Treatment of Menière s Disease

Transcription

1 Curr Treat Options Neurol (2015) 17:14 DOI /s x Neurologic Ophthalmology and Otology (RK Shin and DR Gold, Section Editors) Treatment of Menière s Disease Jeffrey D. Sharon, MD * Carolina Trevino, MD Michael C. Schubert, PhD John P. Carey, MD Address * Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA Jsharon2@jhmi.edu * Springer Science+Business Media New York 2015 This article is part of the Topical Collection on Neurologic Ophthalmology and Otology Keywords Meniere s diseasei Vertigo I Intratympanic steroids I Vestibular physical therapy I Intratympanic gentamicin I Pharmacotherapy for Meniere s disease I Unilateral hearing loss Opinion statement Diagnosis of Menière s disease is made with a characteristic patient history, including discrete episodes of vertigo lasting 20 min or longer, accompanied by sensorineural hearing loss, which is typically low frequency at first, aural fullness, and tinnitus. Workup includes audiometry, a contrast enhanced MRI of the internal auditory canals, and exclusion of other diseases that can produce similar symptoms, like otosyphilis, autoimmune inner ear disease, perilymphatic fistula, superior semicircular canal syndrome, Lyme disease, multiple sclerosis, vestibular paroxysmia, and temporal bone tumors. A history of migraine should be sought as well because of a high rate of cooccurrence (Rauch, Otolaryngol Clin North Am 43: , 2010). Treatment begins with conservative measures, including low salt diet, avoidance of stress and caffeine, and sleep hygiene. Medical therapy with a diuretic is the usual next step. If that fails to control symptoms, then the options of intratympanic (IT) steroids and betahistine are discussed. Next tier treatments include the Meniett device and endolymphatic sac surgery, but the efficacy of both is controversial. If the above measures fail to provide symptomatic control of vertigo, then ablative therapies like intratympanic gentamicin are considered. Rarely, vestibular nerve section or labyrinthectomy is considered for a patient with severe symptoms who does not show a reduction in vestibular function with gentamicin. Benzodiazepines and anti-emetics are used for symptomatic control during vertigo episodes. Rehabilitative options for unilateral vestibular weakness include physical therapy and for unilateral hearing loss include conventional hearing aids, contralateral routing of sound (CROS) and osseointegrated hearing aids.

2 14 Page 2 of 16 Curr Treat Options Neurol (2015) 17:14 Introduction Menière s disease is named after the French neurologist Prosper Menière, who in 1861 argued that symptoms of episodic vertigo and hearing loss could be caused by an inner ear disorder [1]. While much has been learned since then, there are still many unanswered questions, including the underlying pathophysiology, how to diagnose Menière s disease with certainty, whether or not current treatments are effective, and how to prevent end organ damage. Current diagnosis is usually based around 1995 American Academy of Otolaryngology (AAO) criteria [2 ]. In that schema, definite Menière s diseaseis diagnosed with two or more spontaneous episodes of vertigo lasting at least 20 min, audiometrically documented hearing loss on at least one occasion, tinnitus or aural fullness, and exclusion of other causes. Diagnosis can be upgraded to certain Menière s disease with histopathologic confirmation of hydrops, which refers to distension of the endolymphatic space within the membranous labyrinth. At the time of writing, the Barany Society, an international collaboration of vestibular researchers, was working on ratifying a new schema for diagnosis of Menière s disease[3]. Their criteria for diagnosis include two or more spontaneous episodes of vertigo lasting 20 min to 12 h, audiometrically documented low to medium frequency sensorineural hearing loss, fluctuating aural symptoms in the affected ear, and no better diagnosis. The finding of hydrops is considered the pathological hallmark of the disease and is found consistently in post-mortem temporal bones of subjects with clinical Menière s disease; however, it is also found in temporal bones of subjects without that clinical history. Therefore, it is unclear if endolymphatic hydrops is a byproduct of the underlying pathology or directly causative [4 ]. Various forms of vestibular testing, including electrocochleography (ECoG) and vestibular evoked myogenic potentials (VEMPs), have been used with the goal of diagnosing Menière s disease, with variable results. Cervical VEMPs, in which loud sounds produce brief inhibitory potentials of the ipsilateral sternocleidomastoid muscle through a saccule mediated reflex arc, have higher frequency specific thresholds and lower amplitudes, consistent with the histologically observed distention of the saccule [5]. However, they have not been found to be helpful in distinguishing Menière s disease from migraine, which is a common diagnostic dilemma [6]. ECoG, in which an acoustic stimulus produces an electric response from the cochlea and eight nerve, has been shown by some authors to reliably diagnose Menière s disease, while others have not found it to be helpful [7, 8]. With newer high resolution T2 MRI, and perilymphatic uptake of contrast agents, it is becoming possible to visualize in vivo distention of the endolymphatic space, and therefore diagnostic criteria may change [9, 10]. Furthermore, it is becoming possible to correlate endolymphatic distention on MRI with symptomatology and findings on vestibular testing and to assess changes in hydrops in response to treatment [11, 12]. No cure currently exists, nor a reliable method of arresting disease progression, which may result in permanent sensorineural hearing loss and vestibular hypofunction in the affected ear. Long-term observation studies have shown mean decreases in the word recognition score to 67 % in medically treated Menière s disease and 44 % in surgical treated Menière s disease, with quality of life indicators showing moderate handicaps related to hearing impairment, dizziness, and tinnitus [13]. Numerous treatment options are currently used with the aims of reducing the severity and incidence of dizziness attacks, preventing disease progression, treating the effects of end organ damage like hearing loss, tinnitus, and chronic imbalance, and providing symptomatic relief (Fig. 1). These include dietary modifications like salt restriction, oral pharmacologic therapy like diuretics and betahistine, intratympanic pharmacologic therapies like gentamicin and steroids, ablative surgical therapies like vestibular nerve section or labyrinthectomy, and other therapies like the Meniett device, or endolymphatic sac surgery [14]. Overall, the evidence for each of these therapeutic modalities, except for ablation and intratympanic steroids, is somewhat lacking (Table 1). Studies are hampered by the variability and natural course of the disease, in which vertiginous symptoms do tend to improve over time as hearing worsens, consistent with the cumulative effects of end organ damage. In addition, many patients exhibit a waxing and waning pattern to their symptoms and the degree of end organ impairment. Therefore, any study that does not consider time to be therapeutic, and therefore omits a placebo arm in which similar time elapses but without the proposed therapeutic intervention, should be considered flawed. Furthermore, since patients generally seek treatment when most symptomatic, even without the natural history of the disease causing improvement over time, regression to the mean in terms of symptom frequency and severity will also create the illusion of therapeutic efficacy.

3 Curr Treat Options Neurol (2015) 17:14 Page 3 of Fig. 1. Treatment algorithm for Menière s disease. Blue arrows refer to decisions that should be made in all patients; red arrows refer to disease progression. This algorithm was designed for treating unilateral disease. Table 1. Level of evidence for treatment options in Menière s disease Type of treatment Specific treatment Level of Comment evidence [66] Dietary modification Salt restriction 5 Expert opinion [15] Oral pharmacotherapy Diuretics 2b Low quality RTCs showing benefit [18] Betahistine 2b Low quality RCTs showing benefit [21 ] Intratympanic pharmacotherapy Steroids 1b RCT with clear benefit [26 ] Gentamicin 1b RCT with clear benefit [33 ] Surgical therapy Endolymphatic sac surgery 2b Two RCTs found no benefit, multiple cohort studies with benefit [41] Vestibular nerve section 2b Cohort studies with clear benefit [46] Labyrinthectomy 2b Cohort studies with clear benefit [67] Other Meniett device 2b 4 RCTs with no benefit, multiple cohort studies with benefit [68] RCT randomized controlled trial. Level of evidence is based on a grading scale from the Oxford Centre for evidence-based medicine [66]

4 14 Page 4 of 16 Curr Treat Options Neurol (2015) 17:14 Treatment Treatments in Menière s disease are generally aimed at reducing symptomology from the acute vertiginous episodes. To date, no treatment has been convincingly shown to be effective in altering the natural course of the disease, thereby preventing end organ damage which results in hearing loss and vestibular impairment. Diet and lifestyle Low salt diet is widely used as a first line treatment option [15, 16]. Daily sodium intake is recommended to be under 2000 mg, with some recommending keeping intake below 1500 or 1000 mg. The low salt intake is believed to be helpful in lowering endolymphatic pressure; however, this is highly speculative. Currently, strong evidence that salt restriction is beneficial does not exist. However, it is commonly used as first line treatment because of anecdotal experience [17]. Stress reduction and avoidance of caffeine and alcohol are also commonly recommended. Pharmacologic treatment Pharmacologic therapy can be aimed at addressing the pathophysiology of the disease, as with diuretics and betahistine, or at relieving symptomatology from acute vertiginous episodes, as with benzodiazepines. Diuretics Diuretics are thought to alter endolymphatic electrolyte concentrations, leading to decreased volume and pressure. Although they are commonly used as first line treatments, a recent Cochrane review did not find any quality evidence to argue for or against their usage [18]. However, other smaller studies have found benefit in reduction of vertiginous episodes [19]. Thiazide diuretics, with or without a potassium sparing diuretic, are most commonly used for this purpose. However, many other diuretics have been tried, such as acetazolamide, furosemide, and spironolactone, thelastofthesebeingusefulinpatientswithsulfaallergy. Dyazide (hydrochlorothiazide/triamterene) Standard dosage 25 mg hydrochlorothiazide with 37.5 mg triamterene taken orally once daily

5 Curr Treat Options Neurol (2015) 17:14 Page 5 of Main drug interactions Main side effects Renal impairment, hyperkalemia, concurrent potassium supplementation, hypersensitivity to thiazides, sulfonamides, or triamterene Caution with other drugs that increase serum potassium concentration to avoid hyperkalemia, and also with antiarrhythmic drugs as Dyazide can potentiate toxicity. Also interacts with methotrexate, lithium, cyclophosphamide, pixantrone, and others. Common: weakness, dizziness, headache. Serious: cardiac arrhythmias, hyperkalemia, renal failure, hypersensitivity. Generic, inexpensive Betahistine Betahistine is widely used in Europe as a first line treatment agent for Menière s disease. It is an H1 agonist and an H3 antagonist and is thought to promote blood flow through the stria vascularis into the cochlea in a dose-dependent fashion [20]. In addition, it may decrease activity in the vestibular nuclei through neurotransmitter release. A Cochrane review found some evidence for its efficacy but called for larger trials [21 ]. The most effective dose is controversial, with recent studies showing greater efficacy of 48 mg TID compared to 16 mg TID and other studies showing further efficacy of doses up to 480 mg daily [22, 23]. Betahistine Standard dosage Main drug interactions Main side effects 8 to 48 mg orally three times daily Hypersensitivity, pheochromocytoma. Caution with asthma, gastric ulcers, and liver disease. Anti-histamines may block effects. Nausea, headache, insomnia, GI disturbance, hypersensitivity reactions, rash, pruritis, urinary frequency Generic drug. Not FDA approved, so it can be difficult to obtain in the United States, and requires a compounding pharmacy, which adds cost. Benzodiazepines Benzodiazepines are used as vestibular suppressants for symptomatic control during acute vertiginous attacks. Centrally acting H1 antagonists can also be used for this purpose. Diazepam Standard dosage Main drug interactions 2 5 mg orally three times daily as needed for nausea Hypersensitivity, liver disease, glaucoma Caution with other drugs that cause CNS depression and drugs metabolized by the liver

6 14 Page 6 of 16 Curr Treat Options Neurol (2015) 17:14 Main side effects Special points Serious: respiratory depression, depression, suicidal thoughts. Common: somnolence, ataxia, dizziness Benzodiazepines should only be used on an as needed basis Inexpensive Intratympanic pharmacotherapy Intratympanic drug injections are aimed at delivering high doses of drug to the inner ear via round window absorption while avoiding systemic side effects. They carry a 1 % risk of creating a tympanic membrane perforation and can induce middle ear inflammation [24]. Intratympanic steroid injection Standard procedure Although originally assumed to have anti-inflammatory effects, IT steroids like dexamethasone may have much more potent mineralocorticoid effects in the inner ear than predicted from renal studies. Dexamethasone, for example, increases the principal epithelial sodium transporter of semicircular canals by threefold [25]. In one placebo-controlled randomized clinical trial, intratympanic dexamethasone was found to promote resolution of vertigo in 82 % of subjects, as opposed to 57 % of controls [26, 27 ]. In another trial using the concept of survival curves, 91 % of patients with Menière s disease had adequate symptom control with dexamethasone injections and did not progress to require more ablative therapies [28]. One study compared intratympanic gentamicin to dexamethasone in a randomized controlled trial, and found greater control of vertigo with gentamicin, with minimal hearing damage [29]. IT steroids are well tolerated, and have proven efficacy in a majority of individuals, and are therefore offered to patients who fail first line therapy. An ongoing clinical trial is looking at a sustained-release formulation of intratympanic dexamethasone to assess its efficacy in treating Menière s disease (clinicaltrials.gov, NCT ) Risks and benefits are discussed, and consent is signed. The procedure is performed in outpatient setting under an otologic operating microscope. The tympanic membrane is topically anesthetized with either phenol or EMLA (lidocaine 2.5 % and prilocaine 2.5 %) cream. A small ventilation hole is made with a 25 gauge needle anteriorly, and then the drug is injected posteriorly/ inferiorly until the inferior middle ear space is full (~0.4 ml). The patient is then instructed to lie with the injected ear facing up for 20 min to allow for round window absorption. Active middle ear disease. Anatomy that would preclude round window uptake of drug.

7 Curr Treat Options Neurol (2015) 17:14 Page 7 of Complications Tympanic membrane perforation, middle ear inflammation. Typically several hundred dollars per injection; however, usually, this provides several months of symptomatic relief Intratympanic gentamicin injection Standard procedure Complications Gentamicin is an antibiotic that is both vestibulotoxic and cochleotoxic. However, it has a high affinity for type 1 vestibular hair cells and therefore produces relatively more vestibular impairment than hearing loss. [30 ]. Streptomycin works in a similar fashion. It should be noted that the aim of treatment, similar to other ablative procedures, is reduction of acute vertiginous episodes, but the price paid is unilateral vestibular hypofunction, which can cause symptoms of imbalance with rapid ipsilateral head turns [31 ]. Rarely, postural instability and oscillopsia are seen. Pharmacologic ablation with gentamicin has been studied in a randomized controlled trial, which showed a much greater reduction in the frequency of acute vertiginous episodes as compared with saline injections, with no change in hearing thresholds [32 ]. Therefore, it is thought that with proper dosing, there is a therapeutic window available in which symptom reduction can be achieved with only subclinical deleterious effects on hearing and symptomatic balance function. In another randomized controlled trial comparing intratympanic gentamicin to saline, significant reduction in vertigo scores were seen in the gentamicin arm, along a small reduction in hearing thresholds (mean 8 db) [33 ]. Another paper showed a 17 % risk of worsening hearing [34]. It is important to emphasize that gentamicin is effective for vertigo control while only producing a partial vestibular loss, while ablative surgical options create a total unilateral vestibular loss [31 ]. Sometimes, multiple injections are required, and these can be titrated to control vertigo symptoms, although some argue for titration until there are signs of unilateral vestibular weakness, such as a positive head thrust sign, post-headshake nystagmus, or spontaneous nystagmus beating towards the opposite ear. Titration of gentamicin until there is complete loss of unilateral vestibular function, with absent ice water caloric responses, is usually unnecessary and can result in worse hearing and balance outcomes. Same procedure as with intratympanic steroid injection, see above for description. Only ear with hearing or balance function. Active middle ear infection. Hearing loss, unilateral vestibular hypofunction. Typically several hundred dollars per injection; however, 54 % of patients only require one injection, and 96 % are able to avoid ablative surgery through injections [35].

8 14 Page 8 of 16 Curr Treat Options Neurol (2015) 17:14 Surgery Ablative surgery involves surgical interruption of unilateral peripheral vestibular input. While this guarantees unilateral vestibular weakness, central compensation for a static unilateral deficit occurs with time. This compensation can be accelerated with vestibular physical therapy. However, the potential for development of bilateral disease, which one paper conservatively estimated at a 5 % risk, decreases the attractiveness of totally ablative options [36]. The specific surgical procedure chosen depends on the hearing status: for cases with residual hearing, vestibular nerve section is preferred, and for cases without residual hearing, labyrinthectomy is chosen. It should also be noted that since gentamicin can achieve a partial but effective chemical labyrinthectomy in most cases, these surgeries are usually now only performed for gentamicin non-responders. Furthermore, there is clinical evidence that in most gentamicin non-responders, anatomic factors like adhesions or bone dust are physically obstructing the round window membrane, precluding drug uptake. Therefore, middle ear exploration with exposure of the round window membrane and direct application of gentamicin pledgets is effective at controlling vertigo in 75 % of gentamicin non-responders, thereby avoiding the need for more invasive surgery [37]. Endolymphatic sac surgery The endolymphatic sac is an outpouching of the endolymphatic membrane into the dura beneath the posterior fossa plate of bone. The sac is connected to the membranous utricle through the endolymphatic duct. It was classically thought to be involved in resorption of endolymph. However, there is also evidence that the sac is involved in immune function of the inner ear, possibly initiating immune responses after antigen processing and presentation [38]. Endolymphatic sac surgery is aimed at shunting, draining, or decompressing the sac, thereby preventing hydrops by facilitating outflow of endolymph. This is considered a non-destructive procedure. It was originally described by Portmann in 1927 and has been widely performed and hotly contested since then [39]. A Cochrane review in 2013 examined the evidence for surgery in the treatment of Menière s disease [40, 41]. They included 2 RCTs, both of which involved endolymphatic sac surgery compared to either pressure equalization tube insertion or sham mastoid surgery. No differences were seen between treatment and placebo groups. However, this remains a very controversial area [42]. One histologic study looked at temporal bones after sac surgery and found that correct placement of the shunt into the sac had no relation to postoperative relief of vertigo, which was commonly seen [43]. In terms of surgical technique, similar results are seen with decompression of the sac versus shunting [44].

9 Curr Treat Options Neurol (2015) 17:14 Page 9 of Standard procedure Complications The patient is placed under general anesthesia, and facial nerve monitoring electrodes are placed. Antibiotics are administered, and a standard mastoidectomy is performed, with decompression of the sigmoid sinus. Next, the endolymphatic sac is identified posterior to the posterior semicircular canal, along the posterior fossa plate, below Donaldson s line. In a decompression surgery, the bone over the sac is widely removed. In a shunting procedure, a stent, usually Silastic, is placed into the sac, which directs endolymph either into the mastoid or CSF compartment. Active mastoid or middle ear disease is considered a contraindication. Complications of mastoid surgery include hearing loss, dizziness, CSF leak, damage to the sigmoid sinus, facial paralysis, and general risks of surgery and anesthesia. Furthermore, bone dust from surgery can be spread to the ossicles, causing a conductive hearing loss, or to the round window niche, which may impair future intratympanic drug administration [45]. Endolymphatic sac surgery is an outpatient surgical procedure that takes approximately 2 3 h under general anesthesia. Vestibular nerve section Standard procedure Complications Special points Introduced by Dandy in 1928, vestibular nerve section can be accomplished through a retrosigmoid or retrolabyrinthine approach. In the former, a suboccipital craniotomy is performed with monitoring of the facial nerve and auditory evoked potentials. The inferior and superior vestibular nerves are identified and sectioned at the porus acusticus, taking care not to injure the facial or cochlear nerve. Identification of the vestibular nerves can be facilitated by decompression of the internal auditory canal laterally so as to definitively locate landmarks such as the horizontal and vertical crests (Bill s bar) and the singular nerve to the posterior semicircular canal ampulla. The wound is then closed in standard fashion after cranioplasty. In the retrolabyrinthine approach, a mastoidectomy is performed, with decompression of the sigmoid sinus and identification of the posterior canal and the vertical segment of the facial nerve. The posterior fossa dura is then entered between the sigmoid and the otic capsule, and the internal auditory canal is decompressed to visualize the individual nerves. The vestibular, cochlear, and facial nerves are identified, and the vestibular nerves are then carefully sectioned. A fat graft is placed within the mastoid cavity to prevent CSF leak, and the wound is closed. If there is no useful hearing, then labyrinthectomy is preferred because of lower risk profile. Complications from posterior fossa surgery include CSF leak, meningitis, cranial neuropathies, seizure, stroke, death, in addition, the usual risks of surgery and anesthesia. The retrolabyrinthine route reduces the risks of posterior fossa surgery but adds some risk from the mastoidectomy. In one large study, the risk of greater than 10 db sensorineural hearing loss for retrolabyrinthine vestibular nerve sectioning surgery was estimated at 10 % [46]. These procedures are now rarely performed because less risky and costly alternatives for vestibular ablation are available. Vestibular physical therapy is helpful postoperatively to assist with central compensation and return to functionality. Inpatient surgery with 2 to 5-day hospital stay.

10 14 Page 10 of 16 Curr Treat Options Neurol (2015) 17:14 Labyrinthectomy Standard procedure Complications Special points The goal of surgery is removal of neuroepithelium from the five vestibular end organs: the three semicircular canals, the utricle, and the saccule. The patient is placed under general anesthesia, and facial nerve monitoring electrodes are placed. Antibiotics are administered, and a standard mastoidectomy is performed. The tegmen, sigmoid sinus, horizontal canal, and facial nerve are all identified. The horizontal semicircular canal is then entered, and followed posteriorly to the posterior semicircular canal, which in turn is followed to the common crus to identify the superior canal. Great care is taken at the anterior aspects of the horizontal and posterior canals to avoid injury to the facial nerve. The canals are then followed into the vestibule. The neuroepithelium is then removed from the ampullated end of each semicircular canal, and the utricle is removed from the elliptical recess superiorly in the vestibule, and the saccule from the inferiorly located spherical recess. Once all neuroepithelium has been removed, the wound is closed in layers, and a mastoid dressing is applied. The procedure produces hearing loss and unilateral vestibular weakness, and is therefore contraindicated in an only hearing ear, and also with contralateral vestibular impairment. Complications are related to mastoid surgery; they include dizziness, CSF leak, damage to the sigmoid sinus, facial paralysis, and general risks of surgery and anesthesia. After surgery, depending on preoperative vestibular function, it is normal to have a horizontal rotary nystagmus with the fast phase directed towards the non-operated ear. This usually resolved in a few days. In addition, a skew deviation can occasionally be observed due to acute disruption of unilateral utricular input. Vestibular physical therapy is helpful postoperatively to assist with central compensation and return to functionality. Surgery usually takes 3 to 5 h, and an inpatient hospital stay of 1 to 3 days is expected. Assistive devices Over time, many patients with Menière s disease develop permanent unilateral hearing loss. Treatment options include conventional hearing aids if there is still useful hearing in the affected ear, and contralateral routing of sound (CROS) hearing aids or osseointegrated hearing aids if hearing is not useful in the affected ear. Useful hearing is usually defined as a speech discrimination score above 50 %. In addition, cochlear implants are being studied for their utility in single-sided deafness, and their use in bilateral end-stage Menière s diseaseiswell supported [47]. Conventional hearing aid Usage A hearing aid consists of, at minimum, a microphone that picks up sounds from the environment, an amplifier that increases the sound intensity, and a receiver that acts like a speaker delivering sound to the ear. Modern hearing aids include on-board or remote processing circuitry to improve the quality of the transmitted sound by fixed filters or context-specific filters that aim to increase the signal to noise ratio.

11 Curr Treat Options Neurol (2015) 17:14 Page 11 of Insurance coverage for hearing aids is limited and they may cost several thousand dollars. CROS (contralateral routing of sound) hearing aid Usage This is a specialized hearing aid system in which a transmitter is placed on the poorer hearing ear to collect sounds and wirelessly transmit them to a receiver placed on the better hearing ear. This allows sound information to be collected from the side of the head with hearing impairment, which helps with speech understanding and sound localization. Insurance coverage for hearing aids is limited and they may cost several thousand dollars. Osseointegrated mastoid implant + bone-conduction processor Usage Special points Osseointegrated mastoid implants coupled with bone-conduction processors, commonly called bone-anchored hearing aids, depend on bone-mounted hardware placed during a brief outpatient surgical procedure that can be performed under general or local anesthesia. Once the implant is placed, there is a waiting period up to several months during which osseointegration occurs. After that, a sound processor is placed on the abutment, and sounds are then transmitted via bone conduction through the skull base to the contralateral cochlea, reducing the hearing impairment of single sided deafness. Wound care issues can occur, and local treatments are generally effective; however, occasionally revision surgery is required. Brief outpatient surgical procedure. The cost of the processor, which is several thousand dollars, is usually covered by insurance as part of the procedure cost. Physical/speech therapy and exercise In addition to the acute vertiginous episodes, patients with Menière s disease will usually experience a gradual decline in vestibular function on the affected side. This may result in baseline imbalance if the brain does not properly adapt to asymmetric peripheral vestibular input. Therefore, vestibular physical therapy (VPT) is often helpful to assist with central compensation for the progressive unilateral loss. Numerous trials have shown benefit for vestibular therapy in improving function with unilateral vestibular loss [48 ]. Vestibular physical therapy Usage VPT is a specialized rehabilitation that instructs patients in home exercise routines that improve gaze and postural stability while reducing fall risk. The gaze stability exercises are designed to challenge the brain to keep the eyes still in space during head rotation, when the vestibulo-ocular reflex (VOR) is deficient in doing so. Evidence suggests that this occurs from two means: an increase in the vestibular generated slow phase eye velocity (VOR gain) and an increase in the frequency of compensatory saccades [49, 50, 51]. Postural exercises challenge balance by altering the visual and proprioceptive afferents. There is now strong evidence summarized via Cochrane reviews that VPT is an efficient means to improve balance, gait, and reduce fall risk [48, 52, 53].

12 14 Page 12 of 16 Curr Treat Options Neurol (2015) 17:14 Recently, VPT using virtual reality methods was shown to reduce perception of handicap due to dizziness and improve postural stability in patients with Menière s disease[54 ]. VPT is generally covered by insurance. The duration of physical therapy will depend on the extent of vestibular hypofunction. Most patients tolerate a home-based exercise program with weekly or biweekly outpatient visits for exercise progression over 4 to 8 weeks [55, 56]. Estimates suggest VPT costs from $ per month depending on need. Other treatments The Meniett Device (Medtronic Xomed, Jacksonville, Florida, USA) is a handheld air pressure generator which delivers brief pulses of pressure to the inner ear. Treatments are given for 5 min, three times daily. Meniett device Standard procedure Complications Special points Usage of the Meniett device requires placement of a pressure equalization tube within the tympanic membrane. The device is then placed within the external auditory canal, and pulses of air pressure are generated that are transmitted from the external ear to the middle ear, and are thought to vibrate the round window. This is thought to aid in endolymphatic redistribution and turnover. Three treatments of 5-min duration are administered daily. The Meniett device is safe and well tolerated. It cannot be used if a pressure equalization tube cannot be placed. Relative contraindications include disorders of the external ear like chronic otitis externa that would complicate frequent placement of a device within the ear canal and any middle ear disease that blocks access to the round window. Complications are rare with the Meniett device. Most reported complications are related to the PE tube, which can cause otitis media or a tympanic membrane perforation. Several recent meta-analyses looking at the effectiveness of the Meniett device have found conflicting results. One study looked at 4 randomized clinical trials and found no evidence for effectiveness of the device over placebo [57]. Another meta-analysis included 12 studies, including 2 RCTs, 3 prospective studies, 4 retrospective studies, and 3 cross-sectional/unknown studies, and found that the Meniett device was effective at restoring some hearing (3.5 db pure tone average gain) and in reducing vertigo frequency. However, that study mostly pooled single armed studies without control groups, and should therefore be interpreted with caution [58]. The Meniett device costs approximately $2500, and this is usually not covered by insurance. In addition, a PE tube must be placed. Emerging therapies OTO-104 is a novel formulation for sustained release of dexamethasone. It has been evaluated in a recent single-dose and placebocontrolled clinical trial. The steroid is contained in a solution with a thermoreversible polymer excipient which gels once exposed to body

13 Curr Treat Options Neurol (2015) 17:14 Page 13 of Pediatric considerations temperature after it injected into the middle ear. This delivery method allows prolonged steroid exposure to the inner ear. The results demonstrated OTO-104 to be safe and suggested a decrease in vertigo frequency at 3 months as well as tinnitus handicap [59 ]. At the time of writing, this drug was being evaluated in a multicenter clinical trial for Menière s disease [60]. Perhaps because of its rare occurrence, only a few case series have investigated Menière s disease in pediatric populations. They reported low incidences ranging from 0.4 % by Stahle et al. [61], approximately 3 % by Meyerhoff et al. [62], and 7 % by Filipo et al. [63]. There are no large-scale studies that evaluate the effectiveness of Menière s disease therapies in children. In published case series, treatment was offered in a stepwise manner starting with dietary restriction of sodium. Medications can be offered if there is insufficient control over symptomatology; diuretics are suggested as a first line therapy. Vestibular depressants and anti-histamines can be administered as well. Placement of transtympanic ventilation tubes and intratympanic administration of gentamicin have also been reported to provide symptomatic relief [64, 65]. Endolymphatic sac drainage surgery can be pursued if more conservative treatments fails [62, 63]. Acknowledgments A grant from Otonomy to the Johns Hopkins School of Medicine funds this work. The contract is approved and monitored by the institution s Office of Research Administration, the Conflict of Interest Committee and the Institutional Review Board. Compliance With Ethics Guidelines Conflict of Interest Jeffrey D. Sharon, Carolina Trevino, and Michael C. Schubert declare no conflicts of interest. John P. Carey declares that he is a site investigator for a clinical trial of OTO-104 for control of vertigo in MD. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance

14 14 Page 14 of 16 Curr Treat Options Neurol (2015) 17:14 1. Baloh RW. Prosper Meniere and his disease. Arch Neurol. 2001;58(7): Monsell EM et al. Committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere s disease. Otolaryngol Head Neck Surg. 1995;113D3]: This article established commonly used guidelines for diagnosing Menière s disease and evaluating treatment efficacy. 3. Society B. Diagnostic criteria for Menière s disease. Available from: Lopez-Escamez.pdf Rauch SD, Merchant SN, Thedinger BA. Meniere s syndrome and endolymphatic hydrops. Double-blind temporal bone study. Ann Otol Rhinol Laryngol. 1989;98D11]: A temporal bone study that helped clarify the relationship of histological endolymphatic hydrops and clinical Menière s disease. 5. Rauch SD et al. Vestibular evoked myogenic potentials show altered tuning in patients with Meniere s disease. Otol Neurotol. 2004;25(3): Zuniga MG et al. Can vestibular-evoked myogenic potentials help differentiate Meniere disease from vestibular migraine? Otolaryngol Head Neck Surg. 2012;146(5): Hornibrook J et al. Transtympanic electrocochleography for the diagnosis of Meniere s disease. Int J Otolaryngol. 2012;2012: Claes GM et al. The Meniere s disease index: an objective correlate of Meniere s disease, based on audiometric and electrocochleographic data. Otol Neurotol. 2011;32(5): Nakashima T et al. Visualization of endolymphatic hydrops in patients with Meniere s disease. Laryngoscope. 2007;117D3]: This important paper showed that it was possible to visualize endolymphatic hydrops in Menière s disease using high resolution MRI and intratympanic contrast. 10. Pyykko I et al. Magnetic resonance imaging of the inner ear in Meniere s disease. Otolaryngol Clin North Am. 2010;43(5): Gurkov R et al. Herniation of the membranous labyrinth into the horizontal semicircular canal is correlated with impaired caloric response in Meniere sdisease.otol Neurotol. 2012;33D8]: This study is important because it showed that novel MRI techniques used to visualize endolymphatic hydrops in vivo do correlate with objective measures like vestibular testing. 12. Gurkov R et al. In vivo visualization of endolymphatic hydrops in patients with Meniere s disease:correlation with audiovestibular function. Eur Arch Otorhinolaryngol. 2011;268(12): Kinney SE, Sandridge SA, Newman CW. Long-term effects of Meniere s disease on hearing and quality of life. Am J Otol. 1997;18(1): Sajjadi H, Paparella MM. Meniere s disease. Lancet. 2008;372(9636): Minor LB, Schessel DA, Carey JP. Meniere s disease. Curr Opin Neurol. 2004;17(1): Smith WK, Sankar V, Pfleiderer AG. A national survey amongst UK otolaryngologists regarding the treatment of Meniere s disease. J Laryngol Otol. 2005;119(2): Greenberg SL, Nedzelski JM. Medical and noninvasive therapy for Meniere s disease. Otolaryngol Clin North Am. 2010;43(5): Thirlwall AS, Kundu S. Diuretics for Meniere s disease or syndrome. Cochrane Database Syst Rev. 2006;3:CD van Deelen GW, Huizing EH. Use of a diuretic (Dyazide) in the treatment of Meniere s disease.a double-blind cross-over placebo-controlled study. ORL J Otorhinolaryngol Relat Spec. 1986;48(5): Ihler F et al. Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo. PLoS One. 2012;7(6):e James AL and Burton MJ. Betahistine for Meniere s disease or syndrome. Cochrane Database Syst Rev. 2001(1):CD This systematic review examined the evidence for betahistine, which is widely used around the world as a treatment for Menière s disease. 22. Strupp M et al. Long-term prophylactic treatment of attacks of vertigo in Meniere s disease comparison of a high with a low dosage of betahistine in an open trial. Acta Otolaryngol. 2008;128(5): Lezius F et al. High-dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Meniere s disease: a case series. Eur Arch Otorhinolaryngol. 2011;268(8): Rauch SD et al. Oral vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: a randomized trial. JAMA. 2011;305(20): Pondugula SR et al. Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel. Am J Physiol Renal Physiol. 2004;286(6):F Garduno-Anaya MA et al. Dexamethasone inner ear perfusion by intratympanic injection in unilateral Meniere s disease: a two-year prospective, placebocontrolled, double-blind, randomized trial. Otolaryngol Head Neck Surg. 2005;133D2]: A well-conducted trial that helped establish the utility of intratympanic steroids as a treatment for Menière s disease. 27. Phillips JS and Westerberg B. Intratympanic steroids for Meniere s disease or syndrome. Cochrane Database Syst Rev. 2011(7):CD Systematic review that looked at evidence for intratympanic steroids in treating Menière s disease. 28. Boleas-Aguirre MS et al. Longitudinal results with intratympanic dexamethasone in the treatment of Meniere s disease. Otol Neurotol. 2008;29(1): Casani AP et al. Intratympanic treatment of intractable unilateral Meniere disease: gentamicin or dexamethasone? A randomized controlled trial. Otolaryngol Head Neck Surg. 2012;146(3):430 7.

15 Curr Treat Options Neurol (2015) 17:14 Page 15 of Lyford-Pike S et al. Gentamicin is primarily localized in vestibular type I hair cells after intratympanic administration. J Assoc Res Otolaryngol. 2007;8D4]: This animal study showed the differential uptake of gentamicin by type 1 vestibular hair cells. 31. Carey JP et al. Changes in the three-dimensional angular vestibulo-ocular reflex following intratympanic gentamicin for Meniere s disease. J Assoc Res Otolaryngol. 2002;3D4]: This study examined the physiologic changes that occurred to the vestibulo-ocular reflex after gentamicin administration. 32. Stokroos R, Kingma H. Selective vestibular ablation by intratympanic gentamicin in patients with unilateral active Meniere s disease: a prospective, double-blind, placebo-controlled, randomized clinical trial. Acta Otolaryngol. 2004;124D2]: A placebo controlled study that added to the body of literature establishing the effectiveness of gentamicin in treating Menière s disease. 33. Postema RJ et al. Intratympanic gentamicin therapy for control of vertigo in unilateral Meniere s disease:a prospective, double-blind, randomized, placebo-controlled trial. Acta Otolaryngol. 2008;128D8]: Another well conducted study that showed the effectiveness of gentamicin for treating Menière s disease. 34. Wu IC, Minor LB. Long-term hearing outcome in patients receiving intratympanic gentamicin for Meniere s disease. Laryngoscope. 2003;113(5): Nguyen KD et al. Time course of repeated intratympanic gentamicin for Meniere s disease.laryngoscope. 2009;119(4): Perez R, Chen JM, Nedzelski JM. The status of the contralateral ear in established unilateral Meniere s disease. Laryngoscope. 2004;114(8): Crane BT et al. Middle ear exploration in patients with Meniere s disease who have failed outpatient intratympanic gentamicin therapy. Otol Neurotol. 2009;30(5): Satoh H et al. Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol. 2003;4(2): Portmann G. The saccus endolymphaticus and an operation for draining for the relief of vertigo. Proc R Soc Med. 1927;20(12): Sood AJ et al. Endolymphatic sac surgery for Meniere s disease: a systematic review and meta-analysis. Otol Neurotol. 2014;35D6]: A systematic review that examined the evidence for endolymphatic sac surgery in Menière's diease. 41. Pullens B, Verschuur HP, van Benthem PP. Surgery for Meniere s disease. Cochrane Database Syst Rev. 2013;2:CD Welling DB, Nagaraja HN. Endolymphatic mastoid shunt: a reevaluation of efficacy. Otolaryngol Head Neck Surg. 2000;122(3): Chung JW et al. Histopathology after endolymphatic sac surgery for Meniere s syndrome. Otol Neurotol. 2011;32(4): Brinson GM, Chen DA, Arriaga MA. Endolymphatic mastoid shunt versus endolymphatic sac decompression for Meniere s disease. Otolaryngol Head Neck Surg. 2007;136(3): Minor LB. Intratympanic gentamicin for control of vertigo in Meniere s disease:vestibularsignsthat specify completion of therapy. Am J Otol. 1999;20(2): Goksu N et al. Combined retrosigmoid retrolabyrinthine vestibular nerve section: results of our experience over 10 years. Otol Neurotol. 2005;26(3): Lustig LR et al. Cochlear implantation in patients with bilateral Meniere s syndrome. Otol Neurotol. 2003;24(3): Hillier SL and McDonnell M. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev. 2011(2):CD A systematic review that provided strong evidence that vestibular physical therapy is helpful in Menière s disease. 49. Schubert MC et al. Mechanism of dynamic visual acuity recovery with vestibular rehabilitation. Arch Phys Med Rehabil. 2008;89D3]: An important study that helped elucidate the physiologic changes that occur with vestibular physical therapy. 50. Schubert MC et al. Oculomotor strategies and their effect on reducing gaze position error. Otol Neurotol. 2010;31(2): Scherer M, Migliaccio AA, Schubert MC. Effect of vestibular rehabilitation on passive dynamic visual acuity. J Vestib Res. 2008;18(2 3): Hall CD, Schubert MC, Herdman SJ. Prediction of fall risk reduction as measured by dynamic gait index in individuals with unilateral vestibular hypofunction. Otol Neurotol. 2004;25(5): McDonnell MN, Hillier SL. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev. 2015;1:CD Garcia AP et al. Vestibular rehabilitation with virtual reality in Meniere s disease. Braz J Otorhinolaryngol. 2013;79D3]: This study is important because it highlighted the use of virtual reality to deliver vestibular rehabilitation therapy to Menière s patient, and showed it to be highly effective. 55. Herdman SJ et al. Recovery of dynamic visual acuity in bilateral vestibular hypofunction. Arch Otolaryngol Head Neck Surg. 2007;133(4): Herdman SJ et al. Recovery of dynamic visual acuity in unilateral vestibular hypofunction. Arch Otolaryngol Head Neck Surg. 2003;129(8): Syed MI et al. Positive pressure therapy for Meniere s syndrome/ disease with a Meniett device: A systematic review of randomised controlled trials. Clin Otolaryngol A systematic review that examined the evidence for the Meniett device. 58. Ahsan SF, Standring R and Wang Y. Systematic review and meta-analysis of Meniett therapy for Meniere s disease. Laryngoscope Another systematic review that looked at evidence for the Meniett device

16 14 Page 16 of 16 Curr Treat Options Neurol (2015) 17: Lambert PR 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 Meniere's disease. Otol Neurotol. 2012;33D7]: This study is important because it examined a novel delivery vehicle for intratympanic dexamethesone, which has been proven to be an effective, non-ablative treatment. 60. ClinicalTrials.gov. OTO-104 for the Treatment of Meniere s Disease. Available from: gov/ct2/show/study/nct ?term=meniere% 27srank=4 61. Stahle J, Stahle C, Arenberg IK. Incidence of Meniere s disease. Arch Otolaryngol. 1978;104(2): Meyerhoff WL, Paparella MM, Shea D. Meniere s disease in children. Laryngoscope. 1978;88(9 Pt 1): Filipo R, Barbara M. Juvenile Meniere s disease.j Laryngol Otol. 1985;99(2): Hausler R et al. Meniere s disease in children. Am J Otolaryngol. 1987;8(4): Akagi H et al. Meniere s disease in childhood. Int J Pediatr Otorhinolaryngol. 2001;61(3): Medicine, O.C.f.E.B. Levels of Evidence [cited 2015 Jan 16]; Available from: oxford-centre-evidence-based-medicine-levelsevidence-march-2009/ 67. Diaz RC et al. Quality-of-life assessment of Meniere s disease patients after surgical labyrinthectomy. Otol Neurotol. 2007;28(1): Syed I, Aldren C. Meniere s disease: an evidence based approach to assessment and management. Int J Clin Pract. 2012;66(2): Rauch SD. Clinical hints and precipitating factors in patients suffering from Meniere s disease. Otolaryngol Clin North Am. 2010;43(5):