Bone remodeling disorders have been identified as potential candidates for the etiology underlying some forms of otologic disease. Here, four clinical cases are presented to demonstrate a novel approach to tinnitus management that focuses on two fundamental etiologic bases. First, is the effect of bone remodeling abnormalities of the otic capsule and second, the effect of blood sugar and insulin abnormalities upon the function of the inner ear and self-reports of tinnitus. This report presents the effect of treatment directed at bone remodeling abnormalities of the otic capsule and abnormalities of blood sugar and insulin. The treatment effects led to a substantial reduction in subjective tinnitus. These findings suggest a potential convergence between bone pathophysiology and some forms of tinnitus.
Keywords: Bisphosphonates, blood sugar, bone remodeling, insulin, osteoclastogenesis, tinnitus
|How to cite this article:|
Brookler KH. Illustrative cases of unorthodox tinnitus management. Noise Health 2013;15:143-7
| Introduction|| |
Bone remodeling disorders of the otic capsule are characterized as a decreased density of the otic capsule. Clinically, we have found that in a number of neurotologic cases, inclusive of tinnitus, there is evidence of bone remodeling disorders. We have identified these underlying bone remodeling disorders by Polytomography X-ray or Computerized tomography imaging of temporal bones.
As imaging technologies have improved  bone remodeling disorders of the otic capsule, driven by osteoclasts, have become more easily identified. Along with the increased ease of identifying these otic capsule abnormalities, the science of osteocastogenesis  has evolved. Osteoclastogenesis has demonstrated the process by which osteoclasts form from macrophages and the effect of cytokines in this process. As a result, the bisphosphonate group of medications  was developed and became available in the 1990's. These medications target apoptosis of osteoclasts or prevent osteoclast production.
A second etiologic abnormality associated with tinnitus was discovered in the realm of abnormalities of blood sugar and insulin. ,, Based upon 5-h glucose tolerance testing with simultaneous insulin levels, it was evident that many patients with tinnitus demonstrated abnormalities that could be addressed by dietary management. As experience in the management of these abnormalities of blood sugar and insulin has evolved, so has an understanding of insulin resistance syndrome and related disorders. ,, With better understanding of insulin resistance syndrome dynamics came concepts regarding non-insulin dependent diabetes, acute coronary syndrome, non-alcoholic fatty liver disease and polycystic ovary syndrome. ,,,
More recently, studies have demonstrated a convergence of bone remodeling and abnormalities of blood sugar and insulin in understanding the relationship between bone and the whole body through a complex signaling system. ,,,,
To illustrate how these pathologies may be related to tinnitus, we present four clinical cases from a large cohort collected over 40 years. These four cases are characterized by their clinical presentation of tinnitus as an annoyance, tinnitus disability, tinnitus severity with suicidal ideation and tinnitus in association with other neurotologic disorders. Whereas the onset of tinnitus may be considered acute, the symptom of tinnitus remained a chronic ailment requiring prolonged duration of some of the treatments. Because these treatments attempt to address the underlying causes of tinnitus, the onset of a benefit was found to take from weeks to months to reveal efficacy.
| Cases|| |
A 30-year-old female patient with a family history of tinnitus presented with persistent bilateral tinnitus on December 1, 1980. The tinnitus began in the left ear 11 months prior to her visit and in the right 5 months after that. Initially the tinnitus began after a "bad cold" and was reported as worse during her regular menstrual cycle, anxiety, food consumption and levofloxacin treatment. An otolaryngologist informed her that the tinnitus could be related to some previous dental work. She described the tinnitus as a constant ringing or hissing with fluctuating loudness more prevalent in the left ear. She described the effect as annoying. Pure tone audiometry revealed a mild conductive component in the left ear and normal hearing in the right ear with thresholds less than 25 dB bilaterally. High frequency audiometry revealed hearing to 12.1 kHz in the right ear and 11.2 kHz in the left ear with normal hearing for speech. Polytomography X-ray imaging of the temporal bones revealed evidence of demineralization of the otic capsule in both ears. The 5-h glucose tolerance test revealed a flat curve, indicating no significant change in blood sugar from fasting through the 5 th h. These results were considered abnormal for the functioning of the inner ear.
A diet was recommended to address the flat curve Glucose Tolerance Test findings and sodium fluoride and calcium carbonate associated with the demineralized otic capsule. There were as many as 5 years between visits and varying dosing schedules of the sodium fluoride and calcium carbonate to as high as 6 per day. Prior to the visit the treatment had been discontinued. She had taken the sodium fluoride for a total of 243 months (1980-2008). When bisphosphonates medications became available to treat demineralized bone, it was recommended that she take etidronate followed by alendrolate. The purpose of the drug intervention was to target the osteoclasts underlying the de-mineralization by preventing their formation and accelerating their cell death or apoptosis. Because she could not tolerate these early bisphosphonates, risedronate was attempted on a twice-weekly 30 mgm dosing schedule. Unfortunately she was unable to tolerate this dosing scheme. Eventually she settled on risedronate 30 mgm weekly for 40 months. The tinnitus disappeared after 28 months on the lower risedronate dose.
During the time of managing this patient there was a measurable progressive decline in audiometry evidenced by both poorer air and bone conduction audiometry. When the patient finally settled on a once weekly regimen of the risedronate, bone conduction thresholds improved and speech reception threshold was 45 dB on conventional audiometry with air-bone gap differences still present. Stapedectomy was offered to her on several occasions. While there was no baseline otoacoustic emissions (OAE), there was progressive improvement in two post risedronate treatment measures of both transient otoacoustic emissions (TOAE) and distortion product otoacoustic emissions (DPOAE) on the ear without the mixed hearing loss (right ear).
A 60-year-old male presented with a 1-year history of constant tinnitus in the left ear on March 1992. Family history was negative for tinnitus but positive for hearing loss. Tinnitus was described as a pulsing/swishing sound that increased with stress, drinking wine and eating desserts. In order to sleep at night the patient resorted to a "noise" machine which was reported as occasionally helpful. Hearing was found to be within normal limits with a mild conductive component at 250 and 500 Hz and speech reception thresholds of 5 dB HL.
Computerized tomography of the temporal bones revealed demineralization of the otic capsule more evident in the left ear than the right ear. A 5-h glucose tolerance test revealed an exaggerated response with wide swings in blood sugar (glucose) reaching 56 mgm% at the 3 rd h. There were no abnormalities in simultaneous insulin levels. He was started on a diet to control the fluctuations in blood sugar and was initially compliant. The patient was first put on an alternating regimen of etidronate and calcium after which sodium fluoride was added. Adequate calcium intake was necessary since calcium is the basic building block of bone. After 11 months on etidronate he reported not needing the "sound machine" at night. After 17 months on etidronate the tinnitus disappeared. It was not subjectively present and there was no tinnitus to match audiometrically. The regimen was continued for a total of 51 months. Thereafter he remained on a low dose sodium fluoride. He followed the diet for 70 months after which he became less compliant and would notice on rare occasions after too much dessert or sugars a resurgence of transient tinnitus. The patient was later found to be vitamin D insufficient and was placed on vitamin D. The absence of tinnitus has remained at the most recent follow up 16.5 years later. He had taken sodium fluoride for a total of 61 months, etidronate for 51 months; thereafter he remained on sodium fluoride.
Severe disabling tinnitus
A 48-year-old male concert pianist/piano teacher presented with a 2-year history of severe disabling tinnitus. Family history was negative for tinnitus and hearing loss.
His past illnesses were positive for hypothyroidism secondary to Hashimoto's thyroiditis, managed with thyroid replacement and chondromalacia. He was so severely affected by tinnitus that he was placed on anti-depressants and electroconvulsive therapy. The tinnitus was described as a constant hissing in both ears. A hearing evaluation revealed hearing within normal limits bilaterally. High frequency audiometry showed hearing out up to 11 kHz binaurally: 40 dB at 11 kHz in the right ear and 40 dB at 10 kHz in the left ear. Tinnitus pitch was matched at 9.9 kHz in the right ear and at 9.2 kHz in the left ear with loudness of 50 dB in both ears. On attempted sound suppression of the matched tinnitus, the stimulus blended with the tinnitus but did not appear to suppress it. The patient also reported subjective hyperacusis that appeared intermittently and had been more constant prior to the visit.
Computerized tomography of the temporal bones revealed bilateral demineralization of the otic capsule more on the left. The 5-h glucose tolerance test was exaggerated with wide swings in blood sugar while simultaneous insulin levels were normal. He was placed on a diet to address the glucose tolerance results and sodium fluoride and combinations of different bisphosphonates. He was taking the sodium fluoride for 78 months. He was initially started on etidronate for 3 months, followed by alendrolate for 3 months, risedronate for 30 months and a combination of risedronate and etidronate alternately for 43 months.
At the first visit on etidronate while sleep deprived from his tinnitus symptoms and louder than usual tinnitus, he was able to achieve a close match of his tinnitus in both ears indicating the accuracy of the stimulus in replicating his tinnitus. With attempted suppression of the matched tinnitus, the tinnitus became quieter in both ears. This represented an improvement over the pretreatment attempt to suppress the tinnitus and would suggest that the treatment was having a beneficial effect. The tinnitus improved on alendrolate then became worse with additional anti-depressants. Eventually after a discussion with his psychiatrist regarding the organic rather than a psychological nature of the tinnitus, he was taken off all anti-depressants and electroconvulsive therapy. Thereafter, the tinnitus became tolerable and disappeared for periods of time on the alternate dosing of etidronate and risedronate.
While he was initially unaware of any benefit on his subjective hyperacusis, after 9 months on treatment he was aware that it was better. Thereafter, the hyperacusis increasingly improved and finally disappeared.
He had taken sodium fluoride for a total of 78 months, etidronate alone at different times for 6 months, alendrolate for 3 months, risedronate for 30 months and etidronate and risedronate on an alternating schedule for 43 months.
Tinnitus with associated other neurotologic disorder
A 42-year-old woman presented in November 1993 with a history of significant hearing loss, aural fullness, dizziness and tinnitus. There was no hearing in the left ear and she reported a fluctuating hearing loss in the right ear. Tinnitus had been present in the left ear but was not the primary complaint as it was described as "occasional". Family history was positive for hearing loss, tinnitus and Meniere syndrome.
The patient reported that sugar intake had a negative impact on her hearing and her dizziness. At the time of presentation she was taking low dose prednisone and hydrochlorothiazide.
Computerized tomography of the temporal bones revealed demineralization in both otic capsules. The 5-h glucose tolerance test revealed an exaggerated response. No simultaneous insulin levels were obtained.
The low dose prednisone and hydrochlorothiazide regimen prescribed for her hearing loss was discontinued. She was placed on a diet to address the glucose tolerance test results. She had repeated problems with remaining compliant with the diet especially during holidays. Etidronate was instituted along with calcium carbonate.
Treatment resulted in a general improvement with the disappearance of the tinnitus and vertigo. The hearing loss continued to fluctuate with her menses and during etidronate treatment, but she reported intervals of improved hearing. Sodium fluoride was added to the regimen as it is an essential element in bone health. As bone turns over, new bone will be a fluoroapatite rather than a hydroxyapatite and the fluoroapatite is more resistant to demineralization.
She was later switched to alendrolate and noted on the return visit that the tinnitus had re-emerged and was much more noticeable. She was switched to tiludronate, a different bisphosphonate, but did not remain on it long enough to note a response. At a subsequent visit, she was placed on risedronate resulting in a decrease in tinnitus. The tinnitus disappeared 7 months into a regimen combining risedronate and etidronate alternately. It remained so as long as she was followed for 21 months. She had taken sodium fluoride for a total of 135 months, etidronate alone at different times for 9 months, alendrolate for 3 months, tiludronate on and off for 11 months, risedronate for 78 months and etidronate and risedronate on an alternating schedule for 21 months.
| Discussion|| |
The purpose in discussing these case presentations is to present a novel approach to tinnitus management with attention to the state of the otic capsule and to metabolic factors that may interfere with cochlear function. , The rationale for the treatments prescribed to these patients with tinnitus is based upon two hypotheses. One is based upon the effect of blood sugar and insulin upon inner ear functioning ,,,,, and the other upon directing a treatment at an otic capsule bone remodeling disorder. ,,,
The emerging field of osteoclastogenesis sheds light upon how otic capsule disorders can affect inner ear function. This is believed to be mediated through a signaling pathway initially triggered by cytokines released as a result of infection, trauma or other incidents. These cytokines transform macrophages to osteoclasts resulting in the process of bone remodeling. The osteoclasts form a tight  seal with the bone interface and secrete an acid that breaks down the bone. The by-products of osteoclast activity include cytokines that are presumably toxic to inner ear hair cells. One of these cytokines, Tumor necrosis factor-alphs, ,, is known to be toxic to hair cells and as a consequence alters inner ear function. An example of preventing these toxic effects is the use of corticosteroid drug eluting cochlear implants to mitigate further loss of residual hearing from cochlear implantation.
The bisphosphonates used in this report target osteoclasts that cause cell death or apoptosis. As evidenced from the patient self-reports presented here, the effect of the bisphosphonates on auditory symptoms included in some instances reversibility of tinnitus, reduced hearing loss and improvement of OAE.  The data also suggest a difference in the efficacy of the various bisphosphonates with alendrolate having the least effect and the combination of alternate risedronate and etidronate having the greatest clinical benefit. The latter combination represents the alternate use of an amine bisphosphonate (risedronate) and a non-amine bisphosphonate (etidronate). The effects of treatment became apparent after 3 or more months based on improvements in hearing tests as well as improvements in DPOAE. Clinically, the time course of osteoporosis treatments takes from 1 to 2 years before bone mineral density changes can be identified. As a result of this prolonged time course, clinicians managing osteoporosis often do not see differences in efficacy based upon chemical configuration of the bisphosphonate.
The secondary focus on blood sugar and insulin also added an important element in the evaluation and management of the patients presented here. Abnormalities of blood sugar and insulin were identified in patients by obtaining a 5-h glucose tolerance test with simultaneous insulin levels. , The two blood sugar curves that were of interest were the flat curves and the exaggerated curve. The flat curve is not commonly seen and is characterized by no significant change in blood sugar from fasting to the 5 th h. This is usually found in patients with a low calorie diet or may arise from failure of glucose absorption. Looking at the simultaneous insulin values revealed a rise and fall during the 5 hours confirming the absorption of glucose. This flat curve is abnormal for the inner ear since some fluctuation in the blood sugar is required for the inner ear to function within a normal range. This finding contrasts the exaggerated curve where the fasting blood sugar is normal and the ½ h and/or 1-h blood sugar rose abnormally high (≥180 mgm%) or fell rapidly. One explanation for the fall is a blood sugar 30 mgm% below the fasting level at the 2 nd h or a fall of 30 mgm% from the 2 nd to the 3 rd , 4 th , or 5 th h. While some endocrinologists consider this to be just outside normal limits, these findings are abnormal for the inner ear. ,, In the instance of the exaggerated glucose response, the insulin levels may be elevated either at the less common fasting level or the combined second and 3 rd h insulin adding up to ≥60 μU/mL.
Whereas, patients presenting with a history of diabetes do not typically require a 5-h glucose tolerance test, an inquiry into the efficacy of the management of their diabetes must be obtained. If they are non-insulin dependent, then insulin levels should be measured both fasting and postprandial.
A fourth possible response on the 5-h glucose tolerance test is hypoglycemia; a diagnosis triggered by blood sugar drops to 35-40 mgm% or lower. Note that many patients do not experience any overt symptoms when the blood sugar is hypoglycemic.
Regardless of the pattern of response on the glucose tolerance test, patients should be placed on what is considered a modified hypoglycemic diet, low in fat with three meals and three snacks per day. The diet can be calorie restricted if weight loss is a secondary goal. If diabetes is found more attention is required in regard to the selection of carbohydrates.
In the present study, when some of the beneficially treated patients returned, they related that reoccurrence of tinnitus or tinnitus increases were related to deviations from the controlled diet. In some patients, before the controlled diet was instituted, tinnitus was often noted to increase with elevated consumption of simple carbohydrates or alcohol.
Recent findings have suggested a possible relationship of insulin levels on osteocalcin effecting bone and bone remodeling. ,,,,,, If bone remodeling disorders affect cochlear function then it is reasonable to hypothesize that these disorders could lead to some forms of peripheral tinnitus. Current hypotheses of tinnitus acknowledge peripheral cochlear level triggers followed by a focus on the upstream effects at the brain stem and cortical level. Because of the focus on the central aspects of tinnitus, ongoing cochlear events are often overlooked in the chronicity of the symptoms and in the consideration of treatment protocols. Because of some of the shortcomings of this approach in yielding effective treatment, cochlear events such as the effect of blood sugar, insulin and demineralization disorders of the otic capsule are worthy of exploration and may reveal the locus of at least some forms of tinnitus.
The proposed treatment paradigm presented here appears unorthodox and is certainly not a mainstream method of tinnitus management. However, the theoretical basis, rationale, and present results suggest a potential alternative to current treatment protocols. The above patient presentations serve to highlight novel etiologic factors to consider when faced with patient who report tinnitus.
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Kenneth H Brookler
119 Gregory Blvd., #49, Norwalk, CT 06855
Source of Support: None, Conflict of Interest: None