Keywords
antivirals - balance diseases - dehydration test - intratympanic treatment - migraine
Introduction
Prosper Meniere first described Meniere's disease (MD) in 1861.[1] Meniere described this pathology as being associated with the peripheral end organ
of the inner ear rather than the brain. He and other investigators called it “glaucoma
of the ear.”[2]
[3] MD remains a difficult disease to diagnose, especially in the early stages when
not all of the symptoms may be present. Most studies suggest a female preponderance
of up to one to three times than in men. The disease seems to be much more common
in adults in their fourth and fifth decades than in younger people, although it has
been reported to occur in children.[4] Several studies have indicated that up to 20% of family members have similar symptoms.[5]
[6]
Sensorineural hearing loss, tinnitus, and recurrent vertigo constitute the hallmark
symptoms of MD.[7] It has been classified into typical MD, with all the before-mentioned cochlear and
vestibular symptoms, and atypical MD, with either cochlear symptoms (e.g., hearing
loss, tinnitus, and aural pressure) or vestibular symptoms (e.g., vertigo with aural
pressure).[8]
Usually MD is clinically manifest in one ear with the chance of becoming bilateral
ranging from 15 to 50%.[9] Endolymphatic hydrops (EH) has been described as the responsible pathology in MD.[10]
[11] Since that description, the medical and surgical treatment of MD has been directed
at reducing the volume of endolymph.[12]
[13] Unfortunately, these approaches have had equivocal success in the control of vertigo
and recovery of hearing.[14]
[15]
[16] So, a routine treatment directed at resolution of EH may not be suitable for all
patients. Treatment has to be directed at the cause of EH whenever possible.
Pathophysiology
The primary histopathological correlation of MD is EH. Paparella used the notion of
a “lake, river, and pond” to explain the occurrence of malabsorption of endolymph
leading to hydrops.[17]
Furthermore, primary and secondary EH have been documented in the temporal bones of
subjects without symptoms of MD[18]; thus, hydrops is likely an epiphenomenon.
Viral Hypothesis
Obstruction of endolymph flow has been implicated as the cause of EH.[19]
[20] Significant questions to this proposed pathophysiological mechanism persist. First,
although EH is readily produced by surgical obliteration of the endolymphatic sac
in lower organisms (guinea pig, chinchilla, gerbil), it does not occur in higher mammals
(cat, monkey).[21] Second, vertigo has not been observed in these animal models. Third, the temporal
bones of animal models with experimentally induced EH do not contain fibrous tissue
adjacent to the stapes footplate with attachment to the saccular wall.
For this reason, many studies have been carried out to verify whether viruses such
as the neurotropic viruses, herpes simplex virus (HSV) types 1 and 2,[22] varicella zoster virus (VZV), and cytomegalovirus (CMV)[23] can cause MD by invading the endolymphatic sac. The endolymphatic sac is known to
be the site of immune reaction due to the existence of lymphocytes and immunoglobulins
in addition to the resorption of endolymphatic fluid.[24]
[25]
Arnold and Niedermeyer[22] evaluated the presence of higher immunoglobulin G (IgG) antibodies against HSV in
the perilymph of patients with MD. This result supported the hypothesis that the HSV
may play an important role in the etiopathogenesis of MD. Higher titers of IgG against
adenovirus (ADV) and VZV were found in patients with MD compared with a control group.[26]
Viral invasion of the endolymphatic sac is impeded by immunological mechanisms under
normal conditions.[27] Release or exposure of the virus may occur as a result of cell damage or destruction
during viral infection. Such previously sequestered antigens would be recognized as
foreign by the host, and the resulting immune response may lead to the production
of autoantibodies and possibly to a further cycle of tissue damage through autoimmunity.
Aims and Objectives
The aim and objectives of this study are as follows:
-
To define new findings in clinical tests and modes of treatment in MD.
-
To determine the outcome of vertigo and hearing in patients after treatment.
-
To describe treatment which will prevent long term deterioration of hearing.
Materials and Methods
Forty-six new patients who satisfied the requirements for a diagnosis of MD were seen
from October 1, 2015 to October 15, 2017. Institutional ethical committee clearance
was obtained prior to study. The requirements included recurrent vertigo with duration
of 20 minutes to several hours, sensorineural hearing loss in one or both ears, tinnitus
and aural fullness in the involved ears. Complete otolaryngological examination was
normal. Tympanograms were done to exclude middle ear pathology.
All patients underwent a routine dehydration test. Patients with hypertension/diabetes
were given frusemide for testing instead of glycerol. To determine therapeutic benefits
from diuretic therapy, dehydration testing was ordered. Patients were kept nil per
os for about 4 hours prior to testing and then they were given the dehydrating agent
(1.5 g/kg of glycerol/40 mg of frusemide according to patient). Post-dehydration audiogram
was taken 3 hours after ingestion of dehydrating agent. Audiometry was done using
a Decos audiometer (version 2.5.2). A positive response was taken if it revealed a
10- to 15-dB threshold improvement, with speech understanding showing an improvement
of 20%. A reverse or negative response was noted if there is a 10 to 15 dB lowering
of threshold and a decrease in speech understanding by 20%. No response when the hearing
threshold and SD remained the same.
Patients with positive response and no response on dehydration testing were started
on diuretics and low salt (<1500 to 2000 mg/day) diet. They were reassessed at 3 weeks
for control of vertigo and improvement in hearing. If there was improvement, they
were asked to continue Diamox (acetazolamide) 500 mg once daily for 3 months. If there
was no improvement, they were started on antiviral treatment with acyclovir 800 mg
five times a day for first 5 days followed by once daily for 3 months. If there had
been no improvement with either of these drugs, they were taken up for intratympanic
treatment (ITT) with gentamicin. Patients with reverse or negative response were started
only on antivirals and were not advised specifically to restrict salt. If there was
improvement at 3 weeks, antivirals were continued for 3 months, and if there was no
improvement, ITT with gentamicin was suggested.
Hearing test including air and bone frequency thresholds and word discrimination scores
were recorded. Tympa-nograms were normal. The hearing test was repeated after 1 to
2 months of treatment, then at 5 to 6 months, 1 year, and 2 years.
Results
The ages of patients ranged from 20 to 70 years. Most were in the fifth, sixth, and
seventh decades. Twenty-six female patients (56.5%) and 20 male patients (43.47%)
were involved in the study and the side involved was unilateral in 40 cases (86.9%)
and bilateral in 6 (13.04%) cases.
Twenty (43.47%) patients with positive dehydration testing and 6 patients (13.04%)
with no response on dehydration testing were started on diuretics ([Table 1]). All 20 (100%) patients in positive dehydration test group showed improvement at
3 weeks and treatment was continued for 3 months ([Chart 1]). In the no response group that had six patients, one (16.6%) patient had improvement
with diuretic, four (66.6%) patients had no improvement so they were started on antivirals
and did well, one (16.6%) patient did not do well with neither diuretic/antiviral,
hence was taken up for ITT. Twenty patients (43.47%) had a negative response on dehydration
testing and were directly started on antivirals. Eighteen (90%) patients reported
improvement ([Chart 2]) and two patients (10%) who did not show a response to treatment were taken up for
ITT. A total of 43 patients had improved on medical management that was attributed
to diuretics ([Fig. 1]) in 21 patients (45.6%) and antivirals ([Fig. 2]) in 22 (47.8%) patients ([Table 2]). A total of three (6.5%) patients have undergone ITT in our study. Two patients
in the positive response group were shifted to hydrochlorothiazide 25 mg OD because
of their intolerance (severe muscle cramps, fatiguability) to Diamox.
Table 1
Response to drugs in each group
|
Positive dehydration test
|
No response dehydration test
|
Negative dehydration test
|
|
No of patient
|
20
|
6
|
20
|
|
Response to diuretics
|
20
|
1
|
–
|
|
Response to antivirals
|
–
|
4
|
18
|
|
Intratympanic treatment
|
–
|
1
|
2
|
Chart 1 Hearing improvement and vertigo control in the positive dehydration test group.
Fig. 1 (A) Pre- and (B) post-treatment audiograms in a patient treated with diuretics.
Fig. 2 (A) Pre- and (B) post-treatment audiograms in a patient on antiviral treatment showing an improvement
in hearing.
Table 2
Vertigo control in the no response to dehydration test group
|
No response group, n = 6
|
Vertigo control 1st month
|
Vertigo control 3rd month
|
Vertigo control 6th month
|
|
Patients on diuretics, n = 1
|
1/1
|
1/1
|
1/1
|
|
Patients shifted to antivirals, n = 4
|
4/4
|
4/4
|
4/4
|
Those patients who did not experience hearing improvement recorded worse pre-treatment
audiometric values PTA of 50 dB or higher and word discrimination scores of 50% or
lower ([Table 3]). These values suggest damage to more than just outer hair cells. Degeneration of
inner hair cells (IHC) and/or spiral ganglion cell is likely present in these failures.
Table 3
Hearing improvement in no response dehydration group
|
Hearing improvement 1st month
|
Hearing improvement 3rd month
|
Hearing improvement 6th month
|
|
Patients on diuretics, n = 1
|
1/1
|
1/1
|
1/1
|
|
Patients shifted to antivirals, n = 4
|
¾
|
¾
|
¾
|
New Approaches in Diagnosis
1. Migraine causing MD
The prevalence of migraine in patients with MD was 56% and prevalence in cases with
bilateral disease was 85%. In our study, 4 out of 46 patients (8.7%) had a classical
migraine history before an attack of vertigo along with other prodromal symptoms like
tinnitus and aural fullness. These patients were given prophylactic treatment (sodium
valproate 250–500 mg BID) for migraine in addition to their medications for MD. Common
migraine culprits were eliminated from their diet. We also encourage a regular sleep
schedule and physical exercise program.
Weber lateralizing to the side of migraine in MD patients
We have found that patients with migraine-associated MD have Weber’s test lateralizing
to the side of migraine headache as nervous system remains hyperexcitable. This causes
the nervous system to amplify sounds on that side by sensitizing cochlear transduction
and recruitment.
Chart 2 Hearing improvement and vertigo control in the negative response dehydration group.
3. Taste in migraine-associated MD
Our findings revealed that there was close association between taste, migraine, and
MD. Altered taste thresholds were recorded when patients with MD underwent electrogustometry.
It was done using a Tekyard TR-06 Electrogu-stometer.
Most patients with migraine reported increased taste perception on the side of migraine.
4. Why shift to antivirals early if there is no response to diuretics?
With increased duration of MD, there is increased fibroblast activity surrounding
vestibular ganglion cells and obliteration of the synaptic cleft in both the auditory
and vestibular sense organs. This may represent an increase in the blood–brain barrier
for the antiviral drug to cross before reaching the virus containing neuron. Therefore,
early medical treatment of virus activity may be effective in controlling the number
of failures.
5. Intratympanic treatment for best results in vertigo control and to avoid hearing
loss
We advocate ITT as the last resort in patients those who have intractable vertigo.
Most studies have achieved control of vertigo in more than 85% of patients treated
with intratympanic gentamicin, whatever protocol or technique they used. In our method,
few drops of gentamicin is instilled into a Gelfoam placed in round window (one should
make sure Gelfoam is bloodless) after creating a tympanomeatal flap ([Fig. 3]). In this way, targeted low-dose gentamicin can be administered avoiding the need
of multiple injections.
Fig. 3 Intratympanic treatment with gentamicin using Gelfoam in round window as delivery
material.
Discussion
Based on the experimental demonstration of EH, medical and surgical treatments designed
to reduce endolymph volume were widely employed but these approaches have not proved
to be effective in all patients.
Evidence for Antiviral-Based Treatment
It is well established that the axonal transport of viral proteins in sensory neurons
is strain specific. Some strains of HSV-I (McIntyre) transport nucleic acids peripherally
(toward the labyrinth), while other strains (HS 129) transport centrally (toward the
brain)[28]
[29]. Therefore, activation of retrograde transport virus in the vestibular ganglion
([Fig. 4]) can release infectious nucleic acids[30] into perilymph from vestibular nerve branches. Fluctuation in symptoms reflects
the decrease and increase in neural discharge caused by the intermittent release of
toxins by vestibular neurons containing the virus genome. Thus, EH in MD can be regarded
as the labyrinthine response to recurrent episodes of labyrinthitis caused by repeated
release of toxic proteins into the perilymphatic space.[31]
Fig. 4 Electron microscope) view of ganglion cell from a patient. Arrows point to virus
particles enclosed in transport vesicles. Mag = 13,000×.
As the duration and toxicity of the nucleic acid contamination of the Organ of Corti
continue, these deficits are likely to become permanent because of IHC and spiral
ganglion cell loss.
The hypothesis that MD is a viral neuropathy is supported by the significant loss
of vestibular ganglion cells compared to age-matched temporal bones.[32]
[33] Reactivation of the latent neurotropic virus is dependent on viral load.[34] When the viral load reaches a critical level, reactivation of the virus overcomes
the host immune response with the release of viral nucleic acids. Release of such
toxic products in the labyrinth causes a labyrinthitis, which eventually leads to
fibrosis in the vestibular cistern and EH.
It is not surprising that control of vertigo was not greater than 85 to 90%, with
antivirals, as mutant strains of the herpes virus group would be resistant to the
acyclovir class of antivirals.
Potassium toxicity due to rupture of distended membranous labyrinth would induce a
diffuse pattern of neural degeneration because the dendrites of vestibular ganglion
cells are scattered in a haphazard fashion. However, the focal axonal degeneration
observed in MD can only be produced by loss of a tight cluster of ganglion cells[32]
[35] because of the organization of vestibular axons and their ganglion cells.
This neural pattern of focal axonal degeneration has been observed in temporal bone
from patients with MD[35] and with vestibular neuronitis (VN).[32] The subsequent demonstration by transmission electron microscopy of fully formed
viral particles in the cytoplasm of vestibular ganglion cells excised from patients
with MD provides direct evidence[36] to support the indirect evidence of HSV DNA in MD ([Fig. 4]). This evidence has formed the basis for an antiviral treatment approach in patients
with MD and VN.[37] Gacek demonstrated significant hearing and vertigo control in patients with MD can
be achieved with orally administered antiviral drugs(acyclovir/Valacyclovir). Over
the past 10 years, this approach demonstrated control of vertigo in 90% of patients.
Side effects of acyclovir administration are minimal and usually involve gastrointestinal
tract hyperactivity, which is eased by decreasing the dosage. Rare side effects are
skin rash, headache, or tremors. The antiviral approach to the very common disabling
balance symptoms experienced by patients with MD has virtually eliminated the use
of various surgical methods used in the past. The high (90%) rate of vertigo control
with orally administered antivirals should be considered as a frontline treatment
for vertigo.
Migraine-Associated MD
It has been recently discovered that tiny blood vessels in the inner ear are innervated
by branches of trigeminal nerve that innervates the intracranial blood vessels. Interestingly,
experiments have shown that stimulation of this nerve causes release of peptides and
inflammation of local blood vessels in the cranium and the same mechanism causes the
inner ear to become “leaky” as well. This may cause the fluid changes in the inner
ear that could cause symptoms like MD.
We have found in our study that those patients treated effectively for migraine have
experienced an improvement in their MD symptoms.
Conclusion
MD is still an obscure disease entity, even though it was first described more than
150 years ago.
Using dehydration testing as a selection basis, our disease control rates have improved
to 93.5%. Clinical tests of Weber tuning fork test, electrogustometry are used in
identifying migraine associated MD.
It would be prudent for us to continue to be conservative by preserving the structures
of the inner ear and working to alleviate patient symptoms without destroying these
structures, as much as possible.
