Abstract
This paper provides a new hypothetical explanation for the etiopathology and pathophysiology of Menière’s Disease (MD), which to date remain unexplained, or incompletely understood. The suggested hypothesis will explain the close connection of MD and Migraine, the coexistence of endolymphatic hydrops (ELH) and Menière attacks and the signs of inflammation detected in the inner ears of MD patients. Although as yet unproven, the explanations provided appear highly plausible and could pave the way for the generation of the first animal model of MD – an invaluable asset for developing new treatment strategies. Furthermore, if proven correct, this hypothesis could redefine and also reset the actual name of Menière’s Syndrome to Menière’s Disease.
Introduction
MD is clinically defined by attacks of spinning vertigo, lasting between 20 minutes and 12 hours, sensorineural hearing loss, tinnitus and/or auricular pressure [1, 2]. In more than 50% of MD patients only one ear is affected but bilateral affliction is reported to develop in about 35–47% during long term follow up from within 5 to 10 years or more, although it usually starts in one ear and both ears are affected only in 2% from the onset of the disease (for overview see Huppert et al. [3]). Estimates of the time between first unilateral appearance and bilateral affection of MD differs between studies, but is generally considered to be anywhere between 2 months and 20 years [3].
The histopathological hallmark for MD is endolymphatic hydrops (ELH), which is detected in almost all Menière patients, with the exception of 1 to 2 percent of patients in whom the correct diagnosis is debated [4]. Although almost every MD patient shows ELH, it is known that ELH is not the cause of individual attacks. ELH can be induced in animals, yet they do not develop the characteristic attacks with MD-symptoms [5]. In addition to this, there are descriptions of patients with ELH but without Menière-symptoms [6]. Nevertheless, the role of ELH in initiating Menière-attacks is still debated [7]. Owing to this and the fact that there is no concluding pathophysiologic explanation for MD, no animal model for MD exists to this day. It is also not known whether ELH is caused by increased production or decreased absorption of endolymphatic fluid. In addition to ELH, signs of inflammation have also been detected in the inner ears of MD patients (see review [8]), with viral infections [9], autoimmune inflammation [8], or allergy [10, 11] being proposed as possible etiologies. A modest association between MD and Cytomegalovirus (CMV) has also been described [12, 13].
A strong correlation exists between MD and migraine, and Menière-attacks can be triggered in many patients through increased stress which also triggers migraines [14, 15]. The findings from a study of 37 MD-patients demonstrated that 51% had migrainous headaches, with 95% having migraine-features including sensitivity to visual motion, light, sound, head motion, smells, weather changes, or medication [16]. A literature review [17] estimated that about 40% of MD patients have concomitant migraine, and up to 79% of all MD patients also suffer from migraine with the vestibular episodes accompanied by migrainous symptoms such as headache, visual aura, phono- and/or photophobia. According to Tabet and Saliba “there are no known definitive diagnostic tests that can reliably distinguish the two conditions” [17]. Thus, to the best of my knowledge and clinical experience, neither history taking nor any testing can clearly differentiate between MD, vestibular migraine (VM), and MD plus vestibular migraine (MDVM) in an individual patient, although some statistical differences are described between groups. Prosper Menière himself wrote [18]: “If it is incontestable that individuals who are a prey to vertigo with syncope and vomiting have at the same time head noises and rapidly become deaf, it is not less certain that cerebral states, called migraine, give place in the end to similar attacks, and the deafness which arises in these circumstances would seem to us inevitably to be related to a disease of the same nature.” and: “I suggest that MS is caused at least in the many patients with MD and Migraine symptoms (i.e. ≈50%) by a common etiology”.
In summary, the etiology of MD is still unknown and definitely undetectable in a living patient. Many different histopathological findings have led to several conclusions about different etiologies in MD. Therefore, MD is nowadays preferentially called Menière’s syndrome by many specialists because it is believed that different etiologies are responsible.
The lack of a suitable animal model for MD has almost certainly hindered progress in the development of evidence based therapy for MD. Attacks of vertigo can become controlled by intratympanic injection of steroids [19], ablative treatments of the vestibular organ using intratympanic injection of gentamicin, first described by Lange [20], or vestibular neurotomy. Nevertheless, no therapy has been developed to improve hearing, tinnitus or pressure feeling, or at least to prevent deterioration of hearing and/or tinnitus.
Hypothesis
Because of the close association between MD and migraine, I herewith propose and explain many logical - but so far unproven - reasons for a common etiology of MD and migraine, as well as MD and ELH, and finally for the described signs of inflammation and MD. I suspect that calcitonin gene-related peptide (CGRP) could explain most of the so far unexplained findings in MD patients.
CGRP is a 37-amino acid neuropeptide (C163H273N51O49S2) detected in numerous tissues throughout the body. It is commonly accepted to play the mayor role in initiating migraine attacks and can possibly also induce aura symptoms when released from the trigeminal nerve (for review see [21]). Since CGRP is also a very strong vasodilator, it can induce edema as demonstrated in the skin [22]. Vasodilation also causes plasma protein extravasation in the dura mater, leading to aseptic neurogenic inflammation [23]. This inflammation also induces edema in the brain after brain trauma [24, 25]. Although edema has to my knowledge not yet been described in human migraineurs, the occurrence of plasma extravasation was confirmed over 30 years ago [26].
The trigeminal nerve also innervates the inner ear vessels, including the stria vascularis [27], which consists of a dense capillary network producing endolymph. Blood flow in the stria vascularis is critical for maintaining ion transport and endolymphatic fluid balance, and pericytes appear to play a major role in this blood flow autoregulation [28, 29]. Unfortunately, to date, the effect on CGRP on blood flow autoregulation remains poorly investigated, although plans are in place to address this gap in knowledge (see acknowledgment). Nevertheless, transient endolymphatic hydrops has been shown after a migraine attack [30], thereby supporting my hypothesis that CGRP represents a major factor involved in the dysregulation of cochlear and vestibular vessels responsible for production of ELH as well as the transient cochlear and vestibular symptoms seen in MD.
A recent study showed that in αCGRP deficient mice, the vestibulo-ocular reflex (VOR) gain was reduced by about 50% [31]. Thus, CGRP seems to be relevant for the sensitivity of semicircular-canals (SCC). Based on this observation, I suggest that increased CGRP-levels could cause an initial hyperexcitability of SCC, resulting in nystagmus beating towards the affected side as often described during the initial nystagmus in MD. Maybe such an overstimulation could lead to longer lasting depolarization, thereby explaining the nystagmus towards the non-affected side. To my knowledge, no studies have yet been undertaken to examine the effects of CGRP overproduction in animals with normal CGRP receptors, although plans are now in place to perform such an experiment (see acknowledgment). On the other hand, CGRP-overproduction causes migraine attacks, being connected to noise sensitivity. Noise sensitivity is explained by disturbed cochlear efferent stimulation, since otoacoustic emissions (OAEs) remain unchanged, or are less reduced in migraineurs compared to normal patients during contralateral stimulation with white noise [32]. Whether CGRP plays a major role in noise sensitivity is not yet established, but certainly possible. MD patients often report noise sensitivity during the attacks even with simultaneous hearing loss. Interestingly, a loss in pericytes has been implicated as playing a major role in numerous pathologies of the cochlea, including sudden sensorineural hearing loss, acoustic trauma, and inflammation [33]. Unfortunately, the vestibular pathologies were not considered in these studies, but are also possible according to the proposed hypothesis.
In summary, overexpression of CGRP in the inner ear could explain cochlear symptoms such as tinnitus, hearing loss and noise sensitivity, as well as vestibular symptoms like vertigo and nystagmus, either by stimulation or inhibition of semicircular canals as described during MD-attacks. In addition, overproduction of endolymph, and the resulting dilation of capillaries in the stria vascularis, could induce endolymphatic hydrops. CGRP could also induce neurogenic inflammation in the inner ear, thereby offering an explanation for the localized inflammation. Thus, CGRP could answer many, or possibly all, of the so far unresolved questions, and in doing so, reduce the multiple suspected etiologies to just one single etiology of Menière’s disease. Investigations into the potential role of CGRP in MD have just begun, and it is envisaged that many more studies will need to be performed before we can claim to truly understand this debilitating disease.
Footnotes
Acknowledgments
I thank PD Dr. M. Bertlich for reviewing the manuscript and for his promise to perform future experimental studies according to my suggestions to prove my hypothesis in close collaboration and coauthorship with me. I also thank PD Dr. Peter J. Richards for correcting the first and resubmitted version as a native speaker.