10.14639/0392-100X-N1543
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.
text/xml
1827-675X
1543
en
António Miguéis
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
acute vertigo
Vascular mechanisms in acute unilateral peripheral vestibulopathy: a systematic review
Text.Serial.Journal
https://www.actaitalica.it/
41
Reviews
2021-11-05
2021-03-06
2021-11-02
2021-11-02
401-409
1
António Miguéis
2021/11/05
10.14639/0392-100X-N1543
401
University Clinic of Otorhinolaryngology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
1827-675X
acute vertigo
409
Vascular mechanisms in acute unilateral peripheral vestibulopathy: a systematic review
https://www.actaitalica.it/article/download/1543/675
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:401-409; doi: 10.14639/0392-100X-N1543




Review


Vascular mechanisms in acute unilateral peripheral
vestibulopathy: a systematic review
Meccanismi vascolari nella vestibolopatia periferica acuta unilaterale:
una revisione sistematica
João Simões1,2, Stephan Vlaminck1, Raquel Seiça2, Frederic Acke3, António Miguéis4
1
 Department of Otorhinolaryngology, Centre Hospitalier de Mouscron, Mouscron, Réseau Santé Louvain, Belgium; 2 Faculty
of Medicine, University of Coimbra, Coimbra, Portugal; 3 Department of Otorhinolaryngology, Ghent University Hospital, Ghent,
Belgium; 4 University Clinic of Otorhinolaryngology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal


SUMMARY
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 vascu-
lar 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 review-
ers. 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           Received: March 6, 2021
meta-analysis was not performed because the studies were too heterogeneous in terms of            Accepted: April 8, 2021
methodology. Indirect arguments for vascular mechanisms in AUPVP were found. These
findings indicate that larger prospective well-controlled studies are needed to clarify the       Correspondence
vascular aetiology of AUPVP.                                                                      João Simões
                                                                                                  Department of Otorhinolaryngology, Centre Hospi-
KEY WORDS: acute unilateral vestibulopathy, risk factors, vestibular neuritis, vascular,          talier de Mouscron, Avenue de Fécamp 49, B-7700
acute vertigo                                                                                     Mouscron, Belgium
                                                                                                  Tel. +32 467065968
                                                                                                  E-mail: jofsim@gmail.com
RIASSUNTO
La vestibolopatia periferica unilaterale acuta (AUPVP) è causa frequente di perdita del-
                                                                                                  Funding
la funzione vestibolare. Sono state proposte diverse eziologie, ma il meccanismo esatto
                                                                                                  None.
rimane sconosciuto. Lo scopo di questo studio è condurre un’analisi sistematica della
letteratura per valutare l’eziologia vascolare dell’AUPVP. Una ricerca sistematica della
                                                                                                  Conflict of interest
letteratura è stata eseguita mediante PubMed, Cochrane Library ed Embase, includendo
                                                                                                  The Authors declare no conflict of interest.
articoli pubblicati dal 1 gennaio 2010 al 30 novembre 2020. Due revisori hanno selezio-
nato in modo indipendente articoli che studiano un collegamento tra AUPVP e malattie
vascolari. Sono state estratte le seguenti informazioni: anno di pubblicazione, paese,              How to cite this article: Simões J, Vlaminck S,
livello di evidenza, fattori di rischio vascolare valutati e numero di pazienti. In totale          Seiça R, et al. Vascular mechanisms in acute uni-
sono stati identificati 450 articoli. Tra questi sono stati considerati gli undici su cui vi        lateral peripheral vestibulopathy: a systematic re-
era completo accordo fra i due revisori. In una popolazione aggregata di 805 pazienti,              view. Acta Otorhinolaryngol Ital 2021;41:401-
                                                                                                    409. https://doi.org/10.14639/0392-100X-N1543
i risultati principali sono stati il più alto rapporto tra neutrofili e linfociti e la maggiore
prevalenza di fattori di rischio vascolare tra i pazienti con AUPVP. Non è stata eseguita
                                                                                                  © Società Italiana di Otorinolaringoiatria
una meta-analisi perché gli studi erano troppo eterogenei per quanto riguarda la me-              e Chirurgia Cervico-Facciale
todologia. Sono stati trovati argomenti indiretti per i meccanismi vascolari in AUPVP.
Questi risultati indicano che sono necessari studi prospettici più ampi e ben controllati                        OPEN ACCESS
per chiarire l’eziologia vascolare in AUPVP.
                                                                                                  This is an open access article distributed in accordance with
PAROLE CHIAVE: vestibolopatia unilaterale acuta, fattori di rischio, neurite vestibolare,         the CC-BY-NC-ND (Creative Commons Attribution-Non-
vascolare, vertigini acute                                                                        Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
                                                                                                  only in the original version. For further information: https://
                                                                                                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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J. Simões et al.




Introduction                                                     arteries. The CCA divides into the main cochlear artery and
                                                                 the vestibulocochlear artery, the latter forming the posterior
Acute unilateral peripheral vestibulopathy (AUPVP) is            vestibular and the cochlear artery. The apical three fourths
considered the third most common peripheral vestibular           of the cochlea are supplied by the main cochlear artery and
disorder after benign paroxysmal positional vertigo and          the basal one by the cochlear ramus. The AVA supplies the
Meniere’s disease 1,2. Several hypotheses have been pro-         utricle, superior part of the saccule and ampullae of the su-
posed for the aetiology of AUPVP, but the exact mecha-           perior and lateral semicircular canals. In contrast, the pos-
nism remains unknown. Nowadays, the term AUPVP is                terior vestibular artery supplies the inferior part of the sac-
preferred over “vestibular neuritis” because it is unclear       cule and the ampulla of the posterior semicircular canal 13.
whether it is always an inflammation that provokes the dys-      Thus, an overlap exists between inner ear vascular supply
function 3. However, until recently, the vast majority of the    and inner ear innervation. Theoretically, a sudden interrup-
literature contains the term “vestibular neuritis” (VN). In      tion of the blood flow of the anterior vestibular artery could
this work, the term AUPVP will be used henceforth.               affect the same structures of a superior vestibular nerve in-
According to the literature, the most likely origin of AUPVP     flammation, and the symptoms could be the same in the
is viral, namely herpes simplex type 1. This is supported by     setting of an inflammatory or a vascular insult 14. A lon-
a genome wide association study showing a link between           gitudinal population-based cohort study of 1925 individu-
the disease and single nucleotide variants of the host fac-      als concluded that smoking, central adiposity and poorly
tor for HSV1 replication 4. However, other aetiologies have      controlled diabetes mellitus predicted incident hearing
been suggested including thrombosis and an autoimmune            impairment, which may suggest inner ear atherosclerotic
inner ear reaction 5.                                            events 15. The labyrinth is also vulnerable to ischaemia, like
The clinical picture varies according to the extent to which     the other organs mentioned above, because it requires high-
the vestibular end organs or their innervation are affect-       energy metabolism 13. By contrast, the retrocochlear acous-
ed 6. The patient might present a spontaneous horizontal         tic nerve has an abundant collateral blood supply from the
nystagmus beating away from the lesion side and caloric          lateral medullary artery, arteries of the adjacent dura mater
testing paralysis/paresis; a reduced gain in the video head      and petrous bone and the inferior lateral pontine artery 13.
impulse test (vHIT) supports the diagnosis 3. Vestibular-        Thus, the different parts of the inner ear may be more prone
evoked myogenic potentials (VEMPs) are helpful to dis-           to ischaemia than the nerves considering the different pat-
tinguish between involvement of the superior and inferior        terns of vascular supply.
vestibular nerves 7. Acute unilateral peripheral vestibulop-     In this work, we performed a systematic review of the
athy appears to be more common in the superior vestibu-          most recent evidence studying the links between AUPVP
lar labyrinth and its afferents, which could be explained        and vascular disease, exploring if AUPVP patients have a
by the longer and narrower path through its bony canal           higher vascular risk than general population.
and also explains why the posterior semicircular canal and
saccule are less affected 8. A previous history of upper air-
way infection or concomitant findings of herpes infection        Materials and methods
strongly points towards a viral aetiology. However, not all      Identification and selection of studies
patients fit this profile and other causes may be considered,    A systematic review was performed in December 2020 us-
namely a vascular aetiology. Actually, like the inner ear, the   ing three electronic databases: 1) PubMed, 2) the Cochrane
kidney, heart and eyes are supplied with an end artery and       Library and 3) Embase. The search strategy is presented in
many of the diseases that affect these organs are, in fact,      Table I. Studies published in English between January 1st,
mediated by vascular events, a topic that consequently de-       2010 and November 30th, 2020 were retrieved.
serves further research in AUPVP 9-11. Any disturbance in        The term VN was used also considering that the majority of
the cochleovestibular blood supply can provoke an insult         published studies regarding AUPVP use this nomenclature.
in the fluid homeostasis and metabolic supply, and may           The literature search, selection and analysis were indepen-
be related to a variability of inner ear disorders, such as      dently performed by two researchers (JS and AM). The
sudden deafness, autoimmunity, age-related hearing loss,         studies included in our review were eligible if they met the
AUPVP and Meniere’s disease 12.                                  following inclusion criteria: 1) studies in Humans, 2) defi-
The inner ear is supplied by the labyrinthine artery (LA), an    nition of AUPVP clearly stated, 3) studies investigating a
end artery. Usually, the LA derives from the anterior infe-      link between AUPVP and vascular disease and 4) one of
rior cerebellar artery (AICA) and gives two main branches,       the following types of articles: prospective cohort studies
the common cochlear (CCA) and anterior vestibular (AVA)          of consecutive patients, case-control studies of consecutive



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                                                                                             Vascular mechanisms in acute unilateral peripheral vestibulopathy




Table I. Search strategy.
 PubMed         (Vertigo[Other Term]) AND (risk factors[MeSH Terms]); (vertigo[Other Term]) AND (vascular[Other Term]); (acute vestibular neuritis[MeSH
                Terms]) AND vascular; (acute vestibular neuritis[MeSH Terms]) AND (risk factors[MeSH Terms]); (dizziness[MeSH Terms]) AND (risk
                factors[MeSH Terms]); (dizziness[MeSH Terms]) AND (vascular[Other Term])
 Embase         ((acute unilateral peripheral vestibulopathy) OR (vestibular neuritis)) AND ((risk factors) OR (vascular))
 Cochrane       (vestibular loss) OR (vestibular neuritis) OR (vestibular hypofunction)ti,ab,kw



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 con-
sensus. The following information of the included studies
was recorded: author, year of publication, country of publi-
cation, 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 evi-
dence based on the Oxford Centre for Evidence-Based
Medicine 17. Level 1a refers to a systematic review of ran-
domised 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 in-
dividual 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                          Figure 1. PRISMA flow diagram.
out by the two reviewers. In case of disagreement, a third
reviewer was consulted and consensus was stablished.
                                                                                  an interobserver agreement of 100%. The heterogeneity
Results                                                                           of the selected studies and different methodologies made
                                                                                  meta-analysis with pooled comparability impossible.
General results
A total of 450 records were identified in the initial search.                     Level of evidence
After identifying relevant articles based on title or abstract,                   Five studies were attributed with level 3b of evidence and
190 papers were retained, of which 151 were removed after                         6 studies with level 4. The agreement between reviewers
application of exclusion criteria and elimination of dupli-                       regarding the level of evidence was achieved for 9 studies.
cates. Then, the full text was read to confirm the eligibility                    A third observer was needed to judge 2 studies and, after
of the articles according to the inclusion criteria. Twenty-                      discussion, 100% of agreement was obtained.
six articles were further excluded. Two studies were elimi-
nated due to absence of clear definition of AUPVP. Finally,                       Study characteristics
11 articles met all inclusion criteria. This selection process                    The total AUPVP population of the 11 studies was 805
is presented in Figure 1. The final selection of studies had                      adults aged 18-92 years. Nine studies had a gender-bal-



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J. Simões et al.




anced population 18-26. One study had a small number of fe-                               techniques cannot visualise an infarction confined to the
males 27 and another did not provide data regarding gender                                labyrinth 27. Of 10 patients with acute audiovestibulopa-
distribution 28.                                                                          thy, 3 had isolated unilateral vestibulopathy. The embolic
Details of the included articles are shown in Table II and III                            labyrinthine infarction was diagnosed based on the pres-
regarding included patients, nomenclature, measured out-                                  ence of cardiac or artery-to-artery sources of embolism and
comes and main results.                                                                   concurrent embolic infarctions observed in the non-AICA
                                                                                          territories 27. One patient had an atrial fibrillation, one an
Studies investigating haemodynamic dysfunction in AUPVP                                   unknown patent foramen ovale and the other presented an
One of the proposed mechanisms for acute vestibulopathy                                   occlusion of the vertebral artery. All 3 patients had con-
is embolic labyrinthine infarction. Labyrinthine infarction                               comitant infarctions on MRI, but only peripheral vestibular
can be diagnosed only in association with other infarctions                               symptoms. None of the patients presented MRI findings in
involving the brainstem or cerebellar areas supplied by the                               the involved labyrinth.
anterior inferior cerebellar artery, because current imaging                              The vertebral artery hypoplasia (VAH) was also proposed


Table II. Summary of the definition of AUPVP (definition of cases) in each study included.
 First author / year                                             Definition of cases                                                      Terms used
 Adamec I, 2015     18
                                     Vertigo attack lasting no more than 48 h, spontaneous horizontal-torsional                        Vestibular neuritis
                                     nystagmus with the fast phase towards one side, positive head-thrust test to the
                                     other side and absence of skew deviation, a normal brain CT scan
 Chuang YM, 2011 19                  Acute vertigo, nausea and postural imbalance; unilateral deficit of the horizontal              Vestibular neuropathy
                                     semi-circular canal and caloric irrigation showed > 25% canal paresis of the
                                     affected ear, a horizontal spontaneous nystagmus with a rotational component
                                     towards the unaffected ear (fast phase) and the head-thrust test showed an
                                     ipsilateral deficit of the horizontal canal, no hearing symptoms and exclusion of
                                     other vestibular dysfunction
 Chuang YM, 2011 20                  Acute onset of rotatory vertigo, nausea and postural imbalance; unilateral deficit              Vestibular neuropathy
                                     of the horizontal semi-circular canal and caloric irrigation showed > 25% canal
                                     paresis of the affected ear, a horizontal spontaneous nystagmus with a rotational
                                     component towards the unaffected ear (fast phase) and the head-thrust test showed
                                     an ipsilateral deficit of the horizontal canal, no tinnitus or acute hearing loss and
                                     exclusion of central, bilateral or other peripheral vestibular dysfunction
 Chung JH, 2017 21                   Acute vertigo lasting for at least 24 hours, absence of auditory complaints, horizontal           Vestibular neuritis
                                     unidirectional nystagmus present during physical examination, and absence of
                                     neurological symptoms or signs
 Han W, 2018 22                      Strong vertigo attacks, vertigo attack no > 72 h; spontaneous horizontal-torsional                Vestibular neuritis
                                     nystagmus with the fast phase towards one side; obvious loss of vestibular function
                                     as indicated by the video head impulse test; and absence of auditory complaints
                                     and neurological symptoms or signs
 Liqun Z, 2018 27                    Acute peripheral vestibular syndrome with spontaneous horizontal-torsional                Unilateral peripheral vestibulopathy
                                     nystagmus beating toward the nonaffected side and vestibular deficit in VHIT or
                                     caloric test
 Navari E, 2019 23                   Long-lasting vertigo (> 12 h) that was not attributed to other causes screened with         Acute unilateral vestibulopathy
                                     HINTS plus, vestibular deficit in VHIT, caloric test and VEMPS
 Oh EH, 2020 24                      Acute peripheral vestibular syndrome with spontaneous horizontal-torsional                  Acute unilateral vestibulopathy
                                     nystagmus beating toward the nonaffected side and vestibular deficit in VHIT or
                                     caloric test
 Oron Y, 2017 25                     Acute vertigo lasting for at least 24 hours, absence of auditory complaints,                      Vestibular neuritis
                                     horizontal unidirectional nystagmus present during physical examination, and
                                     absence neurological symptoms or signs
 Şahin Mİ, 2019 26                   Acute vertigo, nausea, vomiting, postural instability, horizontal spontaneous                     Vestibular neuritis
                                     nystagmus with a rotational component, and absence of hearing loss and other
                                     neurologic signs
 Uffer DS, 2016 28                   Patients with prolonged acute vertigo and nystagmus without hearing loss, for                 Acute unilateral peripheral
                                     which no other diagnosis or more likely cause was found                                            vestibulopathy
VHIT: video head impulse test; VEMPs: vestibular-evoked myogenic potentials; HINTS: head-impulse, nystagmus, test-of-skew.




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                                                                                                              Vascular mechanisms in acute unilateral peripheral vestibulopathy




 Table III. Overview of the study included.
 First            Level of         Outcome             No. of          Mean age of            Vascular risk          Gender                Summary of results              Country
 author /         Evidence         Measured           patients           patients                factor
 year                                                                 (years, range)
 Adamec I,             4          AUPVP cases            79            52.3 (20-86)      Hypertension,     41 male No evidence of seasonality of AUPVP.     Croatia
 2015 18                           in seasons;                                        diabetes mellitus, 38 female     Significant proportion of patients
                                  vascular risk                                        hyperlipidaemia                    older than 50 years who had
                                      factors                                                                                   vascular risk factors
 Chuang YM,           3b         Vertebral artery        69           52.8 (27-82)      Haemodynamic       29 male    Vertebral artery hypoperfusion may     China
 2011 19                            hypoplasia                                            effect of the   40 female impede blood supply, contributing to
                                                                                        vertebral artery                    the development of AUPVP
                                                                                         hypoplasia on
                                                                                         the vestibular
                                                                                            labyrinth
 Chuang YM,           3b            Vestibular           69           52.8 (27-82)    Effect of vertebral 29 male            Comorbid vertebral artery       China
 2011 20                             paresis                                          artery hypoplasia 40 female      hypoperfusion may predispose to
                                                                                       on prognosis of                    severe AUPVP at acute stage
                                                                                             AUPVP
 Chung JH,            3b        Arterial stiffness       58             53.8 (NA)      Arterial stiffness  25 male         Arterial stiffness and higher     Korea
 2017 21                                                                                    and MetS      27 female     metabolic syndrome scores are
                                                                                                                     associated with the development of
                                                                                                                                       AUPVP
 Han W,               3b        Cerebrovascular          90          43.62 (27-92)    Age, hypertension, 44 male       Prevalence of carotid plaque was      China
 2018 22                          risk factors                                        diabetes mellitus, 46 female        significantly higher in AUPVP
                                                                                         lipids, carotid             patients than in healthy controls. No
                                                                                             plaques                 differences regarding hypertension,
                                                                                                                           diabetes mellitus and lipids
 Liqun Z,              4           Layrinthine           10           57.2 (38-76)      Embolic source      8 male     Three patients developed AUPVP        China
 2018 27                            infarction                                                            2 female         without evidence of auditory
                                                                                                                    involvement. Embolic sources should
                                                                                                                        be sought in patients with acute
                                                                                                                        audiovestibulopathy of unknown
                                                                                                                                      aetiology
 Navari E,             4         Recovery rate           59        Male 54.06 (24-77)          Age         31male      No effects of age in spontaneous        Italy
 2019 23                          and need of                        Female 58.31                         28 female recovery and in need of vestibular
                                 rehabilitation                          (23-81)                                             rehabilitation after AUPVP
 Oh EH,               3b        Gene expression          10           60.2 (40-84)       Inflammation       6 male     The neutrophil-mediated immune        Korea
 2020 24                             NLR                                                                   4 female      pathway may contribute to the
                                                         72             60.6 (NA)                          39 male development of AUPVP by mediating
                                                                                                          33 female       inflammatory and thrombotic
                                                                                                                        changes in the vestibular organ
 Oron Y,               4          Vascular risk         160          56.22 (18-89)      Dyslipidaemia,     64 male     A significantly higher prevalence      Israel
 2017 25                                                                               obesity, diabetes 96 female of vascular risk factors was found
                                                                                             mellitus,               among AUPVP hospitalised patients
                                                                                         hypertension,                    in comparison to the general
                                                                                       ischaemic heart                               population
                                                                                             disease
 Şahin Mİ,             4          NLR and PLR           104            44 (18-71)        Inflammation      53 male       The elevations of NLR and PLR       Turkey
 2019 26                                                                                                  51 female     support the role of inflammation
                                                                                                                       in AUPVP. The high level of mean
                                                                                                                          platelet volume indicates the
                                                                                                                           possible role of the vascular
                                                                                                                     thrombosis in the etiology of AUPVP
 Uffer DS,             4            Vestibular           25            NA (18-80)               NA            NA         The results do not support the    Switzerland
 2016 28                         lesions patterns                                                                        neuritis hypothesis since about
                                                                                                                            3/4 of the patients had an
                                                                                                                         intralabyrinthine lesion pattern
                                                                                                                      inconsistent with an isolated nerve
                                                                                                                                        lesion
AUPVP: acute unilateral peripheral vestibulopathy; MetS: metabolic syndrome; NLR: neutrophil to lymphocyte ratio ; PLR: platelet to lymphocyte ratio; NA: not available.



                                                                                                                                                                             405
J. Simões et al.




as a potential trigger of haemodynamic dysfunction in          mune pathway. They completed the study with comparison
AUPVP patients. Chuang et al. compared 29 VAH (right/          of complete blood count tests in 72 patients and in age-
left: 23/6) in AUPVP subjects and six VAH in controls          matched controls, showing that the NLR was significantly
(right/left: 5/1). There was a high accordance rate between    higher in the patients than in the controls (Tab. IV). Thus,
the side of VAH and AUPVP: 65.5% of the patients had           they concluded that neutrophil-mediated immune pathway
an ipsilateral AUPVP, in which left VAH showed a higher        may contribute to the development of AUPVP by mediat-
accordance rate (83.3%). VAH accordance showed higher          ing inflammatory and thrombotic changes in the vestibular
risk (81%) for AUPVP subjects with a vascular risk com-        organ.
pared to those without (25%) 19. The authors suggested
that VAH contributes as a risk factor for the development      Studies investigating cardiovascular risk factors in AUPVP
of ipsilateral AUPVP, and is enhanced by atherosclerotic       Based on a cross-sectional retrospective study of 160 con-
risk factors. Of interest, the accordance rate of VAH and      firmed VN patients, Oron et al. concluded that cardiovas-
AUPVP was 81% in the vascular risk group compared to           cular pathology and/or cardiovascular risk factors (hyper-
28% in the non-vascular risk group. Comparing VAH pres-        tension, diabetes mellitus, dyslipidaemia, ischaemic heart
ence as a prognostic factor, the same study group showed       disease and prior cerebral vascular accident/TIA) were sig-
vestibular paresis to be higher (56.8%) in AUPVP subjects      nificantly associated with AUPVP compared to the general
with VAH (n = 29) compared to AUPVP subjects (n = 40)          population (Tab. IV) 25. However, Han et al. did not found
without VAH (37.4%) (p = 0.01). The likely conclusion          significant differences regarding hypertension, diabetes
suggested comorbid VAH might predispose to AUPVP 20.           mellitus and dyslipidaemia between AUPVP patients and
Moreover, the arterial stiffness has been proposed as a sur-   controls. Nevertheless, the prevalence of carotid plaques
rogate marker for vascular disease in AUPVP. In a prospec-     was significantly higher in AUPVP patients 22.
tive case-control study including 58 AUPVP patients versus     In a prospective population-based study, 79 patients with
58 controls, arterial stiffness was measured by brachial-an-   recent AUPVP were followed in 2 different Croatian cities,
kle pulse wave velocity 21. Clearly, a higher brachial-ankle   for 2 years (2011-2012) with the evaluation of the impact
pulse wave velocity and higher prevalence of metabolic         of months, seasons and comorbidities 18. No significant dif-
syndrome was observed in the AUPVP group compared to           ferences between months and seasons were detected. They
the control group (p = 0.002 and p = 0.001, respectively,      observed that a significant proportion of AUPVP patients
Tab. IV). The authors concluded that these findings support    older than 50 years had vascular risk factors, namely, hy-
the hypothesis of a vascular aetiology of AUPVP. However,      pertension (30.4%), diabetes mellitus (8.9%), hyperlipi-
cardiovascular risk factors had limited value in predicting    daemia (7.5%) and hypothyreosis (6.3%). Navari studied
the clinical course of AUPVP.                                  the results of caloric tests, VHIT and VEMPs in 59 patients
                                                               with AUPVP 23. They concluded that there was no effect
Studies investigating inflammatory markers in AUPVP            of age regarding spontaneous recovery and vestibular re-
Neutrophil to lymphocyte ratio (NLR) and platelet to lym-      habilitation. Moreover, they observed that most patients
phocyte ratio (PLR) have been considered easily accessible     exhibited total end-organ damage, which could be related
inflammatory markers. Şahin et al. compared 104 AUPVP          to damage of the entire labyrinth or, more probably, due to
patients with 138 healthy subjects showing a significant       a neuritis of the two divisions of the vestibular nerve. Other
higher NLR and PLR value in the AUPVP group (p < 0.001,        studies also sought to analyse the vestibular lesion patterns
Tab. IV), supporting the inflammatory role in AUPVP 26.        and their connection with the distribution of the neurologi-
The same authors have also found an elevated mean platelet     cal afferents.
volume (MPV) in AUPVP patients proposing this finding          In the work of Uffer et al., the authors did not evaluate
as a risk marker for platelet activation, suggesting a vas-    CVRFs, but they tested in what percentage of AUPVP pa-
cular cause. Also, Oh et al. studied the inflammatory and      tients the vestibular lesion pattern was observed at odds
thrombotic pathogenesis of acute unilateral vestibulopathy     with the vestibular innervation anatomy 28. Among the 25
through gene expression profiling combined with bioinfor-      patients, 19 (76%) had a lesion pattern that looked more
matics analysis in 10 AUPVP patients and 10 controls 24.       like an intra-labyrinthine pattern than a neuritis pattern.
They searched differentially expressed genes (DEGs)            Half of the patients with a definite intra-labyrinthine pat-
between these two groups. Interestingly, there were 57         tern had major dysfunction differences in the receptors of
DEGs (50 up-regulated and 7 down-regulated) identified         the superior vestibular nerve, the other half had dysfunc-
in the patient’s group and most of the up-regulated DEGs       tion differences in the receptors of the inferior vestibular
were significantly related to the neutrophil-mediated im-      nerve. The authors concluded that the results do not support



406
                                                                                                           Vascular mechanisms in acute unilateral peripheral vestibulopathy




Table IV. Main results of studies comparing cardiovascular risk factors and inflammation markers.
 Outcome                                             First author                         Patients                                              Controls                        p
 Hypertension                                                 Chung JH 21                                    12                                     8                       0.852
 (n)                                                            Oron Y 25 *                                42.5%                                 11.2%                      < 0.05
                                                                Han W 22                                     39                                    29                       0.592
 Diabetes Mellitus                                            Chung JH 21                                     1                                     1                       0.685
 (n)                                                            Oron Y 25 *                               15.62%                                  6.6%                      < 0.05
                                                                Han W 22                                      5                                     5                       0.749
 Dyslipidaemia                                                  Oron Y 25 *                                 25%                                   6.1%                       0.05
 Cholesterol                                               Chung JH 21 (mg/dL)                         181.3 ± 35.0                          176.4 ± 37.0                   0.575
 (± SD)                                                     Han W 22 (mmol/L)                           4.69 ± 0.95                           4.73 ± 0.87                   0.776
 TG                                                        Chung JH 21 (mg/dL)                         118.2 ± 90.4                          146.1 ± 80.7                   0.111
 (± SD)                                                     Han W 22 (mmol/L)                           1.48 ± 0.96                           1.40 ± 1.15                   0.661
 HDL                                                       Chung JH 21 (mg/dL)                         49.76 ± 13.8                           51.5 ± 13.8                   0.507
 (± SD)
                                                            Han W 22 (mmol/L)                           1.45 ± 0.56                           1.47 ± 0.41                    0.700
 LDL                                                       Chung JH (mg/dL)
                                                                       21
                                                                                                       112.1 ± 32.2                          106.4 ± 32.6                    0.352
 (± SD)                                                     Han W 22 (mmol/L)                           2.57 ± 0.86                           2.64 ± 0.73                    0.577
 MetS Score                                                   Chung JH 21                                1.5 ± 1.2                             2.2 ± 1.3                     0.001
 (± SD)
 NLR                                                      Şahin Mİ 26 (min-max)                     3.23 (0.69-21.21)                       1.91 (0.94-4.63)               < 0.001
                                                              Oh EH   24
                                                                           (± SD)                     2.93 ± 2.25                            1.54 ± 0.64                   < 0.001
 PLR                                                      Şahin Mİ 26 (min-max)                  145.65 (37.83-696.15)                  128.29 (39.63-259.85)              < 0.001
                                                              Oh EH 24 (± SD)                        108.21 ± 51.28                         125.37 ± 33.98                   0.002
MetS: metabolic syndrome; TG: triglycerides; LDL: low-density lipoprotein cholesterol; HDL: high-density lipoprotein cholesterol; NLR: neutrophil to lymphocyte ratio; PLR: platelet to
lymphocyte ratio; SD: Standard Deviation; * Number (n) not available, control group is prevalence among general population.



the neuritis hypothesis since about three-fourths of patients                                  that early symptoms might be caused by early smaller em-
had an intra-labyrinthine lesion pattern inconsistent with an                                  boli deeper in the AICA vascular territory, namely the inner
isolated nerve lesion.                                                                         ear microcirculation. Supportive information are histopa-
                                                                                               thology findings showing vascular occlusion in age-relat-
Discussion                                                                                     ed hearing loss patients who are probably more prone to
                                                                                               vascular accidents. Moreover, several cases of labyrinthine
The physiopathology of AUPVP needs further explora-                                            infarction have been linked to cardioembolism 29-32 and iso-
tion concerning the role of viral inflammation and vascu-                                      lated deafness have also been reported during embolisation
lar events in the vestibular organ, with significant clinical                                  of a meningioma 33 or cardiopulmonary bypass surgery 34.
implications. Acute vertigo may occur due to a labyrinth                                       Moreover, artery-to-artery embolism is another mecha-
infarction, but current imaging techniques do not readily                                      nism of labyrinthine infarction 35. Each compartment of the
allow the identification of isolated labyrinthine infarctions                                  labyrinth may be selectively involved when embolism in-
as a cause of acute audiovestibulopathy 13,27. This system-                                    volves a specific branch of the LA causing isolated vertigo
atic review on the vascular mechanisms of AUPVP showed                                         or hearing loss. For example, isolated vertigo may occur
interesting findings. Our first is that comparison of results                                  without hearing loss when the anterior vestibular artery is
remains difficult due to the variety of terms used in differ-                                  only involved, and hearing loss may be an isolated finding
ent studies (Tab. II). Only recently, the literature has made                                  when the common cochlear artery is selectively affected 27.
the shift to the term of AUPVP 3.                                                              Consequently, the clinical assessment of dizziness/vertigo
Furthermore, it is relevant to discuss the clinical signs in                                   patients, including accompanied neurological symptoms
patients with an AICA stroke diagnosis showing isolated                                        and signs, the presence of vascular risk factors and find-
otovestibular dysfunction (vertigo, hearing loss and/or tin-                                   ings of ocular motor examination to detect stroke is likely
nitus) with normal MRI imaging one to 10 days before the                                       to differentiate between central and peripheral aetiologies,
appearance of neurological symptoms 8. We may speculate                                        but might also give an indication of the eventual origin of



                                                                                                                                                                                    407
J. Simões et al.




AUPVP aetiology. We should then attempt to detect MRI             Limits of the studies and future directions
infarctions in other territories apart from AICA 27.
                                                                  There is some variation in the definition of AUPVP, which
Regarding NLR, interesting evidence points to a vascular
                                                                  poses a challenge when trying to compare studies from dif-
origin of AUPVP. Oh et al. and Şahin et al. found NLR
                                                                  ferent authors or clinics. Indirect arguments provided in
to be significantly higher in the AUPVP patients than in
controls 24,26. These findings suggest a neutrophil-mediated      recent literature sustain some evidence for vascular mecha-
immune pathway in the development of AUPVP by mediat-             nisms. However, we realise that the majority of studies are
ing inflammatory and thrombotic changes in the vestibular         retrospective in their analysis, with relatively small sample
organ. Indeed, viral infections usually induce an increase        sizes, with limited data regarding the control group. Larger
in the lymphocyte count and a decrease in the neutrophil          prospective studies of AUPVP patients could lead to a bet-
counts, leading to lower NLR values 36. Similar results were      ter diagnostic work-up and more precise therapy.
found in sudden sensorineural hearing loss (SSNHL) 37,38.
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