|Year : 2022 | Volume
| Issue : 1 | Page : 1-5
Pharmacotherapy of meniere's disease: A review
Santosh Kumar Swain
Department of Otorhinolaryngology and Head and Neck Surgery, IMS and SUM Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India
|Date of Submission||29-Apr-2022|
|Date of Acceptance||26-May-2022|
|Date of Web Publication||18-Jul-2022|
Prof. Santosh Kumar Swain
Department of Otorhinolaryngology and Head and Neck Surgery, IMS and SUM Hospital, Siksha “O” Anusandhan University, K8, Kalinga Nagar, Bhubaneswar - 751 003, Odisha
Source of Support: None, Conflict of Interest: None
Meniere's disease (MD) is a chronic inner ear disorder characterized by intermittent episodes of vertigo lasting from minutes to hours, with fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops is thought to be the pathological basis for MD and arise due to either excessive production or inadequate absorption of endolymph. The raised endolymphatic pressure causes periodic rupture or leakage in the membrane separating the endolymphatic from perilymphatic space. So, the treatment aims to reduce the production and increased the absorption of endolymph. The clinical objective of treatment is to stop vertigo spells, reduce or abolish tinnitus and preserve or even reverse hearing loss. The majority of the studies have focused on reducing vertigo attacks, which is the severest symptom of MD. There are several therapeutic options for MD, but none is considered effective by the scientific community. The prerequisites for successful pharmacotherapy for MD include correct diagnosis, correct drug, appropriate dosage, and appropriate duration of therapy. There are several groups of drugs that can be used for MD such as betahistine, oral corticosteroids, intratympanic corticosteroids, intratympanic gentamycin injections, and benzodiazepines. The objective of this review article is to discuss the current knowledge of the pharmacotherapy of MD. Appropriate treatment of MD prevents this morbid disease and improves the quality of life.
Keywords: Betahistine, diuretics, intratympanic gentamycin, Meniere's disease, pharmacotherapy
|How to cite this article:|
Swain SK. Pharmacotherapy of meniere's disease: A review. Matrix Sci Pharma 2022;6:1-5
| Introduction|| |
Meniere's disease (MD) is an idiopathic inner ear disorder that is characterized by spontaneous episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops of the inner ear is currently thought to be the pathophysiological mechanism that underlies the typical clinical symptoms of MD. The diagnosis of MD is based on the criteria of the Barany Society. The vertigo spells are typically random, and the clinical diagnosis of MD may take months or even years until the temporal association between vertigo and hearing loss is confirmed. The course of hearing loss in MD is often progressive and vertigo attacks may improve or not over a period of time. There are numerous treatment options available for reducing the severity and incidence of morbid symptoms of MD and decreasing the incidence of episodic attacks of vertigo. The first goal of treatment of MD is to reduce the duration and frequency of vertigo attacks and secondly to prevent hearing impairment and relieve tinnitus. The primary objective of this review is to summarize the best available pharmacological treatment for MD.
| Methods of Literature Search|| |
Multiple systematic methods were used to find current research publications on the current pharmacotherapy for MD. We started by searching the Scopus, Pub Med, Medline, and Google Scholar databases online. A search strategy using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was developed. This search strategy recognized the abstracts of published articles, while other research articles were discovered manually from the citations. Randomized controlled studies, observational studies, comparative studies, case series, and case reports were evaluated for eligibility. There were total number of articles 72 (16 case reports; 24 cases series; 32 original articles) [Figure 1]. This paper focuses only on the current pharmacotherapy of MD. This paper examines the epidemiology, medical treatment, lifestyle modifications, and follow-up of MD. This analysis provides a better understanding of the treatment of MD which will provide prompt relief of disabling symptoms. It will also serve as a catalyst for additional study into a newer treatment protocol for MD.
| Epidemiology|| |
MD is a chronic inner ear disease that affects a substantial number of patients every year worldwide. Its incidence varies between 7.5/100,000 and 160/100,000 persons. Another study reported a prevalence of MD is 43/100,000 and an average yearly incidence of 4.3/100,000 populations. MD remains a difficult clinical entity for diagnosis and treatment especially in the early stages when not all classical symptoms might be found. So, the incidence and prevalence of this disease are difficult to ascertain. Patients with MD often present to the emergency department with a sudden attack of vertigo and are wrongly diagnosed as having labyrinthitis and discharged home., In the early stage of MD, the patient may present with only cochlear symptoms such as aural fullness and hearing impairment without true vertigo or even tinnitus in the ears. There is a slight female preponderance of up to 1.3 times that of males. MD is much more common in adult age groups in their fourth and fifth decades of life than in the younger age population, although it has been documented in children.
| Aim of the Pharmacotherapy in Meniere's Disease|| |
The main objective of pharmacotherapy in MD is to decrease the frequency, duration, and severity of vertigo episodes. The second objective of pharmacotherapy in patients with MD is to stop the progression of hearing loss and decrease tinnitus. However, no drug can slow or stop the progression of the hearing impairment or suppress the tinnitus in the present scenario. The treatment of MD is given in [Table 1].
| Pharmacotherapy|| |
Betahistine is a structural analog to histamine which acts as a partial and weak agonist to postsynaptic H1 receptor and antagonist to presynaptic H3 receptor. There are histamine receptors found in the inner ear, particularly in the endolymphatic sac. There are several mechanisms for explaining the action of betahistine in MD. The experimental models demonstrate that betahistine enhances microcirculation of the cochlea by vasodilation of the arterioles of the stria vascularis and also in the ampulla of the posterior semicircular canal., This increases the blood flow in the labyrinth which appears to be mediated by two metabolites such as aminoethylpyridine and hydroxyethylpyridine, that act on the histamine H3 receptors. Betahistine reduces the endolymphatic pressure by lowering the production of endolymph and also by increasing the reabsorption of endolymph. However, the betahistine also blocks the presynaptic H3 autoreceptors on the histaminergic nerve terminals arising from the tuberomammillary nuclei of the posterior hypothalamus, so increase the synthesis and release of histamine at the vestibular nuclei. Betahistine may also participate in the mechanism of histaminergic modulation of glycine and gamma-Aminobutyric acid release at the vestibular nuclei which may be helpful for rebalancing the spontaneous neuronal firing at vestibular nuclei on both sides. These actions may promote and enhance the central vestibular compensation following an acute unilateral vestibular loss. The upregulation of histamine by betahistine induces excitatory effects in neuronal activity at cortical and subcortical structures. This arousal effect may facilitate sensorimotor and cognitive activity, required for recovery after the loss of vestibular function. The adverse effects of betahistamine are uncommon and usually reversible after the stoppage of this drug. Mild and self-limiting rash, pruritus, and urticaria are commonly reported side effects. Nausea, vomiting, epigastric pain, and headache are sometimes reported, particularly in the case of a higher dose.
Diuretics mostly act by blocking the reabsorption of sodium at different segments of the nephron, which increases the losses of urinary sodium and water. This extracellular volume reduction is thought to decrease the endolymphatic pressure and volume, either through increased drainage of endolymph or a decrease in its production at the stria vascularis. Diuretics are often considered the first line of treatment when lifestyle changes and dietary modifications are not helpful to control vertigo. Loop diuretics (furosemide, torasemide), thiazides (hydrochlorothiazide), potassium sparing diuretics (triamterene, spironolactone), and carbonic anhydrase inhibitors (acetazolamide) have been used MD. However, the efficacy of these diuretics is still scarce. One study showed that oral diuretic treatment may reduce the frequency of vertigo attacks in MD. Moreover, one meta-analysis concludes that diuretics that it is not clear whether diuretics improve vertigo episodes or decrease hearing loss in patients with MD, as certainty of the evidence is very low. An osmotic diuretic such as glycerol improve the hearing thresholds temporarily in patients of MD, so it is occasionally used as a confirmatory test.
Corticosteroids have immunosuppressive, anti-inflammatory, and vasodilator effects, and also theoretical neuroprotective effects by inhibiting lipid peroxidation and apoptosis. The high prevalence of autoimmune disorders in MD supports the use of corticosteroids and role of innate immune system and inflammation associated with pathophysiology of MD. The receptors for glucocorticoids are present in the inner ear, mostly at the spiral lamina, outer and inner hair cells, spiral ligament, and spiral ganglion neurons, but also at the nonampullated end of the semicircular canals and the crista ampullaris. The highest number of receptors of the cochlea are present in the stria vascularis. The exact mechanism of corticosteroid in MD is based on its anti-inflammatory and immunosuppressive effects, as well as its role in the regulation of inner ear homeostasis. The effect of the corticosteroids in the labyrinth appears to be associated with nuclear factor kappa beta family of transcription factors. Aquaporins are a group of membrane proteins that transports water molecules and play a vital role in the maintenance of labyrinthine water homeostasis. Glucocorticoids enhance aquaporin expression in messenger RNA and protein levels, stimulate water reabsorption in the endolymphatic sac. Corticosteroids also may participate in controlling the composition of endolymph by upregulating the genes responsible for transcription of epithelial sodium channels and K +. MD with co-morbid systemic autoimmune diseases, prolonged recurrent attacks of vertigo, or sudden decrease in hearing can be managed by taking high doses of oral steroids within a few weeks.
Intratympanic corticosteroid administration
Intratympanic corticosteroids have been classically administrated to get a more localized anti-inflammatory and vasodilator effect in the inner ear. It has been considered as the first option of intratympanic treatment as the side effects associated with this treatment like hearing impairment, chronic symptoms of dizziness resulting from fixed vestibular loss, or other adverse effects, are very low. After administration of corticosteroid into the middle ear, it reaches the labyrinthine fluids through diffusion via a round window, oval window annular ligament, micro-fractures of the bony otic capsule as well as small lacunar mesh at the bony wall surrounding the inner ear, achieve greater inner ear drug concentrations than with systemic administration. The concentration of the corticosteroids after intratympanic injection of corticosteroids is higher in the endolymph than in the perilymph which exhibits a gradient from the basal turn of the cochlea to the apical portion with potentially insufficient levels at the basal area. The important advantage of intratympanic corticosteroid injection over intratympanic gentamycin injection is the lack of hearing loss. The common corticosteroids used for intratympanic administration are dexamethasone and methylprednisolone, although triamcinolone is also an option. A study shows that methylprednisolone yields greater concentrations in endolymph and perilymph than dexamethasone, however, the latter methylprednisolone may be more efficacious as it is absorbed rapidly by endocytosis into the stria vascularis and surrounding tissues, where it works intracellularly. A randomized control study showed no statistically significant difference between dexamethasone and methylprednisolone in regards to controlling vertigo, although significant improvement in hearing by methylprednisolone.
Intratympanic injection of gentamycin
Gentamycin is an aminoglycoside antibiotic having more vestibulotoxic than cochleotoxic effect. It usually causes atrophy of type-1 vestibular cells as well as neuroepithelium. Although intratympanic injection of gentamycin (ITG) poses a chance of hearing loss, several clinical studies have been designed to find out the lowest chance of its use with maximum control of vertigo in MD. So, due to its toxic effect on peripheral vestibular end-organ, vertigo and unsteadiness following the injection of gentamycin can be a minor problems that can be resolved by vestibular rehabilitation. ITG is probably the most effective nonsurgical treatment option for eradicating vertigo in MD. It is also an ablative technique that causes a nonnegligible risk of hearing impairment. ITG is often recommended as a destructive method preferentially when the hearing function is impaired for patients having a good contralateral vestibular function. ITG injections (40 mg/ml) are being repeated until the disappearance of vertigo attacks. This tailored protocol is done for preventing hearing loss more than systematic weekly or a monthly injections. The ITG has received more interest because of its strong effect on Meniere's episode, which also suppresses the frequency of vestibular neurecties. The recommended application of gentamycin is one injection of 26.7 mg/ml concentration and scanning of the vestibular physiology responses by the number of vestibular attacks, a bedside assessment, vestibular-evoked myogenic potentials, and video head impulse tests.
Benzodiazepines are used as vestibular suppressants to control symptoms such as an acute episode of vertigo in MD. Centrally acting H1 antagonists can be used for this purpose. The standard dose of diazepam is 2–5 mg orally three times daily as required for nausea. Contraindications for diazepam are hypersensitivity, liver disease, and glaucoma. The drug interactions include caution with other drugs such as those that cause central nervous system depression and drugs metabolized by the liver. The serious side effects of benzodiazepines are respiratory depression, suicidal thoughts, and depression. Common side effects are somnolence, ataxia and dizziness. Benzodiazepines should only be used on an as needed basis.
| Lifestyle Modification|| |
Avoidance or cessation of tobacco and alcohol and caffeine restriction is advised as these could reduce blood supply to the inner ear. A low salt diet may be helpful to increase plasma aldosterone concentration that stimulates ion transport and absorption of endolymph in the endolymphatic sac. The avoidance of migraine food such as monosodium glutamate triggers the symptoms of MD with migraine. Glucose intake control has also been suggested., The use of specially processed cereals that enhances the synthesis of endogenous antisecretory factor to decrease the episodes of vertigo spells is still controversial. The most important recommendations in the dietary modification are high water intake (2 L/day) and a very low sodium diet (not more than1.5 g/day).
| Follow-Up|| |
As a patient with MD in the early course of disease presents with mild hearing loss, the treatment is purely medical management for absolute control of vertigo. The patient needs 3 monthly follow-ups and the dose of medications needs titration accordingly. If the hearing loss is worsened further, the patient can use a hearing aid. In case, vertigo episodes of a patient present resistant to medical therapy, he/she can require an intratympanic injection of steroids or gentamycin. Approximately 80% of patients with MD are likely to respond to pharmacotherapy alone.
| Conclusion|| |
MD is a multifactorial disorder where the patient often presents with episodic vertigo, nausea, vomiting, and aural symptoms such as tinnitus, hearing loss, and aural fullness. The treatment options for MD should be selected in order of invasiveness, the severity of disease, and the response to each treatment. Pharmacotherapy in MD is often aiming to control the most disabling symptom such as vertigo. Acute symptoms of MD require labyrinthine suppressants while prophylactic treatment needs lifestyle modifications such as salt-restricted diet, betahistine and diuretics.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Swain SK, Achary S, Das SR. Vertigo in pediatric age: Often challenge to clinicians. Int J Cur Res Rev 2020;12:136-41.
Swain SK, Samal S, Sahu MC, Debta P. Biomarker for evaluating peripheral vertigo – A study at a tertiary care teaching hospital of Eastern India. Indian J Public Health Res Dev 2018;9:2352-6.
Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandalà M, et al.
Diagnostic criteria for Meniere's disease according to the Classification Committee of the Barany Society. HNO 2017;65:887-93.
Espinosa-Sanchez JM, Lopez-Escamez JA. Menière's disease. Handb Clin Neurol 2016;137:257-77.
Swain SK. Acute brain stem vertigo without neurological deficits. BLDE Univ J Health Sci 2021;6:206-8. [Full text]
Basura GJ, Adams ME, Monfared A, Schwartz SR, Antonelli PJ, Burkard R, et al.
Clinical practice guideline: Ménière's disease. Otolaryngol Head Neck Surg 2020;162:1-55.
Minor LB, Schessel DA, Carey JP. Ménière's disease. Curr Opin Neurol 2004;17:9-16.
Kotimaki J, Sorri M, Aantaa E, Nuutinen J. Prevalence of Meniere's disease in Finland. Laryngoscope 1999;109:748-53.
Swain SK, Mohanty S, Sahu MC. Migraine-related vertigo in an elderly male. Apollo Medicine 2018;15:112-5.
Swain SK, Munjal S, Pradhan S. Vestibular migraine. Apollo Med 2021;18:179-83. [Full text]
Swain S, Behera IC, Sahu MC. Prevalence of Benign Paroxysmal Positional Vertigo: Our experiences at a tertiary care hospital of India. Egypt J Ear Nose Throat Allied Sci 2018;19:87-92.
Magnan J, Özgirgin ON, Trabalzini F, Lacour M, Escamez AL, Magnusson M, et al.
European position statement on diagnosis, and treatment of Meniere's disease. J Int Adv Otol 2018;14:317-21.
Gbahou F, Davenas E, Morisset S, Arrang JM. Effects of betahistine at histamine H3 receptors: Mixed inverse agonism/agonism in vitro
and partial inverse agonism in vivo
. J Pharmacol Exp Ther 2010;334:945-54.
Møller MN, Kirkeby S, Vikeså J, Nielsen FC, Cayé-Thomasen P. Gene expression in the human endolymphatic sac: The solute carrier molecules in endolymphatic fluid homeostasis. Otol Neurotol 2015;36:915-22.
Ihler F, Bertlich M, Sharaf K, Strieth S, Strupp M, Canis M. Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo
. PLoS One 2012;7:e39086.
Bertlich M, Ihler F, Freytag S, Weiss BG, Strupp M, Canis M. Histaminergic H3-heteroreceptors as a potential mediator of betahistine-induced increase in cochlear blood flow. Audiol Neurootol 2015;20:283-93.
Bertlich M, Ihler F, Sharaf K, Weiss BG, Strupp M, Canis M. Betahistine metabolites, aminoethylpyridine, and hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo
. Int J Audiol 2014;53:753-9.
Lacour M. Betahistine treatment in managing vertigo and improving vestibular compensation: Clarification. J Vestib Res 2013;23:139-51.
Bergquist F, Ruthven A, Ludwig M, Dutia MB. Histaminergic and glycinergic modulation of GABA release in the vestibular nuclei of normal and labyrinthectomised rats. J Physiol 2006;577:857-68.
Tighilet B, Mourre C, Trottier S, Lacour M. Histaminergic ligands improve vestibular compensation in the cat: Behavioural, neurochemical and molecular evidence. Eur J Pharmacol 2007;568:149-63.
Lin JS, Sakai K, Vanni-Mercier G, Arrang JM, Garbarg M, Schwartz JC, et al.
Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res 1990;523:325-30.
Benecke H, Pérez-Garrigues H, Bin Sidek D, Uloziene I, Kuessner D, Sondag E, et al.
Effects of betahistine on patient-reported outcomes in routine practice in patients with vestibular vertigo and appraisal of tolerability: Experience in the OSVaLD study. Int Tinnitus J 2010;16:14-24.
Stern Shavit S, Lalwani AK. Are diuretics useful in the treatment of meniere disease? Laryngoscope 2019;129:2206-7.
Crowson MG, Patki A, Tucci DL. A systematic review of diuretics in the medical management of Ménière's disease. Otolaryngol Head Neck Surg 2016;154:824-34.
Rosenbaum A, Winter M. Are diuretics effective for Ménière's disease? Medwave 2018;18:e7188.
Basel T, Lütkenhöner B. Auditory threshold shifts after glycerol administration to patients with suspected Menière's disease: A retrospective analysis. Ear Hear 2013;34:370-84.
Farhood Z, Lambert PR. The physiologic role of corticosteroids in Ménière's disease. Am J Otolaryngol 2016;37:455-8.
Flook M, Lopez Escamez JA. Meniere's disease: Genetics and the immune system. Curr Otorhinolaryngol Rep 2018;6:24-31.
Froehlich MH, Lambert PR. The physiologic role of corticosteroids in Menière's disease: An update on glucocorticoid-mediated pathophysiology and corticosteroid inner ear distribution. Otol Neurotol 2020;41:271-6.
Dong SH, Kim SS, Kim SH, Yeo SG. Expression of aquaporins in inner ear disease. Laryngoscope 2020;130:1532-9.
Nevoux J, Viengchareun S, Lema I, Lecoq AL, Ferrary E, Lombès M. Glucocorticoids stimulate endolymphatic water reabsorption in inner ear through aquaporin 3 regulation. Pflugers Arch 2015;467:1931-43.
Patel M. Intratympanic corticosteroids in Ménière's disease: A mini-review. J Otol 2017;12:117-24.
Salt AN, Hirose K. Communication pathways to and from the inner ear and their contributions to drug delivery. Hear Res 2018;362:25-37.
Swain SK, Behera IC, Sahoo L. Vestibular migraine: Our experiences at a tertiary care teaching hospital of Eastern India. Med J Dr DY Patil Vidyapeeth 2020;13:636-41.
Salt AN, Hartsock JJ, Hou J, Piu F. Comparison of the pharmacokinetic properties of triamcinolone and dexamethasone for local therapy of the inner ear. Front Cell Neurosci 2019;13:347.
Hamid M, Trune D. Issues, indications, and controversies regarding intratympanic steroid perfusion. Curr Opin Otolaryngol Head Neck Surg 2008;16:434-40.
Masoumi E, Dabiri S, Ashtiani MT, Erfanian R, Sohrabpour S, Yazdani N, et al.
Methylprednisolone versus dexamethasone for control of vertigo in patients with definite Meniere's disease. Iran J Otorhinolaryngol 2017;29:341-6.
Patel M, Agarwal K, Arshad Q, Hariri M, Rea P, Seemungal BM, et al.
Intratympanic methylprednisolone versus gentamicin in patients with unilateral Ménière's disease: A randomised, double-blind, comparative effectiveness trial. Lancet 2016;388:2753-62.
Schoo DP, Tan GX, Ehrenburg MR, Pross SE, Ward BK, Carey JP. Intratympanic (IT) therapies for Menière's Disease: Some consensus among the confusion. Curr Otorhinolaryngol Rep 2017;5:132-41.
Pullens B, van Benthem PP. Intratympanic gentamicin for Ménière's disease or syndrome. Cochrane Database Syst Rev 2011;3:CD008234.
Swain SK, Paul RR. Herpes zoster oticus: A morbid clinical entity. MAMC J Med Sci 2021;7:99-103. [Full text]
Swain SK, Debta P, Lenka S, Samal S, Dani A, Mahapatra S. Vestibular migraine – A challenging clinical entity. Indian J Forensic Med Toxicol 2020;14:8835-41.
Sánchez-Sellero I, San-Román-Rodríguez E, Santos-Pérez S, Rossi-Izquierdo M, Soto-Varela A. Caffeine intake and Menière's disease: Is there relationship? Nutr Neurosci 2018;21:624-31.
Swain SK, Shajahan N, Acharya S. A scoping review of vestibular paroxysmia: An acute disabling clinical entity. J Acute Dis 2020;9:248-52. [Full text]
Gioacchini FM, Albera R, Re M, Scarpa A, Cassandro C, Cassandro E. Hyperglycemia and diabetes mellitus are related to vestibular organs dysfunction: Truth or suggestion? A literature review. Acta Diabetol 2018;55:1201-7.
Swain SK. Vertigo following cochlear implantation: A review. Int J Res Med Sci 2022;10:572-7.
Naganuma H, Kawahara K, Tokumasu K, Okamoto M. Water may cure patients with Meniere disease. Laryngoscope 2006;116:1455-60.