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The meniere attack: an ischemia/reperfusion disorder of inner ear sensory tissues
Contents lists available at Medical Hypotheses The Meniere attack: An ischemia/reperfusion disorder of inner earsensory tissues q,qq C.A. Foster R.E. Breeze a University of Colorado School of Medicine, Dept. of Otolaryngology, 12631 E. 17th Ave., B-205, Aurora, CO 80045, United Statesb University of Colorado School of Medicine, Dept. of Neurosurgery, United States We believe Meniere attacks arise as a chance association of endolymphatic hydrops and vascular risk fac- Received 16 September 2013 tors for intracerebral ischemia. Hydrops acts as a variable Starling resistor upon the inner ear vasculature Accepted 11 October 2013 that is capable of inducing ischemic attacks only in people with reduced perfusion pressure in the ear.
The unique characteristics of the attacks (loss of vestibular response and hearing acutely followed by areturn to apparent normalcy over hours) are explained by the differential sensitivity of the inner ear tis-sues to transient ischemia, with the sensory tissues (dendrites, hair cells) vulnerable to hours-long ische-mia/reperfusion injury, and the stria vulnerable to ischemia due to its high metabolic rate. Permanenthearing loss and vestibular damage after many attacks would result when small areas of irreversible sen-sory cell damage accumulate and become conﬂuent.
theory is supported by the strong correlation of hydrops with Meniere attacks, the ﬁnding that autoregulation of cochlear blood ﬂow is impaired in the hydropic ear, and studies demonstrating thatsymptoms and signs in people and in animal models vary with conditions that alter perfusion pressurein the inner ear. Induction of Meniere attacks in animal models requires both hydrops and a mechanismthat reduces perfusion pressure, such as epinephrine injection or head dependency. There is a strong clin-ical association between Meniere attacks and disorders that increase the risk for cerebrovascular ische-mia, such as migraine. The excitable tissues in the sensory structures have long been known to be morevulnerable to ischemia than the remaining aural tissues, and are now known to be vulnerable to excito-toxicity induced by ischemia/reperfusion. This correlates well with autopsy evidence of damage to den-drites and hair cells and with strial atrophy in late Meniere disease cases.
this hypothesis is conﬁrmed, treatment of vascular risk factors may allow control of symptoms and result in a decreased need for ablative procedures in this disorder. If attacks are controlled, the previouslyinevitable progression to severe hearing loss may be preventable in some cases.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
be dilated and endolymph is increased in volume with respect toperilymph, called endolymphatic hydrops (EH). There is no deﬁni- disease is an idiopathic aural disorder that is deﬁned as tive objective test for Meniere disease other than ﬁnding EH at au- recurrent self-limited attacks of acute hearing loss, tinnitus and topsy; diagnosis is based on the characteristic attacks and clinical vertigo, which are followed by the gradual development of deaf- course. The presence of attacks meeting 1995 American Academy ness in the affected ear The inner ear is a delicate membranous of Otolaryngology/Head and Neck Surgery (AAOHNS) criteria for structure ﬁlled with endolymph and suspended in perilymph with- Meniere disease is highly speciﬁc for the presence of EH Since in a convoluted bony cavity of the temporal bone. In people with the ﬁrst linkage of EH and Meniere disease in 1938 a variety of Meniere disease the affected membranous labyrinth is found to mechanisms have been proposed to explain the attacks and theprogressive deafness, but no answer has explained all aspects ofthe disorder, and no treatment based on these theories has proven Grant Support: University of Colorado Foundation capable of controlling the progression of the disease. A model that This is an open-access article distributed under the terms of the Creative fully explains the condition is still needed.
Commons Attribution-NonCommercial-ShareAlike License, which permits non- An adequate model must provide explanations for all the key commercial use, distribution, and reproduction in any medium, provided theoriginal author and source are credited.
components of the disorder, including symptoms, signs, pathology, ⇑ Corresponding author. Address: 12631 E. 17th Ave., Mailstop B205, Aurora, CO and epidemiology. The symptoms and signs of Meniere attacks 80045, United States. Tel.: +1 303 724 1967; fax: +1 303 724 1961.
(MAs) are well known During spells the affected ear has an E-mail address: (C.A. Foster).
0306-9877/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 acute, widespread but incomplete loss of function. There is aural potassium intoxication theory has since been widely re- fullness and a roaring tinnitus in the ear that corresponds to an futed Pressures in endolymph relative to perilymph are not acute hearing loss, usually in the low frequencies. There is pro- elevated enough to cause ruptures during attacks nor are found vertigo with vomiting that is associated with a decrease in ruptures found in all cases. Ruptures are incapable of healing over caloric responsiveness in the affected ear, and a horizontal-rota- the minutes to hours of a typical attack. A permanent rupture does tory nystagmus is visible. This continues for 20 min to several not provide an explanation for a slowly progressing hearing loss hours, with a complete resolution of symptoms as the attack ends.
over many years. Direct injection of a potassium-rich solution in Attacks recur repeatedly. Although each attack appears to be animal models does not result in signs typical for MA and reversible, over time the affected ear gradually loses hearing and potassium levels in endolymph and perilymph show no changes balance function. The ear will usually ‘‘burn out'' with cessation in the presence of hydrops The rupture model does not pro- of vertigo spells when the hearing loss becomes severe, but often vide any reason for the frequent association of MD and migraine.
some residual hearing is still detectable. In addition to the classic Bilateral strial atrophy in unilateral Meniere disease and the devel- MA, Meniere patients experience other forms of dizziness due to opment of hair cell and epithelial abnormalities is also not ex- this progressive damage, such as benign positional vertigo and plained. As this EH-based theory lost favor, the role of EH in the the dizziness prior to compensation for permanent vestibular loss.
production of symptoms of MD in general has itself been seriously There are characteristic pathologic ﬁndings on autopsy. EH is questioned However, EH remains strongly linked to a history of ubiquitous in Meniere disease and is found in the affected ear in Meniere attacks and this linkage is likely to be causative .
unilateral cases, and is sometimes bilateral .Normal hair cell vascular theory of attack etiology has recently been resur- populations may be found in the cristae and cochlea until the dis- rected. For several decades, an association between Meniere disease ease is advanced With progression, atrophy of dendrites and of and migraine has been noted Migrainous vertigo does not hair cells may be found . Neuroepithelial degeneration with frequently damage the ear , but there are case reports linking thickening of the basement membrane and loss of stereocilia have migraine to inner ear damage . Since migraine is believed also been reported . Strial atrophy and loss of dark cells in the to be a genetic channelopathy with a vasospastic component, this cristae are often found, and strial abnormalities have also been raises the possibility that some cases of Meniere disease share this identiﬁed in the contralateral ear in unilateral MD pathophysiology However, Meniere disease is usually charac- Epidemiologic characteristics have also been identiﬁed. EH is terized by recurrent spells of vertigo in just one ear, but migraine is found in all cases of Meniere disease, but many cases of EH are a cerebrovascular condition that should affect both ears and so does asymptomatic or show only hearing loss . There is also an asso- not explain the focality of the disorder. Migraine does not provide a ciation with migraine in about half of MD cases MD is rare in simple reason for the ﬁnding of hydrops in Meniere disease, nor has children and increases in prevalence over the lifespan Identi- there been any published causative connection between hydrops cal attacks associated with EH occur in other disorders such as and migraine. Migraine has never been shown to result in hydrops, otosyphilis and neuroborreliosis nor has hydrops been shown to cause the onset of migraine head-aches or aura. In the only autopsied case of Meniere disease withmigraine, EH was found in the affected ear, suggesting that a chance combination of EH and migraine may be sufﬁcient to cause MAsHowever, a large percentage of Meniere patients lack any per- Prior to the 1938 Hallpike article, the mechanism of MAs was sonal or family history of migraine. Migraine, then, is neither neces- attributed to causes as disparate as viruses, hyperemia, and allergy.
sary nor sufﬁcient to cause MAs, but it has some connection to these Many articles noted an association with migraine, leading to theo- attacks in a subpopulation of Meniere patients.
ries that vasospasm with resultant ischemia caused vertigo spells migraine, EH provides an explanation for the focality of The Hallpike paper ascribed the symptoms to hypoxemia of the attacks. Most Meniere disease affects a single ear, and on au- the labyrinth due to impaired blood ﬂow; this was believed to re- topsy, hydrops is found in the affected ear. However, EH cannot sult from sudden large increases in endolymph pressure that im- alone explain Meniere disease. Most temporal bones with EH lack paired circulation within the ear . Following the Hallpike a history of MAs during life . Animal models of EH have failed to paper, theories involving ischemia as a mechanism declined. Au- provide a mechanism for attacks, because they do not show spon- topsy specimens showed an intact inner ear with few or no hair taneous attacks of vertigo and hearing loss. This suggests that EH is cell losses in some cases which would have been difﬁcult to necessary but not sufﬁcient to cause MAs. If EH is causative, there explain if widespread aural ischemia was the cause. A consensus must be one or more other factors that are also necessary before arose that hydrops alone was a sufﬁcient cause for the symptoms MAs occur However, no prior theory of attack etiology has re- through an unknown mechanism. Some authors suggested that in- quired an interaction between hydrops and one or more other dis- creased endolymph pressure caused a direct mechanical effect on orders. Syphilis, neuroborreliosis, and migraine have already been the sensory structures, but this remained unproven.
linked to MAs and so these disorders must share one or more char- In 1952 a new EH-based theory to explain completely revers- acteristics that give rise to this association, but not all MA patients ible, non-damaging spells arose–the potassium intoxication theory have one of these disorders.
. Lawrence and McCabe autopsied a case of MD with a few summary, pre-existing hydrops appears to be necessary but areas of rupture along Reissner's membrane. They hypothesized not sufﬁcient to cause MAs; migraine is strongly associated but that rupture could result in contamination of perilymph with alone is neither necessary nor sufﬁcient to cause MAs; and mi- potassium-rich endolymph. This could acutely elevate potassium graine, syphilis or neuroborreliosis when combined with hydrops in perilymph that would theoretically inhibit hair cell transduction appear to be sufﬁcient but not necessary to cause MAs. Therefore, and silence the sensory structures of the ear, presumably causing there must be some characteristic of migraine that is also shared the spells. Sudden elevations in endolymph pressure were said to with syphilis, neuroborreliosis, and with other as-yet-unidentiﬁed cause the ruptures. They went onto speculate that the vertigo spell disorders that, when combined with hydrops, reliably gives rise to ended as the pressure was released and the membrane healed, attacks. We believe this shared characteristic is a heightened risk allowing a return of normal function without damage to the inner for ischemia, usually due to cerebrovascular disease sufﬁcient to ear. The formation of a permanent rupture would permanently si- reduce perfusion pressure in the sensory structures of the inner lence the cochlea, resulting in deafness.
ear, and we therefore present the following model for attacks.
C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 We hypothesize that MAs occur when, due to a variety of cere- brovascular impairments listed above, perfusion pressure has been theory posits that there are three major interacting factors lowered to just above the ischemic threshold in an ear with pre- that combine to cause MAs. First, we believe that all patients with existing hydrops. In such a marginally-perfused ear, the relatively MAs have pre-existing hydrops in at the affected ear. Second, we minor ﬂuid pressure ﬂuctuations caused by hydrops now become believe that all individuals with MAs have a lowered threshold capable of resulting in ischemia in the stria vascularis and in the for intracerebral and intra-aural ischemia during the spells. Third, excitable tissues of the inner ear whenever inner ear pressures rise.
we believe the unique attack characteristics arise because aural tis- We expect the stria to be the most sensitive, followed by the distal sues show a differential sensitivity to ischemia.
processes of sensory neurons, with the hair cells showing the least hypothesize that the ﬁrst key abnormality in hydrops is that sensitivity of these excitable tissues. The remainder of the ear is inner ear pressures (perilymph and endolymph) ﬂuctuate to a relatively insensitive to ischemia and so will show no evidence of greater extent than in normal ears in response to exogenous pres- damage over time. The often slow onset of the attack, with increas- sure changes such as changes in atmospheric pressure, intracere- ing tinnitus and low tone hearing loss, reﬂect marginal ischemia bral ﬂuid pressure, head position, and state of hydration. The that affects the stria vascularis at the apex of the cochlea, at the sensory structures of the ear and the associated neural tissues lie most distal branches of the internal auditory artery. An abrupt loss between these two compartments. This exposes the sensory tis- of strial blood ﬂow results in acute low tone hearing loss with tin- sues and vasculature of the ear to intermittent mild over- and un- nitus due to loss of the endocochlear potential. Distal branches of der-pressure. The hydropic ear thus acts as an intermittent Starling the labyrinthine artery throughout the ear are affected in a patchy resistor to blood ﬂow within the inner ear. In young individuals distribution and vertigo ensues when many of the calyces or bou- with hydrops who have normal vasculature and normal oxygen tons of sensory neurons in one or more cristae and maculae be- levels, the highest pressure reached does not exceed the critical come ischemic. The distal processes of neurons serving cochlear perfusion pressure for the tissues and is therefore not sufﬁcient hair cells and the spiral ganglia also become ischemic. Perfusion to result in ischemia, explaining the presence of asymptomatic hy- is not impaired long enough to cause necrotic tissue death, which drops in young people. However, we believe this relationship is would present as a sudden permanent sensorineural hearing loss greatly changed by cerebrovascular disorders and other risk factors with or without vestibular injury; during the MA it is only neces- for ischemia.
sary that it last for between 5 and 60 min. During ischemia, gluta- structures perfused by intracerebral vessels such as the in- mate is released into the synaptic cleft. When adequate perfusion ner ear, perfusion is determined by arterial pressure, venous out- is restored, non-sensory tissues quickly recover without damage, ﬂow resistance and intracerebral ﬂuid pressure and is further while ischemia/reperfusion pathways are activated in the most se- modulated by oxygen supply Typically perfusion pressures verely affected sensory structures. This is an hours-long metabolic of greater than 50–60 mmHg are sufﬁcient to prevent ischemia process triggered by massive binding of the excess released gluta- in the properly oxygenated brain, while higher pressures are mate to calcium channels. The calcium inﬂux is taken up by mito- needed in the face of hypoxia. Any process that reduces intracere- chondria and if very great in extent overwhelms them, resulting in bral arterial pressure, increases venous outﬂow resistance, chroni- sensory cell death only in the most severely ischemic sensory tis- cally raises intracerebral CSF pressure or results in chronic hypoxia sues, surrounded by a zone of marginal ischemia, the penumbra, can lower the effective perfusion. These processes include migrain- that recovers function over the next several hours. In the penum- ous vasospasm, atherosclerotic narrowing of arteries, autoimmune bra are calyces and boutons that are permanently damaged but or infectious vasculitides, arteriovenous malformations, venous with sparing of their associated neuronal cell bodies, as well as outﬂow obstructions, hypertension, hyperviscosity, and other re- transiently impaired hair cells. This process is responsible for the lated vascular disorders. Hydrocephalus and post-traumatic eleva- hours-long duration of the spell and the gradual return to apparent tions of intracerebral pressure impair perfusion. Acute or chronic normalcy. Because these zones of permanent cell death and caly- hypoxia due to sleep apnea, carbon monoxide exposure, anemia, ceal damage are often small in the initial attacks, vestibular and or pulmonary disorders also lower the effective perfusion. Because auditory testing is not able to detect changes in function until sev- the vascular supply to the ear is entirely intracranial and without eral severe attacks have accumulated larger areas of sensory cell collaterals, it has the same or greater vulnerability to ischemia as damage. Repeated destruction of calyces and boutons and hair cell the adjoining brain.
ischemia eventually results in sensory neuron death and degener- tissues of the inner ear vary in sensitivity to ischemia. The ation of hair cells. This results in slowly progressive hearing and stria vascularis is particularly sensitive; ischemia results in imme- vestibular impairments. Over time this patchy damage gradually diate loss of the endocochlear potential and ultimately results in becomes conﬂuent in all the inner ear areas most vulnerable to strial atrophy . The sensory structures of the inner ear includ- ischemia, leading to the nearly dead ear of late stage Meniere's ing the hair cells and associated sensory neurons are excitatory cells, and like the neurons of the brain are vulnerable to ische-mia/reperfusion injury (excitotoxicity) While non-excit-atory tissues at normal body temperature may be able to tolerate of the hypothesis ischemia for hours, this is reduced to minutes in excitatory tissues. During ischemia in excitable tissues glutamate is released into the extracellular cleft . Upon reperfusion, the excess gluta-mate binds to NMDA, AMPA and other calcium channels, resulting Our theory requires that hydrops is found on autopsy in the af- in rapid uptake of large amounts of calcium by the cell . This fected ear of every individual who has had recurrent MAs leading is sequestered by mitochondria, resulting in opening of the perme- to SNHL in the ear. This has been demonstrated based on large dou- ability transition pore, and activates intracellular proteases such as ble-blinded autopsy studies using 1995 AAOHNS criteria and caspase and calpain. These factors result in the production of nitric in a large review of autopsied cases oxide and reactive oxygen species, leading to apoptosis and death The mechanism we propose also applies to bilateral MD, but of the cell. This process is slow, with a duration of up to 6 h after an this diagnosis cannot be made deﬁnitively without autopsy speci- isolated ischemic event mens. In order to be considered bilateral MD, each ear must be C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 shown to have had recurrent spells meeting 1995 AAOHNS criteria, reduced by these methods. The use of hydrochlorthiazide with tri- with development of progressive hearing loss and vestibular dam- amterene to control vertigo symptoms is very common and has age in each. However, attacks affecting both ears simultaneously been supported by a double blind crossover study . Andrews will not cause symptoms of classic MAs because simultaneous reported an association between MAs and perimenstrual ﬂuid bilateral vestibular loss causes oscillopsia rather than rotational shifts; this was attributed to hyperviscosity with resultant de- vertigo. It is also difﬁcult to determine the source ear for a given creased inner ear perfusion .
attack, leading to the risk of over-diagnosis of bilateral disease. Au-topsy studies with very careful clinical correlation will be neces- Atmospheric pressure sary to prove or disprove our theory when applied to bilateralcases.
to 70% of patients prone to MAs note symptoms are brought on by weather changes and 45% with elevation changes . A ear acts as a variable Starling resistor study of cold fronts, which are associated with larger and moresudden atmospheric pressure changes than warm fronts, identiﬁed In order for the hydropic ear to act as a variable Starling resistor, worsening of symptoms in 36/70 Meniere patients studied our theory requires that pressures in the sensory tissues of hydropic MAs can be ended by acutely lowering atmospheric pressure in a ears vary with pressure changes external to the ear to a greater ex- pressure chamber .
tent than in non-hydropic ears. The inner ear is ﬂuid-ﬁlled but its observations support our hypothesis that hydropic ears ﬂuid volume is limited by its bony shell. Increases in ﬂuid volume become symptomatic in response to pressure changes external to in either compartment must result in ﬂuid displacement through the ear. However, some have stated that EH cannot affect blood ﬂow the cochlear aqueduct, endolymphatic duct, or through compres- because the vessels pass through the perilymph space, and so are sion of the soft tissues. According to our theory, the effect of EH not affected by changes in endolymph volume . Our theory must be to impair ﬂuid displacement via these ducts in favor of avoids this problem because it is the pressure in the sensory tissues compression of the soft tissues. Bohmer states that ﬂuid pressure containing the capillary bed vasculature that changes, rather than changes in the inner ear are buffered by the compliance of the soft pressure differences between endolymph and perilymph.
tissues, particularly the veins within the inner ear. When ﬂuid vol- of a detailed model of the resistor will require in- umes increase, this directly compresses venules, increasing venous tra-aural measurement of perivascular interstitial ﬂuid, arterial outﬂow resistance This is the deﬁnition of a Starling resistor.
and venous pressures during attacks in varying head positions with EH has been shown to impair autoregulation of blood ﬂow to the co- respect to the heart, and under varying barometric conditions. We chlea, which is an anticipated effect of a Starling resistor .
suspect that the time course to equilibration of these pressures in There is a large literature on pressure ﬂuctuation in the endo- normal and hydropic ears will differ.
lymph and perilymph compartments in normal subjects and ani-mal models of hydrops. Because the membrane separating these Vascular risk in every case compartments is distensible, pressures are rapidly equilibrated be-tween the compartments and so pressure in either compartment hypothesis suggests that every person with MAs has one or can be used as a proxy for pressure in the sensory tissues within more major risk factors for cerebral ischemia, including vascular which the vasculature arborizes To the present, most studies disorders and/or chronic hypoxia. The presence of many cases of have examined the differences in pressure between the two com- EH with no history of MAs is consistent with our theory be- partments and so the pressures to which the vasculature is ex- cause we predict that those without vascular risk factors will not posed have not yet been studied. We predict that these pressures have such attacks. Since hydrops and cerebrovascular risk are will ﬂuctuate to a greater extent than in non-hydropic ears.
linked in our theory by chance (hydrops is not caused by ischemia, We state that pressure ﬂuctuations in the hydropic inner ear and vascular risk factors do not result from hydrops), the propor- due to atmospheric pressure, intracerebral ﬂuid pressure, head po- tion of Meniere cases caused by each risk factor should reﬂect sition and state of hydration can raise intra-aural tissue pressures the relative frequency of that risk factor found in the general pop- high enough to impair blood ﬂow in a marginally-perfused ear. The ulation. Not all vascular risk factors are yet known, nor are all inner ear is exposed to atmospheric pressure via the round and known risk factors easily testable, so we expect that some people oval windows, and to intracerebral pressures via the endolym- may be found who seem to lack vascular risk. The proportion of phatic duct, the cochlear aqueduct, and via the venous system. A Meniere cases without clear risk factors should be inversely number of papers have discussed exogenous pressure effects on proportional to the number of vascular risk factors evaluated in a the inner ear of Meniere's disease patients that our theory identi-ﬁes as important.
l ﬂuid pressure and head position Stroke risk factors by frequency in the general population.
Prevalence % (in US adult population) CSF pressures range from <0 to >30 mmHg during daily physio- Dyslipidemia, any type logic perturbations, higher with the head inverted or when supine, and lowest in the standing position. The relationship between CSF pressures and inner ear pressures in hydrops suggests that intra- 21 (of total population) aural ﬂuid pressures are elevated in the hydropic ear Meniere patients report worsening with head dependency Attacks of nystagmus can be initiated in hydropic ears in the guinea pig mod- el by inverting the head of the animal .
History of myocardial infarction History of stroke If Meniere attacks occur only in those with vascular risk factors for stroke, then the Reduced sodium intake and diuretics have long been mainstays prevalence of the disorders listed above should be increased in patients with a of therapy of MAs with the belief that hydropic volume was diagnosis of Meniere disease compared to the general adult population.
C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 given study. lists the most common vascular risk factors in vasculitis/Eales disease , and perimenstrual ﬂuid shifts with the general population and their frequency No studies have hyperviscosity These directly support our theory.
yet been performed to assess vascular risk factors in Meniere Our deﬁnition of MAs does not exclude already known causes of hydrops with similar attacks, such as otosyphilis and neuroborreli- models of Meniere disease support our contention that osis. Our theory predicts that all such known causes should have vascular risk factors combine with EH to cause MAs. Most animal elevated cerebrovascular risk factors in addition to hydrops. Both models of EH do not demonstrate spontaneous MAs These syphilis and neuroborreliosis cause meningovasculitis and have can be triggered in EH models by injection of epinephrine into an enhanced risk for stroke, as predicted by our theory the middle ear or by venous occlusion (blocking the vein ofthe vestibular aqueduct Both of these factors are known to sensitivity of inner ear tissues to ischemia impair perfusion pressure: epinephrine through arterial constric-tion, and venous occlusion by raising venous outﬂow resistance.
In a series of papers from 1956 to 58, Kimura and Perlman dem- Kimura states that EH causes hypoxia of the inner ear through im- onstrated differential sensitivity of the vestibular and cochlear tis- paired autoregulation of blood ﬂow . Autoregulation is imper- sues to arterial and venous obstruction by electrocautery. They ative to prevent ischemia when cerebrovascular disease is present, demonstrated evidence of damage caused by arterial obstruction so its impairment in the hydropic ear would increase the risk of as follows: within 30 min in inner > outer hair cells, by 60 min in ischemia over that seen in adjacent brain.
the stria vascularis, spiral ganglion, cochlear nerve ﬁbers, hair cells risk factors in Meniere's disease have not been exten- of the cristae and maculae with sparing of the rest of the ear by sively studied; the focus on research has been on the development several hours In a test of ischemia–reperfusion injury to of hydrops. We feel that the timing of onset and prevalence of at- the cochlea, synaptic endings of cochlear dendrites showed swell- tacks during the lifespan should reﬂect the development of vascu- ing indicating ischemic injury after as little as 15 min of ischemia, lar risk factors, since hydrops has been identiﬁed in people of all with outer hair cells less severely affected at 15 min and showing ages Migraine occurs throughout the lifespan but peaks in marked changes after 45–60 min of ischemia Inner hair cells the teen and young adult years and is the most common risk factor were less affected than outer hair cells, with damage requiring for cerebrovascular ischemia in that age group. Our hypothesis is greater than 60 min of ischemia followed by reperfusion supported by articles describing a strong correlation between For acute venous obstruction, by 60 min the stria vascularis MAs and migraine in children and young adults . Migraine showed changes, followed hours later by the outer > inner hair can be difﬁcult to diagnose because there is no objective test for cells, the saccular, utricular and ampullary hair cells and their asso- it, vasospasm can occur without headache and headaches can re- ciated dendrites, with sparing of the remainder of inner ear struc- mit for many years or begin later in life. This means that some tures for days to weeks . In 1961 Grifﬁth reconﬁrmed the young people with MAs and migraine may be misclassiﬁed as hav- differential sensitivity to ischemia induced by venous obstruction ing no vascular risk factors because they have not yet developed in the following order: stria, spiral ganglion, outer hair cells, then typical headaches, so prolonged follow up of such cases may be re- inner hair cells with sparing of the remainder of the inner ear epi- quired. Some forms of migraine are genetic channelopathies thelium; in the vestibular labyrinth the utricular and saccular hair so a family history of migraine should be sought, and inclusion of cells were the most vulnerable. Chou in 1962 showed that the stria other migraine-associated symptoms such as motion intolerance, is more sensitive to ischemia than the maculae cyclical vomiting, depression and anxiety may be helpful in classi-ﬁcation. If objective tests become available for migraine diagnosis, ischemia initiates the spells this would be of great beneﬁt in such studies.
vascular risk factors other than migraine arise in middle The increased sensitivity of the stria to ischemia compared to age, with strokes, myocardial infarction and death from these risk hair cells and dendrites provides an explanation for the hearing factors following with a lag of several years. The average age of on- loss and tinnitus that usually initiate the classic Meniere attack.
set of Meniere disease should occur earlier than the average age for Typically the hearing loss is low tone, which we feel indicates api- stroke onset, since our theory predicts that hydrops makes the ear cal ischemia of the stria Our theory predicts that the apex will more vulnerable to ischemia than the adjoining brain. The mean be affected ﬁrst because its vessels are the most distal; these ves- age of onset of Meniere disease is 45, with myocardial infarction sels have been described as narrower and simpler than at the base showing an epidemiologic increase at age 55–59 and stroke The immediate effect of strial ischemia is acute loss of the following in the 65–74 age group Meniere disease prevalence endocochlear potential, with resultant silencing of the affected increases with age as do vascular risk factors, stroke and myo- portion of the cochlea. Strial atrophy is a common ﬁnding in Men- cardial infarction as reported above. Aging has been shown to im- iere disease, and is also a known outcome of aural ischemia pair blood ﬂow and result in capillary changes in the vestibular A recent paper has shown bilateral strial atrophy in Men- system and cochlea In older individuals, we predict that iere disease , which suggests enhanced vascular risk in Meniere smoking, atherosclerosis, sleep apnea, diabetes, obesity, hyperten- patients as our theory posits. According to our theory, strial atro- sion, elevated cholesterol, and a history of stroke, TIA or MI will be phy must be a marker for impaired cerebral perfusion and vascular common associations ). Examples of rare causes should in- risk, but should be more severe and occur earlier in the hydropic clude coagulation disorders, sickle cell disease, genetic and auto- ear because that ear is more prone to ischemia compared to the non-hydropic ear in the affected individual. This has not yet been malformations near the ear, and chronic carbon monoxide expo- sure. The more exhaustively vascular risk factors are sought, thestronger the association with MD should be. Studies have already sion injury during spells documented the association of Meniere disease with sickle cell dis-ease antiphospholipid antibody syndrome giant cell For our theory to be correct, the sensory tissues of the inner ear arteritis , polyarteritis nodosa systemic lupus erythema- must be vulnerable to excitotoxicity and must respond to it with a tosis , Behcet's disease , homocystinuria with jugu- cascade similar to that already identiﬁed in central neurons .
lar thrombosis branch retinal artery occlusion , retinal Several studies have shown excitotoxic responses in hair cells C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 and in vestibular calyces The stria vascularis is also part of sodium restriction has also been advocated . MSG is a selectively vulnerable to ischemia due to its high metabolic rate common migraine trigger and can enhance the risk of excitotoxic- . The remainder of the inner ear structures are less vul- ity, so avoidance of this eliminates a dietary vascular risk factor.
nerable It is this differential response to ischemia that ex- Diuretics such as hydrochlorthiazide with triamterene or furose- plains the apparent normalcy of non-sensory inner ear structures mide are used both in Meniere disease and in hypertension. A on autopsy in Meniere disease.
number of authors are reporting successful results with migraine We explain the hours-long duration of spells on the basis of the prophylactic medications in Meniere disease, some of which are prolonged time course of the excitotoxic cascade. This has been also antihypertensives, such as propranolol or verapamil . By shown in neurons , and also occurs in hair cells Dys- reducing migrainous vasospasm, another vascular risk factor is function of the stria vascularis and damage to spiral ganglion cells controlled in these patients. Acetazolamide is a diuretic thought have been shown in Meniere disease and have been found to to reduce intra-aural pressure, but it also reduces vasospasm in occur with ischemia–reperfusion injury to the inner ear migraineurs and lowers CSF pressure, which can improve perfusion Because our theory predicts that damage to sensory cells is cumulative, the severity of vertigo during attacks and measures there are many other treatable vascular risk factors of remaining vestibular function should decline over time, more that presently are not addressed in Meniere patients. Sleep apnea rapidly when attacks are more frequent. A decline in both vestibu- is common and the vascular side effects are serious, including lar and auditory function over time has long been noted in this dis- stroke and MI . If our theory is conﬁrmed, all patients with order. Attacks also have been shown to decline in severity over MAs should be questioned regarding snoring and nighttime apne- time The relationship between attack frequency and the rate as, and a sleep study should be performed in positive cases. We of decline has not yet been studied.
have treated a number of Meniere disease patients with CPAPand have noted a resolution of MAs after previous medical treat-ment failures.
ve excitable tissue damage with sparing of nonexcitable is likely to be the most common vascular risk factor for MAs in people under the age of 40 . It would behoove otol-ogists to develop a migraine treatment protocol to be used in these To conﬁrm this hypothesis, autopsy specimens should show patients, with referral to neurologists specializing in the disorder preferential damage to the stria vascularis, dendrites, neurons, co- for patients who fail to respond. In our practice, migraine prophy- chlear hair cells, and neuroepithelia of the cristae & maculae with lactic treatments such as tricyclic antidepressants, calcium channel sparing of non-excitatory tissues. Damage to calyces and boutons blockers, and topiramate are helpful, while medications for acute should occur earlier than damage to the neurons themselves.
headache control such as the triptans are of no beneﬁt. The use Autopsies in cases early in the course of the disease should show of exogenous hormones in female patients increases migraine patchy or minimal damage in sensory structures with complete and overall vascular risk and these should therefore be withheld sparing of non-excitatory tissues. In late-stage cases, there should in Meniere patients if our model is correct.
be more widespread damage in sensory tissues.
and treatment for common vascular risk factors, Structural changes are more likely to be reported in more recent such as obesity, hypertension, diabetes, elevated cholesterol, and studies using electron microscopy than in earlier studies using only a history of myocardial infarction or stroke should be provided light microscopy. Nadol and Thornton have shown damage to syn- for these patients. Smoking is a major vascular risk factor and all apses at the base of inner and outer hair cells in hydropic ears .
patients with MAs should received counseling and medication Others have shown loss of hair cell stereocilia, formation of an epi- needed to end this addiction. If we are correct, the presence of thelial monolayer, perinuclear vacuolization, and thickening of the MAs indicates an elevated potential for stroke. The hydropic inner basement membrane in the cristae and maculae of Meniere pa- ear acts as a ‘‘canary in the coal mine'', the ﬁrst to experience ische- tients . The stria vascularis is often noted to be atrophic in Men- mic symptoms. Treatment of this symptom may protect the pa- iere disease . Ischemic damage has been shown to result in strial tient against more disabling cerebrovascular ischemia in later life.
dysfunction that may alter endolymph production and so have a will need to work closely with internists, rheumatol- feedback effect on EH Loss of stereocilia and vacuolization ogists and hematologists when treating Meniere patients with less of sensory cells has also been demonstrated in ischemic animal common vascular disorders such as temporal arteritis, autoim- models of hydrops .
mune vasculitides, clotting disorders, and inﬂammatory diseases.
Neurosurgical consultation may be needed for those with vascular ces of the hypothesis and discussion malformations, particularly those in or near the ear that alter per-fusion. Not all vascular disorders are presently treatable, and for Present treatment for Meniere disease relies upon methods that these patients who also have Meniere disease, other modalities are thought to reduce ﬂuid pressure in the inner ear, such as such as transtympanic steroids and ablative procedures will likely diuretics and sodium restriction, and anti-inﬂammatory treat- remain the treatment of choice. However, if this theory is correct, ments such as steroids. Treatment failures are often followed by the majority of patients with Meniere disease should have new destructive procedures such as gentamicin perfusion. If our theory treatment options available to prevent or reduce disabling vertigo is correct, treatment of vascular risk factors should result in a de- spells and progressive deafness.
crease in the need for ablative surgeries. No prior treatments havebeen shown to prevent progressive hearing loss or vestibular dam- Conﬂict of interest age in Meniere disease. Treatment of vascular risk factors holds thepotential to delay or prevent this progression.
authors have no conﬂicts of interest to disclose.
Some of the well-known treatments for Meniere disease may be useful because of their effects on vascular risk factors rather than solely because they regulate inner ear pressure. For example, alow salt diet is a mainstay of Meniere treatment but is also fre- This work was supported by a grant from the University of Col- quently prescribed for treatment of hypertension, a common vas- orado Foundation. The sponsor had no involvement in any part of cular risk factor. Avoidance of monosodium glutamate (MSG) as the study or in publication decisions.
C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115 Salt A. A survey of the effects of pressure on Meniere's disease symptoms.
 Hill L, Gwinnutt C. Cerebral blood ﬂow and intracranial pressure, update in anesthesia, vol. 24, > 2007. pp. 30–35.
C.A. Foster, R.E. Breeze / Medical Hypotheses 81 (2013) 1108–1115
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