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The prevalence of tinnitus has been estimated to be as high as 30% in the adult ..... examination of the ears, pneumatic otoscopy, tuning fork examination, and ..... 3 and 6 Hz on audiometry) when compared to patients with tinnitus that is not ...

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Rehabilitation: Tinnitus Introduction Tinnitus, “ringing in the ears”, is one of the most common problems encountered in everyday otolaryngology or audiology practice. Fortunately, the majority of people with tinnitus are not bothered by it, or their level of annoyance is mild. For some, it can be debilitating problem. In spite of a long history tinnitus research and a rapid increase in the understanding of the auditory system, tinnitus remains a mystery. A relatively recent shift towards recognizing that tinnitus is a phantom auditory perception and the importance of various structures and systems in the brain have yielded significant progress in the understanding and treatment of tinnitus. Last, but not least, the development of valid animal models of tinnitus have expanded research of this challenging phenomenon from purely clinical into laboratories models. Many treatments have been proposed during last 30 years and the effectiveness of these treatments have increased substantially during this time.

History The word “tinnitus” is derived from Latin, meaning a “jingling, clink”. Tinnitus is the sensation of noises in the ears that have been described as any number of sounds- ringing, whistling, blowing, booming, sizzling. There is a long history of the treatment of tinnitus. For “the bewitched ear”, ancient Egyptians would administer “oil, frankincense, tree sap, herbs and soil” via the external ear. Hippocrates and Aristotle later introduced the idea of masking to diminish the perception of tinnitus. During the Middle Ages, the Welsh placed hot loaves of bread onto each ear, thinking that the subsequent perspiration and “help of God” would cure you. The Renaissance introduced surgery as a potential cure. Trephination of the mastoid was performed to release the air that was thought to be trapped in the ear, causing the tinnitus. Jean Marie Gaspard of

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France was credited for advancing the field of tinnitus management during the 19th century. Also known for his work with deaf-mutes, he gave the earliest descriptions of so called objective versus subjective tinnitus.1,2

Epidemiology The prevalence of tinnitus has been estimated to be as high as 30% in the adult population, with approximately 8% of this population reporting bothersome tinnitus.3,4 The severity of tinnitus can range from trivial to completely disabling. While tinnitus patients sometimes are driven to extremely high levels of anxiety and report committing suicide, a systematic study showed that the prevalence of suicide is statistically the same in tinnitus sufferers and the general population. An Internet search (Google) for “tinnitus” revealed over 4,300,000 sites, including countless self-help websites, information blogs, and non-profit organizations devoted to a tinnitus “cure”. Tinnitus presents a difficult clinical problem as it can be the result of any number of medical reasons and in many cases, a definitive cause cannot be identified. Various approaches to the classification of tinnitus have been proposed.

Classification and Etiology It is hoped that the classification of tinnitus can aid in its diagnosis and management. There is consensus that subjective tinnitus is a phantom auditory perception and that objective tinnitus is called somatosounds. Tinnitus is perceived only by the patient; somatosounds are generated either by the structures within or adjacent to the ear or by structures that transmit sound to the ear (e.g., clicking associated with artificial heart valves). Theoretically, an examiner may be able to detect somatosound, such as carotid bruits, but all the factors that can cause these sounds are not often easy to detect clinically.

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Kari/Mattox/Jastreboff Auditory imagery (a.k.a. musical hallucinations) is the phantom perception of well-known

musical tunes, or of voices without any understandable speech.5-8 This perception is much less frequent than other forms of tinnitus, nevertheless it is well documented and occurs primarily in older people with hearing loss. It is presumably a central type of tinnitus involving reverberatory activity within neural loops at a high level in the auditory cortex.5-8 Somatosounds can be either pulsatile or non-pulsatile. Pulsatile somatosounds are usually secondary to vascular (e.g., arteriovenous fistulas or malformations, paragangliomas, carotid artery stenosis, atherosclerotic disease, arterial dissection, persistent stapedial artery, intratympanic carotid artery, vascular compression of the eighth cranial nerve, increased cardiac output, pseudotumor cerebri, venous hum, jugular bulb anomalies) or nonvascular causes (palatal myoclonus, tensor tympani or stapedius muscle myoclonus, vascular neoplasms of the skull base).2 Tinnitus can be secondary to a number of medical conditions but often exists in the absence of an identifiable cause. This is by far the most common form of tinnitus. Furthermore, there is significant variation in the severity of the degree that tinnitus affects an individualranging from benign to devastating, with associated affective disorders such as hyperacusis, misophonia, depression. Notably, there is no correlation between tinnitus severity and its psychoacoustical characterizartion (i.e., pitch and loudness match, minimal masking level).9

Pathophysiology Risk Factors Many risk factors leading to the development of tinnitus have been reported based on epidemiological studies. Specifically, age, cardiovascular or cerebrovascular disease, drugs, ear infections/inflammation, head or neck trauma, thyroid abnormalities, loud noise exposure, Meniere’s disease, otosclerosis, sudden deafness, vestibular schwannoma, anxiety, depression,

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familial inheritance, health status, body mass index, education, socioeconomic status, cigarette use have all been associated with tinnitus.4 The same data indicate that alcohol, in moderation, can actually be beneficial. The Norway Hearing Study (1996-1998)4 reported that people who consumed 1-14 alcoholic beverages over the last 2 weeks were less likely to report bothersome tinnitus than those that reported having no alcoholic beverages over the same time frame. A statistically significant relationship between tinnitus and alcohol for those individuals consuming more than that, however, could not be identified. The same study as well as the US NHIS Disability Supplement4, demonstrated that individuals with hearing loss were much more likely to report bothersome and chronic tinnitus. In addition, the more the severe the hearing loss, the more likely individuals were to report chronic or bothersome tinnitus. Hearing loss and noise exposure alone have also been associated. Ototoxic agents and multiple drugs have also been found to be likely culprits.2,10 There have been a number of case reports of specific agents that have appeared to cause tinnitus, but there are specific agents that have been consistently reported, such cisplatin11 or quinine.

The Study of Tinnitus While many disorders have been associated with tinnitus, the exact pathophysiology of tinnitus is unclear. Tinnitus is felt to originate from deterioration, damage or alterations involving the inner ear hair cells and/or peripheral or central nervous system auditory pathways. The pathophysiology that leads to such a deterioration or alteration is myriad, and in many cases, unclear. Even in cases of well-defined dysfunction of the innear ear (e.g., hearing loss) there are variety of proposed mechanisms but none have been definitely proven, as of yet. The study of tinnitus in humans is challenging. A common goal has been to identify differences between the cochlear and brain functions of tinnitus sufferers and those who do not

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suffer from tinnitus. The tests we have available to us, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), otoacoustic emissions, and evoked potentials, can vary considerably based on patients’ age, sex, and degree of hearing loss12 and provide limited amount of useful information. A number of animal models have evolved in the last 20 years and have greatly added to our understanding in the neuropathophysiology of tinnitus. In 1988, Jastreboff et al.13 proposed a rat model of tinnitus using a conditioned suppression procedure. The animals were trained to associate silence with a shock that subsequently evoked fear (Pavlovian suppression training). Jastreboff used water deprivation to motivate the animals to lick from a waterspout. Fear induced a decrease of drinking which has been used to asses the extent of fear. When tinnitus was introduced after animals were already trained to be afraid of silence then rats were not as afraid when external background noise was switched off as they did not perceive silence, but tinnitus. Consequently, suppression of drinking was smaller and extinction of learned fear of silence occurred faster. When, on the other hand, animals were trained to be afraid of tinnitus rather than silence (by inducing tinnitus before Pavlovian suppression training), suppression was stronger and extinction of trained fear occurred slower. Other models have evolved since Jastreboff’s work that have also used conditioned responses to reflect tinnitus, such as pole jumping avoidance14, conditioned lick reward15, conditioned polydipsia avoidance16, conditioned two-choice Left/Right responses17, and gap detection reflexes18,19.

The Discordant Dysfunction Theory The discordant dysfunction theory20-22 postulates that tinnitus can result from an imbalance that results from damaged or dysfunctional outer hair cells (OHCs) and relatively better functioning inner hair cells (IHCs). It is postulated that increased neuronal activity in the dorsal cochlear nucleus (DCN) is generated as a response to the decreased or absent signal

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from type II auditory nerve fibers (OHCs) due to neuronal disinhibition in DCN. This increased neuronal activity is thought to be the signal source for tinnitus that is perceived at a high cortical level.22 Kaltenbach’s work with cisplatin and hamsters has supported the theory that loss of OHC function may be a trigger of tinnitus-related hyperactivity in the DCN.11 Their group demonstrated that cisplatin-treated animals showed DCN hyperactivity and that the degree of hyperactivity correlated with degree of OHC loss/damage. Furthermore, the portion of the DCN exhibiting hyperactivity represented the higher frequency half of the animals’ audiometric range and corresponded to the OHC loss in the mainly basal half of the cochlea. Their work also demonstrated that increases in DCN activity were not related to degree of inner hair cell (IHC) damage. Their data, in fact, suggested that damage to IHCs may offset the condition of hyperactivity triggered by OHC loss, as predicted by discordant damage theory. Hyperactivity of the spontaneous activity of the central auditory system has also been observed at the inferior colliculus (IC) and auditory cortex (AC) in patients with tinnitus.23 The DCN receives direct innervation from the auditory nerve and its output is relayed to higher order auditory centers. Kaltenbach’s presented several lines of evidence for the role of the DCN contributing to tinnitus.23 His work, however, has been criticized. Namely, the finding that the DCN is involved in the network involved in tinnitus does not prove that DCN stimulation causes tinnitus. Also, note should be made that the time course of noise-induced hyperactivity in the DCN is completely different from the time course of noise-induced tinnitus. Finally, his data do not present reasonable proof that observed effects are not due simply to hearing loss that was induced simultaneously. Work involving the ototoxic effects of salicylate were used hoping to elucidate the mechanisms of tinnitus. The use of high doses of salicylate analgesics has been consistently associated with acute tinnitus and date back to 1877 in the works by Sée and Müller.24,25 In fact, the dosage of salicylate for the treatment of rheumatoid arthritis was used to titrate the dose of

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salicylate by increasing the dose until tinnitus appeared and then decreasing the dose a little.26 Cazals review discusses many reports and studies of the ototoxic effects of salicylate.26 Symptoms include alterations of sound perception, loss of absolute acoustic sensitivity and vertigo. Data have suggested that this toxicity is, in fact, reversible.27,28 Tinnitus has been consistently reported after ingestion of 3 or more grams of salicylate.24,27,28 Cazals reviewed the data of multiple studies that showed that tinnitus “loudness” increased in linear proportion to the plasma salicylate levels and that spontaneous otoacoustic emissions (OAEs) were greatly reduced or eliminated after salicylate ingestion. Further work on isolated outer hair cells and cochlear mechanics suggest that salicylate can interfere with baseline electromechanical properties, but these in vitro studies have employed levels of salicylate that are beyond what is considered beyond the physiologic range. Other groups, however, have shown similar findings using levels of salicylate that are closer to or within physiologic levels.29,30 Salicylate use has also been shown to increase the spontaneous auditory neural activity. Cazals’ review also examined studies which argued that salicylate does not cause significant changes in the electrocochlear potential, cochlear microphonic, summating potential.26 While salicylate is a useful tool to establish animal models of tinnitus it is argued that this type of tinnitus, which has no practical clinical significance, does not represent clinically-relevant tinnitus and its mechanisms may be different. Therefore, in current animal models overexposure of noise is used to evoke tinnitus. As this procedure typically induces hearing loss as well, it is paramount to have data that allows discrimination of the effects of hearing loss from effects of tinnitus. Currently, the work with salicylate-induced tinnitus is limited to establishing new animal models of tinnitus.

Neural Plasticity

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Kari/Mattox/Jastreboff Neural plasticity is important in understanding both the generation of tinnitus and

explanation of the suffering caused by tinnitus. While many individuals will report experiencing tinnitus at some point in their lives, only a small proportion of them find their tinnitus bothersome to seek intervention or medical treatment. Several studies have indicated that the severe tinnitus that causes suffering is related to changes in the function of nuclei in the ascending auditory pathways or by the redirection of information to regions of the central nervous system (CNS) that do not normally receive auditory input.31-33 Møller has described the non-classical auditory pathway and its role in cross-modulation between the auditory and somatosensory systems.34 The non-classical auditory pathways, also known as the extra-lemniscal pathways, ascend in parallel to the classical pathways. The classical pathways use the central nucleus of the medial geniculate body that project to the auditory cortex. The non-classical auditory pathways, however, start from the DCN and involve parts of subsequent higher-level nuclei. Of particular interest is the connection between the thalamus (via the extralemniscal part of medial geniculate body) and the limbic system (via the lateral nucleus of amygdala. The nonclassical pathways also receive input from sensory organs of other sensory modalities, such as the somatosensory and visual systems.31,34,35 The involvement of the limbic and autonomic nervous systems can cause increased arousal, anxiety, panic, awareness of tinnitus and can enhance the perception of the tinnitus signal, helping to explain how perceived loudness can be related to stress, anxiety and emotional status.22 Notably, there is a direct connection from amygdala to the inferior colliculus, allowing control by the limbic system of processing information within the auditory system. This interconnection between the auditory and the limbic and autonomic nervous systems provides a basis for creating a series of conditioned reflexes with tinnitus as the conditioned stimulus and over-activation of the limbic and sympathetic parts of autonomic nervous systems, which in turn

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lead to a set of emotional and psychological reactions that result in patients’ suffering (see Figure 1).22

Figure 1. The neurophysiological model of tinnitus. Block diagram outlining structures and connections involved in clinically significant tinnitus. The tinnitus signal, typically generated at the periphery of the auditory system, is detected and processed in subconscious pathways of the auditory system and finally perceived a the auditory cortex. If tinnitus is classified as an important negative stimulus, selfenhanving loops, governed by principles of conditioned reflexes, develop. Note existence of two loops: high, involving consciousness, and low, the subconscious 36 loop.

Neural plasticity is necessary to be involved in creating new functional connections, which are responsible for reactions evoked by tinnitus as well as in extinguishing them (by retraining of the brain). Neural plasticity can consist of changes in synaptic efficacy, creation or elimination of synapses, elimination or creation of new connections, or changes in protein synthesis of nerve cells. 31,37 Animal experiments have shown that deprivation of auditory input caused by hearing loss and exposure to loud sounds can cause hyperactivity in the nuclei of the auditory pathways.38-40 The unmasking of dormant synapses can cause redirection of information which has been thought to not only cause tinnitus, but the subjective symptoms of suffering such as hyperacusis and affective disorders.31

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Chronic Pain, Depression, and Psychological Aspects of Tinnitus Similar neurologic changes have been observed in both chronic neuropathic pain and tinnitus sufferers yielding proposal about similar mechanisms. Both lack physical signs and objective tests to confirm or characterize the disorders and are characterized by altered perceptions of physical stimuli. Similarly, both are often accompanied by affective disorders.33,41-44 Other researchers have also looked at the role of personality and psychological characteristics that may contribute to tinnitus severity. Furthermore, the strong placebo effect that is often seen in tinnitus treatment also highlights the importance of psychological factors.45 Langguth et al.46 presented their work in which they identified “the big five personality traits” in affecting the scores on two standard tinnitus grading instruments. They evaluated 72 individuals with chronic tinnitus by administering the tinnitus questionnaire (TQ)47,48, tinnitus handicap inventory (THI)49, Beck depression inventory (BDI)50, and the NEO-Five factor inventory (NEOFFI)51. The five personality traits examined were Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. A low “Agreeableness” score is thought to correlate to people who “highly competitive, self-centered, and more susceptible to anger”.52 A high “Neuroticism” score is thought to correlate to people who “experience more anxiety, fear, sadness, embarrassment, and guilt”.46 They found that tinnitus severity correlated with low “Agreeableness” and high “Neuroticism” and that the degree of correlation depended on which measure of severity was used. They also found that “Neuroticism” correlated strongly to female gender and younger age, independently of tinnitus. In addition, the authors found that 20.8% of subjects exhibited moderate to severe depression, 34.7% exhibited mild depression and that tinnitus severity significantly correlated to depression. Another study by McKenna et al. found that 45% of patients presenting with tinnitus for treatment had “significant levels of psychological distress”.53 Reynolds et al. examined the

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prevalence of psychological comorbidities in patients undergoing treatment for tinnitus in the United Kingdom. They found both depression and anxiety to affect patients with tinnitus with anxiety being the main psychological problem, affecting 28% of the sample reporting.54 The affect of depression and/or anxiety cannot be underestimated in evaluating and treating patients with tinnitus.55 These psychological disorders can precede tinnitus, complicate treatment efforts, play a critical role in the maintenance of tinnitus symptoms, and subsequently become worse themselves as tinnitus symptoms continue.46,47,54 A report on patients with tinnitus compared to a control group of patients presenting for hearing loss revealed that 60% of the tinnitus patients met criteria for a major depressive disorder, or MDD (versus 7% of control patients). They also had higher lifetime prevalence of ever having had a MDD (73% vs 21%).56 Psychological disorders, however, my be evoked by tinnitus and many patients experience depression and anxiety only after they got tinnitus. Therefore the question remains open to which extent tinnitus is facilitated by prior depression, anxiety etc. versus causing these problems.

Diagnostic Techniques History and Physical Exam The evaluation of tinnitus should begin with a complete but focused history and physical. The physician should inquire into the duration, onset, severity, sound quality and intensity, trigger factors, mitigating factors, and laterality of the tinnitus. It is also important to inquire as to whether the sound is constant or intermittent, if the quality changes, if it worsens with additional noise or silence, and if the patient experiences decreased sound tolerance. A complete review of a patient’s past medical history, past surgical history- with particular attention to otologic or neurologic surgery, depression, anxiety, and family history, particularly of ear disease or hearing loss, is helpful.

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A thorough review of the patient’s medications, consumption of herbal or dietary supplements, over-the counter agents, and recreational substances is also sometimes useful to identify any possible causative agents that have been reported to cause tinnitus. It is crucial to assess the degree of distress or handicap the tinnitus causes the patient. Newman et al have described a self-reported Tinnitus Handicap Inventory (THI) to aid in this assessment (please see Appendix).49 Other inventories have also been developed- the Tinnitus Effects Questionnaire, Tinnitus Handicap Questionnaire, Tinnitus Severity Scale, and Tinnitus Coping Style Questionnaire.57,58 Recently, a new questionnaire, Tinnitus Functional Index, developed as results of extensive 3-year project, has been presented,59 but it is not in public domain, yet. The physical exam should include a full head and neck examination. Microscopic examination of the ears, pneumatic otoscopy, tuning fork examination, and cranial nerve testing should be included. If the patient is complaining of pulsatile tinnitus, one should auscultate for vascular bruits. Similarly, compression of the internal jugular vein can cause an increase in tinnitus perception in some vascular causes of tinnitus.

Audiometry Evaluation should always include pure-tone (air and bone conduction), Loudness Discomfort Levels and speech discrimination to assess extent and functional impact of hearing loss. Tinnitus pitch, loudness match and minimal masking levels are typically evaluated as well even though they do not provide insight into diagnosis and proposed treatment. High frequency resolution Distortion Product Otoacoustic Emission (DPOAE) is very useful for counseling purposes, particularly considering the discordant dysfunction theory. Frequency range of all measurements can be enhanced into higher frequency range, i.e., 12.5 kHz for audiometry and 10 kHz for DPOAE.

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Imaging Additional diagnostic testing, such as imaging should ultimately be guided by indications in the history and physical exam. A gadolinium-enhanced magnetic resonance imaging study is recommended in cases of clear indication for possibilities of vestibular schwannoma, i.e., obvious asymmetry on audiogram, impaired speech discrimination, rollover in speech discrimination, acoustic reflex decay.2 Note that tinnitus alone is not a good indicator of vestibular schwannoma. In patients with decreased sound tolerance it is advisable not to perform acoustic reflexes evaluation, and furthermore to use “wait and monitor” approach with treatment aimed first at decreasing / removing decreased sound tolerance before imaging study.

Treatment Physician Counseling and Reassurance One of the most important aspects of treating tinnitus is the dialog that should take place between the patient and the physician. Most patients arriving in an otolaryngology clinic have already been evaluated by many other health professionals and often arrive frustrated and discouraged, having been told to “just learn to live with it” and that “there is nothing I can do for you.” Also crucial is the reassurance that the tinnitus is not a sign of another, more serious health malady, such as a brain tumor or severe illness. Negative counseling plays a large role in how patients develop problems with their tinnitus. Our practice has had the experience of encountering many patients whose tinnitus has caused them much greater distress after they have been told there are no cures. Additionally, it is crucial to emphasize the benign implications of tinnitus. It should be made clear to the patient that tinnitus is not a predictor or harbinger of hearing loss or deafness, brain tumor, aneurysm, stroke, psychiatric problems or other serious medical illness. While there is no cure for tinnitus, there are many management options that have shown variable degrees of success.

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As previously noted, most cases of tinnitus do not have an easily identifiable cause. The following review medical and surgical management is meant to address tinnitus. Note, that there is probably less than 1% of cases when a medical or surgical management offers some improvement for tinnitus. In cases in which the patient’s evaluation has led to the identification of an offending drug or agent that can cause tinnitus, efforts should be made to eliminate this agent from the patient’s medications. For example, benzodiazepine withdrawal is a known cause of tinnitus.60 What follows is a review of many of the strategies and agents that have been examined in the treatment of tinnitus. We have grouped these into HEARING AID / MASKING THERAPY, TINNITUS RETRAINING THERAPY (TRT), PSYCHOLOGIC, PHARMACOLOGIC, SURGICAL, AND OTHER. The successes of these therapies are extremely variable and the data that support them also vary significantly in their quality. Therapies directed at causes of somatosounds (typically pulsatile) are beyond the scope of this chapter. Note, that TRT is an effective method for treating somatosounds as well.

Hearing Aids and Masking Therapy The use of hearing aids and masking therapy for tinnitus dates back to the work of Goodhill,61 Saltzman and Ersner.62 The principle being “…by amplification much outside sound is enabled to reach the cochlea, crowding out and masking the patient’s head noises”.62 Some work has described the concept of residual inhibition, in which tinnitus perception is reduced or eliminated by employing masking sound designed to precisely match various sounds to a person's tinnitus.63 In spite of high expectations, after over 30 years of investigation, residual inhibition has never reached a level of clinical usefulness, as it typically last seconds - single minutes. Vernon64 discussed the utility of hearing aids in those individuals with high-frequency hearing loss. He did, however, highlight that hearing aids will likely not be successful in patients in whom the tinnitus is so high-pitched that it is above the frequency capability of the hearing

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aid. Others, however, have shown this to not be true. Classical experiments of Feldman have shown that suppression of tinnitus perception is based on the neuronal suppression of the tinnitus signal and it is not based on acoustic masking with interaction of two traveling waves at the basilar membrane of the cochlea.65 Specifically, he has shown that there is no phenomenon of critical band, there is no “V” shaped dependence of intensity of masker around pitch of tinnitus and that it is equally easy to suppress tinnitus perception by sounds from wide range of frequencies, or sometimes even contralateral suppression is easier than ispilateral. Unfortunately, the label “masking” became associated with tinnitus suppression creating the incorrect opinion that it is easier to suppress tinnitus perception by sounds covering tinnitus pitch. Vernon reported that tinnitus was “maskable in 95% of tinnitus patients”.66 These findings, however, have not been confirmed by other groups, including reports showing that masking is not better than placebo.67 Others have found that the masking therapy only resulted in short term benefit in a small group of patients.13,68,69 The fact that continuous use of “maskers” after 6 months have been used as criterion of success in Vernon’s and some other authors’ papers hindered validity of these reports. Jastreboff and Jastreboff70 highlighted some of the limitations of masking therapy. There have been cases in which hearing aids have worsened tinnitus. These have been mostly in cases involving occlusive hearing aids that act as earplugs. Folmer71 reported on the efficacy of ear-level devices (hearing aids or sounds generators) in 150 patients. By use of a mailed questionnaire, 50 patients used hearing aids, 50 used in-ear sound generators, and 50 did not use ear-level devices. Follow-up was assessed from 6 to 48 months. They found significant reductions in Tinnitus Severity Index in all groups, but more improvement was appreciated in the groups who used hearing aids or ear-level devices.

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Studies have also examined the role of “pink noise”, or a variety of artificial sounds mimicking sounds of flowing water or air. Various compact discs and noise machines have been marketed and studied, but the efficacy of these have not yet been proven or confirmed with independent studies.69 Neuromonics® Tinnitus Treatment employs the use of a device with headphones that patients wear for a prescribed period of time per day. According to the manufacturer, this device plays “music [which] is spectrally modified and customized with an embedded neural stimulus based upon the patient’s audiological and tinnitus profile”. It is available by prescription only but is often not covered by major insurance carriers. Subsequently, the cost (~$5000) can be prohibitive for many patients. It is not clear, however, if this approach is substantially better than using an iPod with high quality earphones and playing music for a few hours a day. There have been only two published studies that reported success with this program, but the researchers were shareholders of the Neuromonics company, and one of the studies did not include a control group.72,73

Tinnitus Retraining Therapy Tinnitus Retraining Therapy (TRT) is aimed at “habituation of reactions evoked by tinnitus, and subsequently habituation of the tinnitus perception.”74 It incorporates two components that follow the principles of the neurophysiological model of tinnitus as described by Jastreboff (Figure 1).20 These two components are (1) counseling, aimed at the “reclassification of tinnitus to a category of neutral signals” and (2) sound therapy, aimed at “weakening tinnitus-related neuronal activity.”74 Both components are strictly based on the neurophysiological model of tinnitus. The therapy attempts to achieve extinction of the abnormal conditioned reflex arc between the tinnitus signal within the auditory pathways and the emotional and physiological responses involving the limbic and sympathetic part of the

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autonomic nervous systems. The primary goal is to habituate tinnitus-evoked reactions. The final goal is to reach a stage when tinnitus does not interfere with patients’ lives. In an evaluation of 303 patients, the author found that 82% of patients showed statistically significant decrease in THI scores at 12 months of treatment.74 Other researchers have reported similar success with both short- and long-term follow-up.75,76 The most interesting study, so far, was reported by Henry et al. (2006).77 In a randomized systematic study, Henry compared relief therapy, which he labeled “masking therapy” in which any sound that provided immediate decrease of tinnitus was accepted, with TRT. Results showed superiority of and a high level of effectiveness of TRT. In a prospective, non-randomized, un-blinded study of 152 patients with tinnitus, Herraiz et al.76 found that 82% of patients had significant improvement in their tinnitus with TRT when compared to patients who received no intervention and were on a waiting list to be seen in the authors’ clinic in addition to patients who were partially treated but refused the recommended prostheses. Herraiz et al.78 went on to publish that certain prognostic factors can help predict success with TRT. Specifically, they found that more severe cases of tinnitus tend to have better results. In addition, they found that patients who use the recommended sound generating instrumentation also tend to have better results. Wilson et al79 reported a critical analysis of TRT in 1998. They identified problems with the “distinction between directive counseling and cognitive therapy, the adequacy of the cognitive therapy components, the nature of the outcome data which have been presented to date, the theoretical basis for the treatment, and the conceptual clarity of terms such as perception, attention and coping.” They also highlighted the need for more controlled-studies with no-treatment or placebo arms, and in which the efficacy of the counseling and white noise components could be clearly isolated. Many of these critical points have been clarified in subsequent studies, such as those mentioned above.

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Psychological Treatment Although not widely employed in the United States, psychologically-based therapy has been used as the sole mode of therapy for tinnitus is other countries, particularly Germany and Sweden. Cognitive-behavior therapy is a psychotherapeutic approach that aims to influence problematic and dysfunctional emotions, behaviors and cognitions through a goal-oriented, systematic procedure based on behavioristic learning theory and cognitive psychology. It has been described as an approach to help patients cope with tinnitus better.80 Others have reported on their success in treating the discomfort associated with tinnitus, but they had less success in decreasing depression, irritation and tinnitus loudness.81

Pharmacologic Therapy An overall view of pharmacologic therapy demonstrates that there are no proven medications for the treatment of tinnitus. The review that follows discusses some of the data that have reported success, but much of the data is confounded by the lack of rigorous research standards (i.e., double-blinded randomized control trials) or they demonstrated a benefit over a placebo effect which itself was quite high (40% in some series). At this time, it is the position of the authors of this chapter that medical therapy is not generally effective, deleterious in some cases, and should not be considered first-line therapy in the treatment of tinnitus.

Antidepressants The significant link between psychiatric disorders such as depression and anxiety with tinnitus has led researchers to treat tinnitus with various antidepressants. Dobie et al.45 reported in 1993 on the use of nortriptyline for tinnitus treatment in a double-blinded randomized clinical trial in 92 patients with and without depression. Tinnitus, depression and anxiety were

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assessed using the Iowa Tinnitus Handicap Questionnaire, Beck Depression Inventory, and Hamilton Anxiety Rating scale, respectively. Their results indicated that 67% of patients stated that the drug “helped them”, versus 40% of placebo. However, tinnitus severity was not significantly different between the placebo and nortriptyline groups, although both improved throughout the study.55,82 Their work has also highlighted the importance of the placebo effect and that the regular contact with health care teams may not be inconsequential.45 Zöger et al.83 reported in a double-blind, placebo-controlled study involving 76 patients with severe tinnitus that the use of sertraline was more effective than placebo in decreasing tinnitus severity, decreasing perceived tinnitus loudness, and improving symptoms of anxiety and depression. Tinnitus severity was assessed with the Tinnitus Severity Questionnaire (TSQ) and with a Visual Analog Scale (VAS) for tinnitus loudness and annoyance. The Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale were used in the assessment of depression and anxiety. Psychiatric assessments were also performed by an experienced psychiatrist. They reported a dropout rate of 13 participants, however, these individuals did not differ significantly in age, sex, or duration of tinnitus or scores for depression and anxiety. At the conclusion of 16 weeks, the TSQ scores for the placebo group decreased from 22.68 to 19.99, whereas they had decreased from 21.96 to 17.28 in the treatment group. There were similar statistically significant decreases in depression in anxiety scores in the treatment group. While these differences were found to be statistically significant, they also highlight the placebo effect. Other studies have been published and reviewed with regards to the use of other SSRIs and antidepressants and overall have found them to be more helpful in patients with coexistent depression and anxiety.84,85 In all these studies improvement in depression was shown, but there was no clear indication that drugs have direct beneficial effect on tinnitus.

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Anti-Epileptics: Gabapentin The relationship between chronic pain and tinnitus has been suggested and reviewed in the references noted above. A case report by Zapp86 in 2001 discussed a patient with chronic pain and a 10-month history of tinnitus. He was prescribed a 2-week course of gabapentin and was found to have significant improvement in his tinnitus symptoms, which continued with continued therapy. Other researchers have attempted to reproduce these findings with randomized clinical studies without success. Piccirillo87 reported in a double-blind randomized clinical study involving 135 patients that gabapentin was no more effective than placebo in relieving tinnitus (11.3 vs. 11.0 point-reduction in the Tinnitus Handicap Inventory score, respectively). Witsell88 reported similar findings in a randomized double-blind randomized clinical trial. Seventy-six patients with tinnitus were treated either with placebo or gabapentin (1800mg daily) for 5 weeks. Outcomes were assessed with the Tinnitus Handicap Inventory, Profile of Mood States rating scale and subjective tinnitus severity. At the conclusion of the study, no significant differences could be identified between the two groups. In fact, as in the Piccirillo data, there were similar reductions in THI in both groups. Bauer and Brozoski89, however, postulated that gabapentin would be beneficial in patients who have tinnitus associated with acoustic trauma (as evidenced by a “notch” between 3 and 6 Hz on audiometry) when compared to patients with tinnitus that is not associated with acoustic trauma. In a placebo-controlled, single-blinded trial of 39 patients, they demonstrated a statistically significant improvement in tinnitus annoyance, and 20% or better improvement in subjective loudness in 6 out of 20 acoustic trauma patients and 4 out of 19 nontrauma patients. However, other subjective assessments, such as Tinnitus Handicap Questionnaire (THQ), which are much better assessments of efficacy in the treatment of tinnitus, were not significantly different between treatment and placebo groups.

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Benzodiazepines Anecdotally, there have been practitioners that rely on the use of benzodiazepines in the treatment of tinnitus. In contrast, however, there are few well-designed studies that have shown that benzodiazepines are effective at controlling tinnitus and improving the suffering associated with tinnitus. 90 In a double-blind, randomized clinical trial using alprazolam over 12 weeks, researchers found that 76% of those taking alprazolam reported reduction of their tinnitus loudness, compared to only 5% of the placebo group.91 However, this study did not evaluate the effect on tinnitus severity, quality of life or the consequences upon discontinuing therapy and problems related to dependence. The study has been criticized in subsequent publications as not being in reality blind as subjects were able to determine whether they were on placebo or active substance by side effects. Others have advocated the use of benzodiazepines in the treatment of tinnitus and hyperacusis,66 largely based on anecdotal experience rather than data from randomized control trials. Note must be made that upon discontinuation of therapy, patients noted a return of their tinnitus symptoms and in some cases, their symptoms had worsened.92,93 In a report by Busto,94 three patients developed new-onset tinnitus after cessation of long-term diazepam therapy. One patient had resolution of symptoms after 6 months, another persisted with symptoms after one year, and the third patient resumed diazepam therapy to control the tinnitus. Much attention has been drawn to the habit-forming dependence that can form with the use of benzodiazepines.60 There are also significant side effects from the use of benzodiazepines, such as tachycardia, hypotension, dizziness, sedation, and headache. Furthermore, some have argued that benzodiazepine dependence can limit an individual’s ability to habituate to tinnitus symptoms, thereby worsening long-term management.95 Furthermore, it has been documented that infusion of benzodiazepines into the amygdala blocks even very basic learning (Pavlovian conditioning pairing tone with electrical shock) showing that benzodiazeines impairs neural plasticity. They are, therefore, counterproductive in

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any treatment aimed at achieving modification of connections in the brain such as TRT or psychological therapies.

Alternative Therapies A number of nontraditional pharmacologic, over-the-counter and herbal remedies for tinnitus have been examined. A detailed examination into all of the agents available on the market would be beyond the scope of this chapter. We will, however, highlight some of the therapies examined. As with pharmacologic therapy, there are no agents that have been shown to be effective in double-blinded randomized control studies. Piccirillo96 has examined melatonin and found that it can help patients with tinnitus and sleep disturbance, but that it does not seem to modify strength or frequency of tinnitus. Hilton97 performed a systematic review of the literature available on gingko biloba and identified only 3 studies that met inclusion criteria. These studies revealed no evidence to support that tinnitus improved with ginko therapy. Savastano98 reported a nonrandomized trial with no placebo arm in which 31 patients with tinnitus were treated with antioxidant vitamins. They observed that patients reported “great improvement in the reduction of tinnitus.” However, in light of previous placebo-controlled studies, the placebo effect cannot be excluded in this study. Furthermore, in a review of various antioxidants, minerals, vitamins, and herbal remedies, Enrico99 found many of these studies to be fraught with insubstantial scientific evidence, significant placebo effects, and potential harm from these substances. Park100 performed a review of acupuncture therapy for tinnitus and identified 6 randomized clinical trials. Two of these were unblinded and showed improvement in tinnitus, while the 4 that were blinded showed no difference.

Transtympanic Therapy

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Transtympanic therapy falls into 4 classes: (1) anesthetic agents (lidocaine), (2) ototoxic agents (gentamicin), (3) steroid, and (4) neuroactive agents (e.g. antioxidants).101 The tinnitusreducing effects of lidocaine was discovered accidentally in 1935102 and led to later use of anesthetic agents intravenously.103 The effects, both transtympanic and intravenous, have proven to be short-term. Interest in transtympanic gentamicin has garnered interest after its success with Ménière’s disease. Hoffer et al101 have reported on their work with transtympanic gentamicin for the treatment of Ménière’s and transtympanic steroids in the treatment of tinnitus in two nonrandomized, unblinded studies without placebo controls. In the Ménière’s study, 65% of patients reported a reduction in their tinnitus.104 Another group also reported success in treating Ménière’s as well as Ménière’s-related tinnitus in two small prospective trials that were also nonrandomized, unblinded studies without placebo controls.105,106 Given that most tinnitus sufferers do not carry a diagnosis of Ménière’s, the use of transtympanic gentamicin may actually be deleterious to a patient’s hearing and vestibular function. In a study examining transtympanic steroids101, 3/10 patients had almost complete resolution of their tinnitus and 3/10 had significant reduction in their tinnitus. Of note, those patients with sudden sensorineural hearing loss were those that had complete tinnitus resolution with transtympanic steroids. The three with significant reduction were patients with noiseinduced hearing loss. Two other reports have reported similar findings.107,108

Surgical Intervention The management of tinnitus is, overall, non-surgical. However, a handful of surgical procedures have been identified as beneficial in some groups of tinnitus sufferers. Each of these, however, has specific inclusion criteria that most tinnitus sufferers would likely not meet.

Cochlear Implantation

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As tinnitus is often associated with hearing loss, the implementation of cochlear implants for hearing rehabilitation has led to the examination of how cochlear implantation affects tinnitus. Various studies have been performed on cochlear implant patients and evaluated their subjective rating of their tinnitus pre- and post-implantation.109-113 In a comprehensive review, Baguley and Atlas114 examined over 18 studies in which the response to cochlear implantation was variable. The tinnitus prevalence varied from 35-100% of study subjects and the severity was often not quantified in a comparable manner across the studies. Success rates have overall been positive for tinnitus elimination or reduction (40%, up to 92% in some series), but some reports have indicated worsening of tinnitus in 2-15% of implanted patients studied.114 In order to undergo cochlear implantation, it is recommended that adults have an audiogram that demonstrates a pure-tone audiometry (PTA) threshold for both ears should equal or exceed 70 dB. If the patient can detect speech with best-fit hearing aids in place, a speech-recognition test in a sound field of 55 dB HL (Hearing Level) is performed. Current US Food and Drug Administration (FDA) guidelines permit implantation in patients whose open-set sentence recognition (e.g., HINT) is 60% or less in the best-aided condition. This may vary depending on the third-party payer.115

Microvascular decompression (MVD) It has been postulated that vascular compression of cranial nerves are causative or associated with hyperactive disorders, such as trigeminal neuralgia, hemifacial spasm and tinnitus.116,117 Microvascular decompression surgery involves moving the blood vessel off of the intracranial portion of the nerve involved.116,118 In a study of 72 patients,116 inclusion criteria were severe tinnitus and signs of change in the conduction properties of the auditory nerve as measured by narrow dips in the pure-tone audiogram and poorer speech discrimination. Thirteen patients, or 18.2%, had significant improvement, 22.2% had marked improvement, 11.1% had slight improvement, 45.8% had no improvement, and 2.8% became worse. The

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authors found that better results were observed in patients who had had tinnitus for less than 3 years and in those with unilateral tinnitus. In another series by Brookes,117 vascular compression was assessed with the use of air computed tomography cisternography and later with MRI. Microvascular decompression surgery was performed in 9 patients with severe tinnitus and resulted in complete abolition of symptoms in 3 (33%) patients, significant reduction in 5 patients, and unchanged in 2 patients. These data suggest that MVD could be considered in a very highly selected group of patients, but the data are limited to small series of patients and were not overwhelming in their success. Given the risks inherent to the procedure described, we would not consider this firstline therapy.

Cochlear nerve section Other authors have discussed severing the cochlear nerve in order to alleviate tinnitus. This decision would clearly eliminate all hearing on that side. Others would argue that this surgery may make no difference given that individuals who are already deaf still experience tinnitus. Pulec119 published data in a series of 151 patients in which the tinnitus was found to originate within the cochlea. The cochlear nerve was severed medial to the spiral ganglion for tinnitus and resulted in 101 patients had complete resolution post-operatively, 43 who had improvement, 7 who had none. The length of follow-up was not clear, however. Given the elimination of all hearing coupled with the possibility that tinnitus could persist or worsen, the authors of this chapter would not recommend this line of therapy.

Other Transcranial Magnetic Stimulation PET scans have provided researchers with data that may indicate that tinnitus is associated with cortical areas involved in the perception and processing of sounds and

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speech.120,121 Regional cerebral blood flow was assessed in patients with tinnitus during tinnitus perception and after tinnitus reduction by lidocaine injection.120,122 Based on these findings, Plewnia 2006123 investigated the use of PET-navigated repetitive transcranial magnetic stimulation (TMS) with the objective being to interfere with the neuronal activity in the affected areas. While short-term results were promising,124 all but 1 out of the 6 patients in their study returned to their baseline level of tinnitus after 2 weeks of therapy. Various other studies have examined TMS using various cortical targets, stimulation frequencies, and control groups. Kleinjung et al.125 reviewed 11 clinical trials and the results varied considerably with regards to short- and long-term control. At this time, the data do not seem to indicate that this modality of therapy is widely effective.

Transcutaneous Electrical Stimulation Tinnitus suppression via transcutaneous electrical stimulation has been reported since 1890s.126-128 Although success rate up to 66% has been reported, relief was often transient.129 A more recent study by Steenerson and Cronin126 reported data on the transcutaneous electrical stimulation in 500 patients. A hand-held probe was used to deliver electrical stimulation to approximately 20 arbitrarily selected points on the external pinna and tragus of each ear. Patients were simultaneously guided through tinnitus-reduction activities, such as relaxation, breathing exercises, or biofeedback. Of the 500 patients, 53% received significant benefit as measured by subjective tinnitus intensity scores. The study did not, however, employ a validated questionnaire and 13 patients reported worsening tinnitus after therapy that returned to pretreatment levels in 11 of these patients. Furthermore, as the patients were treated simultaneously with other methods, one cannot conclude that the benefits were due to transcutaneous electrical stimulation.

Electrical Suppression with High-Rate Pulse Trains

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The basis for the work of Rubinstein et al. 130 is predicated on the hypothesis that tinnitus is the result of the loss or alteration of normal spontaneous activity in certain regions of the cochlea or auditory nerve. In a prospective, non-randomized trial without a control group, 11 subjects with tinnitus were treated with myringotomy and placement of a temporary round window electrode. High-rate pulse train stimuli (close to 5 kHz) were presented at various intensities. Five of the 11 subjects (45%) experienced substantial or complete temporal resolution of their tinnitus. Three subjects showed tinnitus suppression only in association with the perception of the stimulus and three showed no effect. At this time, however, there has only been this study and more work needs to be performed demonstrating the efficacy of this therapy prior to being recommended for widespread use.

Sound therapy A wide variety of sound therapies have been promoted over the years (e.g., pink noise therapy dynamic tinnitus mitigation system, phase shift tinnitus reduction, auditory integration training). There are no clear results showing their effectiveness. It is generally recognized, that sound enrichment can be helpful and proper utilization of sound is important for number of therapies such as music therapies, Neuromonics, relief therapy, and TRT.

Conclusions Mechanisms of tinnitus are still disputable and there is no cure that removes tinnitus perception. A number of treatments, however, offer a possibility of substantial improvement. Of crucial importance is avoiding negative counseling (e.g., “nothing can be done, you will have to live up to end of your life with tinnitus, tinnitus may get worse with aging and worsening of hearing.”). Negative counseling can enhance pre-existing tinnitus, annoyance and anxiety level and turn a subject who is just experiencing tinnitus into a patient who is suffering because of it.

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While there is no drug that is consistently recommended for tinnitus, there are ongoing studies with hopes to find a medication that would at least partially attenuate tinnitus. Notably, some drugs, (e.g., benzodiazepines) may make the treatment more difficult, in addition to creating significant side effects. No surgical procedure can consistently be recommended at this time. There is a consensus that sound enrichment of the auditory background can be helpful and avoiding silence is of paramount importance. Most effective therapies combine counseling with sound therapy. It appears that therapies aimed at habituation of tinnitus, such as TRT, at the moment offers advantages over other approaches.

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APPENDIX: Tinnitus Handicap Inventory49 This questionnaire is a 25-item, 100-point test with 3 subscales- F-functional, E-Emotional and Ccatastrophic. A pt is asked to respond Yes, Sometimes, or No. A “Yes” response carries 4 points, Sometimes- 2 points, and No- 0 points. What results is a score of 0-100, 100 being extremely severe tinnitus handicap. 1F. Because of your tinnitus is it difficult for you to concentrate? 2F. Does the loudness of your tinnitus make it difficult for you to hear people? 3E. Does your tinnitus make you angry? 4F. Does your tinnitus make you feel confused? 5C. Because of your tinnitus do you feel desperate? 6E. Do you complain a great deal about your tinnitus? 7F. Because of your tinnitus do you have trouble falling asleep at night? 8C. Do you feel as though you cannot escapte your tinnitus? 9F. Does your tinnitus interfere with your ability to enjoy social activities (such as going out to dinner, to the movies)? 10E. Because of your tinnitus, do you feel frustrated? 11C. Because of your tinnitus do you feel that you have a terrible disease? 12F. Does your tinnitus make it difficult for you to enjoy life? 13F. Does your tinnitus interfere with your job or household responsibilities? 14F. Because of your tinnitus do you find that you are often irritable? 15F. Because of your tinnitus is it difficult for you to read? 16E. Does your tinnitus make you upset? 17E. Do you feel that your tinnitus problem has placed stress on your relationship with members of your family and friends? 18F. Do you find it difficult to focus your attention away from your tinnitus and on other things? 19C. Do you feel that you have no control over your tinnitus? 20F. Because of your tinnitus do you often feel tired? 21E. Because of your tinnitus do you feel depressed? 22E. Does your tinnitus make you feel anxious? 23C. Do you feel that you can no longer cope with your tinnitus? 24F. Does your tinnitus get worse when you are under stress? 25E. Does your tinnitus make you feel insecure?

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