Etiology (cause) of Menieres Syndrome
Timothy C. Hain, MD Page last modified: September 20, 2015
|Figure 1a: Normal membranous labyrinth||1b. Dilated membranous labyrinth in Meniere's disease (Endolymphatic Hydrops)|
Most authors feel that Menieres syndrome, which is usually attributed to endolymphatic hydrops (see figure 1 above), which itself has several causes (etiologies). Reasonable possibilities are obstruction of endolymphatic outflow at the endolymphatic duct level, increased production of endolymph, or reduced absorption of endolymph caused by a dysfunctional endolymphatic sac. A recent variant is to propose that hydrops is due to blockage of the reuniting duct, which is located at the bottom of the saccule (Yamane et al, 2010). One might reasonably conjecture that this duct could be blocked by dirigible otoconia. This idea is somewhat more reasonable than the idea that it is due to blockage of the endolymphatic duct, as evidence suggests that endolymph does not flow towards the endolymphatic duct in any case.
Nakashima et al (2007) imaged the inner ear of several patients using intratympanic gadolinium and reported that in patients with endolymphatic hydrops, the perilymphatic space surrounding the endolymph was small or had disappeared. Foster and Breeze(2013) recently published a literature review and suggested that published literature evidence supported the hypothesis that hydrops causes Meniere's disease. Recent studies using imaging reinforce the concept that hydrops (measured by MRI) is correlated with both duration and hearing loss in Meniere's (Wu et al, 2015). In other words, this conjecture is well established.
The central hypothesis that Meniere's syndrome is caused by hydrops is shown below.
|Central hypothesis of Meniere's disease (Merchant et al, 2005)|
Recently, the most generally accepted idea that Meniere's disease and endolymphatic hydrops are always associated has been questioned. Hydrops is not found in all persons with Meniere's disease, and hydrops is also commonly found (6%) on autopsy studies of persons who had no Meniere's type symptoms (Honrubia, 1999; Rauch et al, 2001). Because Meniere's disease occurs in roughly 0.2/100 persons, and Hydrops is found in 6/100 temporal bones, there is more than an order of magnitude more people with hydrops than Meniere's disease. Thus logically, there must be something more than simply hydrops involved in the origin of Meniere's disease
Explanations for Meniere's that depend on unilateral injury to an ear, such as a blockage of a "drainage pipe" in the ear, also seem hard to sustain in view of the known long-term studies that show that Meniere's becomes bilateral in roughly 50% of all people, after 15 years (Stahle et al, 1991).
There is also skepticism that part of the hydrops hypothesis, ruptures of membranes, is correct. Although ruptures of membranes are found at post-mortem, there is no evidence of when they occurred. For ruptures to be the cause of the periodic auditory and vestibular symptoms of Meniere's disease, one would have to accept the idea that there are multiple ruptures of thin membranes that are repaired over and over. This seems very implausible. It is also questionable that even if a rupture were to occur, that the mixture of endolymph and perilymph would be sufficient to create the symptoms of Meniere's disease(Honrubia, 1999). That being said, there is nevertheless very good evidence that hydrops (at least) correlates with symptoms of Meniere's.
Recently attention has been mainly focussed on the immunologic function of the endolymphatic sac -- immune disease may contribute to a substantial percentage of Meniere's disease. Evidence continues to mount that the endolymphatic sac is part of the immune system of the ear, and that it is involved with inflammatory responses. (e.g. Moller et al, 2015)
There also is some thought that Meniere's and Migraine are two faces of the same indistinguishable condition. It is the author's opinion that although this is not always the case, this may be true in a substantial number of people, and perhaps about 20% of cases of Meniere's are actually misdiagnosed Migraine. About 50% of people with Menieres also meet the criteria for Migraine, and for this reason, it is often a good idea to try the large repertoire of migraine treatments in persons with Meniere's disease. See this page for more discussion on Migraine vs Menieres.
A synthesis of present thought is that Menieres syndrome appears to be the final common pathway that the inner ear responds to nearly any injury, and that Menieres syndrome has many separate causes, some of which reflect injury, and others which reflect more generalized metabolic or genetic processes that injure both ears fairly symmetrically.
-- Herpes virus (HSV) antibodies are found more commonly in Meniere's patients (Arnold and Niedermeyer, 1997). Viral DNA from herpes simplex in the vestibular ganglion of persons with Meniere's has been found by Vrabec (2003), but not by Welling, who also did not find CMV or varicella zoster (Welling et al, 1997). HSV antigen and HSV DNA are also found in the endolymphatic sac and epithelium of healthy people. There is some recent pathologic data supporting a viral cause (Gacek and Gacek, 2001). Linthicum has also recently reported that herpes simplex DNA is found in the endolymphatic sacs of 12 of 16 Meniere's cases, vs. 2 of 26 controls (Linthicum, 2001). Japanese researchers have reported finding varicella zoster in 7/10 endolymphatic sacs of persons with Meniere's, 4 with Epstein Barr Virus, and 1 with cytomegalovirus (Yazawa et al, 2003). Peculiarly, none of their cases had HSV1 or 2 found in the sac. Treatment studies using antivirals have rarely shown a positive effect, and we are dubious about the ones that report a response (e.g. Gacek, 2008). Our take on this is that these finding are interesting, somewhat puzzling in that there is some controversy, and need more investigation.
Otosyphilis can produce a clinical picture identical to Meniere's.
Pulec indicated that syphilis is the cause of Meniere's disease in 6% of all cases (1997). This is much higher than the author's experience in whom less than 1% of all patients have a positive FTA for syphilis. We suspect that Pulec's data was based on patients from far in the past, when there was a higher percentage of persons in the population with previous exposure to syphilis than the present.
About one in three patients with Menieres disease have a first-degree relative with Menieres disease. In theory, hereditary predisposition might be related to differences in anatomy of fluid channels within the ear or differences in immune response (see later).
Before discussing some studies, realize that this is a very fuzzy problem, unlikely to produce any clean solution, because Meniere's is a "committee" diagnosis. There could easily be 50 different locii that can produce symptoms that fit into the commitee criteria for Meniere's disease. It would be almost impossible for there to be a single gene that causes a vaguely defined condition such as Meniere's (or Migraine, or other "committee" disorders).
Areweiler-Harbeck reported that 19% of 193 patients with Meniere's had a positive family history. They suggested that chromosome 5 was a "probable" candidate region for MD. Remembering that nearly every linkage study done on Migraine came up with a different candidate region, we think it best to wait for more data.
Lee et al (2015) reported that out of a total of 286 Korean patients with Meniere's, about 9.8% had a probable family member, and 6.3% had a definate family member. This study suggests that familial Meniere's may be less common in Korea than in the rest of the world. Of course, this would be what one would expect in populations that have relatively little genetic heterogeneity.
Renuena et al (2015) reported two mutations in a single Spanish family, in FAM136A and DTNA, with "familial Meniere's". These tiny family studies mean very little by themselves -- once there are a hundred of these, there might be some conclusions to draw.
With respect to allergy, Derebury (1966) has suggested that 30% of patients with Meniere's disease have food allergy, and suggested that allergy may play a role in three ways that allergy may contribute:
- The sac may be the "target organ" of mediator released from systemic inhalant or food reactions.
- Deposition of circulating immune complex may produce inflammation and interfere with the sac's filtering capability;
- A predisposing viral infection may interact with allergies in adulthood and cause the endolymphatic sac to decompensate, resulting in endolymphatic hydrops (Derebery, 1996).
All of these hypotheses involve the endolymphatic sac, but some authors feel that the sac is not necessarily the culprit. In view of the present feeling that hydrops may not be the key pathology in Meniere's at all, these ideas may need revision. It has not been the author's experience that allergy and Menieres are at all closely linked. Immunotherapy for allergy, in the author's experience, is almost never a curative treatment for Meniere's disease.
There is considerable evidence that Menieres disease is caused by autoimmune mechanisms, at least some of the time.
About 60% of patients with Meniere's disease have serum antibodies for inner ear proteins. About 10% of Meniere's patients have well documented autoimmune disorders (but the general population also has a high prevalence of these disorders). A high percentage of patients with Meniere's also have an autoimmune thyroiditis (Brenner et al, 2004). Some Meniere's patients show a change in their immunity around the time of their attacks (Mamikoglu et al, 2002).
There is evidence for cytokines in the cochlea including interleukin-1A, TNF-alpha, NFkB P65 and P50, and IkBa (Adams, 2002). Drugs that block TNF such as etanercept seem to be potentially effective in autoimmune inner ear disease (AIED) which resembles some forms of Meniere's disease (Rahmen et al, 2001).
Currently the best guess is that the immunological pathway for Meniere's disease involves the sac which is the immune organ, or "lymph node" of the ear. Immune stimulation of the sac may disturb its fluid regulatory function, or may cause hydrops via independent mechanisms such as production of inflammatory mediators. Click here for more detail about autoimmune inner ear disease.
This is a controversial topic due to the highly litigeous nature of symptoms after head injuries. As an overview, the literature is not definitive about the connection between Meniere's disease and trauma. This is likely due the lack of clear definition of Meniere's disease and also the intrinsic difficulty in quantifying head injury. It would seem very reasonable to us that Meniere's disease, which has a large number of potential mechanisms and causes and a very inclusive "definition" requring only a single objective abnormality (hearing loss), might be caused by head injury.
There are clearly cases of post-traumatic Meniere's syndrome. These cases are attributed to hydrodynamic changes caused by scarring from bleeding into the inner ear. There are also cases reported of Meniere's after temporal bone fracture, and even simply acceleration-decelleration injuries (Dibiase and Arriaga, 1997). It seems reasonable that Meniere's might be due to loose otoconia (see below).
Heavy exposure to impulse noise (such as gun fire) has been suggested by some as a cause of inner ear disease and symptoms resembling Meniere's disease. There is some controversy here however, and one very large study of 17,245 Israeli veterans suggested that there was no effect (Segal and Eviatar, 2003). In our opinion, loud impulse noise does not cause Meniere's disease.
Some have suggested that hydrops might be caused by obstruction of the duct reunions by loose saccular otoconia (Yamane et al, 2010; 2014). This is a reasonable conjecture.
The inner ear fluid is connected to the spinal fluid through several channels, and low spinal fluid pressure might reasonably be a source of hydrops. CSF leaks cause hearing symptoms similar to Meniere's disease. Glaucoma is also another disorder in which it has been suggested there is a link to spinal fluid pressure (Nakashima et al, 2012). While it seems highly unlikely that much Meniere's disease is caused by low CSF pressure, it seems reasonable that some cases may be due to this mechanism. We have encountered patients with symptoms resembling Meniere's disease with maladjusted shunts for hydrocephalus.