Clinical manifestations

Presentation and course

The key clinical features of Meniere syndrome are recurrent episodes of spontaneous vertigo, fluctuating hearing loss, aural fullness, and subjective tinnitus, with a progressive loss of audiovestibular function. The vertiginous episodes typically last hours (with a range generally of 20 minutes to 12 hours), with residual nonvertiginous disequilibrium lasting possibly several days (151; 155; 138; 18; 19). About a quarter of patients have vertiginous attacks lasting less than 1 hour, 50% have attacks lasting 1 to 2 hours, and a quarter have attacks lasting more than 2 hours (155). Vertigo may be severe and prostrating, with associated autonomic manifestations (eg, nausea, vomiting, diaphoresis, pallor, hypertension, tachycardia). Hearing loss is classically described as fluctuating, particularly early in the course of the disease, but not all patients have fluctuating hearing loss. Furthermore, the hearing loss is characteristically a low- to midfrequency sensorineural hearing loss (18; 19). The tinnitus is subjective and classically described as a low-frequency “buzz” or “roar” (148), but late in the disease patients may develop a high-pitched component. Aural fullness incorporates sensations of pressure, discomfort, or fullness in the ears.

Diagnostic criteria for the diagnosis of Meniere disease have been established by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology--Head and Neck Surgery (05) and subsequently by a consortium of the Classification Committee of the Bárány Society, the Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS), and the Korean Balance Society (see Tables 1 and 2) (70; 124; 125; 166). These criteria have evoked some criticism (77). Similar criteria have been established by other professional societies (138; 18; 19).

Table 1. Diagnostic Criteria for Definite Meniere Disease

Table 2. Diagnostic Criteria for Probable Meniere Disease

The diagnosis of Meniere disease must be made separately for each ear for a case to be considered bilateral Meniere disease.

Current diagnostic criteria probably do not represent patients with monosymptomatic presentation or an early stage very well (96), nor do they consider diagnostic modalities other than audiometry. Atypical presentations with normal vestibular function and hearing are a diagnostic challenge that delay treatment initiation (87).

In patients with unilateral or asymmetric disease, the degree of low-frequency hearing loss (250 Hz to 1 kHz) in combination with auditory symptoms during attacks reliably identifies the ear with the greater extent of endolymphatic hydrops (79).

Other clinical features of Meniere syndrome and Meniere disease may include diplacusis (ie, perception of the same sound with different pitches in the normal and affected ear), recruitment of loudness (suspected when a patient complains that loud sounds are annoying or painful in the ear with poor hearing), a positive Romberg test (although the direction of fall may vary, either toward or away from the affected ear), a positive Fukuda marching test (with significant turning if the patient can stand with eyes closed), Tullio phenomenon (ie, sound-induced vertigo, sound-induced nystagmus, or both), Hennebert sign (ie, pressure-induced vertigo, pressure-induced nystagmus, or both elicited by insufflation of the external auditory canal) (145), a positive Dix-Hallpike test for positioning vertigo (in patients with secondary positioning vertigo), and Tumarkin otolithic crises (ie, drop attacks without warning, associated autonomic or neurologic symptoms, loss of consciousness, or postictal signs) (27; 13; 114; 209; 174; 109). With unilateral disease, the Weber tuning fork test usually lateralizes away from the affected ear, whereas the Rinne test usually indicates better air conduction than bone conduction. Downbeat nystagmus may occur during attacks of Meniere disease due to an asymmetry in the vertical vestibulo-ocular reflex or saccular dysfunction (115).

With otolithic crises (also called “otolithic catastrophe” or "Tumarkin attacks"), patients may report the sensation of being suddenly thrown to the ground without warning. These crises are thought to result from inappropriate stimulation of one of the otolith receptors, probably the saccule (27; 209). Such stimulation causes the brain to interpret the gravity vector as having suddenly changed, before visual and proprioceptive input can be assessed for accuracy, resulting in a sudden fall (27). Patients with Meniere disease who develop Tumarkin attacks are more disabled, have more severely impaired hearing in the asymptomatic ear (especially at low frequencies), and experience autonomic symptoms that are more severe and more frequent than those without Tumarkin attacks (165; 172). They are also more fearful and anxious, self-report greater impairment in work ability, and are more likely to have to apply for work-related disability pensions than Meniere disease patients without Tumarkin attacks (172). Some patients with Tumarkin attacks can also have syncope (171; 173; 172; 109).

Meniere syndrome is a chronic disabling condition with major negative effects on physical and psychosocial functioning and quality of life (206; 110). Anxiety and depression are common in patients with Meniere disease (235; 110). Indeed, in a meta-analysis of 15 studies from eight countries involving 6587 patients, the prevalence of depression in patients with Meniere disease was nearly 50% (162).

Cluster analysis has been used to define subgroups of patients with unilateral Meniere disease (62):

There can be some misclassification between groups 2, 4, and 5, as the group 2 definition focuses on a symptom—hearing loss—which antedates the episodes of vertigo, ignoring comorbid conditions. As a result, some individuals with migraine or autoimmune disorders can be included in group 2 rather than in groups 4 or 5 which focus on comorbid conditions irrespective of the presenting symptom.

Meniere disease may also occur with comorbid benign paroxysmal positioning vertigo (BPPV). A meta-analysis found that the pooled frequency of BPPV in Meniere disease is 14% (95% CI 9% to 18%), but the pooled frequency was lower in cross-sectional studies (8%) than in longitudinal studies (38%) (108).

Prognosis and complications

Endolymphatic hydrops tends to worsen over time (230). Hearing thresholds at low frequencies (125 to 250 Hz) and medium frequencies (500 to 2000 Hz) are proportional to the extent of endolymphatic hydrops in the vestibule and cochlea. However, no significant relationship has been demonstrated between the extent of endolymphatic hydrops and other symptoms and signs (eg, high-frequency hearing loss, subjective tinnitus, and aural fullness).

Remissions and exacerbations are typical of Meniere disease, though generally the frequency of attacks and the severity of associated vegetative symptoms decline over a number of years (151; 134; 167). In at least two thirds of patients, vertigo is successfully controlled with medical management and the natural history of the disease, and many individuals reach a steady-state phase of the disease (38; 167). Still, some patients with Meniere disease can have frequent, severe attacks even 20 years or more after disease onset (89).

Estimates of the frequency of bilateral disease vary widely, in part depending on the sensitivity of the method of identifying contralateral disease (151; 64; 113; 159; 41; 34). Most studies report a frequency of bilateral disease of between 10% and 33%, but a wider range is also reported—from 5% to 50% (63). Some studies suggest that individuals with disabling longstanding unilateral disease are unlikely to develop bilateral disease (164). However, the proportion with contralateral disease does increase with disease duration and may approach 50% after 20 years of follow-up (64; 155). In cross-sectional studies, the onset of disease in patients with bilateral disease is earlier than in patients with unilateral disease (34).

Attempts have been made to identify subgroups of patients with bilateral Meniere disease. One scheme using cluster analysis defined five subgroups: (1) metachronic (ie, not synchronous) hearing loss, without migraine and without associated autoimmune disorders, representing about half of the cases; (2) synchronous hearing loss, without migraine and without associated autoimmune disorders, representing slightly less than a fifth of cases; (3) familial Meniere disease; (4) with associated migraine; and (5) with associated autoimmune disorders—with the latter three categories each representing about 10% of cases (63).

Staging of Meniere disease is based on the average of pure-tone thresholds at 0.5 kHz, 1 kHz, 2 kHz, and 3 kHz of the worst audiogram in the 6-month period prior to treatment (see Table 3) (05). Staging is only done on cases with certain or definite Meniere disease. For reporting purposes, the stage does not change if hearing changes after treatment.

Table 3. Staging of Meniere Disease

Disability, according to the Committee on Hearing and Equilibrium (05), is best measured by standard functional scale, with the patient making the final selection of disability level (see Table 4). The scale assesses the current state of overall function, not just function during attacks.

Table 4. Functional Level Scale for Meniere Disease

At each office visit, the following should be recorded: the frequency of definitive episodes for the previous 6 months, the pure-tone average (for thresholds at 0.5 kHz, 1 kHz, 2 kHz, and 3 kHz), word recognition scores, and the functional level (05).

Meniere disease is independently associated with an increased risk of injuries (229); medical or surgical treatment for Meniere disease does not reduce the risk of injury in these patients.

Biological basis

Etiology and pathogenesis

Endolymphatic hydrops. Endolymph is normally absorbed in the endolymphatic duct and sac. Endolymphatic hydrops is thought to be the pathological substrate of Meniere syndrome, resulting from defects in endolymph absorption. Endolymphatic hydrops refers to increased hydraulic pressure within the endolymphatic system of the inner ear, causing pathologic dilation of the endolymphatic system and an increased volume of endolymph. However, although endolymphatic hydrops is almost universally present on pathological examination of temporal bones from patients with Meniere syndrome who die, not all patients who have endolymphatic hydrops pathologically had clinical Meniere syndrome during life (177).

A critical review concluded that (1) the preponderance of evidence suggests that endolymphatic hydrops is responsible for some of the auditory symptoms of Meniere disease; (2) Meniere disease should be considered part of a larger spectrum of "hydropic inner ear disease" that also includes some cases without vertigo; and (3) endolymphatic hydrops is a hallmark defining feature of Meniere disease and a sensible target for diagnostic detection (69).

Etiologic factors. The etiology is probably multifactorial in most cases, with a genetic predisposition and environmental triggers, such as infection, cranial or otic trauma, otitis media, viral infection, syphilis, otosclerosis, etc. (74; 154; 65; 91; 128). The majority of cases are sporadic, but familial aggregation has been recognized in European and Korean populations (123). The presence of familial cases suggests that shared environmental exposures or genetic factors are important in the etiology (91). A systematic investigation of the family histories of a large set of patients affected with Meniere disease found that a family history of Meniere disease was convincing (confirmed or probable) in nearly a quarter (23.4%) of the patients (91). Genetic studies suggest that Meniere disease may be transmitted as an autosomal dominant trait with reduced penetrance and anticipation (07); a candidate region has been located on chromosome 5 (07). Genes associated with familial Meniere disease include COCH, FAM136A, DTNA, PRKCB, SEMA3D, and DPT (123).

In a study of the genetic etiology of Meniere disease using next-generation sequencing in three families, seven rare variants were identified to cosegregate with Meniere disease: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III (201): dysfunction of CYP2B6 and SLC6A may predispose to Meniere disease via the oxidative stress pathway, where dysfunction of ASPM and KNTC1 may produce dysregulation of mitotic spindle formation.

Immunologic contributions have also been proposed based on higher rates of autoimmune disorders (eg, rheumatoid arthritis, systemic lupus erythematosis, ankylosing spondylitis, atopic dermatitis, vitiligo) in cases than controls (49; 67; 80). At least two inflammatory mechanisms have been involved in Meniere disease: (1) a proinflammatory immune response mediated by interleukin-1 beta, tumor necrosis factor alpha, and IL-6; and (2) a nuclear factor-kappa B-mediated inflammation in the carriers of the single-nucleotide variant rs4947296 (123).

Membrane rupture theory. In the 1960s and later, Schuknecht proposed the “membrane rupture theory” (188; 189; 190), which continues to be popular and has many adherents (175). According to this theory, episodes of vertigo in Meniere syndrome result from breaks in the pathologically dilated membrane that separates the potassium-poor perilymph from the potassium-rich endolymph. The resultant mixture of fluids bathes the vestibular receptors, causing acute depolarization and transient increased function, followed by depolarization blockade and transient loss of function. Symptoms gradually improve as the membrane is repaired or stabilized and sodium and potassium concentrations return to normal.

Problems have been noted with the “membrane rupture theory”: (1) careful pathologic studies have found no evidence of membrane rupture in a significant proportion of patients (155); (2) the initial symptoms and progression of symptoms do not correlate well with pathologically identified ruptures (155); (3) electronystagmographic monitoring has demonstrated that the initial nystagmus during an attack of Meniere syndrome is a paralytic nystagmus beating away from the affected ear, followed by an “irritative-like” secondary nystagmus beating toward the affected ear (136; 135; 32; 160), whereas the initial nystagmus according to the “membrane rupture theory” should be an irritative nystagmus beating toward the affected ear with later development of a paralytic nystagmus as the lesion heals (55). However, the problem is that the irritative nystagmus is brief and typically missed, and an additional phenomenon is not considered, ie, recovery nystagmus.

Irritative nystagmus. Although other labyrinthine disorders typically produce a "paralytic" nystagmus beating toward the "good" ear, in Meniere disease there can be an excitatory phase with so-called "irritative" nystagmus beating toward the "bad" ear, followed by an inhibitory phase beating toward the "good" ear (14; 26). Meniere disease may, thus, present with nystagmus that reverses direction over a period of minutes, reflecting initial irritative nystagmus giving way to paralytic nystagmus.

Bery and Chang presented a case report with video documentation to document the serial changes in nystagmus characteristics in a patient with Meniere disease during and after an acute attack (26). A 65-year-old woman with right-sided Meniere disease had frequent vertigo attacks associated with fluctuating right-sided tinnitus, hearing loss, and vomiting for a period of 6 months. The attacks were spontaneous, occurred every 1 to 2 days, and lasted around 2 hours. She experienced one of these attacks during eye movement recording. She initially demonstrated right-beating nystagmus (that is, beating toward the affected ear), but after 2 minutes the nystagmus gradually reversed and became left-beating (that is, beating toward the good ear). During the reversal, she had transient downbeat nystagmus. The left-beating nystagmus persisted for 2 hours. The case, including the excellent video documentation and supplementary materials, provides an excellent example of the changing character of nystagmus that can be seen in Meniere disease.

The very transient nature of the "irritative" nystagmus during the excitatory phase is one reason many clinicians doubted that an irritative component exists as part of Meniere disease.

Recovery nystagmus. So-called "recovery" nystagmus may also occur after a period of several days, again beating toward the "bad" ear as in the initial "irritative" nystagmus (136; 135). Recovery nystagmus occurs after a unilateral peripheral vestibular lesion, when nystagmus transiently reverses direction as some function is restored in the damaged labyrinth (136; 135). This reflects the effects of a restoration or partial restoration of peripheral vestibular inputs after compensatory central rebalancing of the vestibular nuclei has already taken place.

Alternative theories. A number of alternative theories have been proposed, including Tonndorf’s concept that attacks are precipitated by mechanical membranous distortions resulting from sudden increases in endolymphatic pressure (210). In patients with endolymphatic hydrops, pressure fluctuations in the dilated endolymphatic system stress the nerve-rich structures of the inner ear, causing Meniere syndrome. The observed diphasic pattern of nystagmus is explained by (1) an initial disruption of ipsilateral vestibular function causing a paralytic nystagmus beating away from the affected side, (2) subsequent central adaptation dampening or resolving the initial paralytic nystagmus, (3) restoration of vestibular function with decline in endolymphatic pressure and resolution of mechanical membrane distortion, and (4) development of secondary “recovery nystagmus” beating toward the affected side as a result of the improved ipsilateral vestibular dysfunction after central compensatory mechanisms had partially or fully rebalanced the neural discharges from both sides (136; 135; 32; 160).

Chamber configuration and progression of endolymphatic hydrops. Chamber configuration may be a factor controlling the progression of endolymphatic hydrops in Meniere disease (163). Considerable disparities in pressure-induced membrane stress exist among the vestibular chambers due to variations in membrane shape, size, and thickness (163). The thick and highly curved membranes in the semicircular ducts produce low stress levels, whereas the thin and relatively flat membranes in the saccule produce high stress levels (163).

Familial Meniere disease. Familial Meniere disease has been reported in 6% to 9% of sporadic cases, and mutations in various genes (eg, FAM136A, DTNA, PRKCB, SEMA3D, and DPT) have been implicated in single families, suggesting genetic heterogeneity (179). One heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in two unrelated families (179).

Epidemiology

Meniere syndrome and Meniere disease are common disorders that are estimated to affect more than 2 million people in the United States. According to some studies, males and females are affected about equally (151), whereas other studies reported that females are two or three times more likely than males to develop Meniere disease (34; 03; 104). Age of onset varies widely from 7 to 75 years of age, with onset typically from 30 to 60 years of age (151; 34; 219). Meniere disease is reported to have a prevalence of 200 to 500 per 100,000 (78). Although the reported prevalence of Meniere syndrome varies widely in different studies, the prevalence of Meniere syndrome generally increases with increasing age (03).

In South Korea, annual incidence rates increased rapidly from 2013 to 2017 and showed a seasonal pattern with higher incidence rates in summer and autumn than in winter and spring (104).

Putative underlying etiologies and attack triggers have been mostly identified anecdotally, or presumptively determined in case series, but a few analytic epidemiological studies have been performed. Emotional stress increases the probability of an attack during the next hour, and possibly during the next 3 hours (202).

The frequency of migraine in Meniere disease is higher than in normal subjects (184).

A systematic review and metaanalysis of observational case-control studies using molecular-diagnostics assessed the role of viral infections in the etiology of Meniere disease: 14 studies involving 611 cases with Meniere disease and 373 controls were included (46). Most of the included data concerned the human cytomegalovirus, and meta-analysis of eligible studies showed that evidence of cytomegalovirus infection was associated with an approximately 3-fold increased risk of Meniere disease, although the timing of the infections relative to Meniere disease onset was indeterminate. No association was found for herpes simplex virus 1 or 2 (HSV-1, HSV-2), varicella zoster virus, or Epstein-Barr virus.

In a retrospective population-based case-control cohort study using a data from the Korean National Health Insurance Service database, subjects with Meniere disease were compared with a matched cohort without Meniere disease who were enrolled randomly and matched for sex, age, year of diagnosis, income level, and residential area (103): no significant differences were observed between the groups in the incidence of autoimmune diseases, cerebrovascular disease, or cardiovascular disease.

Prevention

No information is available on prevention of Meniere disease.

Differential diagnosis

Confusing conditions

The diagnosis of Meniere disease depends on careful application of the clinical diagnostic criteria (05). Meniere disease should not be confused with recurrent vestibulopathy without auditory symptoms, vestibular neuritis (typically with a single episode of vertigo lasting days followed by recovery, even with persistent hearing loss and tinnitus), benign paroxysmal positioning (or positional) vertigo (with brief episodes of positioning-induced vertigo lasting less than 1 minute without associated auditory symptoms), or stuttering progression of sensorineural hearing loss (with or without tinnitus) in the absence of vestibular symptoms.

Meniere disease can be confused with vestibular migraine (54; 175; 121; 143), and current diagnostic criteria may not differentiate the two adequately in all patients (175; 121). Episodic vertigo lasting hours and associated headache may indeed occur with both conditions. Many cases of so-called vestibular Meniere disease probably have migraine-associated vertigo instead. A reduced vestibular response with caloric testing is supportive of Meniere disease rather than migraine-associated vertigo (54). Some analytic epidemiologic studies have suggested an association between migraine and Meniere disease (175), but it is still unclear whether migraine can cause inner ear damage that progresses to development of endolymphatic hydrops, or whether migraine can in some cases mimic Meniere syndrome. More recent studies have not found an elevated incidence of migraine headache in patients with Meniere syndrome compared to the general population (71).

Associated or underlying disorders

Meniere syndrome may occur with a variety of conditions that interfere with normal production or resorption of endolymph and might result in endolymphatic hydrops, including head trauma, ear surgery, infections (eg, mumps, syphilis), endocrine abnormalities (eg, thyroid disease), autoimmune-mediated conditions, and possibly impaired venous drainage resulting from internal jugular vein stenosis or occlusion (75; 156; 195; 53; 182; 30; 59). Otosyphilis may have clinical features that include Meniere syndrome and interstitial keratitis, and pathologic findings of endolymphatic hydrops and vasculitis. Classic Cogan syndrome includes Meniere syndrome and interstitial keratitis but without serologic evidence of syphilis, whereas variant Cogan syndrome includes Meniere syndrome and uveitis (or other ocular inflammation) without serologic evidence of syphilis.

Despite repeated suggestions in the medical literature that thyroid dysfunction predisposes to Meniere disease, there is no definitive evidence for this (95). However, a case-control study using health insurance records found significant associations of goiter, hypothyroidism, and hyperthyroidism with Meniere disease (105).

Diagnostic workup

Diagnostic evaluation of patients with Meniere syndrome should include audiograms and various other tests to exclude various potential causes. Laboratory tests advocated for this purpose include urinalysis and various blood tests, including a complete blood count, electrolytes, serum glucose and hemoglobin A1c, thyroid stimulating hormone, erythrocyte sedimentation rate, antinuclear antibody, serologic tests for syphilis, and Lyme disease antibodies (186).

Audiometry. Audiometry is essential for diagnosis, staging, and monitoring. Audiometric changes do not directly correspond with the vestibular ones, so for therapy planning and diagnosis, both categories of tests are necessary (130).

This should include an audiogram with pure-tone and speech discrimination tests and acoustic reflex decay. Low-frequency or mixed low- and high-frequency hearing loss may be observed, but typically the lower frequencies are most severely affected giving an upward-sloping configuration (22). Patients with unilateral disease, in particular, demonstrate a characteristic low-frequency hearing loss, even in advanced stages of the disease (22).

Later in the disease, particularly with bilateral disease, a flat loss (ie, affecting all frequencies) or uncommonly a dome pattern (loss in both high and low frequencies, but minimal loss between 500 Hz and 2000 Hz) (151; 22).

Recruitment can be demonstrated by deafness for sounds with weak or medium intensity, but normal hearing or possibly hyperacusis for sounds with greater intensity. Serial audiograms may document fluctuating hearing loss, as well as progressive hearing loss over periods of years (22). Immittance testing demonstrates a normal tympanogram, confirming normal external auditory canal and middle ear function.

Low-frequency air-bone gaps may occur in Meniere disease, a phenomena that had been puzzling because air-bone gaps are commonly found in patients with conductive or mixed hearing loss due to outer- and/or middle-ear diseases. Analysis of delayed gadolinium-enhanced MRI suggests that direct contact between the distended saccule and the inner surface of the stapes footplate is the likely underlying pathophysiological mechanism (152).

Caloric tests and video- or electro-nystagmography. Caloric tests and either video nystagmography or electronystagmography are recommended (81; 29), particularly before and after surgical treatment or aminoglycoside therapy (05). Horizontal vestibulo-ocular reflex evaluation with caloric testing (a low-frequency test) is more often abnormal than video-head impulse testing (a high-frequency test) in patients with Meniere disease, but both tests can be used to provide complementary information on peripheral vestibular function (29; 142).

Caloric testing and electronystagmography/video nystagmography should be performed on an empty stomach after discontinuing vestibular sedatives for at least 2 weeks. Canal paresis in Meniere syndrome is thought to result from ampullary distortion and resultant disruption of the cupulary attachment of the horizontal semicircular duct (178). Unilateral canal paresis supports symptomatic dysfunction of the paretic ear. Asymmetric caloric function in the presence of normal horizontal head impulse tests is most commonly associated with Meniere disease, compared with other neuro-otological conditions (88; 150); this dissociation may serve as a useful diagnostic marker (88). Like audiometric test results, caloric response reduction may also fluctuate in patients with Meniere syndrome (04; 134). The caloric test can detect abnormalities of vestibular function better than video head impulse tests in all stages of Meniere disease (118).

Caloric responses fluctuate during and between the attacks of Meniere disease (116). During the irritative and recovery phase, less than half of patients show a caloric asymmetry of more than 25%, whereas patients usually show a caloric asymmetry of more than 25% during the paretic phase, with a decreased response almost always in the affected ear. Between attacks, caloric asymmetry is found in less than half of patients, with a decreased response almost always in the affected ear when observed.

A histopathological study using temporal bone specimens and their corresponding clinical testing data found otolith membrane herniation into the horizontal semicircular canal in 69% of Meniere disease ears, with 90% of these ears demonstrating a diminished caloric response, whereas no ears with a normal response had this herniation (196). In addition there was no evidence of semicircular canals duct dilation/hydrops. The authors concluded that otolith membrane herniation, not semicircular canal duct dilation, is associated with decreased caloric responses in Meniere disease.

Spontaneous or positional nystagmus is detected on electronystagmography/video nystagmography in about 20% of cases (with some studies reporting values as high as 50%) (134). Although spontaneous nystagmus is supportive of active Meniere syndrome, it does not reliably indicate the side of the lesion (136; 135; 32; 160). Electronystagmographic or video nystagmographic monitoring may be helpful in verifying the affected side, by identification of recovery nystagmus (136; 135; 32; 160). Such verification is particularly important when planning surgical procedures for treatment. Ideally, monitoring should include direct eye observation or video nystagmography because pure rotatory nystagmus can occur and will not be detected by electronystagmography (160).

Electrophysiological tests. Electrophysiological tests proposed for initial diagnosis or follow-up of patients with Meniere disease include: (1) electrocochleography; (2) otoacoustic emissions; and (3) vestibular evoked myogenic potentials (37). Available data are still limited, and the recommended procedures have not reached an international consensus (37). None of the electrophysiological tests can be considered to be pathognomonic for the diagnosis of Meniere disease, and, thus, they need to be considered as having a supportive role in clinical diagnosis (37).

Electrocochleography and otoacoustic emissions may be helpful, though supportive data are limited (131), but the data are not incorporated into current diagnostic guidelines because these tests are not universally available or standardized (05). The presence of endolymphatic hydrops is generally indicated by either an elevated summating/action potential ratio with click stimulation or a depressed summating potential amplitude with tone burst stimulation (232). Suggested thresholds are a summating/action potential ratio with click stimulation greater than 0.35 using transtympanic electrocochleography, a summating/action potential ratio greater than 0.42 using extratympanic electrocochleography, or a summating potential amplitude of less than 2 microvolts for at least one frequency within the range of 0.5 to 0.8 kHz using transtympanic electrocochleography with tone burst stimulation set at a repetition rate of 30 to 40 stimuli per second (232). Electrocochleography may be particularly helpful in excluding contralateral disease before proceeding with destructive surgical procedures; it appears to be more sensitive for detecting contralateral disease than relying on the presence of auditory dysfunction, tinnitus, and aural fullness (41).

Cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP, respectively) are being studied but have yet to prove to be important in the diagnosis of Meniere disease (226; 236; 217; 58; 111; 129). Preliminary results suggest that cVEMP thresholds can help distinguish Meniere disease from vestibular migraine, and serial cVEMP testing may be a sensitive marker of disease progression in Meniere disease (217). However, according to a Practice Guideline from the American Academy of Neurology, “Evidence is insufficient to determine […] whether vVEMP or oVEMP is useful in diagnosing […] Meniere disease” (58).

Imaging. Brain imaging is generally not necessary unless symptoms and signs support a central nervous system basis for episodic vertigo, but the clinical utility of MRI for Meniere disease is evolving (15; 78; 192; 12; 76; 204; 25; 122; 126).

Endolymphatic hydrops can be demonstrated in vivo by MRI with intratympanic gadolinium contrast administration, and affected ears show variable degrees of impaired perilymphatic enhancement (60; 61; 230; 211). Prior contrast-enhanced MRI techniques used a 3-dimensional fluid-attenuated inversion recovery (FLAIR) sequence after intratympanic gadolinium administration (sometimes after a 4-hour delay) (25). Contrast-enhanced MRI after intratympanic gadolinium can reliably and accurately detect and grade Meniere disease (25). However, the need for intratympanic contrast administration has been obviated by more recent studies (25).

Endolymphatic hydrops can now be detected and graded using 3T MR images of the inner ear acquired by a 3D inversion-recovery sequence 2 to 4 hours after intravenous contrast administration (15; 25; 98; 117; 153; 161; 216; 16; 85) or 24 hours after intravenous contrast administration with a 3D real inversion recovery (3D-real IR) sequence (48). In one study of 54 patients, endolymphatic hydrops was demonstrated in 90% on the clinically affected side and in 22% on the clinically silent side with high levels of interobserver agreement (15). Symptomatic endolymphatic hydrops is reliably on the affected side, and asymptomatic endolymphatic hydrops is detected on the unaffected contralateral side in as many as one fifth of cases (117). In addition, analysis of the vestibular aqueduct by MRI detects symmetric abnormalities in both ears of patients with unilateral Meniere disease (11). Resolution of endolymphatic hydrops on delayed intravenous contrast-enhanced 3D-FLAIR MRI has been demonstrated following acetazolamide therapy (192). The combination of perilymphatic enhancement and endolymphatic hydrops in patients suspected of having Meniere disease increases the positive predictive value in the diagnosis of definite Meniere disease (216). Evaluation of the vestibular endolymphatic space contacting the oval window has high specificity and positive predictive value in differentiating Meniere disease ears from other ears (42); obliteration of the inferior portion of the vestibule and the contact with the stapes footplate by the vestibular endolymphatic space are reliable markers for the diagnosis of Meniere disease (42).

In the absence of access to MRI with 3D reconstruction of the endolymphatic space, measurements of the saccule on routine nonenhanced 3D-T2 MRI can show hydrops and help diagnose Meniere disease (200; 122).

Most imaging studies have been done on a 3-T MRI scanner, and it had been thought that endolymphatic hydrops could only be demonstrated on a 3-T magnet. However, multiple studies have now demonstrated that endolymphatic hydrops can be confidently demonstrated with the current standard 4-h delayed intravenous gadolinium-enhanced 3D-FLAIR sequence on a 1.5-T magnet (86; 102).

MRI may be helpful in select cases in the differentiation of Meniere disease and vestibular migraine (204). In addition, MRI may reveal brain lesions, semicircular canal abnormalities, and perilymphatic fistulae in patients with clinical Meniere disease (12).

However, MRI does not yet seem helpful for diagnosing cases of Meniere disease with early symptoms and the reproducibility of the hydrops protocols with various MRI scan manufacturers is debatable, limiting widespread adoption of these techniques into clinical practice (122).

Endolymphatic hydrops is detectable in a high proportion of Meniere disease cases (99%), but it is not specific for Meniere disease. For example, it is present in about half of cases with vestibular schwannoma (48%) and is also present in "healthy" temporal bones (13%) (213). Therefore, endolymphatic hydrops is not a pathognomonic phenomenon, and detecting this on MRI does not directly indicate a diagnosis of Meniere disease.

Bone mineral density assessment. Dual energy x-ray absorptiometry (DXA) of the hip and spine (not the heel) is recommended to assess bone mineral density in patients with Meniere disease. Meniere disease is associated with low bone mineral density (osteopenia/osteoporosis) as measured by dual energy x-ray absorptiometry at the femoral neck (198), and the vertigo and imbalance associated with the disease present a significantly increased risk of falls and falls with injury. To minimize potential fall-related fractures, dual energy x-ray absorptiometry and monitoring of 25-hydroxy vitamin D levels are recommended.

Other tests. Some authors advocate provocative glycerol or furosemide tests (138); however, the outcome of these tests is highly dependent on patient and provider expectations and suggestion (208).

Management

The aims of management of Meniere disease are to (1) reduce the number and severity of acute vertiginous attacks and their associated symptoms (eg, hearing loss and tinnitus); (2) alleviate chronic symptoms (eg, hearing loss, tinnitus, disequilibrium); and (3) prevent progression of the disease and its associated symptoms (eg, hearing loss, tinnitus, disequilibrium) (38). The treatment plan should be individualized, based on the clinical features, including hearing stage, duration of disease, vertigo attack profile, and comorbidities (57). Many patients with Meniere disease can be managed using nonablative therapy (eg, medical management, intratympanic steroids, and endolymphatic shunt surgery) prior to ablative techniques (eg, intratympanic gentamicin and vestibular neurectomy) (36).

A major problem in the management of Meniere disease is the overall poor quality of supporting studies for various treatments (214; 112; 221; 222; 223; 224; 225). Even many systematic reviews and metaanalyses in this field show a lack of rigor. Few existing clinical guidelines meet the standards of quality established by the AGREE II appraisal instrument (17).

Medical management. Current medical management can control vertiginous attacks in approximately 75% to 80% of patients but does not appear to alter the long-term progression of hearing loss (02). Initial management of Meniere syndrome involves diagnosis and treatment of the primary disease (eg, thyroid disease). Chronic management of Meniere disease should include therapeutic counseling, the use of hearing aids and masking devices, lifestyle modification, salt restriction, and diuretic therapy (57). A diary of vertigo attacks with symptoms during the episodes should be encouraged to improve phenotyping (57).

The use of hearing aids can help with hearing impairment and, in many cases, benefits the subjective tinnitus that accompanies the disorder. Masking devices are also helpful for the management of subjective tinnitus.

The major focus of lifestyle modification is avoiding potential disease triggers, including stress, fatigue, high-salt foods (eg, pizza, processed meats, canned soups, smoked fish, potato chips, peanuts, nuts, beer, etc.), and other potential trigger substances (eg, caffeine, nicotine, alcohol, monosodium glutamate, carbohydrate-rich foods, and foods high in cholesterol and triglycerides).

In patients with Meniere syndrome or Meniere disease, vestibular sedatives (eg, meclizine, dimenhydrinate, prochlorperazine, promethazine, prochlorperazine, benzodiazepines), particularly those with anti-emetic or anxiolytic properties, and intravenous fluids may be helpful in decreasing symptoms acutely during an attack. Although some authors advocate intratympanic or systemic dexamethasone treatment, no definite treatment effect has been demonstrated (92).

A low-sodium diet and diuretics are considered the mainstays of chronic treatment for Meniere disease (227; 72; 231), and sodium restriction has been a foundation of disease management since the 1930s (38; 231; 197). However, these therapies are not based on randomized controlled trials, and evidence of their validity remains inconclusive (38; 47; 197; 221). Nevertheless, clinical experience and expert consensus suggest that a 1.0- to 1.5-gram low-sodium diet and diuretics (eg, hydrochlorothiazide and triamterene) may help to decrease the fluid pressure or volume within the inner ear and decrease the frequency of attacks, although these measures do not help once an acute attack has developed. Vestibular complaints decrease with diuretic therapy, but diuretics have no significant effect on hearing or tinnitus (212; 38). Acetazolamide was recommended for many years, but most authors have become discouraged with its use, and it has not been shown to prevent long-term deterioration in hearing (31; 44; 176; 40). A metaanalysis of the utility of diuretics for Meniere disease identified three systematic reviews that collectively included 19 studies, of which four were randomized trials (180). The authors concluded that it is not clear whether diuretics lead to a symptomatic improvement of vertigo or an objective decrease in hearing loss in patients with Meniere disease.

A longitudinal treatment study using a historical control found that a daily intake of 35 ml of water per kilogram of body weight dramatically relieved vertigo and significantly improved hearing over a 2-year period, whereas in a historical control group patients had some improvement in vertigo but generally had progressive hearing loss over a similar time period (146). The authors concluded that the “deliberate modulation of the intake of water may be the simplest and most cost-effective medical treatment for patients with Meniere disease” (146).

The use of corticosteroids is controversial and largely empiric (38). It may help improve vertigo, but it does not significantly improve hearing or tinnitus.

Preliminary work has suggested a potential role for betahistine in improving hearing function in Meniere disease (140; 193; 231; 120), but this will have to be substantiated with well-designed randomized controlled trials, which are presently lacking (50; 214; 215). An umbrella systematic review concluded that betahistine probably does not reduce Meniere disease symptoms when compared with placebo (215).

Cochrane reviews concluded that the evidence for lifestyle or dietary interventions and for systemic pharmacological interventions for Meniere disease is very uncertain (221; 224); there are few randomized controlled trials that compare these interventions to placebo or no treatment, and the evidence that is currently available from these studies is of low or very low certainty.

Intratympanic steroids. The evidence comparing intratympanic corticosteroids to placebo or no treatment is of low or very low certainty (222). Limited evidence, restricted to one trial, supports the effectiveness of intratympanic steroids for improving vertigo in patients with Meniere disease (168). In an open-label, uncontrolled trial, there was a strong correlation between hearing improvement and dexamethasone treatment (141). Despite the limited evidence, a systematic review suggested that, to achieve both hearing preservation and vertigo control, intratympanic steroids plus high-dose betahistine may be superior to intratympanic gentamicin because of the risk of hearing loss with intratympanic gentamicin despite good control of vertigo (01). The utility of this therapy will have to be substantiated with well-designed randomized controlled trials (215).

A Cochrane review found that the evidence for intratympanic corticosteroids in the treatment of Meniere disease is uncertain because of the relatively few published randomized trials and the concerns about publication bias in this area, given the identification of two large randomized trials that remain unpublished (222).

Ablative aminoglycoside therapies. Ablative therapy is a second-line management approach for failures of medical therapy. Among the various forms of ablative therapy, the most common are intratympanic aminoglycoside administration and vestibular neurectomy (02). Limited evidence from a single trial supports the effectiveness of intratympanic steroids for improving vertigo in patients with Meniere disease (168). The utility of this therapy will have to be substantiated with well-designed randomized controlled trials (215).

Oral aminoglycosides were used historically to treat Meniere syndrome and Meniere disease, but the resulting bilateral vestibular hypofunction was (and remains) extremely debilitating. Schuknecht described middle-ear perfusion with aminoglycosides for treatment of Meniere disease in the late 1950s (187), but transtympanic administration of aminoglycosides did not become popular as a treatment for Meniere disease until the late 1990s, providing an alternative to the disabling bilateral vestibular effects of systemic administration of aminoglycosides. Low-dose intratympanic application of gentamicin can provide a graduated destruction of sensory and epithelial cells in the cochlea in association with the generation of reactive oxygen species and reactive nitrogen species, including oxidation product of nitric oxide in the lateral wall and the organ of Corti (90; 147). Aminoglycosides are now generally applied unilaterally within the middle ear cavity, where they are absorbed into the inner ear through the round window membrane. Various methods of medication delivery to the middle ear have been employed, including injection through tympanostomy tubes or catheters through the tympanic membrane, needle injections through the tympanic membrane, and less commonly with a Eustachian tube catheter (28). No particular combination of method of administration, single versus multiple dosing, or concentration of aminoglycoside injected has yet been established as the most effective (28).

Transtympanic administration of aminoglycosides generally carries relatively low risks, has minimal systemic effects, and can be performed in patients whose comorbidities would preclude surgery (181; 39). Gentamicin is the aminoglycoside most frequently used for this purpose in the United States. Intratympanic gentamicin appears to be an effective treatment for vertigo in patients with Meniere disease but carries a risk of hearing loss (169). Studies indicate approximately 90% to 95% efficacy (complete elimination of vertigo in approximately 80% to 85% and more than 50% reduction in frequency in 10% to 15%), with clinically significant (ie, 10 dB or greater decrement in pure-tone average) worsening of hearing in the treated ear in 10% to 30% of patients (43; 10; 170; 28; 93; 101; 20; 52; 39). Extreme worsening (ie, 30 dB or greater decrement in pure-tone average) of hearing in the treated ear is rare (10; 39), and a significant fraction of treated ears (as much as a quarter in some studies) have a significant improvement in hearing (10). However, many of the available studies were poorly designed and further controlled studies are needed (39).

Patients selected for transtympanic administration of aminoglycosides should be carefully selected and should generally undergo titrated therapy with low-dose gentamicin (39). Transtympanic gentamicin should be used cautiously: given that approximately 20% of patients ultimately develop bilateral disease, there is a significant risk of developing bilateral vestibular hypofunction, either from the disease itself or from the treatment, with incapacitating and irreversible disequilibrium and oscillopsia (38). Titration methods or multiple injections on a daily basis may be used in patients with profound or nonserviceable hearing (234). Treatment protocols with an injection interval of a week or more or those with injections on a monthly basis as "needed" provide the same level of vertigo control with better preservation of hearing and should be used in patients with serviceable hearing (234). Vestibular-evoked myogenic potentials and the head thrust test are more reliable than other vestibular tests for the follow-up of patients undergoing gentamicin treatment (234).

A systematic review showed some benefit of intratympanic gentamicin over intratympanic corticosteroids for subjective outcomes, but no difference regarding objective outcomes or complication rate (233).

A Cochrane review concluded that the evidence for the use of intratympanic gentamicin in the treatment of Meniere disease is very uncertain because there are few published randomized trials, and all these enrolled a very small number of participants (223); because the studies assessed different outcomes, using different methods, and reported at different time points, pooling the results to obtain more reliable estimates of the efficacy of this treatment was not possible.

Surgical treatment. Surgical treatment of Meniere syndrome and Meniere disease is reserved for medical treatment failures but remains controversial (72; 02). The goal of surgery is to control episodic vertigo while maintaining preoperative hearing levels, though practically, surgical treatment typically has a severe impact on hearing function (127). Destructive procedures are generally reserved for severe cases, with associated significant disability, but are contraindicated with bilateral disease (which variously is reported to occur in from 7% to 50% of cases). Provided the contralateral vestibular apparatus functions adequately, the brain eventually compensates for the loss of a single labyrinth.

A Cochrane review was unable to draw clear conclusions about the efficacy of surgical interventions for Meniere disease because limited evidence was identified, and all of it was of low- or very low-certainty (112).

Endolymphatic sac decompression with or without shunt is thought to decrease endolymph pressure by removing the petrous bone overlying the sac; a drainage tube from the sac to either the mastoid space or subarachnoid space can be inserted to further reduce endolymph pressure. Success of endolymphatic sac decompression in controlling vertigo and stabilizing hearing has been reported at between 60% to 94% and 80% to 88% regardless of whether a shunt is also performed (227; 23). Additionally, endolymphatic sac decompression is associated with significantly improved perception of health in patients (56), and it has been reported that this may decrease the incidence of developing Meniere disease in contralateral ears with silent endolymphatic hydrops within the first 5 postoperative years (106). The procedure does not directly destroy or damage hearing or balance organs or pathways, and it can usually be done as an outpatient procedure (227). However, even retrospective comparative studies have suggested that endolymphatic sac decompression does not alter the long-term natural course of vertigo (199), and a critical Danish randomized, double-blind study that included a sham surgical procedure found that endolymphatic sac decompression was no more effective than sham surgery (207). Furthermore, the procedure is associated with worsened hearing in about one third of cases, and about one quarter subsequently have another secondary treatment after endolymphatic sac decompression (94). A systematic review of endolymphatic sac surgery for Meniere disease concluded that "there is still a lack of high-quality research, suggesting that endolymphatic sac surgery provides a significant amount of symptomatic relief for Meniere patients" (51); a subsequent systematic review came to the same conclusion (215). Nevertheless, the procedure remains popular among otolaryngologists (203), and some have concluded, based on longitudinal follow-up of a case series, that endolymphatic shunt surgery provides successful vertigo control at least as well as intratympanic gentamicin injections, with a lower incidence of audiovestibular complications (68).

For patients with useful hearing in the affected ear (ie, better than 80 dB pure-tone average and 20% speech discrimination) and who have failed other treatments, vestibular neurectomy through a retrosigmoid or middle fossa approach has a high rate of vertigo control (over 95%) with a high rate of hearing preservation (approximately 90% to 95%) (159; 181). Adverse outcomes are uncommon, but may include facial nerve damage, hearing loss, exacerbation of tinnitus or dizziness, CSF leakage, meningitis, and hemorrhage. A minimally invasive vestibular neurotomy has been advocated as a safe and effective surgical treatment for these individuals, with reported benefits including improved dizziness and anxiety (137).

Labyrinthectomy also has a high rate of vertigo control (over 95%) and is useful for patients with unilateral disease whose hearing on the affected side has already been destroyed by the disease process (185). This procedure is less invasive than vestibular nerve section and is accomplished using either a transcanal approach (cochleovestibular neurectomy) through the external ear canal or a transmastoid approach with extension of a mastoidectomy by drilling through the semicircular canals. Compared to vestibular nerve section, risk of CSF leakage or meningitis is lower because craniotomy is not required. Patients affected by end stage Meniere disease with vertigo and severe hearing loss can successfully undergo labyrinthectomy and cochlear implantation, although in elderly patients there is a significant risk of persistent instability (205).

Some authorities advocate conservative management of otolithic crises, particularly given that many cases have a flurry of episodes followed by remission (Janzen and Russel 1988; 13). However, the events can be associated with significant injuries, and for some patients, the attacks are so dangerous or intractable that surgery is indicated (13). Otolithic crises have been treated successfully with either surgical ablation (labyrinthectomy) or trans-tympanic gentamicin therapy in the absence of serviceable hearing, or middle fossa vestibular nerve section to preserve serviceable hearing (27; 149; 97; 218). Even older patients can be successfully treated with ablative surgery with excellent compensation and no vertigo or falls up to 10 years after surgery (97). Vestibular nerve section is usually recommended only for patients who have had symptoms for at least 5 years, unless the patient is severely incapacitated or is in danger of severe bodily harm because of otolithic crises (27). Intratympanic gentamicin treatment appears to be a long-lasting and effective treatment for vestibular drop attacks in patients with Meniere disease (218).

Because patients with Meniere disease have symptoms that can fluctuate with ambient air pressure, in the late 1980s Densert and colleagues evaluated the utility of positive-pressure pulses applied to the middle ear and demonstrated that such pulses improved electrocochleographic parameters in these patients (38). Since then, portable low-amplitude, alternating-pressure generators (eg, the Meniett device from Medtronic Xomed, Inc.) have been developed to be worn in the external auditory canal and have been shown to be efficacious and safe in patients with Meniere disease (66; 38; 119). The device requires the placement of a long-term tympanostomy tube. Most patients note gradual improvement in vertigo when using the Meniett device, and consequently this device had been considered a useful option for patients with Meniere disease who had failed medical treatment (38). However, hearing does not improve with use of the device, and the device is expensive and rarely covered by insurers. Moreover, a randomized, double-blind, placebo-controlled, multicenter trial found no difference between the portable Meniett low-pressure pulse generator (Medtronic Xomed, Jacksonville, FL) and the placebo device groups in the treatment of Meniere disease (183).

Positive pressure therapy. Positive pressure therapy employs small pressure pulses for a few minutes several times a day, with the pulses generated by a pump through tubing placed in the ear canal. There is no clear pathophysiologic justification for the therapy. A Cochrane review concluded that the evidence for positive pressure therapy for Meniere disease is very uncertain (225): there are few randomized controlled trials that compare this intervention to placebo or no treatment, and the evidence that is currently available from these studies is of low or very low certainty. A separate umbrella systematic review concluded that positive pressure therapy probably does not reduce Meniere disease symptoms when compared with placebo (215).

Cochlear implantation. Cochlear implantation in advanced Meniere disease is a valid option that can partially restore hearing, regardless of the disease duration, uni- or bilaterality, age at implantation, previous therapeutic procedures, and stage of activity of Meniere disease (24; 107; 133; 220; 100). It is helpful in improving hearing ability and suppressing tinnitus (220). Although cochlear implantation and labyrinthectomy in adult patients with Meniere disease can improve speech recognition and sound source localization for some patients, observed performance may be poorer than with traditional cochlear implantation candidates (191; 35).

Vestibular rehabilitation. Vestibular rehabilitation is generally recommended after aminoglycoside treatment or surgery, and may be helpful in minimizing disability, particularly in older individuals (144; 38; 120).

Certain tasks requiring balance and having a high risk of injury with falls (eg, climbing ladders) should generally be avoided.