Expert Opinion on Pharmacotherapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

The pharmacological management of vertigo in

Meniere disease

Juan Manuel Espinosa-Sanchez & José A. Lopez-Escamez

To cite this article: Juan Manuel Espinosa-Sanchez & José A. Lopez-Escamez (2020): The
pharmacological management of vertigo in Meniere disease, Expert Opinion on Pharmacotherapy,
DOI: 10.1080/14656566.2020.1775812

To link to this article: https://doi.org/10.1080/14656566.2020.1775812

Published online: 15 Jun 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2020.1775812

REVIEW

The pharmacological management of vertigo in Meniere disease

Juan Manuel Espinosa-Sancheza,b and José A. Lopez-Escameza,b,c
a
Department of Otolaryngology, Instituto de Investigación Biosanitaria Ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Universidad de
Granada, Granada, Spain; bOtology & Neurotology Group CTS 495, Department of Genomic Medicine, GENYO. Centre for Genomics and
Oncological Research: Pfizer/University of Granada/Andalusian Regional, Government PTS Granada, Granada, Spain; cDepartment of Surgery,
Division of Otolaryngology, Universidad de Granada, Granada, Spain

ABSTRACT ARTICLE HISTORY

Introduction: The term Meniere disease (MD) gathers a set of rare diseases involving the inner ear Received 15 February 2020
characterized by episodic vertigo associated with fluctuating auditory symptoms. Five clinical sub­ Accepted 26 May 2020
groups of patients have been defined, including familial MD, autoimmune MD, and MD with migraine. KEYWORDS
The diagnosis is based on clinical criteria as no biomarker is available, but genetic factors have Betahistine; corticosteroids;
a significant contribution in familial and non-familial MD. diuretics; gentamicin;
Areas covered: In this review, the authors summarize the pharmacological treatment for vertigo in MD, Meniere´s disease;
providing evidence from preclinical and clinical studies. However, evidence supporting the efficacy for treatment; genetics; vertigo;
betahistine, diuretics, and intratympanic administration of corticosteroids or gentamicin is limited. hearing loss; tinnitus
Expert opinion: Randomized clinical trials should consider stratification by MD clinical subgroups. The
treatment plan should be personalized according to the clinical subgroup, hearing stage, duration of
the disease, vertigo attack profile, and comorbidities. The treatment should include therapeutic coun­
seling, sodium-free diet, high-water intake, and a diary of vertigo attacks with symptoms during the
episodes to improve phenotyping. Migraine or autoimmune comorbidities will also require pharma­
cotherapy. Genetic testing by exome/genome sequencing should be discussed with the patient for
familial MD and individuals with an early onset for genetic counseling and future gene therapies.

KEYWORDS Betahistine; corticosteroids; diuretics; gentamicin; Meniere´s disease; treatment; genetics; vertigo; hearing loss; tinnitus

1. Introduction Autoimmune disorders, migraine, anxiety, and depression

are comorbidities frequently found in MD. By using hierarch­
Meniere´s syndrome is a set of chronic inner ear disorders
ical cluster analyses, five clinical subgroups of patients with
with a low prevalence characterized by recurrent episodes
MD have been described, which anticipates different mechan­
of spontaneous vertigo, associated with fluctuating sensor­
isms of disease, such as genetic factors [3], autoimmunity [4],
ineural hearing loss, tinnitus, and ear fullness. The vertigo
or autoinflammation [5] (Table 1).
attacks are typically random and the clinical diagnosis may
The accumulation of endolymph in the membranous
take months or even years until the temporal association
labyrinth, leading to an increased pressure in the cochlear
between hearing loss and vertigo is confirmed [1]. The
duct, is termed endolymphatic hydrops, and it is considered
natural course of hearing loss in Meniere disease (MD) is
the pathological substrate of the syndrome, but it can be also
usually progressive and vertigo attacks may improve or not
found in other conditions or even in healthy subjects [6]. In
over time. Because of this, the first goal of the treatment is
any case, the endolymphatic hydrops would be the common
to reduce the duration and frequency of vertigo attacks,
denominator of a series of inflammatory processes in differ­
and secondly to prevent hearing loss and to relieve tinni­
ent parts of the cochlea (lateral wall, endolymphatic sac)
tus [2].
leading to cochlear damage with autoinflammation or auto­
The prevalence ranges from 3.5 to 513 cases per 100 000
immunity responses resulting from multiple causes (allergy,
inhabitants, according to the definition and geographic area
viral infection, genetic variants) that affect the inner ear
in the world, with a light female predominance. This syn­
homeostasis, lead to the accumulation of endolymph and
drome usually begins between 30 and 50 years of age, and
manifest with a common core phenotype (episodic vertigo
the prevalence increases with increasing age. Most patients
with fluctuating auditory symptoms) that defines a clinically
report cochlear symptoms in one ear, but bilateral involve­
heterogeneous syndrome. Classically, when this set of symp­
ment varies between 10% and 40% of cases, according to
toms cannot be attributed to a specifically identified cause,
the duration of the disease. Family history is found in
the syndrome is considered idiopathic, and then it is referred
5–15% of sporadic cases, usually with an autosomal-
to as MD.
dominant pattern of inheritance with incomplete pene­
The diagnosis of MD is made by clinical symptoms, as no
trance and partial syndromes in the families [3].
biomarker is available for clinical practice. The current

CONTACT José A. Lopez-Escamez antonio.lopezescamez@genyo.es Otology & Neurotology Group CTS495, GENYO, Centre for Genomics and Oncological
Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avenida de la Ilustración, 114, 18016, Granada, Spain
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 J. M. ESPINOSA-SANCHEZ AND J. A. LOPEZ-ESCAMEZ

Article highlights
● MD is a set of rare inner ear disorders characterized by recurrent
episodes of spontaneous vertigo, associated with fluctuating auditory
symptoms.
● MD pharmacotherapy should be personalized, according to clinical
subgroup, stage of the disease, years from onset, number and profile
of vertigo attacks, degree of hearing loss, and other comorbid
conditions.
● Vestibular suppressants and antiemetic agents are the preferred
drugs for the treatment of the acute phase, whereas the main goal
of pharmacological treatment is to reduce the frequency, duration,
and severity of vertigo attacks.
● The pharmacological options include betahistine, diuretics, intratym­
panic administration of corticosteroids, or gentamicin in a stepped
approach. Nevertheless, evidence supporting drug therapy is lacking
or limited.
● The heterogeneity of the disease makes it necessary to investigate
the efficacy of these drugs in different clinical subgroups. Long-term
multicenter, randomized, placebo-controlled clinical trials are
required in different clinical subgroups of MD.
This box summarizes key points contained in the article.
diagnostic criteria were established in 2015, based on clinical
symptoms [7]. The impact on health-related quality of life may
be high, since the uncertainty of vertigo attacks and the poor
speech discrimination restrict daily routines [1,2]. Although
some consensus and guidelines have been released, there is
a lack of high-level evidence for efficacy of MD treatment [8–
14]. This absence of evidence is explained by both the relap­
sing nature of the disease and the overall quality of studies.
There are some excellent reviews for the treatment of vertigo
in MD [15–18], including a clinical practice guideline [2], but most
of them consider MD as a single disorder. In fact, MD is very
heterogenous, and comorbid conditions, stage of the disease,
years from onset, and mean number of vertigo spells are factors
to be taken into account in the design of clinical trials. Likewise,
sample size, study design, outcome measures, and duration of
follow-up time are important issues.
The primary aim of this review is to summarize the best
available scientific publications to recommend the pharma­
cological treatment for vertigo in MD. Because of the
fluctuating course of auditory symptoms in the first years
and the limited number of studies, the treatment of hear­
ing loss or tinnitus in MD has not been included in this
review.
2. Treatment of acute crisis
Vestibular suppressants and antiemetic agents are the pre­
ferred drugs for the treatment of the acute phase in
patients with MD [19]. Most medications share antivertigi­
nous and antiemetic effects to a greater or lesser degree.
Diphenhydramine and its derivative dimenhydrinate, mecli­
zine, and cyclizine are H1-receptor antagonists that are use­
ful for treating milder attacks orally. The association
cinnarizine plus dimenhydrinate may be also beneficial
[20]. Antidopaminergic drugs including metoclopramide,
sulpiride, promethazine, and prochlorperazine are com­
monly used for severe nausea and vomiting. Setrons are
serotonin 5-HT3 antagonists, they are mainly used when
severe vomiting is a prominent symptom. A short course
of steroids, commonly oral dexamethasone or methylpred­
nisolone, is used to reduce vomiting and vestibular symp­
toms, especially when hearing loss is prominent [21]. Finally,
benzodiazepines can be also used for acute crisis of MD
because they act as vestibular suppressants enhancing the
inhibitory action of GABA in the vestibular nuclei; never­
theless, long-term administration should be avoided, since
they induce tolerance and drug addiction. They are also
effective as antiemetics and to reduce the anxiety often
associated with the episode of vertigo. The use of diuretics
(mannitol, glycerol, acetazolamide, hydrochlorothiazide) in
acute phase is a common practice in some countries [22].
3. Treatment to reduce the frequency and duration
of vertigo attacks
The main goal of pharmacotherapy in MD is to reduce the
frequency, duration, and severity of vertigo attacks [23].
The second aim is to avoid the progression of the hearing loss
and to reduce impact of tinnitus in daily routines. Unfortunately,
no drug can slow or halt the progression of the hearing loss or
suppress tinnitus at the present time.

Table 1. Clinical subgroups and observed frequency in patients with Meniere disease.
Unilateral Meniere disease
Type1 53% Sporadic MD (if concurrent migraine, autoimmune disease, or familial MD is observed, patients do not belong to this subgroup). Elevated levels of
proinflammatory cytokines are found in 70% of patients.
Type2 8% Delayed MD (hearing loss precedes vertigo attacks by months or years)
Type3 13% Familial MD (at least two patients in the first or second degree with complete MD phenotype). Partial syndromes are frequently observed (episodic
vertigo or isolated sensorineural hearing loss).
Type4 15% Sporadic MD with migraine (temporal relationship not required)
Type5 11% Sporadic MD plus an autoimmune disease
Bilateral Meniere disease
Type1 46% Unilateral hearing loss becomes bilateral
Type2 18% Sporadic, simultaneous hearing loss (usually symmetric)
Type3 13% Familial MD (most families have bilateral hearing loss, but unilateral patients may coexist in the same family)
Type4 12% Sporadic MD with migraine
Type5 11% Sporadic MD with an autoimmune disease

We propose a personalized approach according to the
characteristics of the patient, including comorbidities
(migraine, autoimmune diseases), hearing stage, and duration
of the illness [1,2,23]. Genetic testing by exome/genome
sequencing should be discussed with the patient for familial
MD and individuals with an early onset for genetic counseling
[3]. This approach begins providing information to the patient
about the natural history of the disease, discussing the ther­
apeutic options and their potential adverse effects (Figure 1).
Then, the first step is dietary and lifestyle modifications,
even though the efficacy of these measures has not been
demonstrated in randomized-controlled trials [24,25]. The
most important recommendation is a high-water intake (2 L
per day) and a very low sodium diet (no more than 1,500 mg
per day) [26]. A low-salt diet may facilitate an increase in the
plasma aldosterone concentration that can activate ion trans­
port and absorbing endolymph in the endolymphatic sac. The
elimination of migraine food triggers, including monosodium
glutamate, is advocated especially in MD patients with
migraine.
Avoidance of alcohol and tobacco, and caffeine restriction
is recommended as they could decrease blood supply to the
inner ear [27]. Glucose-intake control has also been proposed
[28,29]. The use of specially processed cereals, that increase
the synthesis of endogenous antisecretory factor, to reduce
the frequency of vertigo spells is still controversial.
3.1. Betahistine
Betahistine is a structural analog of histamine that acts as
a weak partial postsynaptic histamine H1 receptor agonist
and presynaptic H3 receptor antagonist [30]. Histamine
receptors have been identified in the inner ear, and specifi­
cally in the endolymphatic sac [31]. The action of betahistine
depends on several mechanisms. Experimental models have
demonstrated that betahistine improves cochlear microcircu­
lation by vasodilation of the arterioles of the stria vascularis,
and also in the posterior semicircular canal ampulla
[32,33]. This increase in labyrinthine blood flow appears to
be mainly mediated by two metabolites, aminoethylpyridine
and hydroxyethylpyridine, that act on histamine H3
Figure 1. Stepped approach for the treatment of vertigo in MD.
ITC, intratympanic corticoids; ITG, intratympanic steroids
EXPERT OPINION ON PHARMACOTHERAPY 3
heteroreceptors [34]. Thereby, in MD patients betahistine
would reduce endolymphatic pressure by achieving
a reduction in the production of, and an increment in the re-
absorption of, endolymph. But betahistine also acts blocking
the presynaptic H3 autoreceptors on the histaminergic nerve
terminals originating from the tuberomammillary nuclei of
the posterior hypothalamus, thus increasing the synthesis
and release of histamine in the vestibular nuclei [35].
Likewise, betahistine may participate in the mechanisms of
histaminergic modulation of glycine and gamma-
aminobutyric acid (GABA) release in the vestibular nuclei
that may contribute to rebalancing the spontaneous neuro­
nal firing at vestibular nuclei on both sides [36]. Furthermore,
experimental data also suggest a decrease in the sensory
input from the vestibular receptors [37,38]. These actions
on the histaminergic system may promote and facilitate
central vestibular compensation after an acute unilateral
vestibular loss [39]. Finally, experimental data suggest that
the upregulation of the histamine caused by the betahistine
would induce excitatory effects on the neuronal activity of
cortical and subcortical structures. This arousal effect would
facilitate sensorimotor and cognitive activity, necessary for
recovery after vestibular function loss [40].
Adverse effects are rare, mild, and reversible after drug
discontinuation. A cutaneous hypersensitivity reaction, with
mild and self-limiting rash, pruritus, and urticaria, is the most
frequently reported complaint. Nausea, vomiting, epigastric
pain, and headache are occasionally reported, especially with
higher doses [41,42].
3.1.1. Clinical trials with betahistine
The clinical efficacy of betahistine has been evaluated in two
systematic reviews and two meta-analysis and there is con­
flicting evidence. This limited evidence could be explained
not only by methodological bias, but also may be related to
the clinical heterogeneity of MD. A first Cochrane review
concluded that there was not enough evidence to say
whether betahistine has any effect on the frequency or dura­
tion of the episodes of vertigo in MD [8]. Subsequently,
a meta-analysis was performed supporting the therapeutic
benefit of betahistine for both MD and vestibular vertigo
4 J. M. ESPINOSA-SANCHEZ AND J. A. LOPEZ-ESCAMEZ
[43]. Later, a second Cochrane review found that, although
there was significant variability in the results of the studies,
a low-quality evidence suggests that in patients suffering
from vertigo from different causes betahistine reduces vertigo
symptoms [14]. Finally, a meta-analysis concluded that beta­
histine could reduce the frequency and intensity of vertigo
attacks in MD although the certainty of evidence is low [44].
These systematic reviews did not include a later long-term,
double-blind, placebo-controlled randomized clinical trial
(RCT) using 48 or 144 mg/day betahistine for 9 months [45].
This study shows that, although treatment with high- and
low-dose betahistine reduces the frequency of the vertigo
attacks in MD, there was no difference as compared with
placebo. Further long-term placebo-controlled RCT with
higher dosages of betahistine is warranted to confirm these
results.
In any case, it would be desirable to identify clinical pre­
dictors or biologic markers for betahistine treatment success
(i.e. an allergy background) which could explain the benefits
of betahistine reported in some studies.
On the other hand, a Cochrane review concludes that there
is an absence of evidence to suggest that betahistine has an
effect on subjective idiopathic tinnitus when compared to
placebo [46].
3.1.2. Methods to improve betahistine efficacy
Several methods have been used to improve the biodispon­
ibility of betahistine in the inner ear and CNS, including a dose
increment, the inhibition of its metabolization, and the intra­
nasal formulation.
The effects of betahistine are dose- and duration-
dependent [30,47]. The standard dosage is 48–96 mg/day,
although a higher dosage between 288 and 480 mg/day is
sometimes used [48,49].
Betahistine is fastly metabolized by the monoamine oxi­
dase a/b. In this sense, selegiline, an inhibitor of the mono­
amine oxidase b, increases the plasma biodisponibility of
betahistine [50,51]. Thus, the combination of betahistine and
selegiline could be an alternative to a high dosage with beta­
histine. Equally, an intranasal formulation of betahistine (AM-
125) is being investigated to bypass the effects of first-pass
metabolism found with oral intake and thus increasing beta­
histine concentrations in blood.
3.2. Diuretics
Most diuretics act by inhibiting the reabsorption of sodium at
different segments in the nephron, thereby increasing urinary
sodium and water losses. This reduction of extracellular
volume is supposed to decrease endolymphatic pressure and
volume, either by increased drainage of endolymph or
a reduction in its production at the stria vascularis.
Diuretics are commonly considered as a first-line treatment
when lifestyle and dietary modifications do not achieve to
stop the vertigo attacks. Thiazides (hydrochlorothiazide,
chlorthalidone), loop diuretics (furosemide, torasemide),
potassium-sparing diuretics (triamterene, spironolactone),
and carbonic anhydrase inhibitors (acetazolamide) have all
been used for decades in MD. Nevertheless, the evidence
supporting their efficacy in this indication is scarce [52]. The
effects of diuretics in patients with MD were analyzed by the
Cochrane Collaboration, concluding that there were no trials
of high enough quality to meet the standard [9]. Later,
Crowson et al. carried out a systematic review with
a broaden inclusion criteria [53]. They found multiple low
evidence–level studies concluding that oral diuretic therapy
may reduce the frequency of vertigo attacks. More recently,
a meta-analysis concludes that it is not clear whether diuretics
lead to a symptomatic improvement of vertigo or an objective
decrease in hearing loss in patients with MD, because the
certainty of the evidence is very low [54].
Glycerol, an osmotic diuretic, improved hearing thresholds
temporally in patients with a suspicion of MD, so that it is
sometimes used as a confirmatory test [55].
3.3. Oral corticosteroids
The use of corticosteroids is mainly supported by the high
prevalence of autoimmune disorders in MD [56] and the role
of the innate immune system and inflammation in the patho­
physiology of MD [57]. Glucocorticoids receptor have been
found in the inner ear, mostly in the spiral lamina, outer and
inner hair cells, spiral ligament, and spiral ganglion neurons,
but also in the non-ampullated end of the semicircular canals
and the cristae ampullaris [58]. The highest concentration of
these receptors in the cochlea is within the stria vascularis.
The mechanism of action of the corticosteroids in MD is
based on their anti-inflammatory and immunosuppressive
effects, as well as their role in the regulation of inner ear
homeostasis. The action of the corticosteroids in the inner
ear appears to be related to the nuclear factor kappa β (NF-
κβ) family of transcription factors. Aquaporins are a family of
membrane proteins that selectively transports water mole­
cules and play a crucial role in the maintenance of inner ear
water homeostasis [59]. Glucocorticoids increase aquaporin
expression at both messenger RNA and protein level, stimulat­
ing endolymphatic water reabsorption [60]. Corticosteroids
also may participate in the control of the composition of
endolymph by upregulating genes responsible for transcrip­
tion of epithelial sodium channels and K+.
Few studies have investigated the effect of oral steroids in
MD [21,61], and there are no randomized clinical trials show­
ing any benefit from oral steroids in MD in the long term.
However, comorbid systemic autoimmune disorders, long-
lasting recurrent episodes of vertigo, or a sudden drop in
hearing thresholds are situations that could be managed
with high doses of oral steroids during few weeks.
3.4. Intratympanic corticosteroids treatment (ITC)
After intratympanic administration, corticosteroids reach the
labyrinth fluids via passive diffusion through the round window,
the oval window annular ligament, the bony otic capsule micro­
fractures as well as the small lacunar mesh in the bony wall

surrounding the inner ear, achieving higher inner-ear drug con­
centrations than with systemic administration [62,63]. This con­
centration of corticosteroids is higher in the endolymph than in
the perilymph, and it exhibits a gradient from basal to apical,
with potentially insufficient levels at the basal regions.
Thus, compared with systemic administration, intratympa­
nic delivery yields higher inner ear drug concentrations, with
minimizing the risk of systemic side effects (osteoporosis,
diabetes mellitus, hypertension, erosive gastritis, glaucoma,
and cataracts). Furthermore, although Eustachian tube contri­
butes to clearance, intracochlear uptake is higher and more
prolonged with intratympanic injection [64].
Intratympanic injection is a low-cost and safe technique,
with very few complications. The main advantage of corticos­
teroids over gentamicin is the absence of risk of hearing
loss [65].
The corticosteroids more commonly used for tympanic
administration are dexamethasone and methylprednisolone,
although triamcinolone is also an option [66,67].
Experimental studies have demonstrated that methylpredni­
solone yields higher concentrations in endolymph and peri­
lymph than dexamethasone, but the latter drug may be more
efficacious as it is absorbed more rapidly by endocytosis into
the stria vascularis and surrounding tissues, where it acts
intracellularly [68,69]. A RCT showed no statistically significant
difference between dexamethasone and methylprednisolone
with regard to control of vertigo, although pure tone average
improvement was statistically significantly higher in the
methylprednisolone group [70].
Various retrospective and several non-randomized or not-
placebo controlled prospective studies have evaluated the
vertigo outcome after ITC [71–74]. These studies are hetero­
genous and differ in study design, delivery protocol, type, and
concentration of steroids. These and other factors may explain
that the reported success of ITC for vertigo control in MD
varies widely. In any way, ITC appears to be effective in con­
trolling vertigo avoiding ablative procedures, even though in
some patients, the injection should be repeated as needed
[75–77]. Equally, it appears that vertigo control rates get
higher as drug concentration rises.
Nevertheless, the natural history of the disease, with
a decrease of vertigo attacks of 60–70% over 2 to 8 years
[78,79], makes necessary to include a placebo group when ana­
lyzing the effects of ITC. In fact, some studies have demonstrated
that the decrease in the frequency of vertigo episodes is signifi­
cant in the first 6 months after a single injection, but the long-
term outcome is unsatisfactory [73,74,80]. For this reason, the
AAO-HNS recommends that evaluation of vertigo control should
be performed more than 2 years after therapy start. Concerning
hearing and tinnitus, most studies found no significant change.
A systematic review from the Cochrane included only
a high-quality RCT [10]. The authors of this RCT found 82%
of complete control of vertigo over placebo (57%) [81]. Thus,
the Cochrane review concluded that, although a single trial
provided limited evidence, ITC had demonstrated
a statistically and clinically significant improvement of the
EXPERT OPINION ON PHARMACOTHERAPY 5
frequency and severity of vertigo. Later, other systematic
reviews included only the same RCT [82–85].
Since the publication of that Cochrane review, two others
RCT have appeared, both using a suspension of dexametha­
sone for sustained release [86,87]. A systematic review has
joined together these two RCT with the study of
Garduño-Anaya with a total of number of 220 patients [88].
The authors of this new review conclude that there is still
a lack of solid confirmation that ITC has a positive effect in MD.
Recent consensus documents and clinical guidelines
recommend ITC as a second echelon pharmacological therapy
when previous treatment interventions have been unsuccess­
ful [16,23,89,90].
This option is especially indicated in patients with bilateral
involvement, with only hearing/vestibular ear or who declined
risky procedures. Equally, corticosteroid injection may be
a first and safe option in patients who suffer from Tumarkin
crisis (vestibular drop attacks) [91].
A subset of patients does not respond to corticosteroid
treatment. As with betahistine, an improved phenotyping of
MD patients could contribute to the use of clinical predictors
(i.e. MD type 5) or biologic markers to forecast treatment
success with corticosteroids.
3.5. Intratympanic gentamicin treatment (ITG)
Fowler in 1948 was the first author that proposed the
intended administration of streptomycin to produce
a chemical labyrinthectomy and in that way reduce vertigo
attacks in MD [92]. Nevertheless, the intramuscular aminogly­
coside injections had several major disadvantages: nephrotoxi­
city, hearing loss, and bilateral vestibular hypofunction, with
disequilibrium and oscillopsia. As compared with systemic
administration, intratympanic therapy avoids damage in the
contralateral ear and kidney, yielding a higher concentration
of drug in the inner ear.
Animal models suggest that permanent ototoxicity appears
when the aminoglycoside enters into the hair cell causing
apoptosis. Death cell result from overproduction of reactive
oxygen species, including oxygen ions, free radicals, nitric
oxide (NO) and hydrogen peroxide (H2O2); moreover, mito­
chondrial stress can result in the production of highly reactive
oxygen species, including free hydroxyl radical (·OH), peroxy­
nitrite (ONOO−), and hypochlorite (−OCl) [93]. There is also
increasing evidence that programmed cell death is
a consequence of aminoglycoside interference with mitochon­
drial protein synthesis, stimulation of N-methyl-D-aspartate
receptors, and activation of the caspase pathway.
Streptomycin, gentamicin, and tobramycin are more vestibulo-
toxic whereas neomycin, kanamycin, amikacin are more
cochleo-toxic.
Gentamicin is the more common aminoglycoside for intra­
tympanic injection, and it appears particularly toxic to type 1
vestibular hair cells because they concentrate more aminogly­
coside [94]. Histologic studies have also shown atrophy of the
neuroepithelium of the semicircular canal cristae ampullaris
6 J. M. ESPINOSA-SANCHEZ AND J. A. LOPEZ-ESCAMEZ
and fibrosis and edema of the stroma, whereas the utricular
macula is relatively spared. Damage to the vestibular dark cells
also has been observed. With regard to the cochlea, outer hair
cells are more damaged than inner hair cells, and the basal
turn is the region most susceptible to permanent loss of hair
cells and replacement by supporting cells, resulting in high-
frequency hearing loss.
Although original protocols intended to ensure
a complete ablation of vestibular function, the aim of cur­
rent ITG protocols is to obtain a partial vestibular ablation
with a long-lasting, nonfluctuating, peripheral vestibular
hypofunction capable of being centrally compensated. In
this way, the severe ataxia and imbalance often observed
following complete ablation are minimized. On the other
hand, low dosing has a lower risk of hearing loss. Moreover,
if patients have a familial history of maternal high-frequency
hearing loss, the mutation A1555Gdel in the mitochondrial
DNA should be screened before considering ITG.
Treatment schedules for ITG can be categorized as fixed-
dose protocols, titration techniques, and instillations on
demand [1]. The dose is preset in the fixed-dose protocols,
which differ depending on the amount of drug delivered and
the frequency and number of doses. Dosing may be daily,
multiple daily, weekly, monthly, or continuous. In the titration
protocol, gentamicin is administered until a certain goal is
achieved, such as the appearance of hearing loss or clinical
signs of vestibular hypofunction, including spontaneous nys­
tagmus, head-shaking nystagmus, or a positive head impulse
test. For this purpose, vHIT has been shown to be a valuable
tool in assessing vestibulo-ocular changes after ITG [95]. This
approach takes into account that ototoxic effects of gentami­
cin usually appear 3 days after injection. When instillations are
performed on demand, a low dose is given, which is repeated
only if vertigo spells persist or recur. Several studies have
shown that ‘on demand’ low-dose protocols yield a lower
risk of hearing loss and post-treatment instability with good
long-term vertigo control [96–98].
This variety of schedules and protocols makes it difficult to
compare results among different studies. A meta-analysis
noted an 87.5% substantial vertigo control rate with signifi­
cant tinnitus improvement, and minimal hearing deterioration
[99]. Two systematic reviews concluded that ITG seems to be
an effective treatment for vertigo complaints in MD, although
it emphasizes the risk of hearing loss [12,82]. These systematic
reviews included only the two prospective placebo-controlled
RCT that are available, both using the titration method
[100,101]. A very recent meta-analysis has evaluated the effi­
cacy and safety of ITG [102]. Pooled data from 2185 MD
patients revealed an overall rate of substantial vertigo control
(classes A and B) of 89% and that of complete control (class A)
of 71%. On the other hand, the overall PTA increase was found
statistically but not clinically significant.
After years of vertigo control, a recurrence rate of 16–30%
after ITG has been observed [103]. Middle ear exploration with
direct application of gentamicin to the round window using
gelatin sponges is an option to be considered in patients who
have failed ITG [104]. Intratympanic gentamicin treatment
must be given with caution as the risk of bilateral involvement
increases as the disease progress. Likewise, sustained-release
formulations, although advantageous in the case of corticos­
teroids, pose a high risk of hearing loss [105].
Two RCTs have compared ITC and ITG. Casani et al. found
that complete vertigo control was achieved in 43% in the
methylprednisolone group compared to 83% in the gentami­
cin group after 2 years of follow-up [106]. On the other hand,
Patel et al. also compared methylprednisolone with gentami­
cin over 2 years, in the first group complete vertigo control
was achieved in 90% compared to 87% in the gentamicin
group. This study showed no significant difference between
methylprednisolone and gentamicin for the control of vertigo
frequency over the final 6 months (18–24 months after injec­
tion) compared with the 6 months before the first injection,
but better speech discrimination after methylprednisolone
[107]. The same cohorts were examined over 48 months in
a later study from the same research group [108]. The results
showed an overall reduction of vertigo attacks at long-term
follow-up compared to the 6 months prior to initial treatment
of 95% for both methylprednisolone and gentamicin. Thus,
although there is a lack of placebo-controlled RCT, the
absence of significant difference between both treatment
groups for the number of vertigo attacks at long-term follow-
up provides a robust evidence to support the use of ITC in MD.
A systematic review with network meta-analysis does not
have found significant differences between gentamicin and
methylprednisolone in terms of efficacy when the outcomes
obtained from studies with a follow-up equal to or more than
24 months were analyzed [109]. A later systematic review
comparing symptom effectiveness of ITG versus ITC found
a significant decrease in vertigo in only three studies, slightly
favoring ITG [110].
3.6. Other drugs
Calcium antagonists are commonly used in Europe for the
treatment of vertigo. Calcium-channel blockers of the dihydro­
pyridine family, such as nimodipine, nicardipine, and nifedi­
pine, are not recommended due to the lack of efficacy in MD.
Nevertheless, verapamil and flunarizine may be helpful as
prophylactic medication, especially in patients who also com­
plain of migraine headaches [111]. Nevertheless, controlled
studies to support this indication are needed.
Latanoprost is a prostaglandin F2α analog widely used for the
treatment of glaucoma. Since the prostaglandin F receptor has
also been found in the inner ear, it was hypothesized that
latanoprost could also reduce endolymphatic hydrops. It was
administered by intratympanic injection once daily for 3 days in
a pilot study with MD patients [112]. Authors found a significant
reduction of vertigo/disequilibrium on visual analogue scale and
a significantly improved speech discrimination; nevertheless, the
very small sample size prevents the results to be extrapolated.
Based on histopathological findings, some authors have
sustained that MD is a viral neuropathy and claimed a 90%
control of vertigo episodes and 38% of improvement of hear­
ing with antiviral treatment [113,114]. Two small-sized

RCTs have investigated the role of antiviral pharmacotherapy
in MD. The results indicated that although oral famciclovir may
suppress hearing fluctuation, it has no statistically significant
effect on the frequency of vertigo spells [115]. Equally, intra­
tympanic ganciclovir did not show differences compared with
placebo [116]. Recently, a systematic review and meta-analysis
have not found any association between herpes simplex virus
1 nor 2 and MD [117].
4. Future perspectives
The therapeutic approach for MD will be more complex, since
each clinical variant will have a differential treatment accord­
ing to the cytokine profile and comorbidities. So, the combi­
nation of clinical and genetic data will define a personalized
profile to guide the pharmacological and non-
pharmacological treatment.
4.1. Drugs and devices under clinical investigation
Ebselen (spi-1005) is a small molecule that acts as a mimic and
inducer of glutathione peroxidase (GPx). GPx reduces reactive
oxygen species by the binding of free radicals to its selenium
moiety. Ebselen, by mimicking the actions of GPx, has strong
anti-inflammatory, anti-oxidant, and cytoprotective activity. It
has been used for the prevention of noise-induced hearing
loss [118], and an unpublished phase 2b study has shown that
after oral administration Ebselen improves tinnitus and hear­
ing loss in patients affected by MD (https://www.clinicaltrials.
gov/ct2/show/NCT03325790).
A further step into local therapeutic delivery to the inner
ear is intracochlear administration into one of the cochlear
scalae, or even intralabyrinthine injection directly into peri­
lymph or endolymph into the cochlea, vestibule, or semicircu­
lar canals. However, the opening of perilymphatic or
endolymphatic spaces increases the risk of severe deafness.
Different approaches can be considered: round or oval win­
dow, cochleostomy, canalostomy, or even endolymphatic sac.
In addition to injection, other delivery methods are micro­
pump, catheter, or even a cochlear implant electrode used
as a carrier of a drug delivery system. Drug formulations
include nanoparticles, magnetic nanoparticles, liposomes, or
polymersomes [119,120].
4.2. Genetic and cytokine testing in MD
MD has a strong genetic contribution and exome and genome
sequencing will become an essential tool to develop gene
therapy in MD. The genetic underpinnings of MD include
some rare monogenic forms in isolated families and
a polygenic contribution in most familial and sporadic cases
[121–123]. So, familial MD has been reported in 6–8% of
sporadic cases and several genes have been described in
single Spanish families with MD including FAM136A, DTNA
[124], PRKCB [125], SEMA3D, and DPT [126], suggesting genetic
heterogeneity. Multiplex rare missense variants [minor allelic
frequency <0.05] in OTOG gene have been reported in 33% of
EXPERT OPINION ON PHARMACOTHERAPY 7
familial MD, suggesting multiallelic inheritance [127].
Moreover, the genetic model of sporadic MD is more complex
and it involves multiplex and novel rare variants in several
SNHL genes such as GJB2, USH1 G, SLC26A4, ESRRB, and
CLDN14 [122] and ‘axonal-guidance signaling genes’ such as
NTN4 and NOX3 [123]. Moreover, singleton and rare variants
have been reported in non-familial cases in ‘familial MD genes’
such as FAM136A, DTNA, and DPT in East Asian popula­
tion [128].
According to the genetic architecture of MD, we should
consider this condition as a set of rare genetic disorders
with a core phenotype showing clinical heterogene­
ity [121].
The genetic model in sporadic cases points to a polygenic
condition that include singleton and rare variants with a large
effect size in coding regions and common non-coding variants
such as rs4947296 with regulatory effects in the inflammatory
response that may explain the variable expressivity in the
phenotype [4]. This regulatory variant is found in 15% of
individual with bilateral MD and regulates the expression of
several genes in the TWEAK/Fn14-NFκβ pathway. The variant
could be used to tag individuals with an increased inflamma­
tory response and develop chemical drugs able to block the
Fn14 receptor and the expression of NFκβ in MD.
A second area of research is autoinflammation in sporadic
MD. So, 20–25% of individuals show high basal levels of
several proinflammatory cytokines such as IL-1β, IL-1RA, IL-6,
and TNF-α when they were compared to healthy controls.
Most patients have no familial history of MD, or migraine
and they could be classified as MD type 1 [5]. Ongoing pro­
spective longitudinal studies will demonstrate if this autoin­
flammatory status is persistent or relapsing and will setup the
background work for cytokine blocker treatments.
5. Conclusions
The pharmacological options to treat the attacks of vertigo in
MD have a weak evidence including betahistine, diuretics, intra­
tympanic administration of corticosteroids, or gentamicin. So,
the heterogeneity of MD makes it necessary to investigate the
efficacy of any drugs in multicenter, randomized, placebo-
controlled clinical trials in the different clinical subgroups of MD.
6. Expert opinion
MD is not a single disease; it is a set of rare disorders and
the treatment of MD should be personalized. First, the
assessment of age of onset, clinical subgroup, and asso­
ciated comorbidities are key factors to plan an individua­
lized treatment.
There is a lack of high-quality RCT in MD. The clinical
heterogeneity of the condition leads to the inclusion of
patients with different comorbidities and probably different
mechanisms of disease. So, future clinical trials should select
patients for a particular clinical subgroup (i.e., MD with auto­
immune background, MD with migraine or MD with autoin­
flammation), preventing a selection bias in RCT. Moreover,
8 J. M. ESPINOSA-SANCHEZ AND J. A. LOPEZ-ESCAMEZ
inclusion criteria should consider the selection of patients in
a specific period of the disease, since the natural history of MD
in terms of number of vertigo attacks is different at 5 years or
at 15 years since the onset of the condition.
Second, MD has a relevant genetic contribution; a familial
history of MD or an early onset (<35 years old) should be a red
flag for genetic testing. A discussion with the individual is
needed to explain expectations and future possibilities for
clinical trials with gene therapy for the patient, including
genetic counseling. There is a need to generate genomic
data in familial MD to provide a better understanding of
genetic variants of unknown significance in a multiallelic
inheritance model. The top candidate gene for familial MD is
OTOG, since rare missense variants are found in 1/3 families
investigated using whole-exome sequencing.
Third, a personal or familial history of autoimmunity could
point to autoimmune bilateral MD and genetic testing of the
allelic variation rs4947296 should be performed. If the patient
is carrier of the risk allele, an immune suppressor approach
should be prioritized.
The bases of the treatment in the absence of persona­
lized genomic or proteomic biomarkers are sodium restric­
tion and high-water intake to increase plasma aldosterone
and prevent sodium overload in the endolymph.
Betahistine is a safe treatment that has proven some ben­
efits in certain patients, but a better characterization of this
subgroup with autoinflammation or with allergy is needed to
improve the outcome using this drug.
There is no evidence to support the use of diuretics or oral
steroids in MD. However, single cases may also benefit from
these therapies, and comorbidities should also be considered
here. There is only a single RCT providing evidence for using
ITC, so further long-term randomized, placebo-controlled clin­
ical trials are warranted to confirm its efficacy.
ITG seems to be an effective treatment to control vertigo
attacks, but it may increase vestibular hypofunction and produce
hearing loss. So, it should not be used during the first 4 years,
since the number of vertigo attacks decreases over time and the
risk of bilateral involvement is a major factor in outcome.
The role of surgery in MD has dramatically changed in the
last 25 years. Endolymphatic sac surgery is not supported by
clinical studies and labyrinthectomy and vestibular neurect­
omy practice has decreased over time, because of the aware­
ness of bilateral involvement.
Funding
Jose Antonio Lopez Escamez [JALE] was partially funded by grants INT18/
00031 and PI17/1644 from the Instituto de Salud Carlos III (ISCIII) from
European Regional Development Funds.
Declaration of interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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89. Nevoux J, Franco-Vidal V, Bouccara D, et al. Diagnostic and ther­
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99. Huon L-K, Fang T-Y, Wang P-C. Outcomes of intratympanic genta­
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•• This RCT compares the effectiveness of intratympanic
methylprednisolone or gentamicin injections, given 2
weeks apart, and followed up for 2 years in patients with
refractory unilateral MD to reduce the vertigo frequency.
The primary outcome did not differ between both groups,
although the gentamicin group showed a significant reduc­
tion in vestibular function.
108. Harcourt JP, Lambert A, Wong PY, et al. Long-term follow-up of intra­
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EXPERT OPINION ON PHARMACOTHERAPY 11
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118. Kil J, Lobarinas E, Spankovich C, et al. Safety and efficacy of ebselen
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123. Gallego-Martinez A, Requena T, Roman-Naranjo P, et al. Enrichment
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124. Requena T, Cabrera S, Martín-Sierra C, et al. Identification of two
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125. Martín-Sierra C, Requena T, Frejo L, et al. A novel missense variant
in PRKCB segregates low-frequency hearing loss in an autosomal
dominant family with Meniere’s disease. Hum Mol Genet. 2016;25
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126. Martín-Sierra C, Gallego-Martinez A, Requena T, et al. Variable
expressivity and genetic heterogeneity involving DPT and
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127. Roman-Naranjo P, Gallego-Martinez A, Soto-Varela A, et al. Burden
of rare variants in the OTOG gene in familial Meniere’s disease. Ear
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• This exome sequencing study in 73 familial cases with MD
reports a burden of rare missense variants in the OTOG gene
in 15 of 46 families (33%), suggesting that otogelin,
a structural protein in the tectorial and otolithic membranes
has a key role in familial MD.
128. Oh EH, Shin J-H, Kim H-S, et al. Rare variants of putative candidate
genes associated with sporadic Meniere’s disease in East Asian
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