**3. Pathophysiology**

MD is characterized during its active phase with the characteristic symptom triad, of epi‐ sodic vertigo and tinnitus with fluctuations in hearing, followed by a symptom‐free period, ultimately resulting in a more permanent dysfunction of the above symptoms. Any theory attempting to explain the pathophysiology of MD has to account for processes that result in a reversible dysfunction of both the cochlea and vestibule, with long‐term chronic deficits. Examples of reversible causes include noise, toxins such as salicylates, viral infections and immune‐mediated mechanisms, most of which do not show morphological changes unless they turn permanent.

This suggests a possibility of a final common pathway in a variety of conditions that could all result in fluctuating cochlear and vestibular dysfunction. The exact mechanisms are not clearly elucidated, with noise‐related damage being a notable exception. In all cases, a persis‐ tence of the metabolic dysfunction results in permanence. Hence, it may be inferred that MD is modeled on the pathophysiology of disorders wherein abnormalities of metabolic dysfunc‐ tion result in a permanent vestibulocochlear dysfunction.

The problem in MD is thought to be malabsorption of endolymph, mainly in the duct or sac. This outflow dysfunction is usually a slow process, the inciting etiological event having occurred possibly years earlier.

## **4. Central theory of Meniere's disease**

Endolymph is the potassium‐rich fluid in the membranous labyrinth, produced by the stria vascularis (cells in the scala media) of the cochlear labyrinth along with some contribution from the dark vestibular cells and planum semilunatum. There is a slow longitudinal flow and a fast radial flow of endolymph, also influenced by osmotic and hydrostatic forces. Endolymphatic hydrops refers to the over‐accumulation of endolymph, pressing upon the perilymphatic space resulting in the characteristic symptom triad. The exact mechanism of this hydrops is unknown and can range from over‐production, decreased absorption, to mechanical obstruction. If the cause of the distension or hydrops is unknown, the syndrome can be termed Meniere's disease (MD); conversely, if the cause is known, it is termed second‐ ary endolymphatic blockage. The chapter intends to outline mechanisms for the hydrops; however, this theory is plagued with controversy as shown in a study of cadaveric temporal bone specimens wherein 100% of the diagnosed MD patients had evidence of hydrops, con‐ trasted by findings of hydrops in 51/79 patients without an MD diagnosis, highlighting gaps

Prosper Meniere in 1861 observed the constellation of symptoms (such as tinnitus, hearing loss, falls, vertigo, nausea and syncope), when he postulated that the ear was the site of the disorder in contrast to the popular theory of apoplectiform cerebral congestion [1]. Building upon Flourens' experiments on pigeons, he further refined the site of the lesion to be the semi‐ circular canals. In 1938, two independent studies by Yamakawa (in Japan) and Hallpike and Cairns (In England) described the hydrops as a pathological finding of the labyrinth; these anatomical findings were confirmed by various investigators through the decade to come [2].

MD is characterized during its active phase with the characteristic symptom triad, of epi‐ sodic vertigo and tinnitus with fluctuations in hearing, followed by a symptom‐free period, ultimately resulting in a more permanent dysfunction of the above symptoms. Any theory attempting to explain the pathophysiology of MD has to account for processes that result in a reversible dysfunction of both the cochlea and vestibule, with long‐term chronic deficits. Examples of reversible causes include noise, toxins such as salicylates, viral infections and immune‐mediated mechanisms, most of which do not show morphological changes unless

This suggests a possibility of a final common pathway in a variety of conditions that could all result in fluctuating cochlear and vestibular dysfunction. The exact mechanisms are not clearly elucidated, with noise‐related damage being a notable exception. In all cases, a persis‐ tence of the metabolic dysfunction results in permanence. Hence, it may be inferred that MD is modeled on the pathophysiology of disorders wherein abnormalities of metabolic dysfunc‐

in this theory [2].

54 Up to Date on Meniere's Disease

**3. Pathophysiology**

they turn permanent.

**2. Historical journey in pathophysiology**

tion result in a permanent vestibulocochlear dysfunction.

In simple terms, the central hypothesis of Meniere's disease pathophysiology is endolymphatic hydrops, due to a varied etiology (auto‐immune, infectious, endocrine, allergic, vascular, auto‐ nomic, dietary, genetic, idiopathic, etc.) and is responsible for the symptoms of MD.

A discussion on the central theory necessarily focuses on the events leading up to the hydrops and the physiological consequences of the hydrops. Endolymphatic hydrops is the only consistently found anatomical abnormality in MD, with volume increases up to 200% in patients of MD versus health patients [3]. This correlation, however, does not imply causal‐ ity, for if hydrops was causative then not only would every patient with Meniere's disease have hydrops but also the reverse; every case of hydrops would have symptoms of Meniere's disease, a statement we know does not stand true [2].

The theory regards that excess endolymph is due to overproduction or reduced resorption, either idiopathic or due to various etiologies, most likely being obstruction at the level of the duct or sac, which results in EH. The acuteness of attacks can be explained by the increased pressures within the scala media which result in a rupture of the membranous labyrinth. These ruptures are expected to occur frequently in MD and have been found in all parts of the inner ear in MD patients along with healed scars. This possibly explains the sudden attacks and fluctuation of symptoms. The Schuknecht theory is prominent for highlighting the ionic changes; ruptures of the membranous labyrinth cause a mixing of potassium‐rich endolymph into the perilymph. This potassium is excitotoxic when exposed to CN VIII and hair cells as it causes depolarization of the nerve cells and subsequent inactivation. This results in decreased cochlear and vestibular function and symptoms of a Meniere's attack. When the ruptured membrane heals, symptoms subside [4].

While other pathological findings in hydrops include membrane ruptures, periductal sclerosis, damage to hair cells and spiral ganglion cells, studies also highlight other differences observed such as abnormal glycoprotein metabolism in the endolymphatic sac. And while fibrosis around the sac need not be present in each case of MD, the widespread glycoprotein imbalance could be of value in explaining EH formation through osmotic effect affecting inner ear homeostasis [5].

Hydrops has been experimentally found to be large enough to extend into the semicircular canal and thus disrupt the crista ampullaris, responsible for vertigo. The mechanical disrup‐ tion of wave conduction by the hydrops is linked to the cochlear dysfunction.

Obstruction sites other than the duct and sac (secondary sites) such as in the ductus reunions may be responsible for the predominance of cochlear symptoms. Other involved sites (such as overactive vestibular cells and planum semilunatum) may result in excess production and mainly vestibular symptoms [6].

A combination of the mechanical and chemical factors is likely to be in play in the pathophysi‐ ology of MD. Since most of the theories on MD are derived from the study of temporal bone anatomy, the pathophysiology of MD has been inferred from the observed pathology. This is not always an ideal correlation as several insults, such as noise, can alter cochlear function without altering structure. Hence, one has to exercise caution while inferring the clinical con‐ dition of Meniere's disease from the pathological condition of hydrops.

#### **4.1. Role played by the central theory**

The central theory has not only dominated the pathophysiological dogma of MD but also influ‐ enced the design of various tests such as glycerol test or potential ratios (AP/SP; explained later) used to diagnose the "hydrops" and by extension MD. Most medical and surgical ther‐ apies in practice and in research are aimed at reducing the "hydrops." Animal models are designed to recreate the "hydrops" as a model for MD. Most research is focused on discovering various etiologies or mechanisms of hydrops.

#### **4.2. Etiology of the hydrops**

Specific causes of hydrops include infectious (viruses and syphilis), allergic, genetic, trauma, autoimmune, otoconia or otoliths and low cerebrospinal fluid (CSF) pressures.

Viruses: Studies testing the endolymphatic sac of MD patients show the presence of viral DNA notably Varicella‐Zoster virus (VZV), Epstein‐Barr virus, cytomegalovirus and conflictingly absence of herpes simples viruses 1 and 2 [7] or its presence in the vestibular ganglion [8], with inactive serum titers during attacks, leading to a statistically based theory of latent inactive viral infections related to MD, with possible early VZV infection in childhood affecting the endo‐ lymphatic sac later in life. However, antiviral medications have no role in the treatment of MD.

Syphilis: Congenital or acquired syphilis was found to be the cause of MD in 6% of all cases, with pathogenesis of endolymphatic hydrops and osteitis of the capsule believed to cause the symptoms. This entity responds to steroid administration [9].

Hereditary: 34% of patients report a family history of hearing loss or recurrent vertigo, with 8.4% of patients having a relative with diagnosed definite MD. While genetic heterogeneity has been observed, most families had an autosomal‐dominant inheritance pattern with antici‐ pation. No clinical differences were found between sporadic and familial MD, except for an expected earlier onset in familial cases [10]. Studies have discovered two heterozygous single‐ nucleotide variants in FAM136A and DTNA genes, both from a Spanish family with three affected cases in consecutive generations, suggestive of autosomal‐dominant inheritance [11] with various other gene mutations being explored in different familial groups.

While other pathological findings in hydrops include membrane ruptures, periductal sclerosis, damage to hair cells and spiral ganglion cells, studies also highlight other differences observed such as abnormal glycoprotein metabolism in the endolymphatic sac. And while fibrosis around the sac need not be present in each case of MD, the widespread glycoprotein imbalance could be of value in explaining EH formation through osmotic effect affecting inner ear homeostasis [5]. Hydrops has been experimentally found to be large enough to extend into the semicircular canal and thus disrupt the crista ampullaris, responsible for vertigo. The mechanical disrup‐

Obstruction sites other than the duct and sac (secondary sites) such as in the ductus reunions may be responsible for the predominance of cochlear symptoms. Other involved sites (such as overactive vestibular cells and planum semilunatum) may result in excess production and

A combination of the mechanical and chemical factors is likely to be in play in the pathophysi‐ ology of MD. Since most of the theories on MD are derived from the study of temporal bone anatomy, the pathophysiology of MD has been inferred from the observed pathology. This is not always an ideal correlation as several insults, such as noise, can alter cochlear function without altering structure. Hence, one has to exercise caution while inferring the clinical con‐

The central theory has not only dominated the pathophysiological dogma of MD but also influ‐ enced the design of various tests such as glycerol test or potential ratios (AP/SP; explained later) used to diagnose the "hydrops" and by extension MD. Most medical and surgical ther‐ apies in practice and in research are aimed at reducing the "hydrops." Animal models are designed to recreate the "hydrops" as a model for MD. Most research is focused on discovering

Specific causes of hydrops include infectious (viruses and syphilis), allergic, genetic, trauma,

Viruses: Studies testing the endolymphatic sac of MD patients show the presence of viral DNA notably Varicella‐Zoster virus (VZV), Epstein‐Barr virus, cytomegalovirus and conflictingly absence of herpes simples viruses 1 and 2 [7] or its presence in the vestibular ganglion [8], with inactive serum titers during attacks, leading to a statistically based theory of latent inactive viral infections related to MD, with possible early VZV infection in childhood affecting the endo‐ lymphatic sac later in life. However, antiviral medications have no role in the treatment of MD. Syphilis: Congenital or acquired syphilis was found to be the cause of MD in 6% of all cases, with pathogenesis of endolymphatic hydrops and osteitis of the capsule believed to cause the

autoimmune, otoconia or otoliths and low cerebrospinal fluid (CSF) pressures.

symptoms. This entity responds to steroid administration [9].

tion of wave conduction by the hydrops is linked to the cochlear dysfunction.

dition of Meniere's disease from the pathological condition of hydrops.

mainly vestibular symptoms [6].

56 Up to Date on Meniere's Disease

**4.1. Role played by the central theory**

various etiologies or mechanisms of hydrops.

**4.2. Etiology of the hydrops**

Allergy: Studies found an inhalant allergy in 41.6% and a food allergy in 40.3% of patients with MD in comparison with rates of 27.6% and 17.4% in their control population [6]. The theory involves antigen exposure leading to a sudden influx of fluid into the endolymphatic sac (which is immunologically active), resulting in a rupture of Reissner's membrane. The resulting influx of potassium and its excitotoxicity causes the symptoms. Other theories involve deposition of circulating immune complex leading to inflammation. Patients on aller‐ gic immunotherapy have shown better control of their vertigo symptoms [6].

Autoimmunity: Immune stimulation of the endolymphatic sac may cause hydrops by dis‐ turbing its fluid regulatory function. This immune involvement is possibly type 2 (tissue antigen‐antibody‐related) or type 3 (circulating immune complex‐related). A higher (30–50%) percentage of MD patients have circulating antigen‐antibody complexes) compared to normal people; however, the detection of antibodies to vestibular antigens was lower (20%) and more variable. The deposition of the immune complexes possibly results in increased vascular per‐ meability and hence an imbalance in the fluid electrolyte concentration [6]. Various cytokines such as interleukin‐1alpha, tumor necrosis factor alpha, NF kappaB P65 and P50 have been found to be produced in cochlear cells such as type 1 fibrocytes and root cells of spiral liga‐ ment, demonstrating that local or systemic production of inflammatory ligands may play a role in cochlear dysfunction [12].

Otoconia: Studies using three‐dimensional (3D) computerized tomography (CT) imaging in patients show that hydrops in MD patients might be caused by obstruction of the duct reunions by loose otoconia in the saccule [13].

Otitis media: Otitis media has been linked to the development of MD either later on in life (in childhood exposures, with vertiginous symptoms predominating) or concurrently with fluctuating hearing loss being the dominant presentation. The postulated pathophysiology involves the development of hydrops linked to labyrinthitis and or otitis media due to the under‐development of the duct and sac due to the associated inflammatory sequelae in the mastoid [14]. Another possibility is the spread of infectious or inflammatory products into the perilymphatic space, which may disrupt the electrolyte homeostasis and osmotic pressures thus resulting in hydrops [6].

Trauma: Physical or acoustic trauma has been linked to MD through the dysfunction of cells involved in endolymphatic homeostasis or the traumatic displacement of cellular debris and otoconia which could physically or chemically result in hydrops [6]; studies in veterans with such trauma, however, do not provide adequate backing to this theory [15]. The bilaterality of MD cannot be explained in cases of unilateral trauma.

Otosclerosis: Patients with otosclerosis have been found to have symptoms of MD due to the otosclerosis enveloping the aqueduct or invading the endosteum, resulting in changes in the flow and chemical composition of endolymph and perilymph [16].

Low cerebrospinal fluid pressures: Connections between the inner ear and CSF allow pres‐ sure changes to be transmitted, notably, a drop in CSF pressures such as postoperatively, leading to decreased perilymphatic pressures and a corresponding relative endolymphatic hydrops [17].

Other mediators: nitric oxide and vasopressin: Overexpression of the inducible nitric oxide synthase enzyme results in morphological (hair cell loss) and functional changes (endoco‐ chlear threshold and potential shifts) and stria vascularis toxicity, implicated in the devel‐ opment of MD, along with other free radicals [18]. Vasopressin levels have been shown to increase before and after a vertigo attack in MD patients, in humans and experimental models possibly contributing to the development of hydrops [19].
