Next Article in Journal
Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics
Previous Article in Journal
Glial Fibrillary Acidic Protein’s Usefulness as an Astrocyte Biomarker Using the Fully Automated LUMIPULSE® System
Previous Article in Special Issue
The Long-Term Effect of Cochlear Implantation on Tinnitus: A Systematic Review and Meta-Analysis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Diagnostics
Volume 14
Issue 22
10.3390/diagnostics14222522
diagnostics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review

by
Jiann-Jy Chen
1,2,†,
Chih-Wei Hsu
3,†,
Yen-Wen Chen
1,†,
Tien-Yu Chen
4,5,
Bing-Yan Zeng
6,7,*,‡ and
Ping-Tao Tseng
1,6,8,9,*,‡
1
Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City 81166, Taiwan
2
Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung 80756, Taiwan
3
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83340, Taiwan
4
Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
5
Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
6
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
7
Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung 80706, Taiwan
8
Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413305, Taiwan
9
Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally as first authors to this work.
‡
These authors contributed equally as corresponding authors to this work.
Diagnostics 2024, 14(22), 2522; https://doi.org/10.3390/diagnostics14222522
Submission received: 22 October 2024 / Revised: 5 November 2024 / Accepted: 6 November 2024 / Published: 11 November 2024
(This article belongs to the Special Issue Etiology, Diagnosis, and Treatment of Congenital Hearing Loss)
Browse Figures
Versions Notes

Abstract

:
Background: Anti-phospholipid syndrome (APS) has emerged as a significant issue in autoimmune diseases over recent decades. Its hallmark feature is thromboembolic events, potentially affecting any vascularized area including the microcirculation of the inner ear. Since the first case report of APS-related audiovestibular dysfunction described in 1993, numerous reports have explored the association between APS-related antibodies and audiovestibular dysfunction. These studies indicate a higher prevalence of APS-related antibodies in patients with sensorineural hearing loss compared to healthy controls. Unlike other idiopathic hearing loss disorders, audiovestibular dysfunction associated with APS may respond to appropriate treatments, highlighting the importance of timely recognition by clinicians to potentially achieve favorable outcomes. Therefore, this systematic review aims to consolidate current evidence on the characteristics, pathophysiology, assessment, and management of audiovestibular dysfunction linked to APS. Methods: This systematic review utilized electronic searches of the PubMed, Embase, ClinicalKey, Web of Science, and ScienceDirect online platforms. The initial search was performed on 27 January 2024, with the final update search completed on 20 June 2024. Results: Based on theoretical pathophysiology, anticoagulation emerges as a pivotal treatment strategy. Additionally, drawing from our preliminary data, we propose a modified protocol combining anticoagulants, steroids, and non-invasive brain stimulation to offer clinicians a novel therapeutic approach for managing these symptoms. Conclusions: Clinicians are encouraged to remain vigilant about the possibility of APS and its complex audiovestibular manifestations, as prompt intervention could stabilize audiovestibular function effectively.

Graphical Abstract

1. Introduction

There has been a long-standing debate regarding the association between audiovestibular dysfunction and autoimmune diseases [1]. Several reports have explored this link in specific autoimmune conditions such as systemic lupus erythematosus [2,3], rheumatoid arthritis [4,5], and autoimmune thyroiditis [6]. However, while some of these conditions have clear physiological evidence supporting their association [3,7,8], others lack satisfactory pathophysiological explanations connecting autoimmune diseases with dysfunction of the audiovestibular system [6]. For instance, only a few diseases have histopathological evidence establishing a direct relationship between autoimmune reactions and the audiovestibular system, such as systemic lupus erythematosus [2]. According to our previous reports, a well-recognized physiopathology of immune-mediated audiovestibular dysfunction would lead to a relatively satisfactory treatment result [3,9,10].
Anti-phospholipid syndrome (APS) is characterized by recurrent thromboembolic events and an inflammatory process [11]. It can sometimes occur alongside other autoimmune diseases, such as systemic lupus erythematosus (present in around one third of cases) [12]. Depending on its association with other autoimmune diseases, APS is classified as “primary” (APS alone) or “secondary” (APS with other autoimmune diseases) [12,13]. Circulating anti-phospholipid antibodies bind to phospholipids and phospholipid-bound proteins on cell membranes, potentially activating endothelial cells, platelets, and leukocytes, thereby promoting thrombus formation and subsequent autoimmune and inflammatory reactions [14,15].
To diagnose APS [16], patients must meet at least one clinical criterion and one laboratory criterion. Clinical criteria include evidence of (1) vascular thrombosis or (2) pregnancy morbidity. Laboratory criteria consist of (1) lupus anticoagulants, (2) anti-cardiolipin antibodies, or (3) anti-β2-glycoprotein I antibodies. Moreover, to meet laboratory criteria, patients must test positive for one or more of these antibodies on at least two occasions separated by at least 12 weeks [16].
Since the first case report by Hisashi and colleagues [17], the role of APS in the pathophysiology of audiovestibular dysfunction has become a significant topic in otolaryngology research [18,19,20,21,22,23]. Before serologically proven, the APS-related audiovestibular dysfunction might mimic the presentation of Meniere disease or idiopathic sensorineural hearing loss [24]. As addressed earlier, macro- or micro-thromboembolism is a key feature of APS [25]. Microcirculation plays a crucial role in maintaining inner ear homeostasis [26]. Therefore, any disruption or occlusion of inner ear microcirculation theoretically leads to subsequent audiovestibular dysfunction. Although not always, it might present as sudden sensorineural hearing loss when the occlusion of microcirculation occurs abruptly [27]. Consequently, there has been an increasing number of reports investigating the association between audiovestibular dysfunction and APS-related antibodies [24,27,28,29,30,31,32,33,34,35,36,37,38]. These studies have demonstrated a higher prevalence of elevated APS-related antibodies in patients with sensorineural hearing loss compared to healthy controls [29,39]. Additionally, a large-scale study examining the risk of sudden sensorineural hearing loss across various autoimmune diseases found that patients with APS had a significantly higher risk compared to those without autoimmune diseases [37]. However, this finding has not been consistently replicated in other studies [40,41,42,43]. Audiovestibular dysfunction related to APS can manifest as either sudden-onset or progressive [11].
Unlike other idiopathic hearing loss disorders, audiovestibular dysfunction associated with APS may respond to appropriate treatments [18,19]. Therefore, timely recognition of this condition could enable clinicians to promptly identify and manage audiovestibular dysfunction related to APS, potentially improving clinical outcomes. Hence, the objective of this systematic review is to summarize the current evidence on the characteristics, pathophysiology, assessment, and treatment of audiovestibular dysfunction associated with APS.

2. Methods and Materials

This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Table S1 and Figure 1) [44]. The review protocol was registered on the INPLASY platform (INPLASY202460076, https://inplasy.com/inplasy-2024-6-0076/, accessed on 21 October 2024).

2.1. Literature Search Strategy

The systematic review utilized electronic searches of the PubMed, Embase, ClinicalKey, Web of Science, and ScienceDirect online platforms. Detailed search strategies and keywords for each platform are provided in Table S2. Additionally, a manual search of reference lists from included articles was conducted. The initial search was performed on 27 January 2024 with the final update search completed on 20 June 2024. If insufficient data were available in the original papers, corresponding authors were contacted via email to request additional information.

2.2. Inclusion and Exclusion Criteria

This systematic review focused on audiovestibular issues related to APS, including characteristics, pathophysiology, examination, and treatment. Inclusion criteria were as follows: (a) studies examining audiovestibular issues related to APS; (b) case reports/series, observational trials, case–control trials, or randomized controlled trials; and (c) studies including patients with APS.
Exclusion criteria were as follows: (a) studies not including patients with APS; (b) studies not addressing characteristics, pathophysiology, examination, or treatment related to audiovestibular dysfunction in APS; and (c) animal studies. Review articles were used for manual extraction of relevant articles from their reference lists. The main reasons for the exclusion of 4122 records at the initial screening stage of “Title–-Abstract Screening” included the studies not being related to APS, not being related to audiovestibular dysfunction, and not being human trials. After passing the initial screening stage, the remaining 50 records entered full-text screening. Among them, 22 records were excluded and the reasons are detailed in Table S3.

2.3. Article Screening Process

Following the electronic searches across all five databases and the application of the inclusion/exclusion criteria based on titles and abstracts, eligible articles were subjected to full-text examination. Duplicate articles were manually removed, and the remaining articles underwent full-text screening to determine final inclusion.

2.4. Data Extraction

Data extraction was performed by Ping-Tao Tseng, who conducted full-text examinations to extract data on characteristics, pathophysiology, examination, and treatment related to APS.

2.5. Article Quality Grading

Clinical studies were assessed for quality using the Newcastle–Ottawa Scale by Jiann-Jy Chen and Ping-Tao Tseng [45] (Table S4).

3. Summary of the Currently Available Evidence

3.1. Characteristics

The core pathophysiology of APS hinges on its thromboembolic effects, affecting arteries or veins in both the central nervous system and peripheral organs [21]. APS can manifest as primary (without concurrent autoimmune diseases) or secondary (often associated with diseases like systemic lupus erythematosus) [21]. Although anti-phospholipid antibodies may be a non-specific response to infections rather than an independent autoimmune disease [46], they are central to the syndrome’s definition rather than termed as anti-phospholipid disease.
APS’s primary features stem from multifocal thrombosis. Unlike other autoimmune conditions such as systemic lupus erythematosus, histological examinations of blood clots typically reveal organized thrombi with platelet aggregation and fibrin, often lacking significant inflammation or vasculitis [27]. Neuroimaging reports show findings like severe stenosis, long-segment vessel wall thickening, and homogeneous vessel wall enhancement in patients with APS [47]. While anti-cardiolipin antibodies may coexist with other autoimmune diseases like mixed connective tissue disorders [48], their presence more strongly correlates with sensorineural hearing loss than with these mixed connective tissue disorders [1].
Audiovestibular dysfunction associated with APS can present unilaterally or bilaterally [49], with a variable course ranging from sudden onset to chronic progression [20,23,31,36]. Rarely, sudden sensorineural hearing loss may spontaneously recover [50]. Often, patients initially present with other APS symptoms before later developing sensorineural hearing loss. Audiovestibular dysfunction as the initial presentation of APS is relatively uncommon [23,51], with the vestibular system less frequently affected compared to the auditory system [52]. Vestibular dysfunction in APS may result from impairment to vestibulo-cerebellar structures or vestibular nuclei [53]. Studies on sensorineural hearing loss suggest significant impairment across various frequencies, particularly in middle to low frequencies, compared to standard levels [54].

3.2. Epidemiology

Increased levels of anti-phospholipid antibodies and anti-HSP-70 antibodies have been noted in idiopathic sudden sensorineural hearing loss, with prevalence rates of 33.3% and 25.4%, respectively [29], higher than those in healthy controls (9.4% [39] and 4.2% [55]). The prevalence of serologically positive anti-cardiolipin antibodies in sudden or progressive sensorineural hearing loss ranges from 0.7% to 27% [35,56]. Similar prevalence rates are found in patients with Meniere’s disease, where 27% of unilateral and 12% of bilateral cases show elevated anti-phospholipid antibodies (population norm 6–9%) [21]. Coexisting antinuclear antibodies are frequently found, with prevalence rates ranging from 17% to 43% [34,57,58], reflecting the interconnected etiology of autoimmune diseases. A recent study reported that 49% of patients with sudden hearing loss and 50% with progressive hearing loss tested positive for anti-phospholipid antibodies [59].

3.3. Physiopathology

The overall pathophysiological reaction involving APS-related antibodies and the formation of thromboembolism, which ultimately contributed to patients’ audiovestibular dysfunction, is illustrated in Figure 2, which was drawn by the first author.

3.3.1. Lupus Anticoagulant

Lupus anticoagulant, often accompanied by anti-cardiolipin antibodies, plays a crucial role in the prothrombotic effects of APS [60,61]. It is considered a stronger risk factor for thrombosis compared to anti-cardiolipin antibodies [62]. In a large-scale case–control study of autoimmune antibodies in idiopathic sudden sensorineural hearing loss, lupus anticoagulant prevalence was significantly higher in patients than in healthy controls (8.4% versus 0.6%) [32]. Patients with lupus anticoagulant are more prone to thrombotic events [62], whereas those primarily with anti-cardiolipin antibodies tend to exhibit more severe disease manifestations [62]. Further, recurrent thrombotic events typically occur in the same vascular bed [63].

3.3.2. Anti-Cardiolipin Antibodies

Research indicates that positivity for anti-cardiolipin antibodies is an independent risk factor for sensorineural hearing loss [32]. Another study linking elevated anti-phosphatidylserine antibodies (a subtype of anti-phospholipid antibodies) with normal-tension glaucoma also associates them with hearing loss [31]. The coexistence of both anti-phosphatidylserine IgM and IgG antibodies suggested an active (IgM) and persistent (IgG) autoimmune process in such patients [31]. These antibodies primarily target negatively charged phospholipids such as cardiolipin and β2-glycoprotein I on tissue surfaces [29]. For example, the cardiolipin resided in the inner mitochondrial membrane [64]. The production of the anti-phospholipid antibodies could be invoked by exposure to viral infection [65,66], such as human immunodeficiency virus and hepatitis C virus [67]. The hypothetic linkage between viral infection and activation of anti-phospholipid antibodies mainly relies on two hypotheses: (1) the viral sequence might mimic the phospholipid-binding site or host self-sequence [29] and (2) the cardiolipin located at the mitochondrial membrane might degrade and release into extracellular area as a result of oxidative stress and infection [68]. Though controversial, these antibodies likely interfere with platelet surface homeostasis or endothelial cell function, contributing to vaso-occlusive manifestations [29]. Microvascular obstruction has been proposed as a link between audiovestibular dysfunction and systemic autoimmune diseases, such as systemic lupus erythematosus [2] or APS [29]. It might be related to (a) the humoral-type antibody [69] and cell-mediated cytotoxicity [70] targeting over the inner ear antigen, (b) the immune complex deposition in the microcirculation of the inner ear [26], or (c) the occlusion in the microcirculation of the internal ear by micro-thrombosis formation [17,19] related to anti-phospholipid antibodies [71]. A high prevalence up to 50% of intra-cranial arterial thrombosis, in either the micro-vascular system or large vessels, and its consequent neuropsychiatric sequalae had been found in patients with APS [72], which could serve as a linkage between APS and an impaired audiovestibular system circulation system. Vessels of any size may be targeted and, in one study, none of the vessels could be spared [73]. To be specific, the anti-phospholipid antibodies could activate cochlear vessel endothelial cells [74], either via direct effect or via the stimulation of free radicals [75]. The aforementioned mechanism would lead to endothelial dysfunction and damage, and finally would result in local micro-thrombus formation and end-organ ischemia [74,75]. From another point of view, in the report by Green and colleagues, the authors concluded that the time association between the onset of sensorineural hearing loss and a subsequent additional thrombotic event and a lack of response to steroid treatment might suggest that the physiopathology pathway relies on a thrombotic pathway but not an inflammatory etiology [76]. Additionally, some rare cases, such as those with persistent stapedial artery, might be prone to be affected earlier by complications of APS due to anatomical variations in the circulation system [77].
However, most of the aforementioned evidence about the linkage between the anti-cardiolipin antibody reaction and audiovestibular dysfunction was derived from the interpretation of case reports and their response to immunosuppressive treatment [78]. Therefore, they were not direct evidence because there were no direct methods to determine cochlear blood flow [32]. On the other hand, researchers tried to find evidence through another aspect, the time association. To be specific, in recent clinical reports, researchers have demonstrated an association of the existence of anti-cardiolipin antibody with acute-phase idiopathic sudden sensorineural hearing loss [29]; however, the aforementioned anti-cardiolipin antibodies disappear 3 months later [34]. This time association between transiently elevated anti-cardiolipin antibodies (either related to viral infection or other causes) and sudden sensorineural hearing loss might explain the transient vascular damage and microthrombosis formation in such patients [34].

3.3.3. Anti-β2-Glycoprotein I Antibodies

Reports suggest that anti-β2-glycoprotein antibodies may be associated with acute events like sudden sensorineural hearing loss, while other anti-phospholipid antibodies may correlate with progressive hearing loss [28]. A case report documented parietal lobe microvascular involvement in sudden sensorineural hearing loss associated with high anti-β2-glycoprotein and anti-cardiolipin antibody titers [20].

3.3.4. Other Associated Autoantibodies

In addition to the aforementioned main autoantibodies, the heat shock protein (HSP) family, which is a set of evolutionarily conserved molecular chaperones [79], also played an important role in sensorineural hearing loss in patients with APS [29]. As we know, the HSP family serves as a protector for our tissues to resist various forms of stress including heat, ischemia, free radicals, and toxic agents [80]. However, because of its highly conserved properties during species’ evolutionary processes [79], it might be similar to HSPs in other infectious micro-organisms [81,82]. Therefore, it might become the source of cross-reaction between autoimmune activities and human HSPs [29]. HSP-70 was one of the HSP family members. HSP-70 in the inner ear system could be the target of immunologic reactions via the cellular immune response in the host during micro-organism infection, which would result in consequent cochlear dysfunction [83]. Further, sensorineural hearing loss accompanied with tinnitus would be more likely to be associated with positive anti-HSP-70 antibodies and anti-phospholipid antibodies than that without tinnitus [29]. However, despite the aforementioned physiopathological link between the HSP-70 immune reaction and cochlea dysfunction, only a few reports focused on serum anti-HSP-70 antibodies in patients with sensorineural hearing loss [29,83,84]. Among these reports, the prevalence of positive serum anti-HSP-70 antibodies in patients with sensorineural hearing loss was around 25.4–76.9% [29,83,84]. However, the application of anti-HSP-70 antibodies as a serologic marker in autoimmune disease-related sensorineural hearing loss remained controversial because of the following two concerns: First, available evidence regarding the detection of anti-HSP-70 antibodies in such patients is currently relatively lacking. Secondary, the anti-HSP-70 antibodies were also sometimes detected in healthy controls in low levels [29]; therefore, we should only take positive anti-HSP-70 antibodies into consideration if they are significantly increased in patients with sensorineural hearing loss.

3.4. Complication

Since APS is a systematic disease, its clinical presentation might vary widely in different organs or systems. To be specific, it could be either isolated to the audiovestibular system or widely disseminated to other organs. This depends on the sites of end organs involved with the physiopathology of thrombotic microangiopathy or thromboembolic events related to ischemia [24]. Further, the aforementioned multi-organ complications could be clinically silent and slow or rapidly progressive [24].

3.5. Diagnostic Tool

Given that anti-phospholipid antibodies primarily induce thrombotic processes in various vessels, assessing vessel health (thrombus formation, vessel wall integrity, blood flow velocity) may serve as an indicator of audiovestibular dysfunction related to APS [24]. Routine immunological laboratory tests, including antinuclear, antineutrophil cytoplasmic, anti-endothelial cell, anti-phospholipid/anti-cardiolipin, and anti-thyroid antibodies, are recommended when evaluating suspected immune-mediated inner ear disorders to enable early diagnosis [58].

3.6. Prognosis

Some researchers have attempted to classify APS into “primary” and “secondary” forms (the latter occurring alongside major autoimmune diseases like systemic lupus erythematosus). However, there appears to be little difference in the prognosis of audiovestibular dysfunction between these subtypes [24].
While several risk factors associated with the prognosis of sensorineural hearing loss have been identified, including the severity of hearing loss, the presence of vestibular symptoms, and patient age [85], only a few attempts have been made to predict the outcome of sensorineural hearing loss using biochemical parameters [29,86,87]. For instance, Gross et al. demonstrated a statistically significant association between anti-HSP-70 antibodies and the Siegel recovery grade in patients with sensorineural hearing loss [29]. Specifically, patients with positive anti-HSP-70 antibodies showed a significantly higher complete recovery rate compared to those without these antibodies [29]. This finding suggests that the presence of anti-HSP-70 antibodies indicates an autoimmune process in such patients, who are potentially responsive to immune modulation therapy such as steroid treatment [29]. Supporting this notion, Hirose et al. proposed that Western blot analysis for HSP-70 is the most effective test for predicting corticosteroid responsiveness, with a positive predictive value of 91% [30]. However, this predictive effect was not observed in another study by Suslu et al., where no association was found between a positive test for anti-HSP-70 antibody and response to corticosteroid treatment [33]. This discrepancy may be attributed to two factors: (1) the relatively small sample size in the study by Suslu et al. [33], and (2) differences in the tools used to detect anti-HSP-70 antibodies. Specifically, Suslu et al. reported only three cases with positive anti-HSP-70 antibodies [33] compared to eleven cases in the study by Hirose et al. [30]. Furthermore, in Suslu et al.’s study, the p-value for corticosteroid response in patients with anti-HSP-70 antibodies was 0.07, indicating proximity to statistical significance [33]. Additionally, while Western blotting showed positive predictive value in Hirose et al.’s study [30], ELISA did not yield significant predictive value in Suslu et al.’s study [33]. Although conclusive evidence regarding the choice of detection tool is lacking [33], Munari et al. reported that the ELISA method has a sensitivity of 84% and specificity of 93% for detecting anti-HSP-70 antibodies in the serum of such patients [88].

3.7. Treatment

3.7.1. Anticoagulants

Currently, there are no definitive conclusions regarding the treatment of audiovestibular dysfunction related to APS. However, some researchers emphasize resolving the thromboembolic events associated with the syndrome. Specifically, regimens combining antithrombotic medications and immunotherapy are theoretically preferable for addressing the underlying physiopathology of APS [75]. Warfarin is identified as one potentially effective regimen for these patients [75].
Regarding the impact of anticoagulants on managing audiovestibular dysfunction in APS patients, there are differing viewpoints [24,89]. For instance, Wang et al. reported unsatisfactory outcomes with warfarin plus low-molecular-weight heparin, showing no improvement in hearing loss [23]. Similarly, Wiles et al. noted poor recovery from sudden sensorineural hearing loss despite continuous warfarin with or without aspirin [27]. In contrast, other reports suggest positive effects of anticoagulants. Cavallasca et al. demonstrated stabilization of hearing function without relapse after adding acenocoumarol therapy (INR 2-3) [19]. Similar stabilization and prevention of relapse were observed by Bir et al. [18], while Kang et al. linked the discontinuation of anticoagulants to the onset of sensorineural hearing loss, which reversed upon resuming therapy [90]. To be specific, in the report by Kang et al., a patient with primary APS continued with warfarin 5 mg/day and acetylsalicylic acid 100 mg/day for several years and had a sudden onset of tinnitus and hearing impairment few days after discontinuing the aforementioned anticoagulants. After resuming warfarin 5 mg/day and acetylsalicylic acid 100 mg/day, his audiometry revealed a recovery of hearing [90]. Vyse et al. illustrated the prophylactic benefits of long-term warfarin treatment (up to 5 years) in preventing recurrent thromboembolic events in these patients [91].
It has been noted that once inner ear thrombotic events occur, they tend to recur [63]. Therefore, some researchers recommend initiating long-term anticoagulant therapy, such as warfarin (target INR 3.0–4.0 for arterial prevention and 2.5–3.0 for venous prevention), to prevent future episodes of sensorineural hearing loss [27,92]. However, there are also reports opposing the long-term prescription of anticoagulants in otherwise healthy patients with APS [21].

3.7.2. Steroids

Steroids have been widely used in various autoimmune inner ear diseases [93,94,95,96], exerting anti-inflammatory, immunosuppressive, and anti-edema effects [2]. This treatment can restore the capacity of otologic vessels by reducing inflammation and edema [2]. Additionally, the associated increase in systemic blood pressure from steroid use may enhance blood perfusion in the auditory artery [2]. Moreover, steroid application may protect neural tissues from ischemic injury, stabilize vascular endothelium, and restore the blood–brain barrier [97]. High-dose steroid therapy has shown beneficial effects in restoring hearing function in patients with APS, as reported by Bir et al., where hearing was recovered after a regimen of prednisolone (80 mg/day initially, tapering over 3 months) [18]. Similarly, in the study by Hisashi et al., combining steroid therapy with prostaglandin E1 or ticlopidine contributed to hearing function restoration in patients with anti-cardiolipin antibodies [98]. However, some studies do not universally support the beneficial effects of steroids in patients with positive anti-phospholipid antibodies [22,76,99]. For instance, in the report by Hisashi et al., hearing loss showed only partial improvement after steroid treatment without additional anticoagulants [17].

3.7.3. Diuretics

Hydrochlorothiazide, with or without glycerol, can alleviate inflammation-induced tissue edema through its diuretic and dehydrating effects [100]. The rationale for using diuretics to alleviate sensorineural hearing loss in autoimmune diseases stems partly from steroids’ ability to reduce edema in autoimmune inner ear diseases [2], thereby potentially restoring otologic vessel capacity [2]. However, diuretic use in sensorineural hearing loss related to APS remains rare due to concerns about exacerbating ischemia in the inner ear microcirculation. Compadretti et al. reported the use of hydrochlorothiazide with glycerol to restore hearing function in a case of APS [101].

3.7.4. Plasmapheresis

Plasmapheresis, or plasma exchange, has been used to manage audiovestibular dysfunction in patients with systemic lupus erythematosus [102,103]. While direct studies on the efficacy of plasmapheresis for managing audiovestibular dysfunction in patients with APS are lacking, there is one case report demonstrating a correlation between decreased anti-phospholipid antibody titers and improved hearing function following plasmapheresis in a systemic lupus erythematosus patient [104].

3.7.5. Modified Anticoagulant, Steroid, and Non-Invasive Brain Stimulation Protocol for Managing Audiovestibular Dysfunction Related to APS

In our preliminary research, we developed a modified treatment protocol combining anticoagulants, steroids, and non-invasive brain stimulation (Figure 3) specifically for managing audiovestibular dysfunction associated with APS. This protocol, based on Alexander’s approach for various autoimmune inner ear diseases, is structured as a three-phase trial [93].
Phase 1 (Prompt Treatment Phase) involves administering aspirin 100 mg/day for 2 weeks to evaluate patients’ response to anticoagulant therapy. A positive response is defined as at least a 15% improvement in pure-tone air-conduction threshold or reduction in vestibular severity.
Phase 2 (Augmentation Phase) targets patients who respond to anticoagulant treatment. They continue aspirin 100 mg/day throughout the treatment period and additionally receive oral prednisolone starting at 5 mg/day for 2 weeks, gradually increasing by 5 mg/day every 2 weeks until reaching a maintenance dosage of prednisolone 20 mg/day. The final dosage is maintained for 3 months.
Phase 3 (Resolution Phase) addresses patients with residual symptoms such as 50% hearing impairment or persistent tinnitus, who undergo non-invasive brain stimulation specifically targeted at tinnitus management [105].

3.8. Limitation

There are several limitations to address in this study, including a lack of direct pathological evidence to prove that APS induces audiovestibular dysfunction, the lack of available full texts for some articles, and limited evidence regarding the proposed treatment protocol.

4. Conclusions

This systematic review has synthesized current knowledge on audiovestibular dysfunction associated with APS. Unlike other autoimmune diseases, the predominant features of audiovestibular dysfunction in these patients stem largely from specific multiple thromboembolic events affecting either a single organ or multiple organs. Consequently, the most relevant and effective treatment strategy focuses on the use of anticoagulants, despite debates surrounding their long-term prescription. Given that APS presents as a syndrome rather than a distinct disease, its manifestations can vary widely and often coexist with other autoimmune conditions. Therefore, clinicians should remain vigilant for potential cases of APS and its complex audiovestibular dysfunction, as timely intervention may aid in stabilizing audiovestibular function, though complete recovery may not always be achievable.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/diagnostics14222522/s1, Table S1: PRISMA 2020 checklist of current systematic review; Table S2: Keyword and search results in each database; Table S3: Excluded studies and reason; Table S4: Newcastle-Ottawa Scale for Observational trial.

Author Contributions

J.-J.C., C.-W.H. and Y.-W.C., who contributed equally as the first authors, took full responsibility for concept formation, study design, and manuscript drafting. T.-Y.C. contributed significantly to concept formation, major revision, and resource support. B.-Y.Z. and P.-T.T., who contributed equally as corresponding authors, took whole responsibility for major revision and submission of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

There was no research funding for this work.

Conflicts of Interest

The authors declare that there were no any potential conflicts of interest in this work.

References

  1. Hajas, A.; Szodoray, P.; Barath, S.; Sipka, S.; Rezes, S.; Zeher, M.; Sziklai, I.; Szegedi, G.; Bodolay, E. Sensorineural hearing loss in patients with mixed connective tissue disease: Immunological markers and cytokine levels. J. Rheumatol. 2009, 36, 1930–1936. [Google Scholar] [CrossRef] [PubMed]
  2. Di Stadio, A.; Ralli, M. Systemic Lupus Erythematosus and hearing disorders: Literature review and meta-analysis of clinical and temporal bone findings. J. Int. Med. Res. 2017, 45, 1470–1480. [Google Scholar] [CrossRef] [PubMed]
  3. Chen, J.J.; Hsu, C.W.; Chen, Y.W.; Chen, T.Y.; Zeng, B.S.; Tseng, P.T. Audiovestibular Dysfunction in Systemic Lupus Erythematosus Patients: A Systematic Review. Diagnostics 2024, 14, 1670. [Google Scholar] [CrossRef] [PubMed]
  4. Murdin, L.; Patel, S.; Walmsley, J.; Yeoh, L.H. Hearing difficulties are common in patients with rheumatoid arthritis. Clin. Rheumatol. 2008, 27, 637–640. [Google Scholar] [CrossRef] [PubMed]
  5. Ozcan, M.; Karakus, M.F.; Gunduz, O.H.; Tuncel, U.; Sahin, H. Hearing loss and middle ear involvement in rheumatoid arthritis. Rheumatol. Int. 2002, 22, 16–19. [Google Scholar] [CrossRef]
  6. Sun, X.M.; Zhuang, S.M.; Xiao, Z.W.; Luo, J.Q.; Long, Z.; Lan, L.C.; Zhang, H.Q.; Zhang, G.P. Autoimmune thyroiditis in patients with sudden sensorineural hearing loss. Laryngoscope Investig. Otolaryngol. 2022, 7, 571–577. [Google Scholar] [CrossRef]
  7. Colletti, V.; Fiorino, F.G.; Bruni, L.; Biasi, D. Middle ear mechanics in subjects with rheumatoid arthritis. Audiology 1997, 36, 136–146. [Google Scholar] [CrossRef]
  8. Frade, C.; Martin, C. Diagnostic value of the multifrequency tympanometry in active rheumatoid arthritis. Auris Nasus Larynx 1998, 25, 131–136. [Google Scholar] [CrossRef]
  9. Chen, J.J.; Zeng, B.Y.; Lui, C.C.; Chen, T.Y.; Chen, Y.W.; Tseng, P.T. Pfizer-BioNTech COVID-19 vaccine associated tinnitus and treatment with transcranial magnetic stimulation. QJM 2022, 115, 623–624. [Google Scholar] [CrossRef]
  10. Tseng, P.T.; Chen, T.Y.; Lui, C.C.; Chen, Y.W.; Chen, J.J. Tinnitus Associated with Mild Osteomyelitis of the Temporal Bone Reversed after Conservative Antibiotic Treatment: A Case Series. Medicina 2022, 58, 318. [Google Scholar] [CrossRef]
  11. Brey, R.L.; Escalante, A. Neurological manifestations of antiphospholipid antibody syndrome. Lupus 1998, 7 (Suppl. S2), S67–S74. [Google Scholar] [CrossRef] [PubMed]
  12. Knight, J.S.; Branch, D.W.; Ortel, T.L. Antiphospholipid syndrome: Advances in diagnosis, pathogenesis, and management. BMJ 2023, 380, e069717. [Google Scholar] [CrossRef] [PubMed]
  13. Etherington, J.; Cooper, A.; Buchanan, N. Antiphospholipid syndrome in rheumatoid arthritis presenting with sensorineural deafness. Lupus 1994, 3, 63–64. [Google Scholar] [CrossRef] [PubMed]
  14. Garcia, D.; Erkan, D. Diagnosis and Management of the Antiphospholipid Syndrome. N. Engl. J. Med. 2018, 378, 2010–2021. [Google Scholar] [CrossRef]
  15. Duarte-Garcia, A.; Pham, M.M.; Crowson, C.S.; Amin, S.; Moder, K.G.; Pruthi, R.K.; Warrington, K.J.; Matteson, E.L. The Epidemiology of Antiphospholipid Syndrome: A Population-Based Study. Arthritis Rheumatol. 2019, 71, 1545–1552. [Google Scholar] [CrossRef]
  16. Miyakis, S.; Lockshin, M.D.; Atsumi, T.; Branch, D.W.; Brey, R.L.; Cervera, R.; Derksen, R.H.W.M.; De Groot, P.G.; Koike, T.; Meroni, P.L.; et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. JTH 2006, 4, 295–306. [Google Scholar] [CrossRef]
  17. Hisashi, K.; Komune, S.; Taira, T.; Uemura, T.; Sadoshima, S.; Tsuda, H. Anticardiolipin antibody-induced sudden profound sensorineural hearing loss. Am. J. Otolaryngol. 1993, 14, 275–277. [Google Scholar] [CrossRef]
  18. Bir, L.S.; Esmeli, F.O.; Ardic, F.N. Sudden sensorineural hearing loss in a patient with primary antiphospholipid syndrome. J. Thromb. Thrombolysis 2006, 21, 277. [Google Scholar] [CrossRef]
  19. Cavallasca, J.A.; Nasswetter, G.G.; Gutierrez, D.M.; Bercellini, E.A.; Brodsky, A.L. Sudden sensorineural hearing loss as a manifestation of primary antiphospholipid syndrome. Joint Bone Spine 2007, 74, 403–404. [Google Scholar] [CrossRef]
  20. Galicia-Lopez, A.; Anda-Garay, J.C.; Garcia de la Pena, M. Bilateral sudden sensorineural hearing loss in a patient with microangiopathic antiphospholipid syndrome. Reumatol. Clin. 2016, 12, 175–177. [Google Scholar] [CrossRef]
  21. Ruckenstein, M.J.; Prasthoffer, A.; Bigelow, D.C.; Von Feldt, J.M.; Kolasinski, S.L. Immunologic and serologic testing in patients with Meniere’s disease. Otol. Neurotol. 2002, 23, 517–520; discussion 520–511. [Google Scholar] [CrossRef] [PubMed]
  22. Tumiati, B.; Casoli, P. Sudden sensorineural hearing loss and anticardiolipin antibody. Am. J. Otolaryngol. 1995, 16, 220. [Google Scholar] [CrossRef] [PubMed]
  23. Wang, J.G.; Xie, Q.B.; Yang, N.P.; Yin, G. Primary antiphospholipid antibody syndrome: A case with bilateral sudden sensorineural hearing loss. Rheumatol. Int. 2009, 29, 467–468. [Google Scholar] [CrossRef] [PubMed]
  24. Mouadeb, D.A.; Ruckenstein, M.J. Antiphospholipid inner ear syndrome. Laryngoscope 2005, 115, 879–883. [Google Scholar] [CrossRef]
  25. Lin, T.S.; Hsu, P.Y.; Chang, C.H.; Ko, C.L.; Kuo, Y.M.; Wu, Y.W.; Yen, R.F.; Wu, C.H.; Li, K.J.; Hsein, Y.C.; et al. Increased heterogeneity of brain perfusion is an early marker of central nervous system involvement in antiphospholipid antibody carriers. PLoS ONE 2017, 12, e0182344. [Google Scholar] [CrossRef]
  26. Veldman, J.E.; Roord, J.J.; O’Connor, A.F.; Shea, J.J. Autoimmunity and inner ear disorders: An immune-complex mediated sensorineural hearing loss. Laryngoscope 1984, 94, 501–507. [Google Scholar] [CrossRef]
  27. Wiles, N.M.; Hunt, B.J.; Callanan, V.; Chevretton, E.B. Sudden sensorineural hearing loss and antiphospholipid syndrome. Haematologica 2006, 91, ECR46. [Google Scholar]
  28. Bachor, E.; Kremmer, S.; Kreuzfelder, E.; Jahnke, K.; Seidahmadi, S. Antiphospholipid antibodies in patients with sensorineural hearing loss. Eur. Arch. Otorhinolaryngol. 2005, 262, 622–626. [Google Scholar] [CrossRef]
  29. Gross, M.; Eliashar, R.; Ben-Yaakov, A.; Ulmansky, R.; Elidan, J. Prevalence and clinical significance of anticardiolipin, anti-beta2-glycoprotein-1, and anti-heat shock protein-70 autoantibodies in sudden sensorineural hearing loss. Audiol. Neurootol. 2008, 13, 231–238. [Google Scholar] [CrossRef]
  30. Hirose, K.; Wener, M.H.; Duckert, L.G. Utility of laboratory testing in autoimmune inner ear disease. Laryngoscope 1999, 109, 1749–1754. [Google Scholar] [CrossRef]
  31. Kremmer, S.; Kreuzfelder, E.; Bachor, E.; Jahnke, K.; Selbach, J.M.; Seidahmadi, S. Coincidence of normal tension glaucoma, progressive sensorineural hearing loss, and elevated antiphosphatidylserine antibodies. Br. J. Ophthalmol. 2004, 88, 1259–1262. [Google Scholar] [CrossRef] [PubMed]
  32. Marcucci, R.; Alessandrello Liotta, A.; Cellai, A.P.; Rogolino, A.; Berloco, P.; Leprini, E.; Pagnini, P.; Abbate, R.; Prisco, D. Cardiovascular and thrombophilic risk factors for idiopathic sudden sensorineural hearing loss. J. Thromb. Haemost. JTH 2005, 3, 929–934. [Google Scholar] [CrossRef] [PubMed]
  33. Suslu, N.; Yilmaz, T.; Gursel, B. Utility of anti-HSP 70, TNF-alpha, ESR, antinuclear antibody, and antiphospholipid antibodies in the diagnosis and treatment of sudden sensorineural hearing loss. Laryngoscope 2009, 119, 341–346. [Google Scholar] [CrossRef] [PubMed]
  34. Toubi, E.; Ben-David, J.; Kessel, A.; Halas, K.; Sabo, E.; Luntz, M. Immune-mediated disorders associated with idiopathic sudden sensorineural hearing loss. Ann. Otol. Rhinol. Laryngol. 2004, 113, 445–449. [Google Scholar] [CrossRef]
  35. Toubi, E.; Ben-David, J.; Kessel, A.; Podoshin, L.; Golan, T.D. Autoimmune aberration in sudden sensorineural hearing loss: Association with anti-cardiolipin antibodies. Lupus 1997, 6, 540–542. [Google Scholar] [CrossRef]
  36. Williamson, K.A.; Sanchez-Alvarez, C.; Duarte-Garcia, A. 28-Year-Old Man With Recurrent Vertigo, Syncope, and Progressive Memory Impairment. Mayo Clin. Proc. 2021, 96, 1309–1314. [Google Scholar] [CrossRef]
  37. Jeong, J.; Lim, H.; Lee, K.; Hong, C.E.; Choi, H.S. High Risk of Sudden Sensorineural Hearing Loss in Several Autoimmune Diseases according to a Population-Based National Sample Cohort Study. Audiol. Neurootol. 2019, 24, 224–230. [Google Scholar] [CrossRef]
  38. Paira, S.O. Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus-like syndrome and antiphospholipid antibodies. J. Rheumatol. 1998, 25, 2476–2477. [Google Scholar] [PubMed]
  39. Vila, P.; Hernandez, M.C.; Lopez-Fernandez, M.F.; Batlle, J. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects. Thromb. Haemost. 1994, 72, 209–213. [Google Scholar] [CrossRef]
  40. Li, X.; Chen, W.; Yi, H.; Xu, J.; Lu, M.; Guo, F.; Li, X.; Ye, J. The association between the levels of autoimmune related indicators and clinical condition in sudden deafness patients. Ann. Palliat. Med. 2021, 10, 10535–10541. [Google Scholar] [CrossRef]
  41. Rajati, M.; Saghafi, M.; Rafatpanah, H.; Rasoulian, B.; Irani, S.; Soltankhah, M. Immunology-Rheumatology Approach to Sudden Sensorineural Hearing Loss. Curr. Rheumatol. Rev. 2018, 14, 70–73. [Google Scholar] [CrossRef] [PubMed]
  42. Passamonti, S.M.; Di Berardino, F.; Bucciarelli, P.; Berto, V.; Artoni, A.; Gianniello, F.; Ambrosetti, U.; Cesarani, A.; Pappalardo, E.; Martinelli, I. Risk factors for idiopathic sudden sensorineural hearing loss and their association with clinical outcome. Thromb. Res. 2015, 135, 508–512. [Google Scholar] [CrossRef] [PubMed]
  43. Ballesteros, F.; Alobid, I.; Tassies, D.; Reverter, J.C.; Scharf, R.E.; Guilemany, J.M.; Bernal-Sprekelsen, M. Is there an overlap between sudden neurosensorial hearing loss and cardiovascular risk factors? Audiol. Neurootol. 2009, 14, 139–145. [Google Scholar] [CrossRef] [PubMed]
  44. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [PubMed]
  45. Wells, G.A.; Shea, B.; O’Connell, D.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available online: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed on 12 June 2024).
  46. Warkentin, T.E.; Aird, W.C.; Rand, J.H. Platelet-endothelial interactions: Sepsis, HIT, and antiphospholipid syndrome. Hematol. Am. Soc. Hematol. Educ. Program 2003, 2033, 497–519. [Google Scholar] [CrossRef]
  47. Yang, D.L.; Thomas, R.; Ford, A.F.; Cucchiara, B.L.; George, D.K.; Song, J.W. Vessel wall imaging in the diagnosis of antiphospholipid syndrome presenting as Moyamoya syndrome—A case report. Neuroradiol. J. 2024; Online ahead of print. [Google Scholar] [CrossRef]
  48. Mendonca, L.L.; Amengual, O.; Atsumi, T.; Khamashta, M.A.; Hughes, G.R. Most anticardiolipin antibodies in mixed connective tissue disease are beta2-glycoprotein independent. J. Rheumatol. 1998, 25, 189–190. [Google Scholar]
  49. Riera, J.L.; Del, R.M.M.; Musuruana, J.L.; Cavallasca, J.A. Sudden Sensorineural Hearing Loss in Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A Clinical Review. Curr. Rheumatol. Rev. 2020, 16, 84–91. [Google Scholar] [CrossRef]
  50. Digiovanni, J.J.; Nair, P. Spontaneous recovery of sudden sensorineural hearing loss: Possible association with autoimmune disorders. J. Am. Acad. Audiol. 2006, 17, 498–505. [Google Scholar] [CrossRef]
  51. Mazzoccoli, C.; Comitangelo, D.; D’Introno, A.; Mastropierro, V.; Sabba, C.; Perrone, A. Antiphospholipid syndrome: A case report with an unusual wide spectrum of clinical manifestations. Autoimmun. Immun. Highlights 2019, 10, 9. [Google Scholar] [CrossRef]
  52. Girasoli, L.; Cazzador, D.; Padoan, R.; Nardello, E.; Felicetti, M.; Zanoletti, E.; Schiavon, F.; Bovo, R. Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment. J. Immunol. Res. 2018, 2018, 5072582. [Google Scholar] [CrossRef] [PubMed]
  53. Lopez-Gentili, L.I.; Garate, G.; Riveros, D.; Ameriso, S.F. [Antiphospholipid antibodies in patients with vestibular manifestations. A study of 16 cases]. Rev. Neurol. 2003, 36, 112–117. [Google Scholar] [PubMed]
  54. Erez, D.; Abarbuch, E.; Natour, A.; Meyer, A.; Natour, A.; Dovrish, Z.; Levy, Y. Audiological disturbances in patients with primary antiphospholipid syndrome. Lupus 2020, 29, 533–538. [Google Scholar] [CrossRef] [PubMed]
  55. Hayem, G.; De Bandt, M.; Palazzo, E.; Roux, S.; Combe, B.; Eliaou, J.F.; Sany, J.; Kahn, M.F.; Meyer, O. Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis. Ann. Rheum. Dis. 1999, 58, 291–296. [Google Scholar] [CrossRef]
  56. Cho, C.H.; Jung, B.S.; Jung, J.H.; Lee, J.H.; Lee, J.H. Expression of autoantibodies in patients with sudden sensorineural hearing loss. Ann. Otol. Rhinol. Laryngol. 2013, 122, 131–134. [Google Scholar] [CrossRef]
  57. Ottaviani, F.; Cadoni, G.; Marinelli, L.; Fetoni, A.R.; De Santis, A.; Romito, A.; Vulpiani, P.; Manna, R. Anti-endothelial autoantibodies in patients with sudden hearing loss. Laryngoscope 1999, 109, 1084–1087. [Google Scholar] [CrossRef]
  58. Agrup, C.; Luxon, L.M. Immune-mediated inner-ear disorders in neuro-otology. Curr. Opin. Neurol. 2006, 19, 26–32. [Google Scholar] [CrossRef]
  59. Heller, U.; Becker, E.W.; Zenner, H.P.; Berg, P.A. [Incidence and clinical relevance of antibodies to phospholipids, serotonin and ganglioside in patients with sudden deafness and progressive inner ear hearing loss]. HNO 1998, 46, 583–586. [Google Scholar] [CrossRef]
  60. Sharma, Y.K.; Chauhan, S. Overlap Syndrome with Rowell’s Syndrome, Antiphospholipid Syndrome, Primary Sterility, and Sensorineural Hearing Loss: A Case Report, Brief Review, and Analysis of Cases of Rowell’s Syndrome Reported from India and Abroad. Indian J. Dermatol. 2018, 63, 418–423. [Google Scholar] [CrossRef]
  61. Carp, H.J.; Shoenfeld, Y. Anti-phospholipid antibodies and infertility. Clin. Rev. Allergy Immunol. 2007, 32, 159–161. [Google Scholar] [CrossRef]
  62. Galli, M.; Luciani, D.; Bertolini, G.; Barbui, T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: A systematic review of the literature. Blood 2003, 101, 1827–1832. [Google Scholar] [CrossRef] [PubMed]
  63. Khamashta, M.A.; Cuadrado, M.J.; Mujic, F.; Taub, N.A.; Hunt, B.J.; Hughes, G.R. The management of thrombosis in the antiphospholipid-antibody syndrome. N. Engl. J. Med. 1995, 332, 993–997. [Google Scholar] [CrossRef] [PubMed]
  64. Nouduri, S.; Padmanabhan, R.; Hicks, R.; Abbott, M.A.; O’Brien, D.; Schlaug, G. Case report: MELAS and concomitant presumed antiphospholipid antibody syndrome in an adult woman. Front. Neurol. 2022, 13, 1043695. [Google Scholar] [CrossRef] [PubMed]
  65. Gharavi, A.E.; Pierangeli, S.S. Origin of antiphospholipid antibodies: Induction of aPL by viral peptides. Lupus 1998, 7 (Suppl. S2), S52–S54. [Google Scholar] [CrossRef]
  66. Shoenfeld, Y.; Blank, M.; Cervera, R.; Font, J.; Raschi, E.; Meroni, P.L. Infectious origin of the antiphospholipid syndrome. Ann. Rheum. Dis. 2006, 65, 2–6. [Google Scholar] [CrossRef]
  67. Cervera, R.; Asherson, R.A.; Acevedo, M.L.; Gomez-Puerta, J.A.; Espinosa, G.; De La Red, G.; Gil, V.; Ramos-Casals, M.; Garcia-Carrasco, M.; Ingelmo, M.; et al. Antiphospholipid syndrome associated with infections: Clinical and microbiological characteristics of 100 patients. Ann. Rheum. Dis. 2004, 63, 1312–1317. [Google Scholar] [CrossRef]
  68. Pointer, C.B.; Wenzel, T.J.; Klegeris, A. Extracellular cardiolipin regulates select immune functions of microglia and microglia-like cells. Brain Res. Bull. 2019, 146, 153–163. [Google Scholar] [CrossRef]
  69. Harris, J.P.; Sharp, P.A. Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope 1990, 100, 516–524. [Google Scholar] [CrossRef]
  70. Bernstein, J.M. The immunobiology of autoimmune disease of the inner ear. In Immunology of the Ear; Bernstein, J., Ogra, P., Eds.; Raven Press: New York, NY, USA, 1987; pp. 419–426. [Google Scholar]
  71. Harris, E.N.; Gharavi, A.E.; Boey, M.L.; Patel, B.M.; Mackworth-Young, C.G.; Loizou, S.; Hughes, G.R. Anticardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983, 2, 1211–1214. [Google Scholar] [CrossRef]
  72. Hanly, J.G. Antiphospholipid syndrome: An overview. CMAJ 2003, 168, 1675–1682. [Google Scholar]
  73. Beynon, H.L.; Walport, M.J. Antiphospholipid antibodies and cardiovascular disease. Br. Heart J. 1992, 67, 281–284. [Google Scholar] [CrossRef] [PubMed]
  74. Yehudai, D.; Shoenfeld, Y.; Toubi, E. The autoimmune characteristics of progressive or sudden sensorineural hearing loss. Autoimmunity 2006, 39, 153–158. [Google Scholar] [CrossRef] [PubMed]
  75. Levine, J.S.; Branch, D.W.; Rauch, J. The antiphospholipid syndrome. N. Engl. J. Med. 2002, 346, 752–763. [Google Scholar] [CrossRef] [PubMed]
  76. Green, L.; Miller, E.B. Sudden sensorineural hearing loss as a first manifestation of systemic lupus erythematosus: Association with anticardiolipin antibodies. Clin. Rheumatol. 2001, 20, 220–222. [Google Scholar] [CrossRef] [PubMed]
  77. Gheorghe, D.C.; Epure, V.; Oprea, D.; Zamfir-Chiru-Anton, A. Persistent Stapedial Artery, Oval Window Atresia and Congenital Stapes Agenesis-Case Report. Medicina 2023, 59, 461. [Google Scholar] [CrossRef]
  78. Naarendorp, M.; Spiera, H. Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus-like syndromes and antiphospholipid antibodies. J. Rheumatol. 1998, 25, 589–592. [Google Scholar] [PubMed]
  79. Liu, D.; Qin, Z.; Wei, M.; Kong, D.; Zheng, Q.; Bai, S.; Lin, S.; Zhang, Z.; Ma, Y. Genome-Wide Analyses of Heat Shock Protein Superfamily Provide New Insights on Adaptation to Sulfide-Rich Environments in Urechis unicinctus (Annelida, Echiura). Int. J. Mol. Sci. 2022, 23, 2715. [Google Scholar] [CrossRef]
  80. Hu, C.; Yang, J.; Qi, Z.; Wu, H.; Wang, B.; Zou, F.; Mei, H.; Liu, J.; Wang, W.; Liu, Q. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm 2022, 3, e161. [Google Scholar] [CrossRef]
  81. Kaufmann, S.H. Heat shock proteins and the immune response. Immunol. Today 1990, 11, 129–136. [Google Scholar] [CrossRef]
  82. Kaufmann, S.H. Heat shock proteins and autoimmunity: A critical appraisal. Int. Arch. Allergy Immunol. 1994, 103, 317–322. [Google Scholar] [CrossRef]
  83. Bloch, D.B.; Gutierrez, J.A.; Guerriero, V., Jr.; Rauch, S.D.; Bloch, K.J. Recognition of a dominant epitope in bovine heat-shock protein 70 in inner ear disease. Laryngoscope 1999, 109, 621–625. [Google Scholar] [CrossRef] [PubMed]
  84. Veldman, J.E. Immune-mediated sensorineural hearing loss with or without endolymphatic hydrops: A clinical and experimental approach. Ann. N. Y. Acad. Sci. 1997, 830, 179–186. [Google Scholar] [CrossRef] [PubMed]
  85. Ceylan, A.; Celenk, F.; Kemaloglu, Y.K.; Bayazit, Y.A.; Goksu, N.; Ozbilen, S. Impact of prognostic factors on recovery from sudden hearing loss. J. Laryngol. Otol. 2007, 121, 1035–1040. [Google Scholar] [CrossRef] [PubMed]
  86. Narozny, W.; Kuczkowski, J.; Kot, J.; Stankiewicz, C.; Sicko, Z.; Mikaszewski, B. Prognostic factors in sudden sensorineural hearing loss: Our experience and a review of the literature. Ann. Otol. Rhinol. Laryngol. 2006, 115, 553–558. [Google Scholar] [CrossRef] [PubMed]
  87. Cadoni, G.; Agostino, S.; Manna, R.; De Santis, A.; Fetoni, A.R.; Vulpiani, P.; Ottaviani, F. Clinical associations of serum antiendothelial cell antibodies in patients with sudden sensorineural hearing loss. Laryngoscope 2003, 113, 797–801. [Google Scholar] [CrossRef]
  88. Munari, L.; Charchat, S.; Rodrigues, L.; von Muhlen, C.A.; Bau, A.R.; Lavinsky, L.; Bonorino, C. An ELISA serum assay for autoantibodies to HSP70 in immune-mediated hearing loss. J. Immunol. Methods 2003, 283, 155–161. [Google Scholar] [CrossRef]
  89. Ali, A.H.; Salahuddin, Z.; Salim, R. Sudden sensorineural hearing loss: A missed opportunity for treatment. Malays. Fam. Physician 2018, 13, 29–30. [Google Scholar]
  90. Kang, K.T.; Young, Y.H. Sudden sensorineural hearing loss in a patient with primary antiphospholipid syndrome. J. Laryngol. Otol. 2008, 122, 204–206. [Google Scholar] [CrossRef]
  91. Vyse, T.; Luxon, L.M.; Walport, M.J. Audiovestibular manifestations of the antiphospholipid syndrome. J. Laryngol. Otol. 1994, 108, 57–59. [Google Scholar] [CrossRef]
  92. Crowther, M.A.; Ginsberg, J.S.; Julian, J.; Denburg, J.; Hirsh, J.; Douketis, J.; Laskin, C.; Fortin, P.; Anderson, D.; Kearon, C.; et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N. Engl. J. Med. 2003, 349, 1133–1138. [Google Scholar] [CrossRef]
  93. Alexander, T.H.; Weisman, M.H.; Derebery, J.M.; Espeland, M.A.; Gantz, B.J.; Gulya, A.J.; Hammerschlag, P.E.; Hannley, M.; Hughes, G.B.; Moscicki, R.; et al. Safety of high-dose corticosteroids for the treatment of autoimmune inner ear disease. Otol. Neurotol. 2009, 30, 443–448. [Google Scholar] [CrossRef] [PubMed]
  94. Chawki, S.; Aouizerate, J.; Trad, S.; Prinseau, J.; Hanslik, T. Bilateral sudden sensorineural hearing loss as a presenting feature of systemic lupus erythematosus: Case report and brief review of other published cases. Medicine 2016, 95, e4345. [Google Scholar] [CrossRef] [PubMed]
  95. Khalidi, N.A.; Rebello, R.; Robertson, D.D. Sensorineural hearing loss in systemic lupus erythematosus: Case report and literature review. J. Laryngol. Otol. 2008, 122, 1371–1376. [Google Scholar] [CrossRef]
  96. McCabe, B.F. Autoimmune sensorineural hearing loss. 1979. Ann. Otol. Rhinol. Laryngol. 2004, 113, 526–530. [Google Scholar] [CrossRef] [PubMed]
  97. Aziz, A.; Conway, M.D.; Robertson, H.J.; Espinoza, L.R.; Wilson, W.A. Acute optic neuropathy and transverse myelopathy in patients with antiphospholipid antibody syndrome: Favorable outcome after treatment with anticoagulants and glucocorticoids. Lupus 2000, 9, 307–310. [Google Scholar] [CrossRef] [PubMed]
  98. Hisashi, K.; Komune, S.; Komiyama, S.; Nakamura, K. [Sudden sensorineural hearing loss associated with anticardiolipin antibody]. Nihon Jibiinkoka Gakkai Kaiho 1996, 99, 1157–1161. [Google Scholar] [CrossRef] [PubMed]
  99. Agarwal, K.S.; Puliyel, J.M.; Khanduri, U. Sudden onset profound deafness in association with antiphospholipid antibodies in a child with SLE. Indian Pediatr. 2000, 37, 1274–1276. [Google Scholar]
  100. Wile, D. Diuretics: A review. Ann. Clin. Biochem. 2012, 49, 419–431. [Google Scholar] [CrossRef]
  101. Compadretti, G.C.; Brandolini, C.; Tasca, I. Sudden sensorineural hearing loss in lupus erythematosus associated with antiphospholipid syndrome: Case report and review. Ann. Otol. Rhinol. Laryngol. 2005, 114, 214–218. [Google Scholar] [CrossRef]
  102. Hamblin, T.J.; Mufti, G.J.; Bracewell, A. Severe deafness in systemic lupus erythematosus: Its immediate relief by plasma exchange. BMJ 1982, 284, 1374. [Google Scholar] [CrossRef]
  103. Agarwal, K.; Thomas, N.; Taneja, V.; Beri, R.S.; Khanduri, U.; Puliyel, J.M. Plasma exchange in a child with systemic lupus erythematosus antiphospholipid antibodies and profound deafness. Ann. Trop. Paediatr. 2002, 22, 109–110. [Google Scholar] [CrossRef] [PubMed]
  104. Kobayashi, S.; Fujishiro, N.; Sugiyama, K. Systemic lupus erythematosus with sensorineural hearing loss and improvement after plasmapheresis using the double filtration method. Intern. Med. 1992, 31, 778–781. [Google Scholar] [CrossRef] [PubMed]
  105. Chen, J.J.; Zeng, B.S.; Wu, C.N.; Stubbs, B.; Carvalho, A.F.; Brunoni, A.R.; Su, K.P.; Tu, Y.K.; Wu, Y.C.; Chen, T.Y.; et al. Association of Central Noninvasive Brain Stimulation Interventions with Efficacy and Safety in Tinnitus Management: A Meta-analysis. JAMA Otolaryngol. Head. Neck Surg. 2020, 146, 801–809. [Google Scholar] [CrossRef] [PubMed]
Diagnostics 14 02522 g001
Figure 1. Flowchart of the whole systematic review procedure.
Figure 1. Flowchart of the whole systematic review procedure.
Diagnostics 14 02522 g001
Diagnostics 14 02522 g002
Figure 2. Schematic diagram of the physiopathology of anti-phospholipid syndrome in audiovestibular dysfunction.
Figure 2. Schematic diagram of the physiopathology of anti-phospholipid syndrome in audiovestibular dysfunction.
Diagnostics 14 02522 g002
Diagnostics 14 02522 g003
Figure 3. Flowchart of the modified anticoagulants plus steroid and non-invasive brain stimulation treatment protocol to manage anti-phospholipid syndrome-related audiovestibular dysfunction. Note: this is a proposal of a future study protocol.
Figure 3. Flowchart of the modified anticoagulants plus steroid and non-invasive brain stimulation treatment protocol to manage anti-phospholipid syndrome-related audiovestibular dysfunction. Note: this is a proposal of a future study protocol.
Diagnostics 14 02522 g003
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chen, J.-J.; Hsu, C.-W.; Chen, Y.-W.; Chen, T.-Y.; Zeng, B.-Y.; Tseng, P.-T. Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review. Diagnostics 2024, 14, 2522. https://doi.org/10.3390/diagnostics14222522

AMA Style

Chen J-J, Hsu C-W, Chen Y-W, Chen T-Y, Zeng B-Y, Tseng P-T. Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review. Diagnostics. 2024; 14(22):2522. https://doi.org/10.3390/diagnostics14222522

Chicago/Turabian Style

Chen, Jiann-Jy, Chih-Wei Hsu, Yen-Wen Chen, Tien-Yu Chen, Bing-Yan Zeng, and Ping-Tao Tseng. 2024. "Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review" Diagnostics 14, no. 22: 2522. https://doi.org/10.3390/diagnostics14222522

APA Style

Chen, J. -J., Hsu, C. -W., Chen, Y. -W., Chen, T. -Y., Zeng, B. -Y., & Tseng, P. -T. (2024). Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review. Diagnostics, 14(22), 2522. https://doi.org/10.3390/diagnostics14222522

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop