Abstract
Multiple options exist to manage Ménière’s disease (MD), ranging from dietary modifications to ablative surgery. Corticosteroids (CS) have long been used to manage MD, but their exact mechanism for disease alleviation is relatively uncertain. Glucocorticoid receptors have been shown to exist in the human inner ear and several studies propose they influence mechanisms of blood flow, fluid regulation, and ion regulation, with recent evidence describing the latter two. Corticosteroids have been shown to upregulate aquaporins and ion channels in the inner ear, and may have a positive effect on labyrinthine blood flow. Additionally, processes have been described in genomic and non-genomic manners. This text will review the literature on the actions of CS on the inner ear relevant to MD.
1
Introduction
Ménière’s disease (MD) is a complex otologic disorder consisting of spontaneous episodes of vertigo, documented sensorineural hearing loss, and tinnitus or aural fullness unexplained by other causes . It is alternatively called endolymphatic hydrops (EH) due to the swelling seen in histological sections of the endolymphatic space. Both acute and chronic models for EH have been described in efforts to explain the pathophysiology in MD . In the acute model, mechanical manipulation of the endolymphatic space is thought to be a main driving force in hydrops. Chronic models describe histological changes such as hair cell loss, changes in endolymphatic composition, and change in biochemical pathways.
Distension and subsequent rupture of Reissner’s membrane, or transient fluid leaks, may contribute to the episodic attacks experienced in MD . The underlying pathophysiology may be an issue of hypersecretion or hypoabsorption of the potassium (K + )-rich endolymph. In the past it was thought that this phenomenon caused the cardinal symptoms of MD, however EH may be a byproduct of a deeper pathologic process as studies have shown that all patients with MD show EH but not all with EH suffer from MD .
Treatment of MD consists of dietary modifications, medical therapy, and surgery. Corticosteroids (CS) have long been prescribed in MD and are increasingly being administered intratympanically (IT). Furthermore, cortisol has been shown to be elevated in patients with MD, representing a potential coping strategy . The actions of CS are diverse and vary depending on the tissue, however their key molecular pathway involves diffusion across cell membranes and binding to intracellular receptors to alter gene expression. This traditional genomic view of steroid action takes hours to alter cellular homeostasis. There is also evidence of non-genomic actions by CS that act on the order of seconds to minutes . Thus there is considerable room for discussion on how CS affect the course of MD. This text shall review the evidence for the physiologic actions of CS in MD.
2
History of CS in MD
Glucocorticoid receptors (GR) have been studied in the inner ear of various mammalian species including rats and guinea pigs . Rarey and Curtis first discovered GRs in the human inner ear in 1996 . When comparing GR concentrations across labyrinthine sub-sites, GRs were found to be relatively highest in the spiral lamina, followed by the nonampullated portions of the semicircular ducts and the crista ampullaris. The lowest concentration was seen in the saccule. The existence of GRs in the human inner ear provides a link to which CS action can be studied to determine their effects in MD. Glucocorticoids may also be able to influence endolymphatic homeostasis through interactions with mineralocorticoid receptors in the inner ear . In guinea pigs with experimentally induced EH, it has been demonstrated that CS prevent the histological formation of EH .
3
Pharmacologic application
CS can be delivered systemically, taken orally or intravenously (IV), or locally via an IT approach. Parnes et al. showed that IT application of CS in guinea pigs yielded higher drug level concentrations in the inner ear than did systemic administration . This study was later applied in humans with similar findings . The advantages of IT administration also include avoidance of side effects from systemic therapy; however IT CS may not be possible in patients with complicated middle ear pathology. Furthermore, adequate concentrations of CS must be applied to the round window (RW), as the majority of injected medication is lost through other mediums such as the Eustachian tube or via mucosal absorption .
Multiple delivery vehicles have been studied, including microwicks and implantable catheter pumps. In a study by Plontke and Salt, a computerized model of inner ear fluid dynamics showed that longer applications of methylprednisolone to the RW result in higher absolute drug levels in the inner ear . Additional advantages include a more uniform distribution of the drug across the inner ear . The choice of using a one-shot application (IT injection) or sustained release depends on the goal of drug administration. In single-shot administration, there is an initially high concentration at the cochlear base with a steep apical gradient . Salt et al. suggested that this strategy be used for aminoglycoside therapy to limit toxic exposure and subsequent hearing loss, and that sustained delivery systems be used for drugs in which a uniform concentration needs to be established across the inner ear .
Recently, there have been developments of sustained release IT CS delivered in a thermoreversible poloxamer hydrogel matrix . Liquid at room temperature, once injected, the solution converts to a hydrogel at body temperature to provide sustained release therapy. One study showed that therapeutic levels persisted in the perilymph for 3 months in guinea pigs, over 1 month in sheep, and showed limited systemic exposure. This delivery vehicle was then studied in a randomized, double blind placebo-controlled trial in 44 humans. The agent was well tolerated and showed clinical improvements in vertigo. Other materials such as silicone-based implants are in development and various drug vehicles will require further study .
4
Molecular pathways
4.1
Aquaporins
As EH is a hallmark finding of MD, dysregulation of water and ion balances, specifically within the endolymph may be a key component of MD pathophysiology. Aquaporins (AQPs) are a group of transmembrane transport proteins that are selectively permeable to water and specific uncharged solutes (e.g. glycerol, urea, ammonia) and play an important role in regulating osmotic pressure at the cellular level. Stanković et al. first noted inner ear AQPs in 1995, and at least 8 have been found in the inner ear .
Takumi et al. showed that the supporting Hensen’s and Claudius cells expressed AQP4 and proposed a pathway for potassium reuptake to the stria vascularis . Dexamethasone has been shown to stimulate transcriptional upregulation of AQP1 and AQP3 in rats . Furthermore, delivery of dexamethasone via different routes upregulates AQP3 mRNA transcription in a dose- and time-dependent manner in the endolymphatic sac (intraperitoneal route) and cochlea (direct endolymphatic sac instillation) . Nevoux et al. recently showed that APQ3 expression as well as water transport from endolymph to perilymph was increased following dexamethasone administration .
4.2
Ion channels
Water and ion homeostasis in the inner ear is vital for hair cell function. As previously stated, in MD there is an associated dysregulation of ion and water balances. Some have suggested that MD may be due to channelopathies; CS may have an effect on ion flux . For example, Lee and Marcus showed that prednisolone application increased the current density across the stria vascularis in gerbils, suggesting increased K + secretion . This occurred in a dose- and time-dependent manner in the order of minutes, consistent with extragenomic action. Potassium plays a crucial role in the maintenance of endocochlear potential and is routinely recycled through the stria vascularis .
Two studies by Pondugula et al. examined the effect of CS on epithelial sodium channels (ENaC) in the semicircular canal duct (SCCD) . In one study they demonstrated cation absorption via ENaC after application of CS. This was shown to increase current and transepithelial voltage and decrease transepithelial resistance in a genomic manner. They proposed that glucocorticoids stimulate sodium absorption through ENaC across the apical epithelium, which is then secreted basolaterally via the Na + -K + -ATPase, contributing to volume restoration of the endolymph. In a later study, they showed that dexamethasone accomplished this by upregulating genes responsible for transcription of ENaC and K + channels. Dexamethasone was also shown to downregulate GRs in a negative-feedback manner.
Reissner’s membrane has also been shown to contain ENaC and respond to glucocorticoids . Kim et al. showed that dexamethasone increased the current density across the membrane in a genomic fashion via ENaC upregulation . A key relationship exists between ENaC, basolateral Na + -K + -ATPase, and K + channels as application of ouabain decreased current in the presence of dexamethasone. Thus, upregulation of ENaC in MD may assist in restoring endolymph composition .
MacArthur et al. recently studied the effects of prednisone and dexamethasone on cytokine and ion homeostasis genes in the inner ear . They found that CS upregulated both sets of genes but speculated that cytokines may have been upregulated due to the vehicle used to deliver the drugs or that the drug caused an initial inflammation. ENaC and AQP1, AQP2, and AQP3 were significantly upregulated by CS. The results of this study suggest that although steroids are known to exert anti-inflammatory effects, they may act more importantly on fluid/ion regulation in the inner ear.
4.3
Autoimmune
Complex interactions between the inner ear and the immune system may underlie the pathophysiology of MD. Violation of the blood-labyrinth barrier via damage or inflammatory signals, molecular mimicry, and genetic predisposition may all affect labyrinthine function . Autoimmunity may be implicated in certain cases of MD and variations in the major histocompatibility complex may predispose individuals . In a study by Gazquez et al., MD patients were observed to have a higher prevalence of rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus . Furthermore, the role of allergens and circulating immune complexes may contribute to fluid alterations in the inner ear . The use of CS in sudden sensorineural hearing loss and the subsequent response supports the idea of immune suppression for MD treatment.
4.4
Hemodynamics
Steroids are known to play a crucial role in regulating blood pressure. Alterations to inner ear blood flow and/or resultant ischemia may be potential explanations to hearing loss or vertiginous episodes and play a part in MD pathophysiology. It has been hypothesized that the hydrops phenomenon in MD acts as a Starling resistor to impair blood flow . However, the studies of CS effects on cochlear blood flow are few and demonstrate conflicting results. Shirwany et al. noted an increase in guinea pig cochlear blood flow while Chiang et al. found no difference following dexamethasone administration . Similarly, Lamm and Arnold found no effect of prednisolone on blood flow the noise-damaged guinea pig cochlea . Instead, it may be that the effects of CS on fluid dynamics have an indirect effect on labyrinthine blood flow.
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