1

Introduction

The onset of tinnitus is often associated with a dysfunction of the outer hair cells (OHCs) of the cochlea. However, the underlying pathomechanisms are still obscure and a matter of debate. Similar to other inner ear disorders such as sudden sensorineural hearing loss, disturbances of cochlear microcirculation are one of the most frequently discussed reasons. Cochlear blood flow is sensitive to changes and even limited impairment of perfusion leads to an immediate dysfunction of the organ of Corti . Animal models and clinical evidence show a negative effect of hyperlipidemia on hearing function . High serum low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) are commonly accepted as major vascular risk factors, not only for large vessels. Histochemical studies of hypercholesterolemic animals disclosed a vacuolar degeneration of the capillary vessels at the stria vascularis and patches of amorphous material in strial marginal cells and in OHCs . Apart from its well-known role in the development of atherosclerosis and in the increase of blood viscosity, cholesterol can impair cochlear microcirculation by diminishing the release of the potent vasodilator nitric oxide (NO) from endothelial cells . A second possible mechanism of hearing impairment by high serum cholesterol is a direct action at the OHC membrane. Isolated OHCs show diminished motility when incubated with a cholesterol-enriched medium, probably due to a loss of flexibility caused by integration of cholesterol molecules into the lateral wall membrane . Immediately lowering serum LDL by means of apheresis accordingly increases cochlear blood flow without additional hemodilution and has been proven to be effective in treatment of idiopathic sudden sensorineural hearing loss. Interestingly, a minor (1.8 dB) but significant improvement of hearing threshold at the contralateral, healthy ear was also observed in the study .

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are highly effective at lowering serum cholesterol levels. They are among the most widely used classes of drugs worldwide for their potential in prevention of vascular diseases such as myocardial infarction and stroke . Apart from their effectiveness in prevention of occlusion of big- and medium-sized vessels, statins act on the endothelium of small vessels. Inhibition of HMG reductase induces activation of endothelial NO synthase and consecutive vasodilatation and thus improves microcirculation. Furthermore, statins reduce plasma viscosity and might improve cochlear microcirculation . Therefore, the question arose if patients with continuing tinnitus also may benefit from lowering plasma LDL levels by the HMG-CoA reductase inhibitor simvastatin. As tinnitus is a disease with a high emotional contribution, the use of a validated questionnaire assessing the impact of tinnitus on the individual and a comparison to another common treatment that has been proven without any efficacy compared to placebo were necessary to investigate this question.

Over all, no significant benefit of treatment with statins on the outcome of tinnitus was observed when compared to patients who received G biloba .

2

Patients and methods

In a retrospective study, remission rates of 58 patients with subacute tinnitus and slightly increased LDL cholesterol were investigated after 4 months of treatment with 40 mg of simvastatin. Because previous studies revealed that treatment of tinnitus with Ginkgo biloba extract is not more effective than placebo , 36 patients after treatment with G biloba extract (120 mg/d) for 4 months served as control group. Patients were treated within the ENT Department of the University of Munich between January 2004 and August 2008. Patients aged between 18 to 80 years and with uni- or bilateral tinnitus tinnitus between 2 and 12 months were enrolled in the study. These patients had serum LDL cholesterol between 130 and 160 mg/dL without any history of cardiocirculatory disease or more than one further risk factor such as hypertension, diabetes, positive family history, smoking, HDL cholesterol lower than 40 mg/dL or age (female > 55 years, male > 45 years). Tinnitus was evaluated using a standardized questionnaire designed by Goebel and Hiller. This questionnaire is a validated and published tool of measurement for the patient’s perception of tinnitus. Patients were eligible if tinnitus score was 30 to 60 (moderate to severe intensity). Audiometric testing included pure-tone audiometry (frequencies 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz) in accordance with ISO 7029, tympanometry, stapedius reflex measurements, and the German speech intelligibility (Freiburger Sprachtest). The sound level in decibels at which 50% of the recorded digits were recognized corresponds to perception of speech. Further masking and matching of tinnitus were performed. Because subacute tinnitus of 12 months duration very probably did not escape from the auditory pathway yet, tinnitus was defined as cochlear tinnitus if masking level was not more than 15 dB above hearing threshold. Laboratory tests were done at the Department of Clinical Chemistry of the University of Munich with standard methods including total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein (a).

Patients were excluded from the investigation if they had previously been treated for tinnitus; had objective or retrocochlear tinnitus; other disorders of the inner ear with known cause; Menière’s disease; subacute, conductive, psychogenic hearing loss; or were under treatment with HMG-CoA reductase inhibitors or Ginkgo or had been treated before. Patients were excluded from treatment with simvastatin if there were contraindications to the use such as active liver disease, cholostasis, persisting elevation of serum transaminases or myopathy, or if they were under treatment with drugs known to critically interact with atorvastatin such as immunosuppressive substances, fibrates, or nicotinic acid.

2

Patients and methods

In a retrospective study, remission rates of 58 patients with subacute tinnitus and slightly increased LDL cholesterol were investigated after 4 months of treatment with 40 mg of simvastatin. Because previous studies revealed that treatment of tinnitus with Ginkgo biloba extract is not more effective than placebo , 36 patients after treatment with G biloba extract (120 mg/d) for 4 months served as control group. Patients were treated within the ENT Department of the University of Munich between January 2004 and August 2008. Patients aged between 18 to 80 years and with uni- or bilateral tinnitus tinnitus between 2 and 12 months were enrolled in the study. These patients had serum LDL cholesterol between 130 and 160 mg/dL without any history of cardiocirculatory disease or more than one further risk factor such as hypertension, diabetes, positive family history, smoking, HDL cholesterol lower than 40 mg/dL or age (female > 55 years, male > 45 years). Tinnitus was evaluated using a standardized questionnaire designed by Goebel and Hiller. This questionnaire is a validated and published tool of measurement for the patient’s perception of tinnitus. Patients were eligible if tinnitus score was 30 to 60 (moderate to severe intensity). Audiometric testing included pure-tone audiometry (frequencies 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz) in accordance with ISO 7029, tympanometry, stapedius reflex measurements, and the German speech intelligibility (Freiburger Sprachtest). The sound level in decibels at which 50% of the recorded digits were recognized corresponds to perception of speech. Further masking and matching of tinnitus were performed. Because subacute tinnitus of 12 months duration very probably did not escape from the auditory pathway yet, tinnitus was defined as cochlear tinnitus if masking level was not more than 15 dB above hearing threshold. Laboratory tests were done at the Department of Clinical Chemistry of the University of Munich with standard methods including total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein (a).

Patients were excluded from the investigation if they had previously been treated for tinnitus; had objective or retrocochlear tinnitus; other disorders of the inner ear with known cause; Menière’s disease; subacute, conductive, psychogenic hearing loss; or were under treatment with HMG-CoA reductase inhibitors or Ginkgo or had been treated before. Patients were excluded from treatment with simvastatin if there were contraindications to the use such as active liver disease, cholostasis, persisting elevation of serum transaminases or myopathy, or if they were under treatment with drugs known to critically interact with atorvastatin such as immunosuppressive substances, fibrates, or nicotinic acid.