Vascular mechanisms in acute unilateral peripheral vestibulopathy: a systematic review| ACTA Otorhinolaryngologica Italica

Abstract

Acute unilateral peripheral vestibulopathy (AUPVP) is a frequent cause of vestibular loss. Several aetiologies have been proposed, but the exact mechanism remains unknown. The aim of this study is a systematic analysis of the literature evaluating the vascular aetiology of AUPVP. A systematic literature search was performed in PubMed, Cochrane Library and Embase, including articles published from January 1st, 2010 to November 30th, 2020. Two reviewers independently selected articles investigating a link between AUPVP and vascular disease. The following information was extracted: year of publication, country, level of evidence, assessed vascular risk factors and number of patients. A total of 450 articles was obtained. Eleven articles were retained with 100% agreement between the two reviewers. In a pooled population of 805 patients, the main results were the higher neutrophil to lymphocyte ratio and higher prevalence of vascular risk factors among AUPVP patients. A meta-analysis was not performed because the studies were too heterogeneous in terms of methodology. Indirect arguments for vascular mechanisms in AUPVP were found. These findings indicate that larger prospective well-controlled studies are needed to clarify the vascular aetiology of AUPVP.

Introduction

Acute unilateral peripheral vestibulopathy (AUPVP) is considered the third most common peripheral vestibular disorder after benign paroxysmal positional vertigo and Meniere’s disease ^1,2. Several hypotheses have been proposed for the aetiology of AUPVP, but the exact mechanism remains unknown. Nowadays, the term AUPVP is preferred over “vestibular neuritis” because it is unclear whether it is always an inflammation that provokes the dysfunction ³. However, until recently, the vast majority of the literature contains the term “vestibular neuritis” (VN). In this work, the term AUPVP will be used henceforth.

According to the literature, the most likely origin of AUPVP is viral, namely herpes simplex type 1. This is supported by a genome wide association study showing a link between the disease and single nucleotide variants of the host factor for HSV1 replication ⁴. However, other aetiologies have been suggested including thrombosis and an autoimmune inner ear reaction ⁵.

The clinical picture varies according to the extent to which the vestibular end organs or their innervation are affected ⁶. The patient might present a spontaneous horizontal nystagmus beating away from the lesion side and caloric testing paralysis/paresis; a reduced gain in the video head impulse test (vHIT) supports the diagnosis ³. Vestibular-evoked myogenic potentials (VEMPs) are helpful to distinguish between involvement of the superior and inferior vestibular nerves ⁷. Acute unilateral peripheral vestibulopathy appears to be more common in the superior vestibular labyrinth and its afferents, which could be explained by the longer and narrower path through its bony canal and also explains why the posterior semicircular canal and saccule are less affected ⁸. A previous history of upper airway infection or concomitant findings of herpes infection strongly points towards a viral aetiology. However, not all patients fit this profile and other causes may be considered, namely a vascular aetiology. Actually, like the inner ear, the kidney, heart and eyes are supplied with an end artery and many of the diseases that affect these organs are, in fact, mediated by vascular events, a topic that consequently deserves further research in AUPVP ^9-11. Any disturbance in the cochleovestibular blood supply can provoke an insult in the fluid homeostasis and metabolic supply, and may be related to a variability of inner ear disorders, such as sudden deafness, autoimmunity, age-related hearing loss, AUPVP and Meniere’s disease ¹².

The inner ear is supplied by the labyrinthine artery (LA), an end artery. Usually, the LA derives from the anterior inferior cerebellar artery (AICA) and gives two main branches, the common cochlear (CCA) and anterior vestibular (AVA) arteries. The CCA divides into the main cochlear artery and the vestibulocochlear artery, the latter forming the posterior vestibular and the cochlear artery. The apical three fourths of the cochlea are supplied by the main cochlear artery and the basal one by the cochlear ramus. The AVA supplies the utricle, superior part of the saccule and ampullae of the superior and lateral semicircular canals. In contrast, the posterior vestibular artery supplies the inferior part of the saccule and the ampulla of the posterior semicircular canal ¹³. Thus, an overlap exists between inner ear vascular supply and inner ear innervation. Theoretically, a sudden interruption of the blood flow of the anterior vestibular artery could affect the same structures of a superior vestibular nerve inflammation, and the symptoms could be the same in the setting of an inflammatory or a vascular insult ¹⁴. A longitudinal population-based cohort study of 1925 individuals concluded that smoking, central adiposity and poorly controlled diabetes mellitus predicted incident hearing impairment, which may suggest inner ear atherosclerotic events ¹⁵. The labyrinth is also vulnerable to ischaemia, like the other organs mentioned above, because it requires high-energy metabolism ¹³. By contrast, the retrocochlear acoustic nerve has an abundant collateral blood supply from the lateral medullary artery, arteries of the adjacent dura mater and petrous bone and the inferior lateral pontine artery ¹³. Thus, the different parts of the inner ear may be more prone to ischaemia than the nerves considering the different patterns of vascular supply.

In this work, we performed a systematic review of the most recent evidence studying the links between AUPVP and vascular disease, exploring if AUPVP patients have a higher vascular risk than general population.

Materials and methods

Identification and selection of studies

A systematic review was performed in December 2020 using three electronic databases: 1) PubMed, 2) the Cochrane Library and 3) Embase. The search strategy is presented in Table I. Studies published in English between January 1^st, 2010 and November 30^th, 2020 were retrieved.

The term VN was used also considering that the majority of published studies regarding AUPVP use this nomenclature. The literature search, selection and analysis were independently performed by two researchers (JS and AM). The studies included in our review were eligible if they met the following inclusion criteria: 1) studies in Humans, 2) definition of AUPVP clearly stated, 3) studies investigating a link between AUPVP and vascular disease and 4) one of the following types of articles: prospective cohort studies of consecutive patients, case-control studies of consecutive patients, retrospective reviews of consecutive patients and selected case series (prospective or retrospective). Studies were excluded if they consisted of expert opinions, reviews, letters or comments, original studies with different themes of interest, experiments on animals or cadavers and in vitro studies. The article selection was performed according to the Primary Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement (Fig. 1) ¹⁶. All the discrepancies between researchers were resolved by consensus. The following information of the included studies was recorded: author, year of publication, country of publication, level of evidence, number of patients with AUPVP and analysed cardiovascular risk factors (CVRFs). Other papers were used to contextualise and discuss the presented studies.

Level of evidence

The included articles were evaluated with a level of evidence based on the Oxford Centre for Evidence-Based Medicine ¹⁷. Level 1a refers to a systematic review of randomised controlled trials, level 1b to an individual RCT, level 2a to a systematic review of cohort studies, level 2b to an individual cohort study/low-quality RCT, level 3a to a systematic review of case-control studies, level 3b to an individual case-control study, level 4 to a case-series or poor-quality cohort/case-control study, level 5 to a case report or expert opinion. An independent assessment was carried out by the two reviewers. In case of disagreement, a third reviewer was consulted and consensus was stablished.

Results

General results

A total of 450 records were identified in the initial search. After identifying relevant articles based on title or abstract, 190 papers were retained, of which 151 were removed after application of exclusion criteria and elimination of duplicates. Then, the full text was read to confirm the eligibility of the articles according to the inclusion criteria. Twenty-six articles were further excluded. Two studies were eliminated due to absence of clear definition of AUPVP. Finally, 11 articles met all inclusion criteria. This selection process is presented in Figure 1. The final selection of studies had an interobserver agreement of 100%. The heterogeneity of the selected studies and different methodologies made meta-analysis with pooled comparability impossible.

Level of evidence

Five studies were attributed with level 3b of evidence and 6 studies with level 4. The agreement between reviewers regarding the level of evidence was achieved for 9 studies. A third observer was needed to judge 2 studies and, after discussion, 100% of agreement was obtained.

Study characteristics

The total AUPVP population of the 11 studies was 805 adults aged 18-92 years. Nine studies had a gender-balanced population ^18-26. One study had a small number of females ²⁷ and another did not provide data regarding gender distribution ²⁸.

Details of the included articles are shown in Table II and III regarding included patients, nomenclature, measured outcomes and main results.

Studies investigating haemodynamic dysfunction in AUPVP

One of the proposed mechanisms for acute vestibulopathy is embolic labyrinthine infarction. Labyrinthine infarction can be diagnosed only in association with other infarctions involving the brainstem or cerebellar areas supplied by the anterior inferior cerebellar artery, because current imaging techniques cannot visualise an infarction confined to the labyrinth ²⁷. Of 10 patients with acute audiovestibulopathy, 3 had isolated unilateral vestibulopathy. The embolic labyrinthine infarction was diagnosed based on the presence of cardiac or artery-to-artery sources of embolism and concurrent embolic infarctions observed in the non-AICA territories ²⁷. One patient had an atrial fibrillation, one an unknown patent foramen ovale and the other presented an occlusion of the vertebral artery. All 3 patients had concomitant infarctions on MRI, but only peripheral vestibular symptoms. None of the patients presented MRI findings in the involved labyrinth.

The vertebral artery hypoplasia (VAH) was also proposed as a potential trigger of haemodynamic dysfunction in AUPVP patients. Chuang et al. compared 29 VAH (right/left: 23/6) in AUPVP subjects and six VAH in controls (right/left: 5/1). There was a high accordance rate between the side of VAH and AUPVP: 65.5% of the patients had an ipsilateral AUPVP, in which left VAH showed a higher accordance rate (83.3%). VAH accordance showed higher risk (81%) for AUPVP subjects with a vascular risk compared to those without (25%) ¹⁹. The authors suggested that VAH contributes as a risk factor for the development of ipsilateral AUPVP, and is enhanced by atherosclerotic risk factors. Of interest, the accordance rate of VAH and AUPVP was 81% in the vascular risk group compared to 28% in the non-vascular risk group. Comparing VAH presence as a prognostic factor, the same study group showed vestibular paresis to be higher (56.8%) in AUPVP subjects with VAH (n = 29) compared to AUPVP subjects (n = 40) without VAH (37.4%) (p = 0.01). The likely conclusion suggested comorbid VAH might predispose to AUPVP ²⁰. Moreover, the arterial stiffness has been proposed as a surrogate marker for vascular disease in AUPVP. In a prospective case-control study including 58 AUPVP patients versus 58 controls, arterial stiffness was measured by brachial-ankle pulse wave velocity ²¹. Clearly, a higher brachial-ankle pulse wave velocity and higher prevalence of metabolic syndrome was observed in the AUPVP group compared to the control group (p = 0.002 and p = 0.001, respectively, Tab. IV). The authors concluded that these findings support the hypothesis of a vascular aetiology of AUPVP. However, cardiovascular risk factors had limited value in predicting the clinical course of AUPVP.

Studies investigating inflammatory markers in AUPVP

Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been considered easily accessible inflammatory markers. Şahin et al. compared 104 AUPVP patients with 138 healthy subjects showing a significant higher NLR and PLR value in the AUPVP group (p < 0.001, Tab. IV), supporting the inflammatory role in AUPVP ²⁶. The same authors have also found an elevated mean platelet volume (MPV) in AUPVP patients proposing this finding as a risk marker for platelet activation, suggesting a vascular cause. Also, Oh et al. studied the inflammatory and thrombotic pathogenesis of acute unilateral vestibulopathy through gene expression profiling combined with bioinformatics analysis in 10 AUPVP patients and 10 controls ²⁴. They searched differentially expressed genes (DEGs) between these two groups. Interestingly, there were 57 DEGs (50 up-regulated and 7 down-regulated) identified in the patient’s group and most of the up-regulated DEGs were significantly related to the neutrophil-mediated immune pathway. They completed the study with comparison of complete blood count tests in 72 patients and in age-matched controls, showing that the NLR was significantly higher in the patients than in the controls (Tab. IV). Thus, they concluded that neutrophil-mediated immune pathway may contribute to the development of AUPVP by mediating inflammatory and thrombotic changes in the vestibular organ.

Studies investigating cardiovascular risk factors in AUPVP

Based on a cross-sectional retrospective study of 160 confirmed VN patients, Oron et al. concluded that cardiovascular pathology and/or cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidaemia, ischaemic heart disease and prior cerebral vascular accident/TIA) were significantly associated with AUPVP compared to the general population (Tab. IV) ²⁵. However, Han et al. did not found significant differences regarding hypertension, diabetes mellitus and dyslipidaemia between AUPVP patients and controls. Nevertheless, the prevalence of carotid plaques was significantly higher in AUPVP patients ²².

In a prospective population-based study, 79 patients with recent AUPVP were followed in 2 different Croatian cities, for 2 years (2011-2012) with the evaluation of the impact of months, seasons and comorbidities ¹⁸. No significant differences between months and seasons were detected. They observed that a significant proportion of AUPVP patients older than 50 years had vascular risk factors, namely, hypertension (30.4%), diabetes mellitus (8.9%), hyperlipidaemia (7.5%) and hypothyreosis (6.3%). Navari studied the results of caloric tests, VHIT and VEMPs in 59 patients with AUPVP ²³. They concluded that there was no effect of age regarding spontaneous recovery and vestibular rehabilitation. Moreover, they observed that most patients exhibited total end-organ damage, which could be related to damage of the entire labyrinth or, more probably, due to a neuritis of the two divisions of the vestibular nerve. Other studies also sought to analyse the vestibular lesion patterns and their connection with the distribution of the neurological afferents.

In the work of Uffer et al., the authors did not evaluate CVRFs, but they tested in what percentage of AUPVP patients the vestibular lesion pattern was observed at odds with the vestibular innervation anatomy ²⁸. Among the 25 patients, 19 (76%) had a lesion pattern that looked more like an intra-labyrinthine pattern than a neuritis pattern. Half of the patients with a definite intra-labyrinthine pattern had major dysfunction differences in the receptors of the superior vestibular nerve, the other half had dysfunction differences in the receptors of the inferior vestibular nerve. The authors concluded that the results do not support the neuritis hypothesis since about three-fourths of patients had an intra-labyrinthine lesion pattern inconsistent with an isolated nerve lesion.

Discussion

The physiopathology of AUPVP needs further exploration concerning the role of viral inflammation and vascular events in the vestibular organ, with significant clinical implications. Acute vertigo may occur due to a labyrinth infarction, but current imaging techniques do not readily allow the identification of isolated labyrinthine infarctions as a cause of acute audiovestibulopathy ^13,27. This systematic review on the vascular mechanisms of AUPVP showed interesting findings. Our first is that comparison of results remains difficult due to the variety of terms used in different studies (Tab. II). Only recently, the literature has made the shift to the term of AUPVP ³.

Furthermore, it is relevant to discuss the clinical signs in patients with an AICA stroke diagnosis showing isolated otovestibular dysfunction (vertigo, hearing loss and/or tinnitus) with normal MRI imaging one to 10 days before the appearance of neurological symptoms ⁸. We may speculate that early symptoms might be caused by early smaller emboli deeper in the AICA vascular territory, namely the inner ear microcirculation. Supportive information are histopathology findings showing vascular occlusion in age-related hearing loss patients who are probably more prone to vascular accidents. Moreover, several cases of labyrinthine infarction have been linked to cardioembolism ^29-32 and isolated deafness have also been reported during embolisation of a meningioma ³³ or cardiopulmonary bypass surgery ³⁴. Moreover, artery-to-artery embolism is another mechanism of labyrinthine infarction ³⁵. Each compartment of the labyrinth may be selectively involved when embolism involves a specific branch of the LA causing isolated vertigo or hearing loss. For example, isolated vertigo may occur without hearing loss when the anterior vestibular artery is only involved, and hearing loss may be an isolated finding when the common cochlear artery is selectively affected ²⁷. Consequently, the clinical assessment of dizziness/vertigo patients, including accompanied neurological symptoms and signs, the presence of vascular risk factors and findings of ocular motor examination to detect stroke is likely to differentiate between central and peripheral aetiologies, but might also give an indication of the eventual origin of AUPVP aetiology. We should then attempt to detect MRI infarctions in other territories apart from AICA ²⁷.

Regarding NLR, interesting evidence points to a vascular origin of AUPVP. Oh et al. and Şahin et al. found NLR to be significantly higher in the AUPVP patients than in controls ^24,26. These findings suggest a neutrophil-mediated immune pathway in the development of AUPVP by mediating inflammatory and thrombotic changes in the vestibular organ. Indeed, viral infections usually induce an increase in the lymphocyte count and a decrease in the neutrophil counts, leading to lower NLR values ³⁶. Similar results were found in sudden sensorineural hearing loss (SSNHL) ^37,38. However, regarding MPV studies, Beyan and Beyan doubted this hypothesis with the argument that MPV-related research was hampered by the differences in MPV measurement standardisation leading to variable results ³⁹.

Aging, as a non-modifiable CVRF, showed no effect on spontaneous recovery and on need of vestibular rehabilitation ²³. In contrast, other CVRFs were significantly associated with AUPVP ²⁵.

Another argument for a distinctive pathogenetic mechanism in AUPVP is the comparison to Bell’s palsy. Commonly, AUPVP is approached analogous to Bell’s palsy, but important differences exist. First of all, corticosteroids have been found to be effective in the treatment of Bell’s palsy, while their effect in AUPVP is less established ⁴⁰. This might suggest a different mechanism rather than a similarity. Then, benign paroxysmal positional vertigo (BPPV) is more prevalent in patients with a history of AUPVP (20% of patients will develop BPPV in their lifetime ⁴¹) which also supports a pathogenetic model with involvement of an intralabyrinthine lesion rather than a neuritis hypothesis ²⁸.

This review identified important gaps in the literature regarding the exploration of a vascular etiology in AUPVP. No cohort studies with a control group were found, in contrast to SSNHL studies ^42-45. Similarly, no studies were identified in this search regarding the risk of future vascular events (stroke and myocardial infarction) compared to the studies available for SSNHL ^46,47. Research on this topic is of paramount importance as it could help to clarify the possible presence of a higher vascular risk in AUPVP patients, with clinical relevance. The registration of clinical background and cardiovascular risk factors seems a simple and useful step in this matter. Adjunctive testing like VHIT and VEMPs may detect a specific lesion pattern for the 5 components of the vestibular system, which might be favourable for a neuritis hypothesis or for a vascular insult. When a high suspicion of vascular origin is present, cardiovascular assessment seems a reasonable approach.

Limits of the studies and future directions

There is some variation in the definition of AUPVP, which poses a challenge when trying to compare studies from different authors or clinics. Indirect arguments provided in recent literature sustain some evidence for vascular mechanisms. However, we realise that the majority of studies are retrospective in their analysis, with relatively small sample sizes, with limited data regarding the control group. Larger prospective studies of AUPVP patients could lead to a better diagnostic work-up and more precise therapy.

Figures and tables

Figure 1.PRISMA flow diagram.

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