The role of vestibular evoked myogenic potentials in multiple sclerosis-related vertigo. A systematic review of the literature

Accepted Manuscript

The role of Vestibular Evoked Myogenic Potentials in multiple sclerosis-related vertigo. A systematic review of the literature Arianna Di Stadio , L. Dipietro , M. Ralli , A Greco , G. Ricci , E. Bernitsas PII: DOI: Reference:

S2211-0348(18)30562-5 https://doi.org/10.1016/j.msard.2018.12.031 MSARD 1094

To appear in:

Multiple Sclerosis and Related Disorders

Received date: Accepted date:

11 October 2018 22 December 2018

Please cite this article as: Arianna Di Stadio , L. Dipietro , M. Ralli , A Greco , G. Ricci , E. Bernitsas , The role of Vestibular Evoked Myogenic Potentials in multiple sclerosis-related vertigo. A systematic review of the literature, Multiple Sclerosis and Related Disorders (2018), doi: https://doi.org/10.1016/j.msard.2018.12.031

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MRI can detect big lesions only; in case of microglia aggression in the vestibular pathways a small lesion can determine a vertigo VEMPs are sensible to detect also small area of neurodegeneration Due to their sensitivity VEMPs may be useful to monitor MS progression in addition to the traditional MRI

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ACCEPTED MANUSCRIPT The role of Vestibular Evoked Myogenic Potentials in multiple sclerosis-related vertigo. A systematic review of the literature.

Di Stadio A1*, Dipietro L2, Ralli M3, Greco A3, Ricci G1 , Bernitsas E4.

2: Highland Instruments, Cambridge (MA), USAmeta

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1: University of Perugia, Otolaryngology Department, Perugia, Italy

3: Department Sense Organs, Sapienza University of Rome, Rome, Italy

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4: Wayne State School of Medicine, Department of Neurology, Detroit (MI), USA

*Corresponding author: Arianna Di Stadio, University of Perugia, Piazza Menghini 1, Perugia, Italy.

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Telephone: +393356236711 E-mail: [email protected]

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ABSTRACT

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Running Head: Vertigo, Multiple Sclerosis and VEMPs

Background: Vertigo is a common symptom of multiple sclerosis (MS) that can be caused by a central or

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peripheral involvement of the vestibular pathways. Magnetic Resonance Imaging (MRI) is commonly used to evaluate progression of MS but is not sensitive enough to detect small lesions. Vestibular evoked myogenic potentials (VEMPs) are commonly used to evaluate function of vestibular-cochlear pathways. The aim of this literature review is to evaluate the role of VEMPs in patients with MS-related vertigo as a tool to detect demyelinating lesions in the vestibular pathways of MS patients and to monitor MS progression. Methods: Following the PRISMA guidelines, we performed a literature search with the following keywords: multiple sclerosis, vertigo, dizziness, equilibrium disorders, vestibular disorders, and VEMPs. Three 2

ACCEPTED MANUSCRIPT different databases (PubMed, Scopus, and Google Scholar) were independently screened by two researchers. Publications in English, Italian, French, and Spanish were considered and reviewed by a native speaker. Details on patients’ gender, age, and stage of MS, as well as VEMPs, MRI, and vertigo features (including their onset as a function of MS stage) were collected. Percentage and odds ratio were calculated. Spearman test was used to correlate vertigo, VEMPs, and MRI features.

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Results: Thirty-five articles and 819 patients were included in the study. Nearly 37% of MS patients suffered from vertigo and 71% showed altered VEMPs. Central vestibular pathways were involved in the MS demyelination mostly in the early stage of the disease, while the peripheral vestibular system was mainly affected in late stage MS. A significant percentage (35.4%) of the patients with altered VEMPs showed

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normal MRI.

Conclusions: Our results suggest that VEMPs may detect very small lesions in the vestibular pathways of MS patients; thus, they could have a role in the diagnosis of MS-related vertigo and in the monitoring of

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vertigo in MS patients as a tool additional to traditional MRI.

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Key words: Multiple Sclerosis, Vertigo, Microglia, VEMPs, MRI, diagnosis

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1. Introduction: Vertigo is a common symptom of MS; it is very debilitating and significantly affects the quality of life of affected patients [Marrie et al, 2013]. Its origin can be peripheral only (i.e., vertigo might be caused by MS involvement of the vestibular apparatus of the ear [Pula et al, 2013]), central only (i.e., caused by lesions

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affecting the vestibular pathways [Mostafa et al, 2014], or combined (i.e., caused by a combined peripheral and central MS involvement of vestibular pathways [Li and Peng 2015]). Central demyelination is thought to be caused by M1 microglia [Jack et al,2005; Luo, 2017], and these cells may also be responsible for

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demyelinating processes affecting inner ear structures [Fuentes-Santamaria et al 2017].

MS lesions can be detected as white matter hyperintensities (WMHs) [Venneti et al, 2013] in T2-weighted sequences of Magnetic Resonance Imaging (MRI). In clinical practice 1.5 Tesla MRI is currently the gold standard for the diagnosis and monitoring of MS; unfortunately, this technology is not sensitive enough to

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detect lesions that are small but can still lead to significant damage and functional impairment [Venneti et al,

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2013; Anagnostou et al, 2008].

Conversely, electrophysiological tests such as VEMPs can detect demyelination [Hu et al 2016]. VEMPs are

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short-latency electromyographic (EMG) potentials, which are elicited by delivering high-intensity acoustic stimuli to stimulate the otolith-mediated response [Hellmann et al, 2011]. They are commonly used in the

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diagnosis of vestibular disorders and more specifically in the evaluation of the function of vestibularcochlear pathways [Dispenza and De Stefano, 2012; Zhou et al, 2004]. In 2016 Oh et al. [Oh et al, 2016]

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showed that VEMPs are sensitive enough to detect lesions that affect vestibular pathways; moreover, it has been shown that VEMPs can detect demyelination affecting central [Skoric et al, 2014] and peripheral vestibular pathways [Magliulo et al, 2018] in patients with MS. Two types of VEMPs can be used to study vestibular disorders during clinical evaluation, namely ocularVEMPs (o-VEMPs) and cervical-VEMPs (c-VEMPs). In this study we focus on c-VEMPS as in relapsing MS a potential involvement of the optic nerve (optic neuritis) could introduce a bias due to the role of vision on the control of balance. In the remainder of this article we will refer to c-VEMPs simply as VEMPs; in 4

ACCEPTED MANUSCRIPT particular we will focus on p13-n23 waves, which evaluate function of vestibular pathways [Anagnostou et al, 2008; Hellmann et al, 2011; Dispenza and De Stefano, 2012; Zhou et al, 2004; Eleftheriadou et al, 2009; Escorihuela Garcia et al, 2013; Itoh et al, 2001, Sartucci and Logi, 2002; Gazioglu and Boz, 2012; Patkò et al 2007; Alpini et al 2004; Parsa et al, 2015; Murofushi et al, 2001; Güven et al, 2014;Gabelic et al, 2015; Versino et al,2002; Magnano et al 2014; Ivankovic et al, 2013; Crnošija et al,2017; Ferber-Viart et al, 1999],

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including the vestibulo-collic arc, vestibular nerve, vestibular nucleus, medial vestibular-spinal tract, and the motor neurons of the spinal cord [Ferber-Viart et al, 1999]. While several studies have shown that VEMPs can detect lesions affecting vestibular pathways with high sensitivity [Magliuolo et al, 2018], these potentials are currently not used routinely for the diagnosis and monitoring of MS in clinical practice.

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We hypothesize that VEMPs can be used to evaluate vestibular dysfunction in patients with vertigo caused by an MS-related dysfunction of the central or peripheral vestibular system. The aim of this literature review is to evaluate whether VEMPs can be used to detect demyelinating lesions in the vestibular pathways in MS patients and to monitor MS progression. To gain insights into this issue, we will compare outcomes of

2.1 Search Strategy

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2. Materials and Methods

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VEMP testing with MRI evidence.

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Following the PRISMA guidelines, two independent researchers conducted a literature search using three different databases (PubMed, Scopus, and Google Scholar) and the following keywords: MS and vertigo

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(210 articles), MS and dizziness (358 articles), equilibrium disorders (52 articles), vestibular disorders (256 articles), and VEMP (24 articles).

2.2 Study selection 5

ACCEPTED MANUSCRIPT All publication types from 1960 to the first trimester of 2018 in English, French, Italian or Spanish were considered for analysis, including case reports, case series, epidemiological studies, case-control studies, prospective studies, and retrospective studies. All articles were evaluated by a native speaker. Both researchers independently selected and reviewed the abstracts that included the term “multiple sclerosis” and at least one of the keywords listed above. All included articles reported data on MS-related vertigo and/or

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VEMPs features. The selected articles (n=76) were then read in detail.

2.3 Data extraction

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The following data were extracted from the selected articles and added to a database: gender; age; stage of MS; vertigo presence only if linkable to MS exclusively (i.e., we included only articles where the authors excluded causes of vertigo different from MS); stage of MS at vertigo onset; VEMPs (signal latency and amplitude, presence/absence of response); presence and location (brain or IAC/cochlea) of WMHs in T2-

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MRI sequences. The MS stage was recorded as reported in each study; MS was defined “early stage” if

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within 3 years post-diagnosis and “late-stage” if 3 years or longer post-diagnosis.

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2.4 Data analysis

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All data were saved into a database for further analysis. Statistical analysis included percentage and odds ratio. Spearman's rank correlation coefficient was used to evaluate the correlation between presence of

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lesions and vertigo and between VEMPs alterations and WMHs. -square was used to test whether there was a significant difference in the distribution of WMHs between the central and peripheral vestibular pathways in patients suffering from vertigo.

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ACCEPTED MANUSCRIPT 3. Results Seventy-six articles were considered, and only the articles that were deemed relevant by both researchers were selected for detailed analysis. Among these, 35 [Marrie et al, 2013; Pula et al, 2013; Anagnostou et al, 2008; Hellmann et al, 2011; Dispenza and De Stefano, 2012; Zhou et al, 2004; Eleftheriadou et al, 2009; Escorihuela Garcia et al, 2013; Itoh et al, 2001, Sartucci and Logi, 2002; Gazioglu and Boz, 2012; Patkò et al

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2007; Alpini et al 2004; Parsa et al, 2015; Murofushi et al, 2001; Güven et al, 2014;Gabelic et al, 2015; Versino et al,2002; Magnano et al 2014; Ivankovic et al, 2013; Crnošija et al, 2017; Ferber-Viart et al, 1999; Oh et al, 2016; Rataj and Miszke 1996; Tabira et al, 1981; Wattjes et al, 2007; Daugherty et al 1983; Shea and Brackmann,1987; Barrat et al,1988; Stach and Delgado-Vilches,1993; Sasaki et al, 1994; Ozünlü et

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al,1998; de Seze et al, 2001; Tu and Young, 2004; Oh et al, 2008; Peyvandi et al, 2010] met the minimum eligibility criteria and were included in our review. The selected articles (n=35) included 819 patients (660

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women and 159 men, age range 17-65) with MS and vestibular symptoms (Figure 1).

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3.1. Vertigo and White Matter Hyperintensities (WMHs) Three-hundred-three patients with MS (36.9%) suffered from MS related vertigo and 287 (94.7%) displayed

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concomitant WMHs as detected by brain MRI in T2-weighted sequences (OR: 0.29; CI 95%: 0.2379 to 0.3759; Spearman: p<0.0001). One-hundred thirty-eight patients (48.1%) presented vertigo in late-

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stage MS, while 149 (51.9%) presented vertigo in early-stage MS. In patients with early stage MS, the lesions as indicated by WMHs were prevalently present in the brain

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(71.8%, 107 patients) while in 28.2% of patients (n=42) they were present in the peripheral vestibular pathways (Internal Auditory Canal (IAC) or cochlea) as shown in temporal bone MRI (Figure 2). In patients with late stage MS, the lesions were prevalently present in the peripheral vestibular pathways (IAC and/or cochlea) (59.4%, n=82), while in 40.6% of patients (n=56) they were present in the brain (Figure 2). By comparing the location of WMHs in the different tracts (central, peripheral) of the vestibular pathways at different MS stages (early vs late MS) we calculated an odds ratio of 3.7304 (95% CI: 2.2791-6.1061; p<0.0001). This data indicates that early stage MS patients were more likely to present lesions in the brain 7

ACCEPTED MANUSCRIPT (central vestibular pathways) than in the peripheral vestibular pathways. By correlating the onset of vertigo with the MS stage (early and late) we found that the lesions in the central vestibular pathways were responsible for vertigo in 163 patients (56.8%) while the MS involvement of the peripheral vestibular system was responsible for vertigo in 124 patients (43.2%). When WMHs were located in the brain, the cerebrum was typically the most affected area (Figure 3).

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The presence of vertigo and presence of WMHs was significantly correlated when the lesions were in the brain (Spearman: p<0.001) both in early and late stage MS; in late stage MS, the correlation was statistically

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significant only for lesions in the peripheral pathways such as the IAC (Spearman: p<0.01).

3.2. Correlation between VEMPs and MRI findings in MS patients

Twenty out of 76 articles (26.3%, for a total of 512 patients) reported details on VEMPs in MS patients [Hellmann et al, 2011; Dispenza and De Stefano, 2012; Zhou et al, 2004; Eleftheriadou et al, 2009;

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Escorihuela Garcia et al, 2013; Itoh et al, 2001, Sartucci and Logi, 2002; Gazioglu and Boz, 2012; Patkò et al 2007; Alpini et al 2004; Parsa et al, 2015; Murofushi et al, 2001; Güven et al, 2014;Gabelic et al, 2015;

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Versino et al,2002; Magnano et al 2014; Ivankovic et al, 2013; Crnošija et al, 2017; Ferber-Viart et al, 1999;

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Oh et al, 2016]. One-hundred seventy-nine patients (34.9%) reported vertigo and 333 (65.1%) reported dizziness. Out of the 179 patients with vertigo, 116 displayed altered VEMPs (64.8%), while VEMPs were

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not recorded in patients suffering from dizziness. VEMP alterations mainly consisted of prolonged latencies and reduced amplitudes of the p13-n23 waves in 103 out of 116 patients (88.8%), and no response in 13 out

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of 116 patients (11.2%). Such VEMP abnormalities suggest demyelination somewhere in the vestibular pathways [33] or in the vestibular nuclei. WMHs as measured by brain MRI were present in the central vestibular pathways of 75 out of 116 patients (64.6%) with VEMPs with prolonged latency and increased amplitude (OR: 1.3; CI 95%: 1.0657 to 1.6453; -square p=0.01) (Figure 4).

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ACCEPTED MANUSCRIPT Vertigo and increased VEMP latencies were significantly correlated (Spearman: p<0.001); VEMP alteration (increased amplitude and prolonged latency) and presence of WMHs in the vestibular central pathways were significantly correlated (Spearman: p<0.05).

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4. Discussion We observed that 36.9% of the patients suffered from MS-related vertigo and that 94.7% of these patients also displayed WMHs (as detected by T2-weighted MRI images) both in central and peripheral vestibular pathways. In 64.8% of patients with MS-related vertigo, VEMPs were altered (prolonged latency or absence

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of response) and 64.6% of these patients displayed lesions in the vestibular pathways as shown by the MRI. In a previous study, Di Stadio et al [Di Stadio et al, 2018] showed that in MS patients suffering from sensorineural hearing loss (HL), the HL was of central origin (i.e., caused by auditory pathways involvement) in early stage MS and of peripheral origin (i.e., caused by peripheral hearing pathway

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involvement) in late stage MS, where involvement was measured by the presence of WHMs in the affected

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areas. In the same study, the authors showed that Auditory Brainstem Response (ABR) (a response similar to VEMPs that is used for evaluating hearing function) was able to detect demyelination in the hearing

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pathways [Di Stadio, 2018], a finding consistent with those of other studies [Range 2015, Shalash 2017, Di Stadio and Ralli, 2018].

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Our literature review found that most patients who displayed VEMPs alterations also presented WMHs in the vestibular pathways. However, 35.4% of patients suffering from MS-related vertigo displayed altered

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VEMPs but did not display brain WMHs. Altered VEMPs in these patients were possibly due to lesions in the peripheral vestibular pathways that were not visible with the MRI technology used in the studies we analyzed. In fact, these studies used a conventional 1.5 Tesla MRI that has a limited sensitivity in detecting very small lesions [Anagnostou et al, 2008] and did not use an additional temporal bone MRI. Wang et al. reported that in MS patients nearly 20% of brain MRI lesions have nominal diameters smaller than 3.5 mm and about 80% less than 8 mm [Wang et al, 1997]. In a postmortem study, Geurts JJ et al. examined normal appearing white matter (NAWM) and cortical lesions at 3T MRI and found that only 63% 9

ACCEPTED MANUSCRIPT of WMH lesions seen on histopathological examination was also seen on T2-weighted spin echo (T2SE) images, while the number increased to 88% on fluid inversion recovery (FLAIR) sequences. Moreover, T2SE detected only 3% of the intracortical and 3D FLAIR showed only 5% [Guerts et al, 2005]. Using a computer model, Davis reported conduction block in demyelinating lesions of four or more mm long, while slower conduction exists in smaller lesions which might not be detectable with 1.5T MRI [Davis, 2014].

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Higher strength MRI may be more effective in detecting pathology. Keiper et al. found that 4T MRI detects lesions smaller than 5 mm within confluent periventricular lesions that are seen only retrospectively at 1.5T MRI. This may pose a limitation in the segmentation of large confluent periventricular lesions imaged by conventional MRI [Keiper et al, 1998].

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In a comparative study between 1.5T and 3T MRI, Stankiewicz et al. reported a higher FLAIR lesion load (FLLV) detected at 3T compared to 1.5T and a significant correlation between 3T FLLV and Expanded Disability Status Scale (EDSS), while correlation between 1.5T FLLV and EDSS was poor [Stankiewicz et al, 2011]. In a prospective study of a large cohort encompassing a variety of neurological diseases, imaging

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at 7T was found to increase lesion conspicuity, detection and characterization compared to 3T and 1.5T MRI

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[Obucez et al, 2018].

Infratentorial lesions in MS may require specific MRI sequences to increase their detection rate. Wattjes et

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al. showed a higher number of infratentorial lesions detected by using double inversion recovery (DIR)

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comparing to FLAIR and T2-weighetd turbo spin-echo (T2 TSE) sequences at 3T. Despite the fact that T2TSE is still the diagnostic standard routinely used for detecting infratentorial pathology, DIR imaging at 3T

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provides the highest sensitivity in the detection of demyelinating infratentorial lesions [Wattjes et al, 2007].

Additionally, we observed that in patients with MS-related vertigo MRI showed lesions prevalently in the central vestibular pathways in early stage MS and that the lesions in the peripheral vestibular pathways (inner ear and vestibular nerve) (which were evaluated with additional temporal bone MRI) were instead commonly observed in late stage MS. The same central involvement of the hearing pathways in MS was previously observed by Di Stadio et al [Di Stadio, 2018]. We suggest that the differential onset of vertigo 10

ACCEPTED MANUSCRIPT related to the involvement of the different vestibular pathways (central or peripheral) we observed (in early and late stage MS, vertigo occur as a result of inflammation in central and peripheral pathways respectively) may be a signature of MS progression. In fact, as demyelination progresses (i.e., lesions increase in size and number) MS progresses from brain to peripheral structures such as the Internal Auditory Canal (IAC) and, in extremely rare cases, to the cochlea [O’ mlley 2016]. Demyelination is induced by microglia, which thanks

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to their ability to move as macrophages (same family but different derivation) may migrate into the peripheral structures [Di Stadio and Ralli, 2018]. Our speculation is supported by the data reported by O’Malley et al. who found microglia-like cells in the cochlea [O’Malley et al 2016] and in the vestibular apparatus [Echard et al 2015] of patients with autoimmune diseases such as Meniere disease. This aggression

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by microglia may be sufficient to generate vertigo [Venneti et al 2013] but too small to be detected by MRI [Anagnostou et al, 2008]. Demyelination affecting the peripheral structures of vestibular pathways (inner ear /vestibular nerve) may alter signal transmission and as a consequence lead to altered VEMPs [Baloh,1998] (figure 5).

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The altered VEMP responses that were recorded in the absence of visible/detectable infratentorial MRI abnormalities (but in presence of vertigo) suggest that VEMPs can be a useful tool to aid in the diagnosis of

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MS-related vertigo and that VEMPs could be used as a valid alternative to temporal bone MRI. In fact, in 2004 Alpini showed that electrophysiological tests may be able to detect small areas of demyelination better

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than MRI [Alpini, 2004] and VEMP alterations could be related to demyelination of central [Skoric et al,

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2014] and peripheral [Magliulo et al, 2018] vestibular pathways. Furthermore, especially in presence of vertigo, VEMPs can detect malfunctioning of electric conduction even when the symptomatology is in a

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regressive phase [Guven et al 2014; Gabelik et al, 2015] suggesting that VEMPs may be useful for monitoring MS progression in patients whose vestibular pathways are affected by demyelination [Davis,2014; Stankiewicz et al, 2011; Shea and Brackmann,1987]. Moreover, VEMPs could be particularly helpful in monitoring relapsing MS because they can detect asymptomatic new or recurrent areas of demyelination even in absence of clinical symptoms and/or MRI abnormalities. Our results are in line with the findings of previous studies on VEMPs as a tool to detect brainstemdemyelinating lesions. In a prospective study of 72 patients, Skoric et al. showed that VEMPS have a higher 11

ACCEPTED MANUSCRIPT sensitivity than clinical examinations, MRI, and ABR for detecting brainstem MS lesions [Skoric et al, 2014]. In a study of 32 MS patients, Ivancovic et al. found that VEMPs are more sensitive than MRI for detecting brainstem involvement in demyelination processes in patients with MS [Ivankovic et al,2013]. Strengths of our study include strict inclusion criteria and extensive literature review (4 languages and 3 databases). Limitations of our study include lack of details on MRI acquisition and lack of details on the

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methods used for evaluating WMHs; also, when VEMPs testing was performed but no response could be recorded, MRI data were not always available.

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5. Conclusions

Our literature review suggests that VEMPs could be used to evaluate the integrity of vestibular pathways and particularly of the inferior vestibular nerve in patients with MS with vertigo. In MS patients altered VEMPS may be indicative of a demyelination process affecting vestibular pathways; thus, in these patients VEMPs

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could be used to identify areas of altered nerve conduction that are not detectable as WMHs by routine MRI

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because of their small dimension (e.g. in early stage MS). Furthermore, VEMPs could be used to investigate peripheral involvement of vestibular pathways as a low cost alternative to temporal bone MRI. Because of

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progression.

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their high sensitivity, VEMPs are potentially suitable to aid in both the diagnosis and monitoring of disease

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Acknowledgements: We thank Professor Kenneth Smith for his critical review of an earlier version of this paper.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

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ACCEPTED MANUSCRIPT Conflict of Interests: The Author(s) declare(s) that there is no conflict of interest pertinent to this study.

Reference:

7. 8. 9. 10. 11. 12.

13. 14.

15. 16. 17.

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Alpini, D., Pugnetti, L., Caputo, D., Cornelio, F., Capobianco, S., Cesarani, A., 2004. Vestibular evoked myogenic potentials in multiple sclerosis: clinical and imaging correlations. Mult Scler. 10(3):316-21. Anagnostou, E., Varaki, K., Anastasopoulos, D., 2008. A minute demyelinating lesion causing acute positional vertigo. J Neurol Sci. 266(1-2):187-9 Baloh, R.W., 1998. Differentiating between peripheral and central causes of vertigo. Otolaryngol Head Neck Surg. 119(1):55-9 Barratt, H.J., Miller, D., Rudge, P., 1988. The site of the lesion causing deafness in multiple sclerosis. Scand Audiol. 17(2):67-71. Crnošija, L., Krbot Skorić, M., Gabelić, T., Adamec, I., Habek, M., 2017.Vestibular evoked myogenic potentials and MRI in early multiple sclerosis: Validation of the VEMP score. J Neurol Sci. 372:28-32. doi: 10.1016/j.jns.2016.11.028. Daugherty,W.T., Lederman, R.J., Nodar, R.H., Conomy, J.P., 1983. Hearing loss in multiple sclerosis. Arch Neurol. 40(1):33-5 Davis FA. 2014. The clinico-radiological paradox in multiple sclerosis: novel implications of lesion size. MSJ 20(4)515516 de Seze, J., Assouad, R., Stojkovic, T., Desaulty, A., Dubus, B., Vermersch, P., 2001. [Hearing loss in multiple sclerosis: clinical, electrophysiologic and radiological study]. Rev Neurol (Paris). 157(11 Pt 1):1403-9. Dispen a, F., De Stefano, A., 2012.Textbook of Vertigo: Diagnosis and Management Int Tinnitus 17(2):111 Di Stadio, A., Ralli, M., 2017. Systemic Lupus Erythematosus and hearing disorders: Literature review and meta-analysis of clinical and temporal bone findings. J Int Med Res. 45(5):1470-1480. Di Stadio, A., Ralli M., 2018. Inner ear involvement in Multiple Sclerosis: an underestimated condition?. Mult Scler. 1352458518750010. doi: 10.1177/1352458518750010. Di Stadio, A., Dipietro, L., Ralli, M., Meneghello, F., Minni, A., Greco, A., Stabile, M.R., Bernitsas, E., 2018. Sudden Hearing loss as early detector Multiple Sclerosis. Biology helps the understanding. Systematic review and meta-analysis. Eureopean Journal Medical and Pharmacologic Review in press Echard A, Santos F, Di Stadio A, O’Malley J, McKenna J. Microglia in Meniere Sindrome. Poster presentation. 7th International Symposium on Meniere Disease and Inner ear disorders. Rome 17-20 October 2015. Eleftheriadou, A., Deftereos, S.N., Zarikas, V., Panagopoulos, G., Sfetsos, S., Karageorgiou, C.L., Ferekidou, E., Kandiloros, D., Korres, S., 2009. The diagnostic value of earlier and later components of Vestibular Evoked Myogenic Potentials (VEMP) in multiple sclerosis. J Vestib Res. 9 (1-2):59-66. Escorihuela García, V., Llópez Carratalá, I., Orts Alborch, M., Marco Algarra, J. 2013. Vestibular evoked myogenic potential findings in multiple sclerosis. Acta Otorrinolaringol Esp. 64(5):352-8. doi: 10.1016/j.otorri.2013.05.006. Ferber-Viart, C., Dubreuil, C., Duclaux, R., 1999. Vestibular evoked myogenic potentials in humans: a review. Acta Otolaryngol. 119(1):6-15. Fuentes-Santamaría V, Alvarado JC, Melgar-Rojas P, Gabaldón-Ull MC, Miller JM, Juiz JM.The Role of Glia in the Peripheral and Central Auditory System Following Noise Overexposure: Contribution of TNF-α and IL-1β to the Pathogenesis of Hearing Loss. Front Neuroanat. 2017 Feb 23;11:9. doi: 10.3389/fnana.2017.00009. eCollection 2017. Gabelić, T., Krbot Skorić, M., Adamec, I., Barun, B., Zadro, I., Habek, M., 2015. The vestibular evoked myogenic potentials (VEMP) score: a promising tool for evaluation of brainstem involvement in multiple sclerosis. Eur J Neurol. 22(2):261-9, e21. Gazioglu, S., Boz, C., 2012. Ocular and cervical vestibular evoked myogenic potentials in multiple sclerosis patients. Clin Neurophysiol. 123(9):1872-9. Guerts, J.J., Bo, L., Pouwels et al. 2005. Cortical lesions in Multiple Sclerosis: Combined Postmortem MR Imaging and Histopathology. AJNR 26:572-577 Güven, H., Bayır, O., Aytaç, E., O dek, A., Comoğlu, S.S., Korkma , H., 2014. Vestibular-evoked myogenic potentials, clinical evaluation, and imaging findings in multiple sclerosis. Neurol Sci. 35(2):221-6. Hellmann, M.A., Steiner, I., Mosberg-Galili, R., 2011. Sudden sensorineural hearing loss in multiple sclerosis: clinical course and possible pathogenesis. Acta Neurol Scand. 124 (4):245-9. Hu B, Arpag S, Zhang X, Möbius W, Werner H, Sosinsky G, Ellisman M, Zhang Y, Hamilton A, Chernoff J, Li J. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP. PLoS Genet. 2016 Sep 1;12(9):e1006290. doi: 10.1371/journal.pgen.1006290. eCollection 2016 Sep.

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24. Itoh, A., Kim, Y.S., Yoshioka, K., Kanaya, M., Enomoto, H., Hiraiwa, F., Mizuno, M., 2001. Clinical study of vestibularevoked myogenic potentials and auditory brainstem responses in patients with brainstem lesions. Acta Otolaryngol Suppl. 545:116-9. 25. Ivanković, A., Nesek Mađarić, V., Starčević, K., Krbot Skorić, M., Gabelić, T., Adamec, I., Habek, M., 2013.Auditory evoked potentials and vestibular evoked myogenic potentials in evaluation of brainstem lesions in multiple sclerosis. J Neurol Sci. 328(1-2):24-7. doi: 10.1016/j.jns.2013.02.005. 26. Jack, C., Ruffini, F., Bar-Or, A., Antel, J.P., 2005. Microglia and multiple sclerosis. J Neurosci Res. 81 (3):363-73. 27. Keiper, M., Grossman, R., Hirsch, J. et al. 1998. MRI identification of White Matter abnormalities in Multiple Sclerosis: A comparison between 1.5 T and 4T. AJNR 19:1489-1493 28. Li, Y., Peng, B., 2015. Pathogenesis, Diagnosis, and Treatment of Cervical Vertigo. Pain Physician. 18(4): E583-95. 29. Luo, C., Jian, C., Liao, Y., Huang, Q., Wu, Y., Liu, X., Zou, D., Wu, Y., 2017. The role of microglia in multiple sclerosis. Neuropsychiatr Dis Treat. 2017 Jun 26; 13:1661-1667. doi: 10.2147/NDT.S140634. 30. Magliulo G, Iannella G, Manno A, Libonati L, Onesti E, Vestri A, Fegatelli DA, Angeletti D, Pace A, Gulotta G, Gagliardi S, Inghilleri M. Chronic inflammatory demyelinating polyneuropathy: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials. Eur Arch Otorhinolaryngol. 2018 Jun;275(6):1507-1512. doi: 10.1007/s00405-018-4981-9. 31. Magnano, I., Pes, G.M., Pilurzi, G., Cabboi, M.P., Ginatempo, F., Giaconi, E., Tolu, E., Achene, A., Salis, A., Rothwell, J.C., Conti, M., Deriu., 2014. F Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol. 125(11):2286-96. 32. Marrie, R.A., Cutter, G.R., Tyry, T., 2013. Substantial burden of dizziness in multiple sclerosis. Mult Scler Relat Disord. 2(1) :21-8. 33. Mostafa, B.E., Kahky, A.O., Kader, H.M., Rizk, M., 2014. Central vestibular dysfunction in an otorhinolaryngological vestibular unit: incidence and diagnostic strategy. Int Arch Otorhinolaryngol. 18(3):235-8. 34. Murofushi, T., Shimizu, K., Takegoshi, H., Cheng, P.W., 2001. Diagnostic value of prolonged latencies in the vestibular evoked myogenic potential. Arch Otolaryngol Head Neck Surg. 127(9):1069-72. 35. Obucez, E.C., Lowe, M., Oh, S.H. et al. 2018. 7T MR of intracranial pathology: Preliminary observations and comparisons to 3T and 1.5T. Neuroimage 168:459-476. doi: 10.1016/j.neuroimage.2016.11.030. 36. Oh, S.Y., Kim, H.J., Kim, J.S., 2016. Vestibular-evoked myogenic potentials in central vestibular disorders. J Neurol. 263(2):210-20. doi: 10.1007/s00415-015-7860-y. 37. Oh, Y.M., Oh, D.H., Jeong, S.H., Koo, J.W., Kim, J.S., 2008. Sequential bilateral hearing loss in multiple sclerosis. Ann Otol Rhinol Laryngol. 117(3):186-91 38. O'Malley, J.T., Nadol, J.B. Jr, McKenna, M.J., 2016. Anti CD163+, Iba1+, and CD68+ Cells in the Adult Human Inner Ear: Normal Distribution of an Unappreciated Class of Macrophages/Microglia and Implications for Inflammatory Otopathology in Humans. Otol Neurotol. 37(1):99-108. 39. Ozünlü, A., Mus, N., Gülhan, M., 1998. Multiple sclerosis: a cause of sudden hearing loss. Audiology. 37(1):52-8. 40. Parsa, M.S., Mohammadkhani, G., Hajabolhassani, F., Jalaee, S., Zakeri, H., 2015. Cervical and ocular vestibular evoked myogenic potentials in multiple sclerosis participants. Med J Islam Repub Iran. 26;29:164. eCollection 2015. 41. Patkó, T., Simó, M., Arányi, Z., 2007. Vestibular click-evoked myogenic potentials: sensitivity and factors determining abnormality in patients with multiple sclerosis. 13(2):193-8. 42. Peyvandi, A., Naghibzadeh, B., Ahmady Roozbahany, N., 2010. Neuro-otologic manifestations of multiple sclerosis. Arch Iran Med. 13(3):188-92 43. Pula, J.H., Newman-Toker, D.E., Kattah, J.C., 2013. Multiple sclerosis as a cause of the acute vestibular syndrome. J Neurol. 260 (6):1649-54. 44. Rance ,G., Starr, A., 2015. Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain. Nov;138(Pt 11):3141-58. doi: 10.1093/brain/awv270. 45. Rataj, R., Miszke, A., 1966. Temporary deafness in multiple sclerosis. A case report. Pol Med Sci Hist Bull. 9(2):65-6. 46. Sartucci,F., Logi, F., 2002. Vestibular-evoked myogenic potentials: a method to assess vestibulo-spinal conduction in multiple sclerosis patients. Brain Res Bull. 15;59(1):59-63. 47. Sasaki, O., Ootsuka, K., Taguchi, K., Kikukawa, M., 1994. Multiple sclerosis presented acute hearing loss and vertigo. ORL J Otorhinolaryngol Relat Spec. 56(1):55-9. 48. Shalash, A.S., Hassan, D.M., Elrassas, H.H., Salama, M.M., Méndez-Hernández, E., Salas-Pacheco, J.M., Arias-Carrión, O., 2017. Auditory- and Vestibular-Evoked Potentials Correlate with Motor and Non-Motor Features of Parkinson's Disease. Front Neurol. Feb; 8:55. doi: 10.3389/fneur.2017.00055. eCollection 2017. 49. Shea, J.J. 3rd, Brackmann D.E., 1987. Multiple sclerosis manifesting as sudden hearing loss. Otolaryngol Head Neck Surg. 97(3):335-8. 50. Skorić, M.K., Adamec, I., Mađarić, V.N., Habek, M., 2014.Evaluation of brainstem involvement in multiple sclerosis. Can J Neurol Sci. 41(3):346-9. 51. Stach, B.A., Delgado-Vilches, G., 1993. Sudden hearing loss in multiple sclerosis: case report. J Am Acad Audiol. 4(6):3705.

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52. Stankiewicz, J.M., Glanz, B.I., Healy B.C. et al. 2011. Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis. Journal of Neuroimaging 21 (2) e50-6. doi: 10.1111/j.1552-6569.2009. 00449.x 53. Tabira, T., Tsuji, S., Nagashima, T., Nakajima, T., Kuroiwa, Y., 1981. Cortical deafness in multiple sclerosis. J Neurol Neurosurg Psychiatry. 44(5):433-6. 54. Tu, C.E., Young, Y.H., 2004. Audiovestibular evolution in a patient with multiple sclerosis. Ann Otol Rhinol Laryngol. 113(9):726-9. 55. Wang, L., Lai, H.M., Thompson, A.J., Miller, D.H., 1997. Survey of the distribution of lesion size in multiple sclerosis: implication for the measurement of total lesion load. Journal of Neurology, Neurosurgery and Psychiatry 63: 452-455 56. Wattjes, M.P., Lutterbey, G.G., Gieseke, J., Träber, F., Klotz, L., Schmidt, S., Schild, H.H. 2007. Double inversion recovery brain imaging at 3T:diagnostic value in the detection of multiple sclerosis lesions. AJNR 28(1):54-9 57. Venneti, S., Lopresti, B.J., Wiley, C.A.,2013. Molecular imaging of microglia/macrophages in the brain. Glia. 61 (1):10-23. 58. Versino, M., Colnaghi, S., Callieco, R., Bergamaschi, R., Romani, A., Cosi, V., 2002. Vestibular evoked myogenic potentials in multiple sclerosis patients. Clin Neurophysiol. 113(9):1464-9. 59. Zhou, G., Cox, L.C., 2004. Vestibular evoked myogenic potentials: history and overview. Am J Audiol. 13(2):135-43.

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Figure Legends:

Fig. 1: PRISMA diagram followed in this review. The flow diagram shows the information flow through the

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different phases of the review, and illustrates the number of records that were identified, included and excluded, as well as reasons for exclusions.

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Fig. 2: Distribution of the WMHs in different tracts of the central vestibular pathways.

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Fig. 3: Distribution of WMHs as a function of presence of vertigo in different MS stages. In patients with

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peripheral lesions, vertigo was significantly more present in late stage MS, while in patients with central

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lesions vertigo occurred mainly during early stage MS.

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Fig. 4: WMHs in MS patients with VEMP alterations. Nearly two-thirds of patients with altered VEMPs

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presented WMHs in the MRI.

Fig. 5: Illustration of the vestibular pathways.

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Graphical abstract

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