Sudden sensorineural hearing loss: Is there a connection with inner ear electrolytic disorders? A literature review

Abstract

Electrolytic disorders of the inner ear represent a model that could be implicated in partially explaining the pathogenesis of sudden sensorineural hearing loss (SSNHL). Different types of electrolytes and different inner-ear loci are involved in cochlear homeostasis physiologically, to ensure the maintenance of an ion-balanced cochlear environment allowing a normal hair cell function. It has been hypothesized that a sudden loss of endocochlear potential, due to a rapid disruption of the inner ear fluid osmolality, could be responsible for a deterioration of the hearing function caused by damaged hair cells. The aim of this paper was to review the current literature and identify sources which might validate/fortify the hypothesis that inner ear electrolytic disorders have a role in the etiopathogenesis of SSNHL. The data in the literature underline the importance of ionic homeostasis in the inner ear, but they do not support a direct link between SSNHL and electrolyte disorders/imbalances. There is marginal evidence from otoacoustic emissions research that an indirect link might be present.

Introduction

Sudden sensorineural hearing loss (SSNHL) is frequently observed in the audiological and otorhinolaryngological practice. It is defined as sensorineural hearing loss of 30 dB or greater over at least three contiguous frequencies, occurring within a 72-h period. ¹ Hearing loss usually arises suddenly, with no preceding signs or symptoms. ² The reported incidence of SSNHL is 5–20 per 100,000, ³ although the true incidence may be higher, as affected individuals who quickly recover do not seek medical care. ⁴ The peak incidence is reported to be between the fifth and sixth decade of life and occurs with equal incidence in men and women. ⁵ Many etiologies have been proposed for the pathogenesis of SSNHL, including vascular disorders, viral infections, endolymphatic hydrops, rupture of labyrinthine membrane, and inner-ear immune-mediated disorders. ²

Nonetheless, only 7–45% of patients affected by SSNHL can receive an etiological definition: ⁶ the majority of SSNHL cases are still idiopathic and the precise etiology remains unknown.^5–7 A sudden imbalance of the inner-ear electrolytes could explain not only the quick onset of SSNHL, but also the possibility of a partial or total hearing recovery, due to the recuperation of the cochlear ionic transport and inner ear osmolality.^8–10 In contrast to the classical theories of SSNHL etiopathogenesis (direct vascular damage to hair cells, cochlear membrane rupture, auto-immunity or immune-mediated disorder, viral infection, stress response theory), it is plausible that cochlear hair cells could be damaged indirectly, by induced ionic imbalances, and that the observed recovery of the hearing function could be the consequence of a recovery of the inner-ear fluid osmolality. In this scenario, an etiological agent should affect those sections of the inner ear that are involved in the electrolytic balance; for example, the stria vascularis or the fibrocytes of the underlying spiral ligament.^9,10 These loci are involved in the transport and the circulation within the cochlea of Na⁺, K⁺, and Fe²⁺ ions.^11–13 Iron metabolism has been claimed to be involved in the homeostasis of the endolymphatic space affecting the volume and the acidification of the endolymph and its role has been recently compared to that of the K⁺. Furthermore, magnesium has been reported to be implicated in the permeability of the sensory cellular membranes, including hair cells, and its deficiency results in a reduction of the electrochemical gradient required for sensory transduction. ¹²

Therefore, several inner-ear loci apart from hair cells could be directly/indirectly involved in the etiopathogenesis of SSNHL. The identification of these loci is important because these represent possible targets of future inner-ear therapies, including local regenerative strategies.

The aim of this paper was to review the current literature and present the available evidence which links inner ear electrolytic disorders to the etiopathogenesis of SSNHL.

Methods

The PubMed database was searched up to January 2016 within a 10-year span. Full text articles were obtained when the title, abstract, or keywords suggested that the study may be eligible for this review. The search was carried out independently and restricted to papers in the English language. Additional papers were also identified from the references in the published literature.

The medical subject heading (MeSH) included terms such as: inner ear; electrolytic disorders; Sudden Sensorineural Hearing Loss; K⁺/Na⁺; Fe²⁺; Ca²⁺/Mg²⁺; and Cl^–.

Results

Inner ear Na⁺/K⁺ homeostasis and SSNHL

The stria vascularis and the spiral ligament are both essential for maintaining the endocochlear potential, as both have been reported to retain Na⁺-K⁺ ATPase activity.^13–17 The Na⁺-K⁺ ATPase activity is also the most studied ion transportation system within the inner ear so far.

The stria vascularis is a complex structure organized into three different cellular layers (marginal cells, intermediate cells, and basal cells). Within this structure, there are also perivascular-resident cells, known as melanocyte-like macrophages that play a role in the regulation of the integrity of the intra-strial blood–labyrinth barrier situated between blood flow and the intrastrial region. ¹⁷ The blood–labyrinth barrier is important not only to prevent the influx of toxic substances into the inner ear, but also for inner-ear homeostasis itself.^18,19 It is composed of endothelial cells (connected to each other by tight junctions ²⁰ ), an underlying basement membrane, a large number of pericytes, ²¹ and perivascular resident macrophages. ¹⁸ This system plays an important role in the transport of metabolites and electrolytes, Na⁺/K⁺ mainly, between the inner-ear endolymph and perilymph. ¹⁹ A specific damage to this delicate structure (i.e. the absence of melanocytes-like macrophages) has been reported to increase vessels permeability through an alteration of the tight junctions with a reduction of the endocochlear potential by altering the Na⁺-K⁺ ATPase activity, therefore causing hearing impairment, as indicated in experiences with melanocytes-deficient mutant rats. ²⁰

Also, fibrocytes of the spiral ligament have been reported to play a crucial role for inner-ear homeostasis; these have been distinguished into four types: in particular, type II fibrocytes show Na⁺/K⁺ ATPases and Na⁺/K⁺/Cl^– co-transporters and are in gap junction continuity with type I fibrocytes and basal cells, suggesting their key role in preserving the ionic environment. ²¹ Basal cells are joined with intermediate cells and fibrocytes of the spiral ligament by gap junctions. ²² The intra-strial space contains fluid comparable to perilymph and is delimited by marginal cells as a barrier against endolymph and by basal cells as a barrier against vessels of spiral ligament.^23,24 These barriers have to separate the fluids of the inner ear in order to maintain of the ionic gradient. The intermediate cells, with their active transport mechanisms (Na⁺/K⁺ ATPase), are co-responsible in generating the endolymphatic potential.^25,26

K⁺ ions are key elements for sensory transduction in the inner ear. The ionic transport system consists of extracellular flow through scala tympani and scala vestibule, and transcellular flow through the organ of Corti, supporting cells, and cells of the lateral wall. ²⁷ Type II and type IV fibrocytes resorb potassium ions from the surrounding perilymph and from outer sulcus cells via the Na⁺/K⁺ ATPase. The potassium ions are then conveyed to type I fibrocytes, strial basal cells, and intermediate cells through gap junctions and are transported into the intra-strial space through the potassium channels. Potassium is incorporated into marginal cells by Na⁺/K⁺ ATPase and the Na⁺/K⁺/Cl^– co-transporter and finally secreted into the endolymph through their channels. Impairment of such an ion transport system has already been assumed to result in hearing loss,^28–30 including sudden sensorineural hearing loss.^28,29

Inner ear Fe²⁺ homeostasis and SSNHL

The Fe²⁺ metabolism has been claimed to be involved in the homeostasis of the endolymphatic space, as it has been reported to interfere with the volume and the acidification of the endolymph, and its role has been recently compared to that of the K⁺.^{13–15,30,31} Iron is present in different sections of the inner ear and it has been reported that it is vehiculated by several proteins such as ferritin, transferrin, and ferroportin, differently available within the cochlea. For this reason, it has been proposed that Fe²⁺ ions could follow a cycle similar to that of potassium, also through gap junctions within the cochlea. ¹⁵ Since ferritin, transferrin, and ferroportin have different localization within the cochlea, respectively, the stria vascularis, the organ of Corti, and the intracellular space, it is likely that the Fe²⁺ is transported within the inner ear from small vessel to the stria vascularis and from the latter to the inner hair cells, as outer and inner hair cells may include a small amount of divalent ions through calcium channels. ¹⁵

Within cells, including hair cells, iron participates in many enzymatic reactions, as it is involved in several metabolic functions, mainly in protection against damage by free radicals. Also among the inner ear, iron is involved in the function of mitochondrial enzymes such as peroxidase;^13,14,30 in case of iron deficiency, it has been reported that its reduced activity generates increased intracellular levels of reactive oxygen.^13,14,30 Similarly, succinic dehydrogenase is another enzyme containing iron involved in the mitochondrial respiration and present within the cochlea. ³⁰ A disorder that reduces the activity of this enzyme, nor an iron depletion, has been reported to cause increased reactive oxygen activity, cellular/tissue damage and therefore hearing loss, including sudden hearing loss.^13–15,30

Inner ear Mg²⁺ homeostasis and SSNHL

It seems that Mg²⁺ (and Ca²⁺) are involved in different inner ear hair cells pathways including those related to cellular apoptosis.^16,32 Vormann and Gunther, in 1991, first demonstrated experimentally that Mg²⁺ deficiency aggravated ototoxic effects of aminoglycoside antibiotics (gentamicin). In particular, Mg²⁺ is reported to be involved in permeability of hair cell membranes, as it has been observed that its deficiency reduces the electrochemical gradient required for hair cell transduction.^32–35 Its deficiency has also been linked to hair cells’ increased susceptibility to reactive oxygen damage. ³⁶ Magnesium is reported to be necessary for axonal and neuronal stabilization ³⁷ and influences the release of neurotransmitters at the neuromuscular junction. ³⁷

Mg²⁺ deficiencies are associated with increased susceptibility of noise-induced hearing loss, ototoxicity, and sudden hearing loss.^34,38 Although the exact mechanisms are unknown, the consequent effects of Mg²⁺ depletion appear to be relevant for hair cells and auditory nerve function. ³⁸ Besides, Mg²⁺ supplementation has already been proposed in the literature for the treatment of SSNHL, with controversial results.^34,38

Also, data in the literature suggest that extracellular Mg²⁺ can interact with the stria vascularis, increasing the cochlear blood flow. The exact mechanism of the Mg²⁺ interaction still remains unclear. ³⁶

Inner-ear anions homeostasis and SSNHL

Anionic disorders as well as cationic disorders could be involved in the onset of SSNHL. The Cl^– imbalance could be responsible for the hearing disorders during furosemide therapies. As a loop diuretic, furosemide inhibits Na⁺-K⁺-2Cl^– co-transporter. ³⁹ This superficial protein is also present in the dark and marginal cells of the stria vascularis: it is possible that its inhibition may determine an ionic imbalance in the endolymph, responsible for a SSNHL. ³⁹ Moreover, hearing loss is often reversible, suggesting that a chloride disorder in the inner ear may be important for the maintenance of hearing function.

Furthermore, there are numerous hereditary syndromes characterized by kidney dysfunctions and associated deafness. For example, one of the most common genetic disorders responsible for sensorineural hearing loss is Pendred syndrome. It is caused by a mutation involving the SLC26A4 gene, or pendrin, gene, an anion exchanger protein localized in the inner ear, thyroid gland, and kidney. ³⁹ In particular, it is involved in the exchange of Cl^– and iodide. Again, it seems that an alteration of the endolymphatic anionic composition could be responsible for the hearing disorder.

The link between kidney diseases and hearing dysfunctions is well-known. ³⁹ Patients affected by renal failure and/or undergoing artificial dialysis are at risk of developing a SSNHL.^40–45 Nevertheless, to the best of our knowledge, there are few cases reported in the literature about SSNHL during hemodialysis,^46–48 but little is known about its etiology. The osmotic disorder induced by artificial dialysis and the disruption of ion homeostasis caused by kidney failure could represent a possible cause of sudden hearing defect.

Other ions in the inner ear and SSNHL

A number of reports in the literature include data on other ions within the cochlear tissues, such as Zn (zinc), Cu²⁺ (copper), and Se (selenium), linking their presence to a normal hearing function.^36–38 There is no evidence so far to connect their depletion to SSNHL. ³⁴

Pathophysiology of SSNHL and inner-ear electrolytic disorders

The majority of SSNHL cases still remain idiopathic.^7,49 Several hypotheses about the pathophysiology of idiopathic SSNHL have already been proposed;^50–63 the most widely accepted theories are direct vascular damage,^40–50 cochlear membrane rupture,^51,52 auto-immunity or immune-mediated disorder,^52–57 viral infection,^4,58–63 and stress response theory. ⁵⁹ However, at least in some cases, an etiologic agent (either vascular, infective, or immune-mediated) could damage hair cells, indirectly, disrupting their metabolic activity, reversibly or irreversibly. A sudden imbalance of the inner ear osmolality could explain either: (1) the quick presentation of SSNHL, based on an acute and selective damage of cochlear districts different from hair cells (i.e. the stria vasularis or spiral ligament fibrocytes) and consequentially causing sudden loss of hearing (partial or total); or (2) the possibility of hearing recovery (partial or total) due to the spontaneous recuperation of the endocochlear ionic environment.^29,60–62

Also, an alteration of inner-ear vascular permeability could explain a sudden hearing defect: an endothelial dysfunction of the microcirculation of the inner ear, for example due to oxidative stress, ⁶⁴ may cause a disruption of the normal ionic exchanges between blood and the stria vascularis and between the stria vascularis and the perilymph. ⁵⁶ Furthermore, the lateral wall of the cochlea participates in the regulation of inner ear pH and, as a consequence, a sudden damage of the stria vascularis and/or spiral ligament could lead to a cochlear pH alteration. Cochlear ionic transport is very sensitive to pH variation: the endocochlear potential may be reduced by an acidification of pH and this could be responsible of a sudden inner-ear dysfunction and hearing loss. ⁶⁵

According to the data in the literature, endocochlear ions that could be involved in this pathological mechanism, might include the following: K⁺/Na⁺;^28–30 Fe²⁺;^13–15,30 Ca²⁺/Mg²⁺;^34,38 and Cl^–. ³⁹

Discussion

The objective of this review was to question the validity of the hypothesis stating that “inner ear electrolytic disorders/imbalances could be involved in the physiopathological mechanisms related to SSNHL.” The assumption included both scenarios, i.e. that electrolytic disorders could be the main factors or the contributing pathogenesis factors of SSNHL.

As of today, the data in the literature connecting SSNHL with an electrolyte inner-ear disorder/imbalance do not support such a direct link. On the other hand, there are numerous papers connecting electrolytic imbalances/disorders with sub-clinical hearing deficits. In this context, it might be plausible that additional findings in this area could support the hypothesis of this review paper. The indirect connection between SSNHL and electrolytic imbalances stems from research conducted with sensitive protocols which assess the function of the inner ear. These protocols are based on the otoacoustic emissions responses (OAEs), which are elicited when the ear is stimulated, or with a transient click signal (TEOAEs), or by a set of two continuous tones (DPOAEs).^66–68 There is adequate evidence supporting the hypothesis that OAEs are very good prognostic descriptors of the status and recovery of SSNHL.^69–71 A 2013 Chinese study by Liang et al. ⁷² correlated the effects of electrolyte disturbances (EDs) and asphyxia in a large newborn sample (>5000 participants), using TEOAEs. The data suggested that EDs have a very important role in the cases which fail to pass the TEOAE tests. The most significant effects were observed in cases presenting with hypocalcemia. These data corroborate with previous findings^28,29,73 showing that a healthy ionic homeostasis is necessary for the functioning of outer hair cells, which are the main generators of OAEs^67,68 and the cochlear amplifier. In this context, OAEs can detect and monitor SSNHL and are diminished in conditions of an electrolytic imbalance. Is it safe to assume that in cases of SSNHL the lack or alteration of the OAE characteristics can suggest am electrolytic imbalance? The answer is a plausible “yes,” but additional data are clearly needed to elucidate this argument.

The data in this review have emphasized the important role of various ions in inner-ear homeostasis and normal function. Nevertheless, to start building a connection between SSNHL and an electrolyte imbalance/disorder, a number of important questions still remain to be answered. For example:

• Which ions are more influential in ensuring the proper functioning of the endocochlear potential?

• What mechanisms are involved in the cases which show an endogenous recovery from SSNHL?

• Are these mechanisms correcting an electrolyte imbalance/disorder?

• Are the endogenous recovery phenomena a consequence of the spontaneous spiral ligament fibrocytes regeneration?

• Would it be possible to set an experimental model that could allow us to improve our knowledge in understanding the pathophysiology of perilymph/endolymph, and therefore the role of inner-ear ions?

• Is it possible to clinically monitor inner-ear ionic concentrations through novel technological approaches in inner-ear research, such as nano-technology sensors?

The true challenge for the future is to measure any ionic imbalances during a SSNHL. It is necessary to expand the knowledge among the physiopathology of several sections of the cochlea, including the stria vascularis and the spiral ligament as these represent affected or damaged sites where SSNHL originates.^32,61 These sites could also represent future targets of new inner-ear therapeutic strategies, including regenerative medicine or tissue engineering, thus representing a possible treatment option for patients affected by SSNHL.^62,63