OA Journal of Otorhinolaryngology

Tinnitus in Meniere’s disease

*Richard S. Tyler
Department Of Otolaryngology, University Of Iowa, United States

*Corresponding Author:
Richard S. Tyler
Department Of Otolaryngology, University Of Iowa, United States
Email:rich-tyler@uiowa.edu

Published on: 2019-01-16

Abstract

Meniere’s disease is a chronic disease characterized by vertigo, hearing loss tinnitus and sensation of aural fullness. Tinnitus is one of Meniere’s disease primary clue symptoms. Various studies were done to assess vertigo and hearing deficit but only few ones relate to the clinical characteristic, diagnosis and treatment of tinnitus. Our paper provides a focus on tinnitus to clarify at what extent Meniere’s disease could play an important role in some types of chronic tinnitus sufferers

Keywords

Tinnitus; hearing loss; Meniere’s disease; vertigo

Introduction

Meniere’s disease [MD] is defined as a chronic disease characterized by tetrad of vertigo, sensori-neural hearing loss, tinnitus and sensation of aural fullness. It was first described by Prosper Ménière in his original publication in 1861 [1]. Individuals with MD experience incapacitating attacks of vertigo, associated with nausea and vomiting lasting for hours. [2] The sudden attacks of vertigo last anywhere from 30 min to several hours, with unilateral hearing loss occurring together with tinnitus; often aural fullness is present as well. Audiological findings show fluctuating low frequency and progressive sensorineural hearing loss with tinnitus and vertigo, course is unpredictable and highly variable among individuals with accompanying periods of remission. Stouffer and Tyler [3] raised the flag showing that tinnitus in MD is typically more severe than in other pathologies.

Pathophysiology Of Meniere’s Disease

A major underlying pathophysiological state in MD is endolymphatic hydrops, which can only be demonstrated with certainty after death by histopathological study of the temporal bones. [4] Hydrops defined as distention of membranous labyrinth which begins at apical part of cochlea then extend to involve whole cochlear duct and the vestibular apparatus (utricle, saccule). [5] Although MD is caused by idiopathic hydrops, some experimental studies in animals had shown that hydrops did not necessarily lead to Meniere’s symptoms and these symptoms could be found without hydrops. For example endolymphatic hydrops can be found in patients with superior canal dehiscence and large vestibular aqueduct syndrome, [6] or in patients with sudden sensorineural hearing loss. [7] Different pathogenic mechanisms can explain the hydrops. These include either:

Obstruction of the endolymphatic duct and/or dysfunction of the endolymphatic sac

• Physiologically the endolymphatic sac has the following functions:

• Pressure changes transmission from the C.S.F to endolymph.

• Hemostasis of endolymph either resorption or secretion.

• Secretion of glycoproteins which causes increase in the longitudinal flow of endolymph thus regulating osmosis.

• Secretion of saccin hormone to increase endolymph production. [8]

• Removal of metabolic and cellular debris.

• Immune defense function of ear.

Thus duct obstruction or/and endolymphatic sac dysfunction are considered to be etiological factors in MD because hydrops can be done experimentally on animals by procedures which cause these same conditions.

Endolymph over secretion

The excess of endolymph in temporal bones of patients with MD could be explained by an overproduction of endolymph. The antidiuretic hormone level has been reported to be significantly higher in patients with MD. [9] Regarding the cochlea,there are two osmotic gradients; first one is between perilymphatic space and endolymphatic sac, and the second is inside the endolymphatic space betweenthe apex and the base of the cochlea. Any disturbances of these two gradients could result in hydrops. [10] Many theories concerning the pathophysiology of MD have been proposed, including changes in endolymph reabsorption due to anatomical variations, perfusion/reperfusion vascular changes, autoimmune mechanisms and changes in water homeostasis [11]. Aquaporins [AQP] are involved in fluid regulation in the inner ear, specifically the subtypes AQP 1, 4 and 6[12]. It has been demonstrated that vasopressin and oxytocin have a direct effect on aquaporin?mediated regulation of inner ear fluids Moreover, cytochemical changes in AQP 4 and 6 expressions in the cochlear supporting cells were demonstrated in MD inner ears.

Pathophysiology of Meniere’s symptoms

Several mechanisms can explain mechanisms of occurrence of Meniere’s disease symptoms; Schuknecht stated that gradual distention of the endolymphatic system that leads to a rupture of membranous labyrinth and that in turn cause sudden release of a large volume of endolymph into perilymphatic space [13]. As a result, sensory and neural structures are injured from exposure to the potassium-rich endolymph, resulting in vertigo and hearing loss. As the rupture heals and hemostasis is restored in the inner ear compartments, the symptoms subside. Dohlman [14] suggested that increase of potassium occurs in the perilymph during a Ménière’s attack and that potassium-rich fluid surrounding the vestibular nerve is the cause of the experienced vertigo (irritative vestibular syndrome) Zenner [15] found that perilymphatic potassium intoxication leads to a longitudinal contraction of the outer hair cells. This results in their decoupling from the tectorial membrane with resultant Meniere’s symptoms. Dulon et al. [16] demonstrated that small changes in the osmolarity of the surrounding in vitro medium induce fast contractions [hypo-osmotic solution] or elongations [hyperosmotic solution] in isolated outer hair cells which in turn lead to disorganized depolarization and repolarization and appearance of Meniere’s symptoms.

Pathophysiology of tinnitus in Meniere’s disease

Tinnitus in MD might be caused by mechanism similar to other forms of tinnitus due to cochlear injuries so hearing loss is the cause of tinnitus as it causes deprivation of auditory input to auditory nervous system with resultant activation of neural plasticity. [17] Activation of neural plasticity will cause tinnitus as these plastic changes may include sprouting of axons, programmed cell death, change in protein synthsis,change in functions of nerve cells together with change in synaptic efficacy which may start a sequence of events that includes formation of new synapses and elimination of others, later on that can create new connections. [18]

Characters of tinnitus in Meniere’s disease

According to the criteria of American Academy of Otolaryngology–Head and Neck Surgery [AAO?HNS], MD clue symptoms are recurrent vertigo, fluctuating hearing loss and tinnitus or aural fullness sensation. [19] and according to the classification committee of the Barany society formulated simplified diagnostic criteria for MD, jointly with several national and international organizations [20] both of classifications included tinnitus as a diagnostic symptom for MD but tinnitus is the least studied symptom as vertigo attacks can override and became more annoying and distressing. Tinnitus may be the first symptom of Ménière’s disease and may precede the remaining symptoms by months or years. Fluctuating cochlear signs, such as tinnitus, hearing impairment, and/or fullness in the ear were present prior to onset of the first vertigo attack in more than 50% of patients. [21]

Tinnitus is reported by 94% of the patients and considered important by 37% of them. [22] At the beginning, the tinnitus complaint is often secondary. Classically, it becomes worse during vertigo attacks but may significantly improve or even disappear afterward. However, with the progression of the disease, the tinnitus can become permanent, more frequent, severe and persisting between attacks with intensity fluctuations. Its evolution is then unfavorable due to a significant increase in anxiety. [23]

As tinnitus usually occur with hearing loss, in MD, it often starts with a low frequencies pitch [125/250Hz], then when disease advances, its pitch can contain many frequencies. [23] Tinnitus that occurs in Ménière’s disease is often described as low pitched, narrow band of noise, usually harsh roaring machinelike or buzzing sound that is more pronounced during vertigo attacks and then with disease progression it became high pitched. Hyperacusis and distortion of sound in the affected ear can also be present [24]. Tinnitus and aural fullness prevail during life in the majority of individuals with MD. [25] Stahle [26] described a study in Sweden and stated that tinnitus quality fluctuated in intensity and then parelled the control of vertigo spells and ear block ,another study performed by him on separate group of patients with controlling of their chief vertigo complain and found that ear block persisted as tinnitus did. Herraiz et al [27]described the relation between tinnitus intensity and hearing loss and found that there was statically association between tinnitus intensity and worse hearing loss in 102 patients with MD non affected by vertigo spells .

Differential diagnosis of tinnitus in some diseases Patient presents with tinnitus duration Less than three weeks;

Assess for recent exposure to excess noise, head and neck trauma, otitis media, or ototoxic medication use. Examine for cerumen impaction, head, neck, or temporo mandibular joint pain or focal neurologic finding. Treat suspected underlying causes and observe. Perform audiometry and Magnetic Resonance Imaging [MRI] for focal neurologic findings. If symptoms persist, start to evaluate tinnitus as lasting for more than3 weeks.

Patients presented with tinnitus for more than three weeks;

If tinnitus associated with intermittent hearing loss and vertigo, evaluate patient for MD with audiometry, electronystagmography, and MRI with special characters of tinnitus in MD previously described.

If tinnitus is pulsatile, suspect vascular origin either arterial or venous, or non-vascular origin as palatal, stapedial and tensor tympani muscle myoclonus. If patient presented with unilateral tinnitus and unilateral asymmetrical hearing loss, perform MRI to evaluate and exclude vestibular schwannoma. If patients presented with change in perception oftinnitus during teeth grinding, side to side movement of head, neck tenderness and pain or crepitus on movement that all indicates that tinnitus is of musculoskeletal origin. [28] It is clearly obvious that two – thirds of patients have bilateral tinnitus; unilateral one is likely in MD, somatosensory or vestibular schwannoma. [29] Family history plays an important role as diseases with tinnitus and family history like MD and otosclerosis. [30]

Treatment of tinnitus in Meniere’s disease

Tinnitus treatment is still a challenge. There is no FDA?approved drug for tinnitus treatment and most of the clinical trials with drugs were not replicated, probably due to differences in the samples, tinnitus characteristics, and methodology and drug dosage [31] According to the recent consensus of the AAO?HNS, treatment should focus on counseling and sound therapy [32]. Some believe that their tinnitus could be pharmacologically targeted, considering the multiple neurotransmitters and receptors involved in tinnitus pathophysiology. [33]

1-Non -invasive therapies

When the Meniere’s symptoms disappear after the crisis, patient only needs dietetic recommendations such as to avoid caffeine, alcohol, tobacco, and aspartame, which supposed to worsen tinnitus and other MD symptoms. A low-salt diet is also recommended.

Betahistine was tested in a retrospective study comparing patients with vestibular disorders that were treated or not with betahistine 24 mg bid, tinnitus improvement was significantly better in the group treated with betahistine [34] although not specific for MD, some encourage further studies, using higher doses of betahistine (even reaching 288–480 mg/day) that have been safely employed to MD treatment could also be tried at patients with tinnitus. [35]

A randomized and controlled clinical study suggested the effectiveness of the combination of diuretics acetazolamide (250 mg/48 h), and prednisone (0.35 mg/kg) on the tinnitus, as well as the frequency and duration of vertigo. [36] Recently, it has been demonstrated that nasal oxytocin could induce an immediate decrease in tinnitus volume. Oxytocin and vasopressin receptors are found at the cochlea and were demonstrated to be related to fluid regulation in the inner ear, via inner ear AQPs [37] it is found that tinnitus loudness and tinnitus distress are reflected by increased activation in networks involving the auditory cortex and the amygdala, respectively and oxytocin can reduce amygdale activation[38] other possible mechanism of relieving tinnitus by oxytocin is Oxytocin receptors [OTR] effect, these ORT are widespread throughout the human body and belong to the family of heterotrimeric G-protein-coupled receptors, which are found in many cell types. OTR promote the inhibition of adenylate-cyclase, thus reducing intracellular levels of cyclic-AMP and subsequently opening potassium channels and closing calcium channels thus reversing hydrops pathology and relief MD symptoms. [39] In addition to the pharmacologic treatments we mentioned before, there are some measures which have a significant clinical benefit for the patients MD. Education is an important part of the treatment of MD as it is a chronic condition so, it could be debilitating for some patients. In an effort to reduce the effect of this disease on quality of patient’s life, it is important that patients understand the likely clinical course of their condition and required treatment paradigms. Appropriate information can help alleviate the frustration and depression many patients experience because of feelings of helplessness or the misunderstanding of treatment options. Vestibular rehabilitation and psychological therapies such as relaxation techniques and cognitive behavioral therapy have a beneficial effect in those patients. Yardley and Kirby [40] investigated effect of that therapy on 360 patients with tinnitus due to MD and they found a significant improvement in patients’ outcomes following this therapy.

Hearing aids play an important role in treatinghearing loss associated with MD. Potential problems related to fluctuating hearing can be overcome if patients are capable of self-programming their own hearing aids [41]. Tinnitus therapy can help patients to cope better with this often distressing symptom.

Intratympanic therapy Intratympanic Gentamicin Injection [ITG]

Lange described the use of ITG therapy for its effects on sensory hair cell death and possible effects on the dark cells that are responsible for endolymph production. [42] ITG has been shown to concentrate in type I hair cells in tissues harvested 1 week after injection in an animal model. [43] There was a subsequent 68 % loss of vestibular sensory hair cells in tissues harvested at 3 weeks, with losses greater in type I relative to type II vestibular hair cells. The Intratympanic administration of low-dose gentamycin provides long-term vertigo control, whilst preserving hearing and it is found that it is too effective in treating tinnitus in patients with MD. [44]

New protocols have been introduced to decrease side effects of gentamycin on hearing especially when treating vertigo and tinnitus in patients with MD and preserved hearing, one –shot injections protocols are goods example for that to minimize risk to hearing. [45]

Intratympanic steroid Injection [ITS]

Although the action of steroids on the inner ear remains speculative, it may involve anti-inflammatory effects, immunosuppression and/or ion homeostasis. [46] As glucocorticoid receptors are present in vast numbers in the vestibular and cochlear systems. Via these receptors, steroids can act specifically and influence aquaporins [47], a family of small trans-membrane water transporters which play important role in regulating inner ear fluids, blood flow and the endocochlear potential. Treatment by corticosteroids can control MD symptoms and improve tinnitus in some patients A prospective double-blind placebo-controlled trial by Garduno- Anayaet et al [48] showed relief of tinnitus in 48% of the patients who were treated withIntratympanic dexamethasone.

On the other hand, Araujo et al [49] reported that a prospective randomized placebo-controlled but single-blind trial showed that intratympanic dexamethasone had no significant effect on severe tinnitus compared to placebo. Recently OTO-104 is tested for patient safety, which is a suspension of dexamethasone in a glycol polymer called poloxamer. The polymer solidifies at body temperature, following intratympanic delivery with a 26-guage Needle. The suspension is meant for sustained steroid delivery at the round window. [50]

Applying Air Puffs to the Inner Ear

It had been shown that applying air pressure to the inner ear can relieve some of the symptoms of Ménière’s disease [51] this was first realized by placing individuals with MD in a pressure chamber. Applying air puffs to inner ear cause stimulation of the receptors in inner ear which in turn have beneficial effect on activation of neural plasticity and that in turn confirm that tinnitus in MD is not limited to inner ear pathology but also the nervous system is involved in creating of such symptoms that led to the idea of the Meniett device. The Meniett device applies pulses of pressure to the inner ear via the ventilation tube. A treatment cycle takes 5 minutes and is repeated 3 times a day. Several studies investigating the efficacy of this treatment have reported promising results. [52] The efficacy of such treatment was studied by Odkvist et al. [53] in a prospective randomized placebo controlled, multicenter clinical trial. The study had 56 participants with active MD, 31 patients use the device for about 2 weeks and 25 patients completed the 2 weeks by using placebo device. The active group showed significant improvement of symptoms together with tinnitus and aural fullness which was assessed using a magnitude estimation of tinnitus loudness. The placebo group stated no change in their symptoms.

Vestibular neurectomy

Vestibular neurectomy is an oto neurological procedure, which can dramatically cure patients with severe disabling vertigo. The surgery consists of sectioning the vestibular nerve from the vestibular apparatus, while leaving the auditory nerve intact, thereby preserving hearing. Role of such operation to relief tinnitus is still an issue of debate, analysis of 18 publications mentioning tinnitus status after vestibular neurectomy in total of 1,318 patients revealed that tinnitus improved in 6-61 % of patients [54], worsened in 0-60% of patients and still the same without any change in 17-27%. So, vestibular neurectomy does not worsen tinnitus but it may help.

Cochlear implantation [CI]

It is clear now that patients with MD will develop bilateral profound sensory neural hearing loss because natural progression of disease , it was emphasized that about 1-6% of patients will go through that[55], so that give the opportunity for considering cochlear implantation in these patients and that make standard CI criteria applicable in cases with bilateral hearing loss. On basis of review and analysis, it is obvious that CIs don’t appear to have any negative effect on aural fullness and tinnitus encountered by patient with MD. It is now clear that CI can change the neural activity caused by lack of input to auditory system and that alteration can address changes of neural plasticity which is responsible for tinnitus. Amoodi et al [56] reported that CI exerted a significant suppressive effect on tinnitus in 66% of their population [including 7 patients with deafness attributed to MD]. Mick et al [57] reviewing 20 patients with MD who underwent CI, showed a significant improvement in tinnitus, as determined from the Tinnitus Handicap Inventory. McRackan et al [58] reported that most patients with active symptoms at the time of CI surgery showed improvement in their symptoms postoperatively. Hansen et al [59] reported a study of CI surgery on 10 patients who had unilateral sensory neural hearing loss due to MD and found that patients had complete resolution of their vertigo attacks and were regarded as class A, and in addition to improved speech perception in the implanted ear, most patients reported subjective improvement in tinnitus.

CONCLUSION

Tinnitus is one of the important symptoms of MD. Although many studies focus, tinnitus can often be a very distressing symptom, and can often persist after the other MD symptoms improve. At present, there is no approved pharmaceutical or surgical treatment for tinnitus but understanding MD as a possible tinnitus subtype Tyler et al. [60] may unveil an important opportunity to study further tinnitus treatment strategies, such as betahistine, oxytocin and cochlear implants.

References

1. Atkinson M. Meniere’s original papers reprinted with an English translation with commentaries and biographical sketch. Acta Otolaryngolica. 1961; 162:1?78.

2. Minor LB, DA Schessel, JP Carey [2004] Ménière’s Disease. Curr Opin Neurol. 17:9–16.

3. Stouffer, J. L., & Tyler, R. S. [1990]. Characterization of tinnitus by tinnitus patients. Journal of Speech and Hearing Disorders, 55[3]: 439 453.

4. Hallpike CS, Cairns H. Observations on the pathology of Ménière’s syndrome. J Laryngol Otol 1938; 53: 625-55.

5. Yamakawa K. Uber die pathologische Veranderung bei einem Menière-Kranken. J Otolaryngol Jpn 1938; 44: 2310-2.

6. Sone M, Yoshida T, Morimoto K, et al. Endolymphatic hydrops in Superior canal dehiscence and large vestibular aqueduct syndromes. Laryngoscope 2016; 126:1446–50.

7. kazaki Y, Yoshida T, Sugimoto S, et al. Significance of endolymphatic hydrops in ears with unilateral sensorineural hearing loss. Otol Neurotol 2017; 38: 1076–80.

8. Qvortrup K, Rostgaard J, Holstein-Rathlou NH. The inner ear produces a natriuretic hormone. Am J Physiol 1996; 270:F1073-7

9. Takeda T, Kakigi A, Saito H. Antidiuretic hormone [ADH] and endolymphatic hydrops. Acta Otolaryngol 1997; Suppl. 526: 27-9.

10. Sterkers O, Ferrari E, Amiel C. Inter and intracompartmental osmotic gradients within the rat cochlea. Am J Physiol 1984; 247: F602-6.

11. Ishiyama G, Lopez IA, Sepahdari AR, Ishiyama A. Meniere’s disease: Histopathology, Cytochemistry and imaging. Annals of the New York Academy of Sciences. 2015; 22:1?9.

12. Eckhard A, Gleiser C, Arnold H, Rask?Andersen H, Kumagami H, Müller M et al. Water Channel proteins in the inner ear and their link to hearing impairment and deafness.Molecular Aspects of Medicine. 2012; 33[5?6]:612?37.

13. Schuknecht HF. Endolymphatic Hydrops. Pathology of the Ear. 2nd ed. Philadelphia, Lea & Febiger 506.1993.

14. Dohlman GF. Mechanism of the Meniere Attack. ORL J Otorhinolaryngol Relat Spec.1980: 42:10–19.

15. Zenner HP. Modern Aspects of Hair Cell Biochemistry, Motility and Tinnitus. In Proceedings, Third International Tinnitus Seminar, Munster Edited by H Feldmann Karlsruhe, Germany, Harsch Verlag.1987

16. Haefely W. The GABAA benzodiazepine receptor: biology and pharmacology. In: Burrows G, RothM, Noyes R, editors. The neurobiology of anxiety. Handbook of anxiety. Amsterdam: Elsevier, 1990: 165-88.

17. Van de Heyning P, K Vermeire, M Diebl et al. Incapacitating unilateral tinnitus in single-sided deafness treated by cochlear implantation. Ann. Otol. Rhinol. Laryngol.2008; 117:645–52.

18. Wall PD.The presence of ineffective synapses and circumstances which unmask them. Philos. Trans. R. Soc[Lond.].1977; 278:361–72.

19. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere’s Disease. American Academy of Otolaryngology – Head and Neck Foundation Inc. Otolaryngology Head Neck Surgery. 1995; 113:181?185.

20. Lopez?Escamez JA, Carey J, ChungW,GoebelJA, Magnusson M, Mandala M et al. Diagnostic criteria for Meniere’s disease. Journal of Vestibular Research. 2015; 25:1?7.

21. Tokumasu K, Fujino A, Naganuma H et al. Initial Symptoms and Retrospective Evaluation of Prognosis in Ménière’s Disease. Acta Otolaryngol Suppl [Stockh].1996; 524:43–49.

22. Yoshida T, Stephens D, Kentala E, Levo H, Auramo Y, Poe D et al. Tinnitus complaint behavior in long?standing Meniere’s disorder: its association with other cardinal symptoms. Clinical Otolaryngology. 2011; 36:461?467.

23. Pienkowski, M, Tyler, R. S, Roncancio, E. R, Jun, H. J, Brozoski, T, Dauman, N, Coelho, C. B, Andersson, G, Keiner, A. J, Cacace, A, Martin, N, & Moore, B. C. JA comprehensive review of hyperacusis and future directions: Part II. Measurement, mechanisms and treatment. Am J Audiol.2014; 23[4]:420-36. PMID:25103984

24. Sánchez IR, Garrigues HP, Rivera VR. Clinical characteristics of tinnitus in Ménière’s disease. Acta Otorrinolaringologica Espanola. 2010; 61[5]:327?331.

25. Green JD Jr, DJ Blum, SG Harner. Longitudinal Followup of Patients with Ménière’s Disease. Otolaryngol Head Neck Surg.1991; 104:783.

26. Stahle J. My Experience with Ménière’s Disease. Audio Digest-39. Pulec JL. Ménière’s Disease – Etiology, Natural History, and Results of Treatment. Otolaryngol Clin North Am.1973; 6.1:25–39.

27. Herraiz C, F Plaza, G De Ios Santos. Tinnitus Re-training Therapy in Meniere Disease. Acta Otorrinolaringol Esp.2006; 57:96–100.

28. Bernhardt O, Gesch D, Schwahn C, et al. Signs of temporomandibu¬lar disorders in tinnitus patients and in a population-based group of volunteers: results of the Study of Health in Pomerania. J Oral Rehabil. 2004; 31[4]:311- 319.

29. Sindhusake D, Mitchell P, Newall P, Golding M, Rochtchina E, Rubin G. Prevalence and characteristics of tinnitus in older adults: the Blue Moun¬tains Hearing Study. Int. J Audiol. 2003; 42[5]:289-294.

30. Kvestad E, Czajkowski N, Engdahl B, and Hoffman HJ, Tambs K. Low heritability of tinnitus: results from the second Nord-Trøndelag health study. Arch Otolaryngol Head Neck Surg. 2010; 136[2]:178-182.

31. Figueiredo RR, Azevedo AA, Penido NO. Pharmacological treatment of tinnitus. In. Watson J, Editor. Tinnitus Epidemiology, Causes and Emerging Therapeutic Treatments. New York: Nova Science Publishers; 2016.pp 25?42.

32. Langguth B, Kreuzer PM, Kleinjung T, De Ridder D. Tinnitus: Causes and clinical management. The Lancet Neurology. 2013; 12[9]:920?930.

33. Langguth B, Salvi R, Elgoyhen AB. Emerging pharmacotherapy of tinnitus. Expert Opinion and Emerging Drugs. 2009; 14[4]:687?702.

34. Ganança MM, Caovilla HH, Gazzola JM, Ganança CF, Ganança FF. Betahistine in the treatment of tinnitus in patients with vestibular disorders. Brazilian journal of otorhinolaryngology.2011; 77[4]:499?503.

35. Lezius F, Adrion C, Mansmann U, Jahn K, Strupp M. High dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Meniere’s disease: A case series. European Archives of Otorhinolaryngology. 2011; 268[8]:1237?1240

36. Morales-Luckie E, A Cornejo-Suarez, MA Zaragoza-Contreras et al [2005] Oral administration of prednisone to control refractory vertigo in Ménière’s disease: a pilot study. Otol Neurotol. 26.5: 1022–1026.

37. Azevedo, A, Figueiredo RR, Schlee W. Immediate effects of nasal oxytocin in tinnitus patients. In: Annals of the 10th International Tinnitus Research Initiative Conference; 16?18 March 2016; Nottingham, England. Nottingham: Tinnitus Research Initiative; 2016. pp 61?62.

38. Kirsch P. Oxytocin in the socioemotional brain: implications for psychiatric disorders. Dialogues Clin Neurosci. 2015; 17[4]:463–76.

39. Wettschureck N, Moers A, Hamalainen T, Lemberger T, Schütz G, Offermanns S. Heterotrimeric G proteins of the Gq/11 family are crucial for the induction of maternal behavior in mice. Mol Cell Biol 2004; 24[18]:8048–54.

40. Yardley L, Kirby S. Evaluation of booklet-based self-management of symptoms in Meniere disease: a randomized controlled trial. Psychocoma Med 2006; 68:762– 769.

41. Mcneill C, Mcmahon CM, Newall P, et al. Hearing aids for Meniere’s syndrome: implications of hearing fluctuation. J Am Acad Audiol 2008; 19:430–434.

42. Lange G. Gentamicin and other ototoxic antibiotics for the transtympanic treatment of Meniere’s disease. Arch Otorhinolaryngol. 1989; 246[5]:269–70.

43. Lyford-Pike S, Vogelheim C, Chu E, Della Santina CC, Carey JP. Gentamicin is primarily localized in vestibular type I hair cells after intratympanic administration. J Assoc Res Otolaryngol. 2007; 8[4]:497–508.

44. Eklund S, I Pyykkö, H Aalto et al. Effect of intratympanic gentamicin on hearing and tinnitus in Ménière’s disease. Am J Otol.1999; 20(30): 350–356.

45. De Beer L, R Stokroos, H Kingma. Intratympanic gentamicin therapy for intractable Ménière’s disease. Acta Otolaryngol. 2007; 127(6): 605–612.

46. Hamid, M, Trune, D.Issues, indications, and controversies regarding intratympanic steroid perfusion. Curr. Opin. Otolaryngol. Head. Neck Surg. 2008; 16 [5]: 434-440.

47. Pondugula, S.R., Sanneman, J.D., Wangemann, P.,Milhaud, P.G., Marcus, D.C., 2004. Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel. Am. J. Physiol. Ren. Physiol. 286 [6]: F1127-F1135.

48. Garduño-Anaya MA, H Couthino De Toledo, R Hinojosa-González et al. Dexamethasone inner ear perfusion by intratympanic injection in unilateral Ménière’s disease: a two-year prospective, placebo-controlled, double-blind, randomized trial. Otolaryngol Head Neck Surg. 2005;133(2):285–294.

49. Araújo MF, CA Oliveira, FM Bahmad. Intratympanic dexamethasone injections as a treatment for severe, disabling tinnitus: does it work? Arch Otolaryngol Head Neck Surg. 2005; 131(2): 113–117.

50. Lambert PR, Nguyen S, Maxwell KS, Tucci DL, Lustig LR, Fletcher M, et al. A randomized, double-blind, placebo-controlled clinical study to assess safety and clinical activity of OTO-104 given as a single intratympanic injection in patients with unilateral Ménière’s disease. Otol Neurotol. 2012; 33[7]:1257–65.

51. Ingelstedt S, A Ivarsson and O Tjernström. Immediate relief of symptoms during acute attacks of Ménière’s disease, using a pressure chamber. Acta Otolaryngol. 1976; 85: 368–378.

52. Gates GA, Verrall A, Green JD, et al. Meniett clinical trial: long-term follow-up. Arch Otolaryngol Head Neck Surg 2006; 132:1311–1316.

53. Odkvist LM, S Arlinger, E Billermark et al. Effects of middle ear pressure changes on clinical symptoms in patients with Ménière’s disease – a clinical multicenter placebo-controlled study. Acta Otolaryngol Suppl. 2000; 543: 99–101.

54. Baguley DM, P Axon, IM Winter et al. The effect of vestibular nerve section upon tinnitus. Clin Otolaryngol Allied Sci.2002; 27(4): 219–226.

55. Fife TA, Lewis MP, May JS, et al: Cochlear implantation in Meniere’s disease. JAMA Otolaryngol Head Neck Surg 140:535-539, 2014.

56. Amoodi HA, Mick PT, Shipp DB, et al. The effects of unilateral cochlear implantation on the Tinnitus handicap inventory and the influence on quality of life. Laryngoscope. 2011; 121[7]:1536-1540.

57. Mick P, Amoodi H, Arnoldner C, et al: Cochlear implantation in patients with advanced Meniere’s disease. Otol Neurotol.2014; 35: 1172-1178.

58. McRackan TR, Gifford RH, Kahue CN, et al: Cochlear implantation in Meniere’s disease patients. Otol Neurotol.2014; 35:421-425.

59. Hansen MR, Gantz BJ, Dunn C: Outcomes after cochlear implantation for patients with single-sided deafness, including those with recalcitrant Meniere’s disease. Otol Neuroto2001 34:1681-1687.

60. Tyler, R, Coelho, C, Tao, P, Ji, H, Noble, W, Gehringer, A, & Gogel, S. Identifying tinnitus subgroups with cluster analysis. American Journal of Audiology.2008; 17[2]:S176- 84.