The Impact of Neuroglia on Vestibular Disorders: Insights and Implications

Abstract

Vestibular disorders significantly affect individuals by impairing balance, spatial orientation, and quality of life. Despite the focus on neuronal mechanisms, emerging research emphasizes the importance of neuroglia—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the onset, progression, and resolution of these conditions. This narrative review explores the roles of neuroglia in vestibular disorders, including vestibular migraines and unilateral and bilateral vestibulopathies. It discusses established facts, challenges, and future perspectives, offering insights into their pathophysiological roles and therapeutic implications, and the limitations of current research. By understanding the interplay between neuroglia and vestibular function, this review aims to advance diagnostic and treatment strategies for these disorders

1. Introduction

Vestibular disorders are a group of conditions that disrupt the vestibular system’s capacity to maintain spatial orientation and postural balance, significantly reducing quality of life [1]. These disorders include a spectrum of conditions such as vestibular migraines, unilateral vestibulopathy (e.g., vestibular neuritis), and bilateral vestibulopathy [1]. Each of these conditions manifests with varying degrees of dizziness, vertigo, imbalance, and, in some cases, cognitive deficits or psychological distress [2,3]. While the neuronal mechanisms underlying these disorders have been extensively investigated, the contribution of neuroglia to their pathophysiology remains underexplored and undervalued [3].

Neuroglia, the non-neuronal cells of the nervous system, play pivotal roles in maintaining homeostasis, supporting neuronal functions, and mediating immune responses [4]. Astrocytes, for instance, regulate the extracellular ionic balance and neurotransmitter clearance, contributing to synaptic stability and function [4]. Microglia, often regarded as the immune sentinels of the central nervous system (CNS), are crucial in responding to injury and infection but can also drive neuroinflammatory processes that exacerbate neural damage [4]. Oligodendrocytes and Schwann cells facilitate efficient nerve signal transmission by producing myelin in the CNS and peripheral nervous system (PNS), respectively [4]. Emerging evidence indicates that these glial cells are not passive supporters but active participants in disease processes, influencing inflammation, repair, and recovery in vestibular disorders [4,5].

Understanding the roles of neuroglia in vestibular disorders is not merely an academic endeavor [5]. It holds profound clinical implications for improving diagnostic accuracy, devising novel therapeutic strategies, and optimizing patient outcomes [5,6]. As vestibular compensation and central adaptation heavily rely on the interplay between neurons and glial cells, a deeper exploration into these processes may uncover new avenues for managing chronic dizziness, incomplete recovery, and refractory symptoms [5,6]. Moreover, such knowledge could help identify biomarkers for early diagnosis and monitor therapeutic efficacy. This review explores the key roles of neuroglia in vestibular disorders, summarizing current knowledge, challenges, and future directions in the field.

2. Materials and Methods

This narrative review was conducted through an extensive literature search using multiple databases, including PubMed, Scopus, and Web of Science. Search terms employed included “neuroglia”, “vestibular disorders”, “vestibular migraine”, “unilateral vestibulopathy”, “bilateral vestibulopathy”, “microglia”, “astrocytes”, “oligodendrocytes”, and “Schwann cells.” The search focused on peer-reviewed articles published in English within the past two decades to ensure contemporary relevance and validity of findings. Articles were included if they provided direct insights into the roles of neuroglia in pathophysiology, diagnosis, or treatment of vestibular disorders. Both animal studies and clinical investigations were reviewed to provide a comprehensive understanding of neuroglial involvement across different experimental models and human conditions. Studies focusing solely on neuronal mechanisms without reference to neuroglia were excluded to maintain the scope of the review. The data extracted from the selected studies were categorized into major themes: established facts, controversies, challenges, future perspectives, and limitations.

3. What Is Known to Date

3.1. Vestibular Migraine

Vestibular migraines represent a multifaceted condition at the intersection of migraine pathology and vestibular dysfunction, presenting significant challenges both in diagnosis and treatment [7]. These episodes are typically characterized by recurrent vertigo or dizziness, accompanied by classic migraine symptoms such as severe headache, photophobia, and phonophobia [8]. However, what distinguishes vestibular migraines from common migraines is the involvement of the vestibular system, leading to disturbances in balance, spatial orientation, and visual processing [9,10]. Over recent years, there has been growing recognition that the pathophysiology of vestibular migraines is deeply intertwined with neuroglial mechanisms, especially those related to central sensitization and neuroinflammation, which play critical roles in both the migraine and vestibular dysfunction observed in these patients [9,10]. Astrocytes, the star-shaped glial cells of the central nervous system, are essential for maintaining the delicate homeostatic environment that neurons require for optimal function [11]. In the context of vestibular migraines, a dysregulation in astrocytic activity has been implicated in several pathological processes [12]. Astrocytes are responsible for maintaining the balance of neurotransmitters such as glutamate, as well as ions like potassium, within the extracellular space [11,12]. When astrocytic function becomes impaired, this balance is disrupted, leading to an environment that fosters neuronal hyperexcitability—one of the core features of migraine disorders [11,12]. Specifically, in vestibular migraines, astrocytes fail to adequately clear excess glutamate from synaptic clefts, which contributes to a phenomenon known as excitotoxicity [13]. This results in sustained neuronal firing, which perpetuates the migrainous state and intensifies the episodic nature of both the vertigo and the headache experienced by patients [14]. Furthermore, disruption of astrocyte-mediated support in areas such as the vestibular cortex may provide an explanation for the integration issues observed between vestibular and visual inputs in these patients, leading to the complex sensory disturbances that define vestibular migraines [15]. In addition to astrocytes, microglia—the resident immune cells of the CNS—play a pivotal role in the neuroinflammatory processes associated with vestibular migraines [16]. Microglial cells become activated in response to a variety of excitatory or inflammatory triggers, such as the elevated levels of glutamate and the associated neuronal hyperactivity seen in these disorders [16,17]. Once activated, microglia release pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which amplify pain pathways and heighten the sensitivity to stimuli [18]. These cytokines also disrupt the normal connectivity of neural networks, exacerbating the sensory and cognitive symptoms of vestibular migraines, including vertigo, dizziness, and cognitive disturbances [18]. Moreover, chronic microglial activation can lead to persistent neuroinflammation, which may contribute to structural changes in key regions such as the vestibular nuclei, thalamus, and cortical areas involved in sensory integration [19]. These changes further impair vestibular processing and contribute to the long-term deficits seen in some patients with vestibular migraines [19]. Despite the growing understanding of the roles that astrocytes and microglia play in vestibular migraines, significant controversies remain, especially concerning the exact nature of their involvement [20]. For instance, it is still unclear whether microglial activation is a primary driver of the disorder, initiating the cascade of symptoms, or if it is merely a secondary response to the heightened neuronal activity and excitotoxicity that occur during episodes [19]. Additionally, while much focus has been placed on the central nervous system’s role in vestibular migraines, the contribution of peripheral elements, such as Schwann cells and oligodendrocytes, remains poorly understood [21]. Schwann cells are involved in the repair of peripheral nerve damage and are integral to maintaining the integrity of peripheral nervous system function, while oligodendrocytes support myelination in the central nervous system [22]. Understanding how these cells interact with central glial mechanisms, particularly in relation to the vestibular system, could offer valuable insights into the pathophysiology of vestibular migraines and help guide the development of more effective treatment strategies [23]. Addressing these gaps in our understanding is crucial for the future of vestibular migraine management [24]. Comprehensive therapeutic strategies must target both the central and peripheral components of the disorder, incorporating approaches that modulate the neuroglial activity in the CNS while also addressing any dysfunction in the peripheral vestibular system [24]. As our knowledge of the neuroglial underpinnings of vestibular migraines continues to expand, it will be essential to explore novel treatment avenues that can more effectively address the complex interplay between the brain’s migraine mechanisms and the vestibular dysfunction, which significantly impacts patients’ quality of life [24].

3.2. Unilateral Vestibulopathy

Unilateral vestibulopathy is a condition often attributed to viral or immune-mediated damage to the vestibular nerve, typically affecting one side of the vestibular system [25]. The acute phase of the disorder is marked by severe vertigo, nausea, and imbalance, primarily due to the sudden loss of sensory input from the affected vestibular system [25]. This sensory discrepancy creates a mismatch in the brain’s ability to integrate signals from the vestibular organs, leading to significant disruptions in spatial orientation and balance [26]. Recovery from unilateral vestibulopathy is predominantly dependent on the central nervous system’s ability to compensate for this lost input, a process that involves complex neuroplastic changes that are intricately regulated by neuroglial activity [27]. Schwann cells, which are key players in the peripheral nervous system, play a vital role in repairing damaged axons and facilitating remyelination following injury [28]. In the context of vestibular neuritis, Schwann cells respond to axonal damage by proliferating and releasing neurotrophic factors that promote neuronal survival and regeneration [28]. This regenerative process is crucial for restoring the function of the affected vestibular nerve [29]. However, the extent of Schwann cell-mediated repair can vary among patients, and some individuals may experience persistent symptoms due to incomplete or insufficient repair, particularly when the damage to the nerve is extensive or when there are delays in regeneration [29]. In the central nervous system (CNS), astrocytes are instrumental in maintaining neural homeostasis, supporting synaptic plasticity, and contributing to the reorganization of neural networks in the vestibular nuclei [30]. Astrocytes release various neurotrophic factors and help regulate extracellular ion concentrations, facilitating the central adaptation required for vestibular compensation [31]. This adaptive process is essential for restoring balance function in patients recovering from vestibular damage [31]. However, chronic activation of microglia in the vestibular nuclei can impede recovery by sustaining an inflammatory state that interferes with neuronal plasticity [32]. This dual role of glial cells—astrocytes supporting recovery and microglia potentially hindering it—underscores the complexity of the neuroglial environment and emphasizes the need for therapeutic strategies that can enhance the beneficial aspects of glial function while minimizing the pathological consequences of chronic inflammation [32]. Recent research has also explored the involvement of oligodendrocytes in the pathophysiology of unilateral vestibulopathy [33]. Damage to the vestibular nerve can lead to secondary degeneration in central pathways, including the vestibular nuclei and thalamus, where myelinated axons play a crucial role in signal transmission [33]. Oligodendrocytes are essential for maintaining the integrity of myelin in these regions, and any dysfunction in oligodendrocyte activity can exacerbate signal transmission deficits and delay recovery [34]. Moreover, the interplay between peripheral Schwann cells and central glial cells suggests that a coordinated repair process is necessary, i.e., one that spans both the peripheral and central nervous systems [35]. Emerging therapeutic approaches that target the interactions between these glial cells hold significant promise for enhancing recovery in patients with unilateral vestibulopathy, offering new avenues for treatment that could improve long-term outcomes and reduce the risk of chronic symptoms [35].

3.3. Bilateral Vestibulopathy

Bilateral vestibulopathy represents a more severe and chronic form of vestibular dysfunction, characterized by the loss of input from both vestibular systems [36]. Common causes include ototoxicity (e.g., aminoglycosides), age-related degeneration, autoimmune conditions, and in some cases, genetic predispositions that are only beginning to be explored [36]. The resultant symptoms—chronic imbalance, oscillopsia, spatial disorientation, and an increased risk of falls—are profoundly disabling, severely impacting patients’ quality of life and autonomy [36]. This condition not only affects physical health but also significantly influences mental well-being, with many patients reporting anxiety and depressive symptoms due to the chronic nature of their disorder [36]. At the peripheral level, Schwann cell degeneration is a critical factor in bilateral vestibulopathy [28,37]. The loss of Schwann cells disrupts myelin integrity, which is essential for the rapid and efficient transmission of signals along vestibular nerves [28,37]. This disruption leads to conduction delays and signal attenuation, which exacerbate sensory deficits [28,37]. Recent studies suggest that Schwann cell degeneration may not only be a consequence of ototoxic damage but could also involve intrinsic cellular vulnerabilities, including mitochondrial dysfunction and oxidative stress [28,37]. These findings highlight the need for interventions that target the underlying mechanisms of Schwann cell degeneration [28,37]. In central vestibular pathways, astrocytes and microglia are pivotal in determining the trajectory of neuronal plasticity following bilateral vestibular loss [38]. Astrocytes, which are responsible for providing metabolic and structural support to neurons, may exhibit dysfunction that impairs these critical roles [39]. For example, disruptions in the astrocytic regulation of glutamate uptake can lead to excitotoxicity, further damaging central vestibular neurons [39,40]. Additionally, astrocytes are key players in forming the blood–brain barrier, and their dysfunction may compromise this barrier, allowing peripheral inflammatory mediators to influence central vestibular circuits [40]. Microglia, the brain’s resident immune cells contribute to both protective and pathological processes in bilateral vestibulopathy [17,41]. During the acute phase of vestibular injury, microglia adopt a protective phenotype, clearing debris and releasing neurotrophic factors to support neuronal survival [17,41]. However, prolonged microglial activation shifts their behavior toward a pro-inflammatory phenotype, characterized by the release of cytokines such as TNF-alpha and IL-1beta [17,41]. This chronic inflammation exacerbates neuronal damage and hinders the compensatory mechanisms needed for recovery [17,41]. Targeting microglial activation states with precision therapeutics could mitigate chronic inflammation and promote a more favorable environment for neuronal repair [17,41]. Emerging evidence suggests that oligodendrocytes, the myelin-producing cells of the central nervous system, also play an underappreciated role in bilateral vestibulopathy [42]. The progressive loss of myelination in central vestibular pathways, such as those connecting the vestibular nuclei to cortical and cerebellar regions, may exacerbate functional deficits [42]. Demyelination reduces the velocity of action potential propagation and impairs the synchronization of the neuronal networks required for vestibular function [43]. Moreover, oligodendrocyte precursor cells (OPCs) may fail to adequately differentiate and replenish the myelin lost during disease progression, further compounding deficits [43]. Understanding the complex interplay of the peripheral and central mechanisms in bilateral vestibulopathy is crucial for developing effective therapies [44]. Current treatments are largely supportive, focusing on vestibular rehabilitation to improve balance and coordination [44]. The roles of neuroglia, including Schwann cells, astrocytes, microglia, and oligodendrocytes, are central to its pathophysiology [44]. In the following chart, some summarized items about the different diseases and their correlations with neuroglia are outlined (

Table 1. Key vestibular disorders and their neuroglial associations.

Vestibular Disorders
Vestibular migraine	Episodic central sensitization. Neuroinflammation and dysregulation of astrocytes and microglia. Symptoms: vertigo episodes, sensitivity to motion, and headaches.
Unilateral vestibulopathy	Loss of function on one side of the vestibular system. Peripheral damage involving Schwann cells and nerve signal disruption. Central compensation hindered by microglial overactivation.
Bilateral vestibulopathy	Symmetric loss of vestibular function. Causes: ototoxicity, aging, autoimmune conditions. Symptoms: chronic imbalance, oscillopsia, spatial disorientation. Involvement of astrocytes, microglia, and oligodendrocytes in central and peripheral pathways.

).

4. Controversies and Clinical Complexities Regarding Neuroglial Implications

4.1. Vestibular Migraine

Despite advances in understanding of the neuroglial mechanisms involved, significant controversies persist regarding the specific roles of astrocytes, microglia, and other glial cells in its pathophysiology [45]. The activation of microglia, the resident immune cells of the central nervous system (CNS), is one of the central controversies in VM [46]. While some studies suggest that microglial activation plays a key role in initiating the neuroinflammatory processes that contribute to both migraine and vestibular symptoms, others argue that microglial activation may be a secondary response to already-altered neurotransmitter dynamics and neuronal hyperexcitability in the CNS [46]. This ongoing debate complicates the understanding of the initial triggers of VM, making it unclear whether targeting microglial activity could offer therapeutic benefits for managing both the migraine and vestibular components of the disorder [9]. In addition to microglial activation, astrocytic dysfunction also plays a significant role in the pathophysiology of VM. Astrocytes are essential for maintaining the balance of extracellular ions and neurotransmitters, such as glutamate, and regulating synaptic activity [9]. In VM, dysregulated astrocytic activity, particularly in the vestibular cortex and related areas, may lead to an accumulation of glutamate, which results in neuronal hyperexcitability—an essential feature of VM [47]. However, the mechanisms by which astrocytes contribute to VM are not fully understood, and why some patients experience more severe symptoms or chronicity despite similar levels of astrocytic dysfunction remains unclear [48]. This discrepancy suggests that factors beyond astrocytic activity—such as genetic predisposition, environmental triggers, or comorbid conditions—may contribute to the pathophysiology of VM [49]. Current treatments for migraine, including triptans and preventive medications, may not always effectively address the vestibular symptoms, highlighting the clinical complexity of VM [50]. The lack of a standardized treatment regimen, coupled with the diverse clinical manifestations and unclear neuroglial mechanisms, underscores the need for continued research to better understand VM and refine therapeutic strategies for patients [50].

4.2. Unilateral Vestibulopathy

This condition is characterized by acute vertigo often followed by a period of central compensation aimed at restoring balance and function [25]. Despite a growing understanding of the underlying mechanisms, there are still significant controversies regarding the roles of Schwann cells, central compensation processes, and neuroglial involvement in the recovery from unilateral vestibulopathy [51]. One of the central controversies revolves around Schwann cell-mediated repair in the peripheral nervous system [35]. Schwann cells are essential for myelination and axonal repair, and their function plays a critical role in recovery following unilateral vestibulopathy [35]. However, the extent to which Schwann cells can fully repair the vestibular nerve remains unclear [35]. Some patients experience complete recovery within weeks to months, while others continue to suffer from persistent symptoms, such as imbalance or dizziness [35]. This variability in recovery suggests that Schwann cells may not always adequately repair the damaged vestibular nerve, and the mechanisms that determine whether peripheral regeneration is successful or incomplete are not yet fully understood [35]. Central compensation, which involves neuroplasticity and the role of astrocytes and other glial cells in the vestibular nuclei and cortex, is crucial for restoring balance following unilateral vestibulopathy [52]. However, the efficiency of these central compensation mechanisms can vary significantly between patients [52]. Some studies have suggested that dysfunction or delayed activation of these compensatory processes may lead to persistent symptoms, even after the acute vestibular insult has resolved [52]. Understanding how neuroglial cells contribute to this process and how factors such as age, comorbidities, or inflammation influence recovery is a key area of ongoing research [52]. The efficiency of central compensation is also influenced by the extent of peripheral nerve damage, complicating efforts to predict and manage recovery outcomes effectively [52]. The clinical complexities associated with unilateral vestibulopathy recovery are further amplified by the unpredictable nature of symptom resolution [53]. Some patients experience long-term symptoms, such as imbalance or dizziness, despite apparent resolution of the acute phase [53]. Factors such as the degree of nerve damage, the effectiveness of central and peripheral repair mechanisms, and individual patient characteristics contribute to the variability in recovery [53]. Vestibular rehabilitation therapy (VRT) is commonly used to aid recovery, but its success can depend on the efficiency of central compensation and the extent of peripheral nerve repair [54]. The integration of both peripheral and central treatment approaches presents a significant challenge for clinicians, underscoring the need for a more individualized treatment plan [54]. The complexity of these clinical presentations and recovery patterns calls for continued research into the mechanisms of neuroglial repair and compensation, as well as the development of more effective treatment modalities that can address both the central and peripheral components of unilateral vestibulopathy [55].

4.3. Bilateral Vestibulopathy

The dual loss of vestibular input results in profound challenges for both central and peripheral compensation mechanisms [56]. Despite increasing awareness of the neuroglial contributions to these processes, significant controversies persist regarding the exact roles of astrocytes, microglia, and other glial cells in BV’s pathophysiology [56]. One of the central debates in BV is the neuroglial contributions to central compensation [57]. Unlike unilateral vestibulopathy, where the central nervous system can often compensate for the loss of input from one vestibular system, the loss of input from both sides in BV poses more significant challenges [57]. Astrocytes, along with other glial cells, are integral to neuroplasticity and the compensation process in the central nervous system [58]. However, in BV, it remains unclear whether these central glial cells can effectively compensate for the loss of bilateral vestibular input, or if their function is overwhelmed, leading to impaired recovery [58]. Some researchers suggest that the central compensation mechanisms are insufficient when both vestibular inputs are lost, while others propose that neuroinflammation or other glial dysfunctions could play a role in hindering recovery, adding another layer of complexity to our understanding of the condition [59]. Another ongoing controversy is the role of inflammation in the chronicity of BV [60]. Chronic inflammation, particularly that involving microglia and astrocytes, may exacerbate the symptoms and extend the recovery time in BV patients [60]. Some studies suggest that the persistent activation of microglia in the vestibular nuclei could disrupt neuroplasticity and delay the return to normal balance function [56]. However, it remains unclear whether this inflammation is a primary pathological process that contributes to the development of BV or a secondary response to ongoing damage or dysfunction in the vestibular system [61]. Additionally, the involvement of oligodendrocytes and Schwann cells, which are crucial for myelination and repair in the peripheral nervous system, in the repair of the bilateral vestibular systems is not well understood [62]. This raises questions about how peripheral and central repair mechanisms may interact and whether these processes can work in tandem to restore balance [62]. The clinical complexities of BV are significant due to the severity of the symptoms and the limited effectiveness of traditional treatment approaches [63]. Patients with BV often experience profound imbalance, difficulty with visual stabilization, and challenges in maintaining upright posture due to the complete loss of vestibular input [63]. The central and peripheral systems are both compromised, and recovery is often hindered by the limited ability of either system to fully compensate for the loss [63]. The complex interplay between central and peripheral compensation and the neuroglial factors involved makes the clinical management of BV particularly challenging and highlights the urgent need for a more comprehensive understanding of the disease process [43]. Controversies and clinical complexities are summarized in

Table 2. Controversies and clinical complexities regarding neuroglial implications.

Disorder	Main Controversies	Clinical Complexities
Vestibular migraine	The role of microglial activation: primary vs. secondary response. The mechanisms of astrocytic dysfunction are not fully understood.	Ineffective treatment of vestibular symptoms with current therapies. Lack of standardized treatment. Diverse clinical manifestations. Unclear neuroglial mechanisms.
Unilateral vestibulopathy	Can Schwann cells fully repair the damaged vestibular nerve? Which mechanisms determine successful versus incomplete repair? How does the extent of peripheral vestibular damage influence the effectiveness of central compensation?	Variability in recovery: ranging from full to persistent symptoms Influence of multiple factors. Challenges in treatment: (VRT) success depends on both peripheral nerve repair and central compensation.
Bilateral vestibulopathy	Neuroglial contribution to central compensation: Is the chronic inflammation observed in BV a primary cause of the condition or a secondary response to ongoing damage? How do oligodendrocytes and Schwann cells interact with central repair mechanisms in BV?	Severity of symptoms: Limited treatment effectiveness: traditional treatments are often insufficient for BV. Compromised systems: both central and peripheral systems are affected, and neither can fully compensate for the other’s loss of function. Complex interplay of factors: the interaction of central/peripheral compensation and neuroglial factors creates significant challenges for clinical management.

.

5. Challenges

Research into neuroglial roles in vestibular disorders faces significant challenges, starting with the heterogeneity of these conditions [64]. Vestibular migraines involve episodic central sensitization, whereas bilateral vestibulopathy is characterized by chronic and progressive degeneration [64]. This variability complicates the identification of universal mechanisms and therapeutic targets [17]. Furthermore, the dynamic and context-dependent roles of neuroglia add another layer of complexity [17]. For instance, microglia can be protective during the acute phase of injury but become detrimental if activation persists [17]. Another major challenge is the lack of specific biomarkers for neuroglial activity in vestibular disorders [65]. While imaging and biochemical assays have advanced, distinguishing between beneficial and pathological glial responses remains elusive [65]. The interplay between neuroglia and systemic factors, such as metabolic syndromes or vascular conditions, is also poorly understood, limiting the ability to translate findings into clinical practice [65]. The multifactorial nature of vestibular disorders also complicates therapeutic development [5]. Treatments targeting neuroglia must account for the interplay between glial cells, neurons, and the broader systemic environment [5]. This requires an integrative approach that combines neurobiological insights with clinical realities, a challenge that current research methodologies are only beginning to address.

This article outlines challenges in vestibular disorders, including the heterogeneity of vestibular disorders, which complicates research, the lack of biomarkers for neuroglial activity, and limited knowledge of neuroglial interactions, while highlighting future goals like biomarker development, targeted therapies addressing both neuroinflammation and regenerative mechanisms, and personalized treatment approaches based on glial contributions to disease mechanisms.

6. Systemic Diseases, Glia, and Vestibular Disorders: Key Interactions

6.1. Diabetes, Neuroglial Dysfunction, and Vestibular Disorders

Metabolic diseases are a major cause of morbidity and mortality today. As their incidence continues to rise, understanding the pathophysiological mechanisms is essential to recognize their relationship and the associated implications for vestibular disorders [66].

Diabetes, considered a major debilitating health condition, is one of the most significant diseases of this century and a major cause of morbidity and mortality due to its complications [67]. This disease, characterized by glucose metabolism disorders resulting from deficiencies in insulin production or action, is closely linked to the development of cardiovascular, renal, ophthalmological, and neurological complications, which severely impact the quality of life of those affected [68]. Diabetes has several effects on glial cells, including chronic activation and inflammation due to the release of pro-inflammatory cytokines, oxidative stress, and myelin loss [69]. One of the most well-known implications is diabetic neuropathy, which affects not only peripheral nerves but also the vestibular nerve, leading to vestibulopathies according to Yan et al., highlighted in their population-based study by a significant association between diabetes mellitus and peripheral vestibular disorders, with unilateral vestibulopathy being a clinically relevant manifestation. The authors suggest that chronic hyperglycemia and underlying vascular damage may impair the function of the peripheral vestibular system, leading to symptoms such as vertigo and dizziness. These findings underscore the importance of monitoring and addressing vestibular complications in diabetic patients to improve their quality of life [70].

The described pathophysiological mechanisms and the established relationship suggest that proper glycemic control could be a crucial aspect of managing patients with vestibulopathies and diabetes.

6.2. Blood Pressure, Vascular Changes, Neuroglial Dysfunction, and Vestibular Disorders

Hypertension, a leading cause of cardiovascular disease, significantly impacts the vestibular system by disrupting its blood flow. The anterior vestibular artery supplies the superior and horizontal semicircular canals, as well as the utricle. Meanwhile, the common cochlear artery bifurcates into the cochlear artery and the posterior vestibular artery, which supply the saccule and posterior semicircular canals. Any disruption or alteration in this blood supply can result in vertigo [71]. Adults with hypertension are especially susceptible to both macrovascular and microvascular complications, unlike those without this condition [72]. Cohen et al. (2023), in their retrospective cohort study, found a significant relationship between hypertension and vestibular disorders in middle-aged women both with and without HIV. The findings underscore the importance of considering blood pressure as a contributing factor in the evaluation and management of vestibular dysfunctions [73].

6.3. Systemic Lupus Erythematosus (SLE) and Neuroglia

Chronic inflammation in systemic lupus erythematosus (SLE) is driven by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [74], which leads to microglial activation by autoantibodies (like anti-NMDA receptor antibodies) and cytokines, promoting neuronal damage [75]. Neuroglial dysfunction has increasingly been recognized as a key factor in the development of vestibulopathies in patients with systemic lupus erythematosus (SLE). A major mechanism contributing to audiovestibular damage in these patients involves the action of autoantibodies, immune complex deposition, and cytotoxic responses, which can directly affect neuroglial cells and the structures of the vestibular system. This highlights the importance of evaluating and addressing audiovestibular involvement in lupus patients to enable early diagnosis and proper management [76].

7. Therapeutic Applications of Glia in Vestibular Disorders

The therapeutic applications of glial cells in vestibular disorders are emerging as a promising treatment option, especially with induced pluripotent stem cells (iPSCs) and neurotrophic factors [77]. These approaches aim to regenerate the affected vestibular structures and restore balance function to mitigate the significant impact of vestibular disorders on quality of life [77].

The regeneration of neural stem cells (hNSCs) through the differentiation of induced pluripotent stem cells (iPSCs) holds potential for regenerating vestibular ganglion cells and hair cells [77]. Induced pluripotent stem cells (iPSCs) are a type of stem cell that can be generated directly from adult cells. By reprogramming somatic cells to an embryonic-like state, they can develop into any type of cell in the body. iPSCs can be induced to differentiate into neural stem cells (hNSCs) through specific culture conditions and the addition of certain chemical factors [77]. Vestibular disorders, which affect balance and spatial orientation, may result from the degeneration of vestibular ganglion cells. Studies have explored how iPSC-derived hNSCs may replace lost vestibular ganglion cells in animal models [77].

Glial Cell-Derived Neurotrophic Factor (GDNF) has been identified as a critical factor in preventing the degeneration of vestibular neurons and hair cells, promoting their survival and function [78,79]. This neurotrophic factor can be administered to improve recovery from sensorineural hearing loss and vestibular disorders. This could lead to new treatment options for patients suffering from these conditions, which are often difficult to manage with existing therapies [78,79]. So far, in vitro and in vivo studies have been conducted to assess the efficacy of GDNF in preventing or treating damage to these neurons [78].

Medications for vestibular disorders where neuroglia are involved focus on restoring vestibular function and alleviating symptoms through various pharmacological approaches [80,81]. Aminopyridines, such as 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), can be effective in treating conditions such as downbeat nystagmus and episodic ataxia type 2 by acting on calcium channels [80,81]. These substances can improve Purkinje cell function by modifying the activity of ion channels, which enhances nerve signal transmission and helps restore the normal activity of these cerebellar cells [80,81]. This modulation helps improve neuronal excitability and motor coordination, which is crucial for conditions like nystagmus and ataxia [80,81]. Therapeutic applications of glia in vestibular disorders are shown in Figure 1.

Although these regenerative therapies hold potential, there are still obstacles to obtaining reliable and successful outcomes in clinical environments. Additional research is required to refine these methods and assess their long-term effectiveness in human patients.

8. Conclusions/Future Directions

In summary, the neuroglial mechanisms implicated in vestibular migraine, unilateral vestibulopathy, and bilateral vestibulopathy represent areas of active and evolving research. Controversies persist regarding the precise contributions of astrocytes, microglia, Schwann cells, and oligodendrocytes to the initiation, progression, and resolution of these disorders. Astrocytic dysfunction has been identified as a key player in neuronal metabolic support and synaptic regulation, yet its exact impact on the persistence of central sensitization in vestibular migraine or maladaptive plasticity in vestibulopathies remains elusive. Similarly, the dual role of microglia as both protectors and mediators of inflammation underscores the complexity of their involvement in these disorders, particularly in the transition from acute to chronic phases of disease. The contributions of Schwann cells to peripheral vestibular nerve integrity and the underexplored role of oligodendrocytes in central myelination deficits add further layers of complexity to the pathophysiological landscape.

The clinical management of these conditions is further complicated by the significant heterogeneity in the symptom presentation, severity, and recovery trajectories among patients. For example, while some individuals exhibit near-complete compensation through central plasticity, others experience persistent imbalance and dizziness despite similar peripheral injury patterns. The variability in treatment responses, influenced by genetic predispositions, systemic factors such as metabolic or vascular comorbidities, and environmental exposures, also limits the standardization of therapeutic protocols. The lack of specific biomarkers to identify neuroglial dysfunction in vestibular disorders further hampers early diagnosis and targeted intervention, delaying potential treatment and increasing the burden of chronic symptoms on patients. Future research must focus on unraveling the complex interplay between neuroglia and neuronal circuits in both the peripheral and central vestibular pathways. Advanced imaging techniques, molecular profiling, and in vivo models could provide greater insights into the dynamic roles of neuroglia during disease onset, progression, and recovery. Such studies are essential for identifying novel therapeutic targets and developing individualized treatments aimed at modulating neuroglial activity to enhance neuroprotection, promote repair, and improve clinical outcomes. By addressing these challenges, the field can advance toward a more comprehensive understanding and effective management of vestibular disorders, ultimately improving the quality of life of affected individuals.