Fluctuating sensorineural hearing loss can present as a part of many disorders, including immune-mediated inner ear disease, sudden sensorineural hearing loss, and Ménière's disease (MD). Managing this condition is challenging not only due to the diverse realm of diagnoses but also because our understanding of the underlying causes in the majority of cases is very theoretical, thereby limiting treatment options. In this article, we describe these causes and the theories behind each disorder, and discuss how some of the latest research on the inner ear may help guide future therapeutic options.
CAUSES & ASSOCIATED DISORDERS
Immune-mediated inner ear disease includes autoimmune inner ear disease (AIED), as well as more recently identified autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS).1,2 AIED typically presents with progressive and usually bilateral sensorineural hearing loss that occurs over weeks to months.3 AIED can present as part of other autoimmune-mediated clinical syndromes, like rheumatoid arthritis or lupus, or as part of a syndrome like Cogan's syndrome, which includes inflammatory ocular symptoms (i.e., glaucoma, conjunctivitis, or uveitis) in addition to hearing loss and vestibular symptoms.4 More recently, autoinflammatory disorders have been recognized as contributing to fluctuating hearing loss.1,2 Theories about the underlying mechanisms of these diseases range from circulating immune complexes to conditioned immune cell-mediated damage in AIED versus dysfunction of the body's existing immune defense system or innate immunity.2 Diagnostic measures for these diseases remain elusive, and, for this reason, diagnosis typically requires audiologic evidence of fluctuating hearing loss and a positive response to immunosuppression.
More commonly seen is sudden sensorineural hearing loss (SSNHL), an umbrella term used to capture hearing loss that manifests within a brief period, typically less than 72 hours. Most cases are unilateral and considered idiopathic, or with no clear cause. Three major theories regarding the underlying cause include vascular compromise, cochlear trauma, and viral infection or reactivation. In individuals with a history of smoking (which causes vascular insult) or hearing loss that occurred during a strenuous activity and may cause trauma to the cochlea, the first two theories are possible. However, in others without these risk factors, the viral theory, which proposes that acute infection or reactivation causes local inflammation and membrane damage, may be considered.5 This theory has been supported by clinical studies showing elevated levels of specific viral antibodies, in vitro animal studies, as well as temporal bone biopsies showing atrophy of inner ear structures. In a few cases with a determinate cause, the causes can be broadly classified into major categories such as infectious, autoimmune, traumatic, vascular, neoplastic, metabolic, and neurologic.
MD is another group of disorders characterized by the variable presentation of a common constellation of symptoms—fluctuating hearing loss, episodic vertigo, and aural symptoms, including tinnitus and aural fullness. The international diagnostic criteria define definite MD as a condition with at least two spontaneous episodes of vertigo lasting longer than 20 minutes but less than 12 hours, an audiogram showing evidence of low- to medium-frequency sensorineural hearing loss in one ear at any point in time, and fluctuating aural symptoms such as hearing loss, tinnitus, or aural fullness.6 It is more commonly unilateral, although it may start as unilateral and progress to bilateral, and very rarely presents as simultaneous onset bilateral disease. Since many other diseases share auditory and vertiginous symptoms, the details of onset, timing, and duration are important to rule out other potential causes, like benign paroxysmal positional vertigo or vestibular migraine, before a diagnosis of MD is made.
Likely underlying this common constellation of symptoms with variable presentation are multiple contributing causes. Recently, in the case of MD, to capture the variety of presentations, five clinical subtypes of both unilateral and bilateral disease presentations have been established.7 The first and second are distinguished by timing and laterality: Type 1 refers to classic unilateral MD and metachronic bilateral MD (symptom onset in one ear followed by the other), while type 2 refers to delayed unilateral MD (hearing loss onset preceding vertigo onset by months or years) or synchronic bilateral MD (simultaneous symptom onset in both ears). The remaining categories include both unilateral and bilateral diseases, and are instead separated by risk factors, including genetic, migraine-, and autoimmune-associated conditions for types 3, 4, and 5, respectively. Among these clinical subtypes, three likely etiologies have been proposed, including those related to genes, autoimmunity, and allergies.7 Epidemiologic studies suggest that some cases of MD may stem from a sporadic mutation or an autosomal dominant inheritance, which has been appreciated in about 10 percent of cases. While various genes have been identified, no singular gene has been associated in all cases. An autoimmune etiology may be suspected in individuals with pre-existing autoimmune disorders like rheumatoid arthritis, lupus, or hypothyroidism, particularly since a common allelic variant has been identified.7 Allergy-related MD, on the other hand, is characterized by provocation by food or environmental allergies. It is thought that the systemic hypersensitivity to allergens may cause inflammation in the inner ear, ultimately triggering MD. While the identification of these possible etiologies represents an important advancement in our understanding of MD, these subtypes represent only a small proportion of MD cases. Therefore, one aim of ongoing MD research is to more confidently describe the different subtypes to more accurately predict disease progression and improve treatment.8,9
While effective treatments, both medical and surgical, exist for vestibular or balance symptoms related to these diseases, treatments for fluctuating hearing loss in these conditions are relatively ineffective and do not appear to alter the course of eventual hearing loss.8,10 Hearing aids and cochlear implants for those who fulfill candidacy requirements are all that remain for patients with these diseases. While patients with MD, a more common form of hearing fluctuation, may benefit from cochlear implants,11-13 only about 15 percent of these patients reach the point of being potential cochlear implant candidates.8 Thus, there remains a significant need to improve our understanding of these disorders to find new treatments for fluctuating hearing loss.
To understand the possible basis of these diseases, some details about the cochlea must be discussed. The cochlea contains three fluid-filled chambers, two of which contain perilymph (scala tympani, scala vestibuli), high in sodium similar to plasma or blood, and one that contains endolymph (scala media), which is high in potassium (Fig. 1). Ionic homeostasis is critical for hearing.14,15 Diseases where hearing fluctuation is a common feature have demonstrated the presence of a common histological feature: endolymphatic hydrops. This feature is defined by the expansion or bulging of the central endolymph-containing compartment of the cochlea, known as the scala media. Endolymphatic hydrops has been appreciated in human temporal bone studies16 and, more recently, with the use of delayed-contrast gadolinium MRI.17,18 This observation is thought to be reflective of an underlying dysfunction in cochlear ionic homeostasis.16,19
In the cochlea, one of the major players in ionic homeostasis is the stria vascularis (SV), which is in the lateral wall of the cochlea and serves as a battery for the inner ear by generating endocochlear potential (Fig. 1). The SV is composed of three main cell layers consisting of marginal cells (directly abutting the endolymph), intermediate cells, and basal cells. These cell types work together to perform functions related to ionic homeostasis. Pathology involving different cell types in the SV has been implicated in disorders with hearing fluctuation, including MD,20-22 AIED,23 and SSNHL.24 Furthermore, a recent study suggests that these three major cell types have unique gene regulatory mechanisms underlying their function.14 Using single-cell RNA-sequencing, Korrapati and colleagues identified gene regulatory networks responsible for SV function, as well as the potential for repurposing FDA-approved drugs to target these networks. Understanding how genes define cell types may enable the identification of cell types involved in fluctuating hearing loss and point to potential treatments for hearing fluctuation.
In diseases where ionic homeostasis or fluid regulation processes are disrupted (potentially including hearing fluctuation disorders), understanding what inner ear cell types are involved and how processes related to fluid dysregulation might be targeted by existing FDA-approved medications could be critical to discovering new treatments. Understanding existing anti-inflammatory mechanisms in the inner ear that could be augmented by repurposed FDA-approved medications may also be a potential avenue for treating diseases wherein the effects of inner ear inflammation induced by viruses might be suppressed. The discovery of these new potentially repurposable medications might create opportunities to test their efficacy in human hearing fluctuation disorders, including sudden sensorineural hearing loss and MD, where the underlying cell types and mechanisms involved are still poorly understood.
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