**10. Physiology of clinical symptoms and hydrops**

#### **10.1. Fluctuating hearing loss and episodic vertigo**

As outlined earlier, a possible explanation for the fluctuating hearing loss and episodic vertigo seen in MD patients is brief, acute rises in pressures resulting in membranous ruptures, resulting in cochleovestibular dysfunction due to ionic disequilibrium (potassium excitotoxicity). Healing of these ruptures sets the stage for symptom resolution. The correlation of electron microscopic damage visualized in animal models of hydrops, such as hair cell loss, neuronal damage and spiral ganglion cell and ligament damage, is purported to be responsible for the hearing deficits.

A physiological basis of the Hennebert sign (vertigo occurring when static pressure is applied to the ear) is the presence of vestibular fibrosis (part of the pathological manifestations of the disease which may form band‐like connections between the footplate of the stapes and the utricular macula [29].

#### **10.2. Aural fullness**

Patients often complain of aural fullness (a blocked or full sensation) which, while colloquially has been attributed to the hydropic swelling, has no scientific basis due to the lack of inner ear receptors to relay this information to the brain and the improbability that a minute increase in endolymphatic volume would be adequate to stretch the round window to results in this full‐ ness sensation. A possible explanation could be the childhood association of a common middle ear disease (otitis media) with its prominent sensation of fullness with the low‐frequency hear‐ ing loss which accompanies middle ear conductive pathologies. In essence, the low‐frequency hearing loss experienced by the patient is accompanied by fullness as a learned association.

#### **10.3. Recruitment**

Loudness intolerance or recruitment also seen in MD patients is due to the loss of the outer hair cell function which serves to fine‐tune or evoke region‐specific responses of the basilar membrane to varying frequencies. As a result, larger regions of the membrane and hence a larger population of neurons are excited for a stimulus which is usually interpreted as increased signal intensity. Altered perception of pitch, a symptom of MD, is similarly explained by the abnormal recruitment of neurons. The brain thus perceives different signals from the "normal" and the "affected" ear for a given sound, resulting in the perception of two sounds. This unusual symptom is notable in MD due to the asymmetry of the disease process.

#### **10.4. Tinnitus**

bones via a micro‐CT and functional electrographic recordings shows that they are not solely responsible for the acute ear dysfunction, rather the hydrops is a continuing, prolonged process with Non‐rupture mechanisms in play, which can be correlated clinically with MD too [28].

The CNS modulates functions of the inner ear by several mechanisms, which may have a bearing on the pathophysiology of MD. Alterations in autonomic activity may modulate vas‐ cular tone which could set off an acute attack with longer term effects resulting in a chronic damage. Since cochlear fine tuning is compromised in MD, it is likely that efferent pathways are likely to be involved in acute attacks. The role of the neuroendocrine system causing meta‐

As outlined earlier, a possible explanation for the fluctuating hearing loss and episodic vertigo seen in MD patients is brief, acute rises in pressures resulting in membranous ruptures, resulting in cochleovestibular dysfunction due to ionic disequilibrium (potassium excitotoxicity). Healing of these ruptures sets the stage for symptom resolution. The correlation of electron microscopic damage visualized in animal models of hydrops, such as hair cell loss, neuronal damage and spiral ganglion cell and ligament damage, is purported to be responsible for the hearing deficits. A physiological basis of the Hennebert sign (vertigo occurring when static pressure is applied to the ear) is the presence of vestibular fibrosis (part of the pathological manifestations of the disease which may form band‐like connections between the footplate of the stapes and the

Patients often complain of aural fullness (a blocked or full sensation) which, while colloquially has been attributed to the hydropic swelling, has no scientific basis due to the lack of inner ear receptors to relay this information to the brain and the improbability that a minute increase in endolymphatic volume would be adequate to stretch the round window to results in this full‐ ness sensation. A possible explanation could be the childhood association of a common middle ear disease (otitis media) with its prominent sensation of fullness with the low‐frequency hear‐ ing loss which accompanies middle ear conductive pathologies. In essence, the low‐frequency hearing loss experienced by the patient is accompanied by fullness as a learned association.

Loudness intolerance or recruitment also seen in MD patients is due to the loss of the outer hair cell function which serves to fine‐tune or evoke region‐specific responses of the basilar

**9. The role of CNS in MD**

60 Up to Date on Meniere's Disease

bolic dysfunction is yet to be elucidated.

utricular macula [29].

**10.2. Aural fullness**

**10.3. Recruitment**

**10. Physiology of clinical symptoms and hydrops**

**10.1. Fluctuating hearing loss and episodic vertigo**

A possible explanation for the tinnitus could be related to a similar broad tuning of the cochlear membrane. A reduced functioning of the receptors and nerves at the cochlear apex may allow the CNS to interpret the boundary zone between the active cochlea and the inac‐ tive apex as tinnitus. Another mechanism could involve channels getting inputs from the inactive area of the nerve fibers, which would optimize their gain, leading to amplification of internal signals thus resulting in tinnitus.

#### **10.5. Chronic symptoms**

Irreversibility of symptoms and chronic deterioration in hearing are explained by the perma‐ nent morphological changes such as distortions in the ampulla walls, utricular macula and atrophy of the cristae. Such distensions of the lateral ampulla have been shown to be associ‐ ated with impaired vestibular function tests [30]. While light microscopy may not always show obvious pathology, electron microscopy showing degeneration of unmyelinated axons may explain the symptoms such as loss of speech discrimination despite intact hair cells and spiral ganglion cells [31].

## **11. The evidence‐based findings between hydrops and symptoms**

Hyperosmolar agents and diuretics, such as glycerol and furosemide, respectively, have been used since several decades in the evaluation of patients with suspected hydrops. Several studies show that the hydrops is temporarily relieved by their mechanism of action [32–34], resulting in an improvement of hearing and or vestibular symptoms in some case, thus strengthening the case for hydrops being responsible for MD symptoms.

The results of electrocochleographic observations in MD patients also support a temporal correlation. This increase of the SP in patients with early MD, along with studies showing a positive temporal correlation of enhanced SP and symptom reporting and finally a decrease of the SP with the use of hyperosmolar agents [35], all strengthen the premise of hydrops being responsible for symptom constellation.

To explain the lack of symptoms in animal models of EH and as an alternative to the argu‐ ment that hydrops cannot occur rapidly enough to cause an acute attack of symptoms, it was postulated that acute attacks of MD can be attributed to the biochemical effects of endolym‐ phatic ruptures (not traditionally seen in animal models) specifically of Reissner's membrane. However, human temporal bone studies also do not consistently reveal theses ruptures or they have been attributed to postmortem‐processing artifacts, strengthening the theory that the pressure effects along with biochemical effects act in concert. With regard to the theory that ruptures are responsible for the acute attacks, studies have questioned the likelihood of a rupture in one anatomical area impacting the function of other areas, or the likelihood of simultaneous rupture of both the cochlear duct and saccule (not supported by histology find‐ ings) affecting cochlear and vestibular functions [36]. It is also logical extension of theory to expect relief of symptoms after rupture, as relief of the pressure should alleviate symptoms.

Vestibular symptoms such as nystagmus were induced in animal models with an injection of artificial endolymph into the perilymphatic space, presumed to represent the actual events in play during an attack of episodic vertigo [37].

Imaging studies in vivo using gadolinium‐contrasted magnetic resonance imaging (MRI) demonstrated that in MD, different areas affected by the EH (vestibular vs. cochlear) were correlated to different symptoms experienced by patients as seen in the distinct cochlear or vestibular variants of Meniere's disease [38]. Such imaging studies also found a correla‐ tion between the progress of the EH imaged with the clinical deterioration of the inner ear functional measurements [39], strengthening the role of hydrops in the pathophysiology of MD.

Measuring the cross‐sectional area of the scala media in vivo overcomes the drawbacks of histological shrinking and other artifacts. It has been used in animal models of hydrops with an endolymphatic marker, to study the temporal relation in the development of hydrops, post duct ablation (occurs within days). Functional deficits, measured electrophysiologically (such as cochlear potentials), were surprisingly initially only small changes and most marked at the 8‐ to 16‐week time period when no further hydrops or endolymphatic expansion occurred. The logical extension, if it holds true in humans, would imply that factors apart from or in addition to the hydrops could be responsible for symptoms and relieving the hydrops may not restore normal functioning [40].

Studies determined that the hydrops causes a displacement of the basilar membrane toward the scala tympani which due to anatomical considerations is predominantly at the apex of the cochlea affecting its mechanical‐electrical properties. This displacement results in sensorineu‐ ral hearing loss of frequency below 100 Hz (due to anatomical locations of receptors) which is unlikely to result in clinically appreciated hearing loss, usually tested at frequencies of 250 HZ and higher. Thus, this in endolymphatic hydrops, the pathological findings do not correlate to the low‐frequency hearing lost observed in Meniere's disease [41].
