (partly quoted from: TRT-ADANO 2000, [219]). The TRT-ADANO therefore represents an extension of the initial Jastreboff concept, in which psychological diagnostics and where appropriate an accompanying psychotherapeutic treatment becomes an integrated component of the TRT. Detailed manuals on cognitive-behavioural treatment as an adjuvant to tinnitus retraining therapy are provided in books by Hesse et al. (1999) and Delb, D'Amelio Archonti and Schonecke (2002) [227], [228].

The reason underlying the great value of a cognitive-behavioural approach towards tinnitus (and also hyperacusis) therapy is a model of "central" tinnitus sensitization that differs fundamentally from the "perceptive" neurophysiological model of tinnitus hyperactivation (Jastreboff). At its heart lies a cognitive hypersensitivity (sensitization) towards the tinnitus [229]. Patients often perceive tinnitus as being much louder although audiological tinnitus matching reveals rather low levels. Acquired centralized tinnitus was hypothesised to be based on centralized cognitive sensitization processes which are suggested to be specific learning processes [229].

A complex cognitive-behavioural treatment is understood under the term tinnitus desensitization therapy (TDT), for which habituation via a primarily cognitive desensitization is striven for as a therapeutic outcome. The cognitive desensitization "…relies on changing patient's cognition, i.e. by changing tinnitus attitudes and beliefs using cognitive procedures specifically designed to fit patient's needs…". Patients "…will experience perceptual changes in tinnitus sounds which will help them to habituate tinnitus (stimulus tolereance)." [229]. Various authors have studied the therapeutic approaches used in TDT in prospective, controlled cohort studies. Individual components of a cognitive-behavioural therapy are described in papers by Delb et al (2002), Kroener-Herwig et al (1995, 1997, 2003) and Greimel and Biesinger (1999) [221], [230], [231], [232], [233].

In two high-quality prospective, controlled studies (evidence level IIb according to the Oxford grading), a structured cognitive-behavioural therapy was found to be statistically significantly and clinically relevantly superior in comparison to cohorts not undergoing this treatment [221], [232].

4.6 Auditory training and sound therapy

Auditory training also plays a role in the therapy of hearing disorders, e.g. as a component of a standardised procedure with provision of a hearing aid. Specialised establishments for treating and rehabilitating hearing disorders with tested, scientifically founded therapeutic concepts employ their own programs for a targeted active auditory training, particularly with serious hearing-loss or when a hearing-aid is also provided.

From that one must distinguish the "sound therapy" after Tomatis or according to Berard, Nyffenegger, or modified procedures. A joint statement by the ADANO, the Association of Neuro-Paediatricians and the German Society for Phoniatry and Paedaudiology (http://www.dgpp.de/cons_tomat.pdf) exists regarding this. According to this statement neither the sound therapy after Tomatis nor modified procedures can be recommended because of the lacking scientific proof and evaluation of these procedures.


5. Conservative treatment of various hearing disorders

5.1 Idiopathic sudden sensorineural hearing loss (ISSNHL)

5.1.1 Spontaneous recovery and placebo treatment

For evaluating therapeutic success a comparison with spontaneous recovery rates or treatment under placebo is necessary. Unfortunately, with ISSNHL only a few studies have been published on this.

Spontaneous healing with null therapy: Mattox and Simmons (1977) reported a complete hearing-recovery in 35 % (10 of 28 patients, Table 3 [Tab. 3] in [15]) and a complete or "good" hearing recovery amongst 57 % (16 of 28 patients, Table 3 [Tab. 3] in [15]) as well as 65 % (from discussion in [15]) of patients without any therapy. Amongst patients that did not provide any consent for a therapy in a clinical study and who therefore received no therapy, Wilson et al (1980) observed a spontaneous, complete hearing-recovery recorded in tone and speech audiograms in 29 of 52 cases (56 %). In cases of mid-frequency hearing loss the authors almost always found a spontaneous remission. But even when only hearing-loss in high and low frequency areas were considered - excluding mid-frequency hearing loss or severe to profound hearing loss (PTA ≥ 90 dB HL) - a spontaneous remission was observed in 17 of 35 (49 %) patients [16]. The largest case series until now involving 63 acute hearing loss patients without therapy (including 24 patients with placebo medication, see below) was published by Weinaug in 1984 [234]. The author reported complete hearing-recovery in 68 % and at least a partial hearing-recovery (full or complete remission) in 89 % of the patients. Patients under 50 had a particularly good prognosis for full remission (89 %), as well as those with an average hearing-loss lower than 30 dB (88%). Moskowitz et al. (1984) reported on hearing recovery in four of nine patients (44 %) without therapy although quantification of "hearing-recovery" was not specified in detail in their paper [17]. Schuknecht reported spontaneous remission rates of 25 % (full remission) and 50 % (at least partial remission), although it was not clear from the publication how these data were obtained [235]. Veldmann et al (1993) reported a hearing-improvement (initial hearing-loss and full or partial remission not indicated) in 6 of 19 patients (32 %) "without specific medication-based therapy". When only those 13 patients with antibodies cross-reacting with heterologous inner ear proteins verified by Western blot were considered, a spontaneous remission rate of 46 % was found [18]. Chen et al. observed a spontaneous remission rate of 32 to 55 % (from 52 patients) depending on which audiological criteria were employed for defining remission [236].

Hearing-improvement under placebo therapy: It is generally assumed that placebo therapies show benefits over null therapies for many disorders [237]. However, this idea was strongly attacked in a recent review. Hrobjartsson and Gotzsche evaluated 156 clinical studies in which more than 11,000 patients undergoing a placebo therapy (pharmacological, physical or psychological) were compared with those not receiving a therapy. This systematic review produced no evidence that a placebo therapy was generally superior to null therapy. One exception appeared to be related to continuous (as opposed to binary), subjective parameters reported by patients with pain and phobias [238], [239]. Because of similarities between pain and tinnitus [210], a comparable situation might be assumed to occur with this symptom. This must be considered particularly when planning case numbers and study durations for placebo-controlled studies relating to tinnitus therapy. With clinical studies on ISSNHL on the other hand, an equivalence of placebo therapy applied until now and a "pure" spontaneous healing observed with null therapy can be assumed. This is supported by two facts: 1) in studies involving hearing loss the parameters are more objective than is the case with the symptoms pain or tinnitus so that a placebo effect can be neglected [238], [239]; and 2) although intravenous infusion with physiological saline over 60 min in animal experiments produced a mild reduction in haematocrit, it induced no significant alteration in oxygen partial pressure in the perilymph, cochlear blood flow or cochlear electrophysiological parameters (cochlear microphonic, summating action potential and acoustically evoked brain stem potentials), so that infusion with physiological saline alone can be considered as equivalent to a placebo treatment [66].

Several randomised clinical studies have compared therapy with physiological saline to that involving intravenous application of dextran and pentoxifylline [21], hydroxyethylstarch and pentoxifylline, [240] physiological (0.9%) saline and pentoxifylline [21], or procaine and dextran [41]. None of these studies found a statistically significant difference in the absolute improvement in hearing thresholds between verum medication and placebo (see Table 1 [Tab. 1]). Michel and Matthias in their randomised study (1991) also found no benefit of therapy with a stable prostacyclin analogue compared to therapy with a small amount of mannitol in physiological saline. The full remission rate reported by the authors lay in both groups at 70 % [33]. Cinamon et al. (2001) in a four-armed randomised study for investigating the efficacy of carbogen inhalants or prednisone (oral) also carried two placebo arms (inhalation of room air or placebo tablets). An average increase in hearing threshold of at least 15 dB was defined as a "hearing improvement". No difference was found between the therapy groups when a binary assessment was applied (hearing-improvement yes/no). If a parametric assessment was carried out on the average hearing-recovery in the pure tone audiogram according to the information provided in their publication, a clear tendency did in fact reveal itself: the patients inhaling carbogen always experienced the least (4.4 to 11.8 dB) and those inhaling room air the largest hearing-improvements (21.4 to 31.2 dB), irrespective of which frequency range was evaluated in the audiogram. The statistical significance could not be evaluated since the confidence intervals and standard deviations were not provided in the paper [241].

Considering all the above-mentioned observations with patient groups of different age and sex, with or without the existence of additional symptoms (tinnitus and vertigo) or cardiovascular risk factors, with various types of initial hearing-loss and audiograms, different monitoring timepoints (initial and end point), various procedures regarding the evaluation of hearing-recovery (absolute and relative), one can probably assume an average value for spontaneous full remission of approx. 50 % for all idiopathic sudden sensorineural hearing loss patients. The usefulness of this estimate is very restricted however, since prognosis depends on many factors. The evaluation of the efficacy of therapy compared to the natural course demands knowledge of spontaneous remission in a well characterised patient collective that corresponds closely to the therapy group, and which can normally only be guaranteed in a randomised, prospective study.

5.1.2 Clinical studies on the therapy of ISSNHL

The present general therapeutic approaches for acute hearing loss are therapy with glucocorticoids, rheological therapy (but not the primary vasodilatory therapy), ionotropic therapy, reduction of the endolymph volume, application of antioxidants, thrombocyte aggregation inhibition, fibrinogen reduction by apheresis, hyperbaric oxygenation and other medication-based and non-medication-based therapeutic procedures already described in full in chapters 2 to 4. These therapeutic approaches are based on pathophysiological considerations and disease models as well as the results of clinical studies. Controlled studies on therapy of ISSNHL over the last three decades are summarised in Table 1 [Tab. 1]. These are usually prospective, randomised comparative studies and so-called add-on studies, and only a few placebo-controlled studies. The detail and quality with which the studies and results are published varies greatly in the listed publications. Even after publication of the "CONSORT statement on improving the quality of reporting of randomised, controlled, clinical studies" (1996) [242] or its updates (2001) [243], [244], most studies have not adhered to these guidelines. The unsatisfactory reporting of results of clinical studies has already been criticised on many occasions in the field of ENT medicine [245]. Frequently, information is missing regarding the screening before randomisation, the randomisation procedure, study interruption and "follow-up" rates and especially the confidence intervals when reporting the results. Assessment of the level of evidence of these studies is therefore complicated.

With the therapy comparison studies listed in Table 1 [Tab. 1], two or several treatment modalities or medications are compared with one another. For the studies termed "add-on" studies the therapy-modality or medication to be tested is given in addition to the "standard" therapy. In some studies the comparator group often received a placebo instead of a test medication in order to blind the patient and/or the examining physician. Testing in comparison or in addition to a "standard" therapy is carried out primarily for ethical reasons. Since therapy with glucocorticoids has more or less established itself as a "standard therapy" worldwide (Table 3 [Tab. 3]), randomised studies comparing a pure placebo or null-therapy in the acute phase can no longer be carried out since they would invariably conflict with guidelines of the World Medical Association. Wherever this is available, a comparison of the efficacy of a test medication with that of a "standard therapy" is now required for clinical studies. This complies with point 29 of the Helsinki declaration of the World Medical Association in the version currently applicable in Germany, i.e. the version produced at the general meeting of the World Medical Association in Somerset West, South Africa in 1996. The placebo effect and the spontaneous healing rate must be considered in such studies with all groups (see above). Provided that the "standard" therapy shows an efficacy (compared to null or placebo therapy), smaller effects are to be expected for therapy comparison studies than would be the case with placebo- or null-controlled studies. Large case numbers can then lead to the demonstration of a statistical significance. However, the relevance, i,e. clinical significance of the extent of hearing-improvement, must always receive due attention.

Placebo-controlled studies provide considerably more information about whether a therapy is in any way effective compared to the natural course of a disease. They present no ethical problem if no current "standard" therapy exists or the possibilities to perform it are exhausted (see also 3.3., Table 2 [Tab. 2]).

So-called cross-over studies are rarely encountered with ISSNHL, since these are better suited to analyse the therapy of chronic disorders. In these kind of studies both therapeutic groups receive the two therapies, but in reverse order with respect to one another.

Retrospective comparative and "add-on" studies represent a special case. These are also known as nonconcurrent cohort studies (synonyms: "outcomes research" or "data base research"). Evaluations are made on already available data, e.g. from a database. Assignment to therapeutic groups after completion of therapy (without knowing the therapeutic result !) along with the often heterogeneous observation time-points and the large number of missing data points are the main reasons underlying their greater vulnerability to distortion than is the case with randomised studies. Despite this, such studies can be of a relatively high informative value if they are implemented correctly.

In Table 1 [Tab. 1] it is clear that controlled studies result in different, sometimes contradictory results. Even randomised controlled studies need to be assessed critically regarding their informative value, since their quality often suffers if there are high "drop-out", i.e. low "follow-up" rates, or "per-protocol" analyses are only performed. Apart from differences in inclusion criteria, time of therapeutic onset, initial hearing-loss, dosing, therapy duration etc., various parameters for evaluating the absolute or relative change in hearing-performance and differences in evaluation timepoints complicate the comparison of different studies with one another. The results of current meta-analyses (Cochrane reviews) on sudden hearing loss therapy with vasodilators, glucocorticoids or HBO have not yet been published at the time of going to press.

Apart from the controlled studies listed in Table 1 [Tab. 1], a large number of uncontrolled studies exist mostly in the form of retrospective evaluations of therapeutic results after treatment with a "standard" therapy. Even the sometimes very large case numbers should not serve to deceive about the clearly compromised informative value of these studies regarding the effectiveness of therapy, since they are lacking control groups. Provided that the patient collectives are well characterised, uncontrolled studies with large case numbers can however be of great benefit for comparing other therapy forms in other comparable patient collectives. They also allow prognoses to be estimated for subpopulations after stratification of the overall group. In this way they provide an excellent opportunity to identify patient collectives (e.g.) for planning (e.g. calculating the number of cases required) a prospective, randomised, controlled clinical study.

The following are mentioned as examples of the large number of case series investigated to date (in alphabetical order):

- Baujat et al. 2002, (n=136, glucocorticoids, dextran, sedatives) [246]

- Byl 1984, (n=225, prednisone) [247]

- Chen et al. 2003, (n=266, prednisone) [236]

- Edamatsu et al. 1985, (n=86, "Drug cocktail", stellate block and carbogen inhalation) [248]

- Fetterman et al. 1996, (n=837, glucocorticoids and vasodilators) [249]

- Hultcrantz et al. 1994, (n=101, dextran, nicotinic acid, vitamin B) [250]

- Inci et al. 2002, (n=51, HBO) [73]

- Kanzaki et al. 1988, (n=183, glucocorticoids) [251]

- Kau et al. 1997, (n=359, HBO after therapeutic failure) [74]

- Leunig et al. 1995, (n=118, HES) [252]

- Linssen and Schultz-Coulon 1997, (n=145, naftidrofuryl) [253]

- Maassen et al. 2002, (n=57, dextran and procaine after delayed therapeutic onset) [254]

- Michel et al. 2000, (n=1001, prednisolone, dextran, pentoxiphylline) [255]

- Michels and Matzker 1988, (n=548, xanthinol nicotinate or naftidrofuryl in fructose or naftidrofuryl in HES or dextran) [256]

- Minoda et al. 2000, (n=250, "Drug cocktail", HBO, stellate block, glucocorticoids) [257]

- Mosnier et al. 1998, (n=144, glucocorticoids, vasodilators) [258]

- Murakawa et al. 2000, (n=522, HBO) [75]

- Nakashima et al. 1998, (n=546, HBO) [76]

- Samim et al. 2004, (n=68, prednisone, dextran and piracetam) [259]

- Shiraishi et al. 1993, (n=98, batroxobin, vasodilator, dextran and vitamins) [260]

- Wilkins et al. 1987, (n=109, medicine cocktail: dextran, histamine, diatrizoate, "steroids", "vasodilators", carbogen) [261]

- Wissen and Aziz 1981, (n=112, medicine cocktail) [262]

- Zadeh et al. 2003, (n=51, glucocorticoids + antiviral agent) [263]

- Zastrow and Arndt 1987, (n=202, naftidrofuryl and dextran, 0.9 % saline, glucose or fructose solution) [264]

The reviewing and commenting of the controlled clinical studies carried out in Table 1 [Tab. 1] should allow the reader to reach his/her own conclusions on the presented external evidence regarding the efficacy of the various treatment procedures for acute hearing loss. Also, with the qualitative, high value, double-blind, randomised, placebo-controlled studies it must not be forgotten that the absence of evidence for efficacy does not prove a procedure's ineffectiveness.

Ultimately, the treatment of acute hearing-loss occurs on an individual basis according to the presumed pathophysiology, including the best available external evidence and considering the risks, side effects, economic aspects and individual treatment needs of the patient. With most sudden hearing loss patients, glucocorticoids appear to achieve the best therapeutic results on average. Their application was the first to be confirmed by external evidence and is therefore now considered internationally as a "standard" (Table 1 [Tab. 1] and 3 [Tab. 3]).

Of special interest is the therapeutic application of magnesium for acute hearing-loss. In a randomised, placebo-controlled study, Nageris et al. found a statistically significantly greater improvement in the mean hearing threshold in response to additional oral application of magnesium aspartate in comparison to therapy with glucocorticoids alone [265].

With raised plasma fibrinogen levels, a fibrinogen/LDL apheresis appears to be suitable. Low frequency hearing loss with a suspected endolymphatic hydrops disorder is currently treated by dehydration therapy. Primary vasodilators are contraindicated for the therapy of ISSNHL since they can lead to a redistribution of blood flow and an inferior circulation to the cochlea (vascular steal effect). With a clinically presumed viral or immunopathological origin, a specific antiviral or immunosuppressive therapy may be the most reasonable approach (see below).

5.1.3 Guidelines of the German Association for Otorhinolaryngology - Head and Neck Surgery for ISSNHL

Unlike many other countries a guideline exists in Germany for the treatment of acute hearing loss (Table 3 [Tab. 3]). The consensus report was prepared by a nominal group process commissioned by the executive committee of the German Society for Otorhinolaryngology and Head and Neck Surgery (DGHNO) (last revision: January 2004) [266]. The national consensus conference provided treatment proposals in this guideline for the differential therapy of acute hearing loss (cited in excerpts with the generous permission of the DGHNO) (Figure 11 [Fig. 11]):

Treatment procedures regarded as obsolete by the commission:

1) Provision of pure oxygen at normal atmospheric pressure

2) Ozone

3) Ultraviolet-light

4) Any form of laser therapy, even in association with ginkgo or similar preparations

5) Suggestive psychotherapy

6) Acupuncture alone

7) Autologous blood treatment

8) Vasodilators (see text)

5.2 Acute acoustic trauma

The therapy of acute acoustic trauma is carried out in a manner oriented towards the therapy of ISSNHL, although fewer controlled, randomised clinical studies have been performed than has been the case with ISSNHL.

In 1980 Eibach and Boerger reported that none of the polypragmatic therapies they applied was superior to placebo and treatment with physiological saline [267]. In contrast, Pilgramm (1991) found a significantly greater hearing-improvement when patients received an intravenous rheological treatment with HES or dextran instead of physiological saline [268]. Additional therapy with naftidrofuryl combined with dextran, however, did not lead to a further improvement in therapeutic outcome [269]. In a prospective, randomised, placebo-controlled study, Probst et al (1992) with acoustic trauma as with ISSNHL found no difference regarding relative hearing-improvement when patients were treated with dextran and pentoxifylline, 0.9 % saline and pentoxifylline or 0.9 % saline and placebo [21].

According to reports by Pilgramm et al., an additional hyperbaric oxygen therapy improves therapeutic outcome regarding hearing-loss and tinnitus after an acute acoustic trauma [270]. The study on 500 patients in 10 groups treated with different medications showed that the best effect was achieved when combining HBO with dextran or HES [271].

Clinical testing of the calcium channel blocker diltiazem for preventing auditory threshold shifts due to drilling noise during ear surgery showed no protective effect of this substance against this minor acoustic trauma [272].

In a randomised, placebo-controlled study on army recruits it could be shown that pre and paraexposure application of magnesium aspartate during a two month phase of regular firing-practices was able to reduce the extent and probability of a permanent hearing-loss [273].

For a review on more recent animal-experimental studies investigating other medications for their ability to protect and treat acute acoustic traumas, see Plontke and Zenner (2004) [83].

5.3 Virus-associated and inflammatory-toxic sensorineural hearing loss

Sensorineural hearing loss can occur with acute inflammations of the middle ear, with bullous haemorrhagic otitis externa ("bullous myringitis", German: "Grippeotitis") and with Herpes zoster oticus infections. While with Herpes zoster oticus a reactivation of varicella zoster viruses is known to be the cause, the mechanism of inner ear damage with acute otitis media and bullous haemorrhagic otitis externa is not yet clarified. Various hypotheses have already been the subject of long-standing research. Numerous animal-experimental and clinical investigations confirm an important role of respiratory viruses in the aetiology and pathogenesis of acute otitis media and bullous haemorrhagic otitis externa. As such, a rheological-anti-inflammatory therapy as with ISSNHL and a specific antiviral therapy are in principle feasible with these diseases in addition to the conventional decongestive and antibiotic therapies. Vaccines (influenza, but also against bacteria: pneumococci, hemophilus influenzae) might reduce the incidence and possibly also the complication rates of acute otitis media. The benefit of an antiviral therapy (e.g. with aciclovir) regarding acute sensorineural hearing loss observed with otitis media or a bullous haemorrhagic otitis externa has not yet been adequately confirmed.

With idiopathic sudden sensorineural hearing loss, a subclinical viral labyrinthitis also represents a possible aetiological factor. The hypothesis is supported by epidemiological findings, observed seroconversions of viral antibody titres, imaging procedures (MRT) showing signs of labyrinthitis, histopathological studies on human petrosal bones as well as functional and histomorphological observations after experimentally-induced labyrinthitis in animals (for reviews see for example [274], [275]). It must be emphasised, however, that a number of prospective, randomised, controlled studies came to the uniform conclusion that supplementary application of aciclovir or valaciclovir provides no additional benefit to the therapy of acute, idiopathic hearing loss [275], [276], [277], [278].

5.4 Immune associated hearing disorders

Hearing-disorders can occur as a symptom as part of a non-organ-specific autoimmune disorder or as an autoimmune inner ear disease "AIED" in its own right. Amongst the first mentioned include Cogan's syndrome, polyarteritis nodosa, recurring polychondritis, Wegener's granulomatosis, cryoglobulinaemia and rarely also sclerodermy, arteritis temporalis, systemic lupus erythematosus and Vogt-Koyanagi-Harada's syndrome. The therapy of non-organ specific autoimmune disorders usually occurs in collaboration and under the supervision of rheumatologists considering all the organ manifestations.

The observation that it in some cases acute or rapidly progressing bilateral sensorineural hearing-losses can be clearly improved or completely corrected by an immunosuppressive therapy involving glucocorticoids has led to the term primary autoimmune inner ear disease [279]. The existence of such an entity is a matter of some controversy since "hard" immunological evidence is lacking. A specific, failsafe diagnostic procedure does not exist; the disease is only defined from the success of therapy and the exclusion of other known causes. The existence of AIED is supported, however, by animal-experimental studies. A number of antigens have been proposed as candidates although no single one can be considered as pathognomonic for all presumed AIED cases. For reviews on the fundamentals of the immunology and autoimmunology of the inner ear see for example Ryan et al. (2002), Gloddek and Arnold (2002), and Solar et al. (2003) [280], [281], [282].

With some patients an immunosuppressant therapy for some weeks followed by gradual tapering off slead to a lasting improvement. Glucocorticoids and other immunosuppressants are available for this purpose whereby the use of medications other than glucocorticoids for AIED should be looked at critically. Veldmann et al. compared the efficacy of prednisone therapy with combined prednisone and cyclophosphamide amongst twelve patients with rapidly progressing sensorineural hearing loss and found a hearing-improvement in 7 of the 12 patients (58 %) irrespective of which group the patients belonged to [18]. Other patients required chronic medication with immunosuppressants. Methotrexate until now has been a typical medication for implementing a chronic immunosuppressive therapy. In a randomised, double-blind, placebo-controlled multicentre study involving 67 patients, it was assessed whether methotrexate is suitable for maintaining hearing-recovery after a successful initial therapy of a presumed AIED with prednisone. In this clinical study with a high level of evidence, no benefit could be found from using methotrexate in comparison with placebo concerning the maintenance of success of a prednisone therapy.

5.5 Hearing-disorders due to ototoxic drugs

The cochleo-vestibulotoxic effect of aminoglycosides still represents a major problem because of the frequent application of these effective and economic antibiotics in many countries. Apart from this important group, numerous other medications with undesirable reversible or irreversible ototoxic side effects also exist: e.g. loop diuretics (furosemide, etacrynic acid), antimalarial drugs (chloroquinol), cytostatics (cisplatin). Various current approaches to prevent ototoxicity are currently aimed at achieving protection by pre and paraexposure drug application (for a review see Lautermann (2003), [283]). Pre-clinical, animal-experimental studies have revealed a protective effect of antioxidants (glutathione, α-liponic acid), iron chelators and salicylate (2-hydroxybenzoate).

From acetylsalicylic acid it is known, that in excessively high doses reversibly causes tinnitus. However, high dose systemic application was also able to decrease the ototoxic effect of aminoglycoside antibiotics as shown in a prospective, randomised, placebo-controlled study in China [284]. For pre-clinical and clinical papers in this field refer to the numerous papers from Jochen Schacht's research group in Ann Arbor, Michigan.

Local application of various medications (especially antioxidants) to the round window membrane for reducing the ototoxic effects of cisplatin is currently being intensively investigated in pre-clinical studies. The aim of local application is to avoid the inhibition of the anti-neoplastic effects of cisplatin that occur after systemic application as a result of drug interactions [155], [285].

5.6 Hearing disorders as accompanying-symptoms of systemic disorders

Acute or rapidly progressing hearing-loss can occur with haematological disorders such as polycythemia, ( sickle cell) anaemia, leukaemia and lymphomas, neurological disorders such as migraine, idiopathic intracranial hypertension and multiple sclerosis, after operations on the open heart or lumbar puncture (e.g. also for a peridural anesthesia), as a paraneoplastic symptom and with chronic renal insufficiency due to haemodialysis. Therapy is provided here on a highly individualised basis in close collaboration with specialists from the appropriate disciplines. No controlled clinical studies on such therapies have as yet been published.

If hearing-disorders occur in association with bacterial infectious diseases such as Lyme disease, Rocky Mountain fever or syphilis, a rheological or antioxidative therapy can be considered as an addition to the primary antibiotic therapy. Possible drug interactions should also be considered. No controlled clinical studies have been published with respect to these clinical states either.

Hearing loss observed in up to 50 % of patients with osteitis deformans (Paget's disease) is in some cases sensorineural and therapeutic successes with calcitonin or bisphosphonates (etidronate) were described [286], [287].

5.7 Chronic sensorineural hearing loss

Current treatment procedures for chronic sensorineural hearing loss involve the fitting of hearing-aids or the implantation of electronic hearing-implants wherever these are indicated [288]. A regenerative therapy with de novo formation of hair cells has only been made possible in animal experiments. The first successes in this field using Math1 gene transfer and initial results from stem-cell transplantation experiments raise hopes that a biologically-oriented therapy shall be available in the future as a replacement for device-based therapies [111], [115], [118], [126], [122].

5.7.1 Syndromal and non-syndromal hereditary sensorineural hearing loss

With hereditary sensorineural hearing disorders one distinguishes non-syndromal (autosomal-dominant, autosomal-recessive, mitochondrial, X-chromosomal) from syndromal (e.g. Usher's syndrome, Waardenburg syndrome, Alport syndrome) hearing disorders. The incidence of especially non-syndromal hereditary hearing disorders is usually underestimated. A specific conservative therapy that does not involve a device-based rehabilitation does not yet exist. The first successes with gene therapy have been described in animal studies. Application of gene therapy in man will only be possible in the long term. For reviews on genetically conditioned hearing disorders see for example Pfister and Blin (2002), and Cremers and Smith (2002) [289], [290].

5.7.2 Sensorineural hearing loss with otosclerosis

An effective medication-based therapy that is relatively free of undesirable effects would represent a reasonable adjuvant to a surgical or device-based therapy for otosclerosis. This applies particularly to cases with a sensorineural component of hearing-loss and patients for whom operations are not possible or desired for a variety of reasons. In a double-blind, randomised study on the effectiveness of etidronate (a first generation bisphosphonate) in the treatment of progressive hearing-loss with otosclerosis, a clear tendency towards a stabilization or improvement of the air and bone conduction thresholds was seen after a two year therapy, although no statistically significant benefit for this medication could be shown [291]. The results of clinical studies with more effective bisphosphonates or newer medications that intervene in bone metabolism shall show whether a conservative-medication-based therapy of otosclerosis is effective.

5.7.3 Presbyacusis

The gradual and largely symmetrical loss of hearing associated with ageing (presbyacusis) can not strictly be distinguished from hearing losses induced by chronic exposure to harmful noxins (such as noise) or hearing-losses conditioned by genetic factors. The therapeutic goal with rehabilitation is to provide a timely device-based treatment using conventional or implantable hearing-aids and to avoid any social isolation that the patient might otherwise endure. A medication-based therapy or prevention does not exist. The influence of statins on the course of hearing loss associated with ageing is a matter of great interest in clinical-epidemiological research today. Statins reduce LDL cholesterol effectively and with that the risk of an acute coronary event or stroke, without increasing the general mortality [292]. Experimental studies on hypercholesterinaemia patients have shown for example that parameters of non-linear mechanical processes in the cochleas (speech comprehension, growth functions of the distortion products of otoacoustic emissions) of these patients are more pathological than they are in a comparative control group [293]. Whether intake of statins can influence a presbyacusis in a clinically relevant manner is still unknown, as are the risks and benefits of their application.

5.8. Menière's disease

The therapy of Menière's disease is dealt with in full in the chapter by Walther in this volume, and shall not therefore be dealt with any further here.

5.9 Tinnitus

5.9.1 Preliminary notes and reviews on the subject of tinnitus therapy

In addition to the thousands of web sites on the subject of tinnitus, a multitude of scientific papers and books regarding the (hypotheses underlying the) pathophysiology, diagnostics and therapy of chronic tinnitus have appeared. From the German-speaking world the following books can be mentioned: Biesinger 2002 [294], Feldmann (ed.) 1998 [295], Goebel 2001 [296], Goebel 2003 [297], Hesse 1999 [228], Kroener-Herwig [231], Schaaf 2002 [298]. Special reference should be made to the recent book by Delb, D'Amelio Archonti and Schonecke 2002 [227] and the tinnitus guidelines of the DGHNO that were last revised in 1998 [299]. In the English-speaking world the following titles are mentioned from the extensive literature available in this field: Andersson 2004 [300], Jastreboff and Hazell 2004 [301], Jastreboff, Gray and Mattox 1999 [302], and Tyler 2000 [303]. Regarding the numerous articles on tinnitus therapy in scientific journals, two detailed meta-analyses by Andersson and Lyttkens (1999 [224]) as well as Schilter et al (2000 [223]), and one review paper on randomised clinical studies by Dobie (1999 [225]) are mentioned here.

5.9.2 Objective and subjective tinnitus

A rational treatment for tinnitus must follow an adequate and thorough diagnostic procedure, as described in detail in the above-mentioned references.

With objective tinnitus, i.e. endogenous acoustic signals that might also be heard by the examiner with his stethoscope in the patient's external auditory canal, diagnostics and therapy are directed towards determining and if possible eliminating the endogenous sound source. If intracranial or extracranial vascular causes (e.g. anomalies in the vascular supply, stenoses, vessel tumours amongst others) are responsible, a surgical therapy e.g. of a paraganglioma of the jugular bulb can be carried out to eliminate the tinnitus. In other cases, e.g. especially a vascular decompression in the cerebellopontile angle, the risks and benefits of a surgical intervention must be carefully weighed up on an individual basis. With myoclonias of the soft palate or the tensor tympani and stapedius muscle with "klicking" ear noises, botulinus toxin injections or carbamazepine can be considered. Breath synchronous "blowing" noises, due e.g. to a patulous Eustachian tube, can be countered by counselling the patient and if necessary surgical intervention.

The therapy of subjective tinnitus is totally dependent on the presumed aetiology, timecourse and severity of impairment by this symptom and the comorbidities that often occur alongside the tinnitus. Therapy is carried out according to a phased concept that shall now be explained in more detail (Table 4 [Tab. 4]). For a comparison of conventional therapies in different countries refer also to the results of our questionnaire survey (Table 3 [Tab. 3]).

Irrespective of time-course and severity, any therapy for ear noise should be based primarily on medical explanation and counselling.

5.9.3 Acute tinnitus

With subjective, acute tinnitus, the main objective of therapy is the complete elimination or at least a reduction in the intensity (loudness) of the tinnitus. Apart from adequate diagnostics, immediate therapy is important, even if all diagnostic measures for clarifying the cause can not be carried out immediately. With a tinnitus that has only been extant for a few hours the patient should be encouraged to wait first (e.g. for 24 to 48 hours) since recovery can occur spontaneously (as is the case with ISSNHL). There is in any case a necessity of placebo-controlled clinical studies on this subject. If recovery does not occur a high-dose glucocorticoid therapy can be initiated. This occurs in a manner dependent on a patient's individual situation (desire for therapy and psychological strain) and the presence of any accompanying audiological symptoms and signs (where tinnitus is not an accompanying-symptom of an acute hearing loss).

The pharmacological therapy of acute tinnitus is oriented towards that of the drug-based therapy of acute hearing loss. The following represent options for parallel or consecutive therapies:

- Glucocorticoids (see 2.1)

- Rheological therapy(see 2.2)

- Ionotropic therapy (see 2.3)

Clinical testing of the efficacy and safety of specific, particularly neuropharmacological therapeutic approaches as described in chapter 2 and in different reviews is therefore of some importance [79], [80], [304], [305]. Initial clinical studies have revealed that the application of neurotransmitter antagonists (e.g. caroverine) is a promising approach [306]. However, a specific medication-based therapy against tinnitus has not yet been developed [303].

5.9.4 Subacute tinnitus

With subjective, subacute tinnitus, the directive counselling of the patient and the identification and treatment of comorbidities that amplify the tinnitus, such as pathologies in the temporo-mandibular joint or cervical vertebra, as well as the application of relaxation techniques (progressive muscle relaxation, biofeedback, autogenic training) are the most important measures after completion of the diagnostics. With hearing-loss, hearing-aids should be fitted early on. The duration and intensity of treatment depends in great measure on the severity of the tinnitus influence (see below). The primary goal is to avoid its transformation into a chronic condition or to preclude a long-term decompensation of the patient. To this end knowledge and abilities must be conveyed to the patient so that he/she may counteract any future fluctuations in tinnitus suffering independently or with the help of a physician. This can occur as part of a habituation training (TDT, TRT-ADANO) related to the severity of the tinnitus. In addition, self-help groups also play an important role, especially in facilitating the exchange of information between afflicted individuals.

5.9.5 Chronic, compensated tinnitus

With subjective, chronic tinnitus it must first be determined whether the patient has a compensated or a decompensated tinnitus. For patients with a completely compensated tinnitus no therapy is usually required. However, such patients should continue to receive tinnitus counselling in addition to diagnostics so that any future decompensation can be prevented.

5.9.6 Chronic, decompensated tinnitus

The goal of the therapy in this phase is to achieve a compensated state. The central aspect of the therapy is an evidence-based, structured habituation training. An active, cognitive-behavioural therapeutic approach (TRT-ADANO, TDT) is preferred over a passive therapy based on treatment with noise generators ("classical TRT") (see 4.4. and 4.5). Anxieties, depression and sleep disorders must often also be treated, e.g. through the application of anxiolytics and antidepressants. Psychosomatic diagnostics in most cases are not just advisable, they are in fact indispensable. Since chronic, decompensated tinnitus is a complex disorder, treatment should be carried out by physicians or psychotherapists specially trained in structured therapy, or by a team of physicians, psychotherapists, audiologists and physiotherapists. An evidence-based structuring of the therapy by specially trained therapeutic teams and a standardised recording of therapeutic results for quality assurance are important for this [219]. In suitable centres a grade III decompensated tinnitus (Biesinger's classification) can be treated ambulantly or on a day care basis. The more complex the disorder and the higher its severity, the more likely shall a hospital-based therapy be indicated in a specialised institution. One should distinguish here between general "tinnitus" health centres and tried and tested, scientifically founded, structured therapeutic concepts in recognised establishments. With a grade IV decompensated tinnitus (Biesinger's classification), a primarily hospital-based multimodal psychotherapy is in general indicated for tinnitus management, which should then take the form of an ambulant psychotherapy.

5.10 Hyperacusis

Hyperacusis as a collective term for acoustic impressions originating from external sources and which are perceived as too loud, too unpleasant or too dangerous [307] can be expressed as generalised hyperacusis (with normal hearing), as hyperacusis with recruitment and as hyperacusis with phonophobia. In the majority of patients it occurs as a neurootological/psychosomatic symptom in association with tinnitus. For this reason therapy is closely oriented towards the above-mentioned strategies for treating tinnitus. The few therapeutic studies that have been carried out usually with re-training therapies, and which are barely comparable mainly because of differences in primary efficacy parameters, reported therapeutic successes of 60-80%. Comprehensive recent reviews on the subject of hyperacusis can be found in Nelting et al (2002) and Goebel et al (2003) [297], [307].


6. Summary and perspectives

A wide range of procedures exist for the conservative therapy of hearing disorders. Ultimately, the treatment of a hearing-disorder is given on an individual basis according to (sometimes only a presumed) pathophysiology and including the best available external evidence considering the risks, side effects, economic aspects and individual treatment needs of the patient. Wherever this is available, external evidence from randomised, double-blind, placebo-controlled, multicentre studies must be given the highest priority. These basic principles apply both for medication-based and non-medication-based therapeutic procedures.

The major discrepancy between the promising animal studies on regeneration and stem-cell transplantation and the dearth of clinical studies of a high evidence level even with medications that have been established for decades is conspicuous. The universal application of glucocorticoids as a standard therapy for the treatment of acute inner ear disorders of different origin would appear at first glance to be a highly unsatisfactory situation. A therapy based on well-founded molecular and cell-biological fundamentals and physiological knowledge is therefore the focus of intensive research now. Some pharmaceuticals appearing to be reasonable from a pathophysiological perspective have shown good results in pre-clinical experiments. Their efficacy and safety should now be tested in high-quality, controlled clinical studies in order to establish specific, efficient therapeutic procedures in clinical practice so that more ineffective therapies can be abandoned. Clinical testing of antioxidants, NMDA receptor antagonists and magnesium in particular would appear to represent a reasonable strategy in the short- and mid-term. Local application of drugs to the inner ear represents a promising adjuvant or alternative to the systemic therapy of inner ear disorders.

The "12th amendment of the German pharmaceutical act (12. AMG-Novelle)" implements the regulations of European directive 2001/20 /EG regarding the application of good clinical practice for the implementation of clinical trials on human drugs under German law. Apart from obvious benefits, implementation according to these directives also unfortunately entails numerous problems that make it very difficult and expensive for universities and other non-commercial institutions to carry out such trials (so-called "Investigator Initiated Trials"). For precisely this reason a major priority is to exploit the advantages of already established networks, e.g. coordination centres for clinical studies (KKS) at universities in Germany in association with existing structures of scientific societies (DGHNO) and workgroups (ADANO). One should also optimise computer and internet resources for physicians and patients so that opportunities can be seized to enrol external patients or trial centres into already running clinical trials, or to participate in trials organised elsewhere.

It would also be desirable if the resources available could be used for example to fund medical assistants to implement clinical trials instead of using them for medical billing and diagnosis related group (DRG) documentation purposes. This would improve the effectiveness of medical care on a scientific basis, also considering the cost-benefit scenario.

Alongside the standards for reporting on clinical studies (CONSORT-statement), it shall also be necessary to agree upon standards for reporting hearing improvement. Until now the parameters employed for evaluating therapeutic results have differed very much both on a domestic and an international basis (see Table 1 [Tab. 1], "Evaluation"). There are of course good reasons for employing differing procedures to describe hearing improvement, but this state of affairs has made it almost impossible to carry out a meaningful comparison of all the studies. Such standards for reporting on audiological results could for example be based on already existing international standards, e.g. of the Committee on Equilibrium and Hearing of the American Academy of Otology and Neurotology. The albeit unsatisfactory standard that they have put forward for various hearing disorders (i.e. the "four frequency pure tone average") might be expanded to include an average hearing threshold that includes the low and high frequency regions. It would also be interesting to look at non-measurable hearing threshold values due to anacusis over the entire or a specific frequency range. Speech audiograms and hearing thresholds of the contralateral ear should also be considered. The development of such reporting standards represents an important means to improve the quality of medical care wherever external evidence is introduced.


Acknowledgements

I would like to thank Prof. Dr. med. Dr. h.c. mult. Hans-Peter Zenner for reviewing the manuscript. Also I would like to offer my gratitude to Dr. med. Ulla Arndt, Dr. med. Robert Mlynski, PD Dr.med. Markus Pfister, Dr. med. Christian Plewnia, Dr. med. Bernhard Hirt and Dipl. Psych. Ilse M. Zalaman for their constructive comments on parts of the manuscript. Much of the author's experimental work described in part 3 (Medication based therapy II. Local application of drugs) was done in the Cochlea fluids laboratory at Washington University in St. Louis in collaboration with Alec. N. Salt, Ph.D. The authors experimental studies were financially supported by the following projects: BfR/ZEBET WK1-1328-162 and WK1-1328-171, UKT- f ortune 1001-0-0 as well as UKT-AKF 66-0-0 and 50-1-0. Some sentences, tables and illustrations are taken from the author's habilitation dissertation.

The English translation of this review article which was originally published in the Journal Laryngorhinootologie (2005) 84;Suppl 1:1-42 was sponsored by a grant from B. Braun Medizintechnologie GmbH, Germany.


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