MULTIPLE SCLEROSIS AND VESTIBULAR SYSTEM

The Role of Vestibular Evoked Myogenic Potential and the Video Head Impulse Test in Patients with Multiple Sclerosis Without Radiologic Findings

Reyhan Sürmeli, Mehmet Sürmeli, Gözde Günay, Ayşe Destina Yalçın, Ayşe Aslı Şahin Yılmaz, Fatma Kulalı

ABSTRACT

Objective: To evaluate the vestibular system using the video head impulse test (vHIT) and vestibular evoked myogenic potentials (VEMP) in patients with multiple sclerosis (MS) without central vestibular involvement in magnetic resonance imaging (MRI), and to determine whether there was subclinical vestibular system impairment.

Materials and Methods: The study comprised 27 patients with MS and 26 healthy participants. The participants had no lesions in the central vestibular system in MRI taken in the last three months. Detailed neurotologic and neuroophthalmologic examinations were performed on all participants. Then, the Dizziness Handicap Inventory was completed for subjective vestibular system evaluation. In addition, vHIT and cVEMP were performed for objective vestibular system evaluation. The results were analyzed statistically.

Results: The mean age of the patients in the MS group was 39.3±11.4 years and 42.7±9.7 years in the control group. The median DHI score was 4 (range, 0-8) in the MS group and 2 (range, 0-6) in the control group. There were no statistically significant differences between the DHI score averages of the groups. The mean VOR gain in vHIT was 0.76 ± 0.21 in the MS group and 0.99 ± 0.13 in the control group. VOR gain was statistically significantly lower in patients with MS. The VOR gain cut-off level was considered as 0.8. Gain level was below the cut-off level in 53.7% of patients with MS. There was no cVEMP response in 31.5% of patients with MS. In addition, patients with MS had prolonged P1 and N1 latencies and decreased P1-N1 peak-to-peak amplitudes.

Conclusion: We found subclinical involvement in electrophysiologic tests (vHIT and cVEMP) in patients with MS without MRI lesions and without subjective vestibular system symptoms. We believe that vHIT and cVEMP can be used for subclinical evaluation in patients with MS without central vestibular system involvement in MRI.

Keywords: Multiple sclerosis, vestibular system, video head impulse test, cervical evoked myogenic potential, dizziness handicap inventory

INTRODUCTION

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). It is thought to be autoimmune, and is characterized by local inflammation, demyelination, axonal loss and gliosis in the brain and spinal cord, and by the formation of multiple plaques in the CNS. Today, there is no single clinical feature or diagnostic test that is sufficient for the diagnosis of MS. The diagnosis is mainly based on clinical findings [1]. Due to emerging technologies, the International Advisory Committee on Clinical Trials in Multiple Sclerosis updated the McDonald's 2010 criteria and published the 2017 revision [2].

MS is the most common chronic CNS disease in young adulthood, and most patients experience their first symptoms by the age of 20 to 40 years. Intermittent or sustained disease activity leads to a gradual or slow increase in disability over time [3]. MS can lead to a wide variety of clinical presentations. Many signs and symptoms are characteristic, and few are pathognomonic for the disease. By contrast, some symptoms are atypical, and others are rare enough to lead to a different diagnosis [4].

Dizziness is a symptom found at a rate of 49-59% in patients with MS. Vertigo is seen in only 5% of patients. Vertigo is a symptom that severely affects the quality of life in these patients (5). This symptom occurs due to impairment of peripheral or central vestibular pathways or combined impairment of both pathways [6-8].

Today, 1.5 Tesla magnetic resonance imaging (MRI) is used as the gold standard for detecting MS lesions, but this technique fails in detecting small lesions that functionally affect patients [9]. However, electrophysiologic tests can be used to detect early demyelination [10]. In recent years, test batteries such as vestibular evoked myogenic potential (VEMP), which assesses the vestibulocollic reflex (VCR), and the video head Impulse test (v-HIT), which assesses the vestibulo ocular reflex (VOR), have been used successfully in the evaluation of vestibular functions. Studies show that VEMP can be used to evaluate the central and peripheral vestibular system in patients with MS [11,12].

vHIT is an objective test method that allows the evaluation of the VOR arising from semicircular channels. It is generally affected by peripheral vestibular diseases, but it has also been shown to be affected in some central diseases [13]. It is the reflex arch that extends from the peripheral vestibular system to the brainstem, and thence to the extraocular muscles. It is the reflex mechanism that allows the image to reach the fovea in a constant manner. In the direction of the axis of the semicircular canal which is being examined, a head movement with high acceleration and low amplitude is applied. Depending on the VOR induced by this movement, eye responses appear in the opposite direction of head movement. It reflects the level of pathology in vestibular system diseases due to its relationship with the brain stem and central connections.

VEMP is the measurement of electromyogenic muscle activities arising from vestibular otolith organs following stimulation of the vestibular system. cVEMP is a reflex arch that begins from the saccular macula, transmitted to the brainstem via the inferior vestibular nerve, and extends to the sternocleidomastoid (SCM) muscle via the accessory (XI) nerve in the brainstem. Basically, the VCR is evaluated. It is mostly used in peripheral diseases such as acoustic neuroma, Meniere's disease, but also provides information about the brainstem.

The aim of this study was to evaluate the vestibular system using vHIT and VEMP in patients with MS without brain stem involvement in MRI imaging, and to determine whether there was subclinical vestibular system impairment.

MATERIALS and METHODS

This prospective and case-control study was conducted at the Neurology and Otorhinolaryngology Clinics of the XXX Hospital, between January 2018 and March 2020. This study was approved by the Ethics Committee of the XXX Hospital (Date: 20.02.20220, number: B. 10.1.TKH.4.34.GP.0.01/32). All participants gave written informed consent.

Study Population

Twenty seven (27) patients with MS and without any involvement in brainstem, optic nerve, central and peripheral vestibular systems and 26 healthy volunteers who were admitted to the outpatient clinic due to tension headache and had no pathology in cranial MRI were included in the study. All patients met the McDonald Multiple Sclerosis Criteria, which were revised in 2017 [2]. Patients with MS had no attacks for the last 30 days, did not use steroids, and had no central vestibular involvement in cranial MRI in the last three months.

Detailed clinical anamnesis was taken from all participants. Neurologic, neuro otologic, and ophthalmologic evaluations were then performed. After the evaluations, all participants completed the Dizziness Handicap Inventory (DHI) for subjective vestibular system evaluation. In addition, vHIT and cVEMP were performed for objective vestibular system evaluation.

Patients who werender 18 years and over 60 years, who had previous or current middle ear disease, previous ear surgery or ablative therapy (steroids or gentamicin), additional vestibular and/or neurologic diseases, vision loss, musculoskeletal system diseases, diabetes mellitus, hypo or hyperthyroidism, attacks due to vertebrobasilar artery insufficiency, MS attack in the last 30 days, and those on steroid treatment were excluded from the study. In addition, patients using vestibular suppressant medication were excluded.

Patients without demyelinating MS plaques in the brain stem, optic nerve, occipital lobe, cerebellum and peripheral vestibular system, with a DHI score below 16 and with normal pathology detected in neurotologic and neuroophthalmologic examinations were included in the study.

MRI

All MRIs were performed on a 1.5T MRI scanner (Siemens Healthcare, Erlangen, Germany). In cranial MRI, 2D/3D sagittal and axial fluid-attenuated inversion recovery (FLAIR); 2D / 3D sagittal, coronal and axial T2; axial diffusion-weighted imaging; and sagittal and axial T1 (non-contrast and postcontrast) sequences were performed. Axial and sagittal T1 and T2, postcontrast T1, phase-sensitive inversion-recovery (first cervical, then thoracic if necessary) sequences were evaluated in spinal MRI. Gadolinium chelate was used as a contrast agent. Within 30 seconds 0.1 mmol/kg gadolinium was given and a postcontrast examination was performed after waiting for at least 5-10 minutes.

Dizziness Handicap Inventory (DHI)

All participants underwent evaluation with the DHI, which has been validated in Turkish [14]. The DHI is a personal disability questionnaire consisting of 25 questions, used in the assessment of dizziness and vertigo. Each question is scored between 0-4 points and the total score is in the range of 0-100 points. Both groups completed DHI questionnaires, and the total scores were evaluated. In the assessment, 0-14 points were accepted as normal, 16-34 points were accepted as mild dizziness, 36-52 points as moderate dizziness, and >54 points as severe dizziness.

vHIT

The EyeSeeCam system (Interacoustics a/s, Middelfart, Denmark) was used for vHIT recordings. For the recording of the vHIT, light and tightly fitting glasses were used, on which a small video camera and a half-silver mirror reflecting the eye image (left side) were mounted. Patients were asked to pin to the target, which was placed on the wall at a distance of 1.2 meters. Calibration was performed prior to each recording. For the test, a head impulse at a velocity of 1500 - 2000/s was applied to 15-20 degrees lateral side of the midline along both lateral semicircular canal axles in a random manner. Fifteen records were held separately on each side. VOR gains at 40-60 and 80 ms were recorded. Mean VOR gain at 60 ms was taken for evaluation. Normal values for VOR gain were considered 0.8-1.2 (26). [ms1]

cVEMP

cVEMP recordings were performed using an evoked potentials device (Eclipse EP-25/VEMP; Interacoustics, Denmark). The active electrode was placed in the middle of the same sternocleidomastoid muscle (SCM), the upper 2/3 of the reference electrode SCM, and the centering electrode in the middle of the forehead. The test was performed once in a silent environment and with the patient awake in the sitting position [ms2] (Fig. 1). A note/alert sound was sent to the right and left ear, and ipsilateral records were obtained. Electrode impedance was <5 kΩ. The acoustic stimuli were 100 dB for 0.1 ms and delivered to each ear separately at 5 Hz. The electromyography (EMG) signal was filtered in the range of 10 to 1000 Hz and averaged over a 100 ms interval. The average was calculated from 200 results. P13 and N23 positive/negative polarity were measured as peak waves. P13 and N23 peak latencies and P13-N23 inter-peak amplitudes were calculated.

Statistical Analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences version 20 for Windows statistical software (SPSS Inc., Chicago, IL). Descriptive statistical data were calculated. The relevance of the variables to normal distribution was analyzed through analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). The Mann–Whitney U test was used to compare the continuous variables between the two groups. The Type-1 error level was identified as 5% for statistical significance.

RESULTS

Participants

The study began with a total of 30 participants in both groups. However, three patients in the MS group and four participants from the control group left the study. The study was completed with 27 patients in the MS group and 26 participants in the control group. The mean age of the patients in the MS group was 39.3 ± 11.4 years and 42.7 ± 9.7 years in the control group. In patients who had MS, the mean disease duration was 35.8 ± 19.5 (range, 12-84) months (Table 1). The treatments that patients received for MS are shown in Table 2.

DHI

The median DHI score was found as 4 (range, 0-8) in the MS group and 2 (range, 0-6) in the control group. The scores in both groups were under <16 and within normal limits. There were no statistically significant differences between the DHI score averages of the groups (Fig 2). [ms3]

vHIT

Out of a total of 53 participants, 106 vHIT records were taken. The mean gain level was 0.76 ± 0.21 in the MS group and 0.99 ± 0.13 in the control group. VOR gain was statistically significantly lower in patients with MS (Table 3). The VOR gain cut-off level was considered as 0.8. The gain level was below the cut-off level in 53.7% of patients with MS. This level was found to be statistically significantly higher compared with the control group (Table 4).

c-VEMP

A total of 106 c-VEMP records were evaluated from both ears. P1 wave latencies in MS and control groups were measured as 17.08 ± 1.93 ms and 15.01 ± 0.63 ms, respectively. N1 wave latencies in the MS and control groups were measured as 26.48 ± 3.04 ms and 24.03 ± 0.94 ms, respectively. In patients with MS, P1 and N1 wave latencies were statistically significantly longer than the control group. In addition, a statistically significant decrease in c-VEMP (P1-N1 peak to peak) amplitudes was present in patients with MS compared with the control group. P1-N1 amplitude averages in the MS and control groups were measured as 59.99 ± 61.62 µV and 129.38 ± 39.67 µV, respectively (Table 5). When c-VEMP responses from both ears were evaluated, no response could be recorded in 31.5% of the total 54 cVEMP entries in patients with MS and 3.8% of the total 52 c-VEMP entries in healthy participants. No cVEMP response could be obtained on one side in five patients with MS and on two sides in six patients.

DISCUSSION

The incidence of dizziness in MS varies between 49-59%. Dizziness and/or vertigo occur due to involvement of central, peripheral or both pathways of the vestibular system. Although MRI is the most important diagnostic tool for diagnostic examination, it is insufficient for the detection of small lesions [9]. Wang et al. found that lesions were smaller than 3.5 mm in 20% and smaller than 8 mm in 80% of patients with MS [15]. Evoked potentials have been shown to reliably predict pathologies in patients with MS [11]. In our study, we found subclinical abnormal results in vestibular evoked responses in patients with MS in whom no pathologic plaques were detected in central vestibular pathways such as brainstem, optic nerve, cerebellum, thalamus, and hypothalamus.

Studies showed abnormal vHIT results in many central vestibular pathologies except vestibular migraine [16-20]. There are a limited number of studies evaluating vHIT results in patients with MS. Pavlović et al. detected abnormal responses in 38% of patients with MS [21]. In our study, one-sided or two-sided abnormal responses were present in 53.7% of patients with MS in horizontal channel vHIT records. Unlike the study by Pavlović et al., the patients included in our study had no central vestibular lesion involvement in their MRI.

In our study, we found longer P1 and N1 wave latencies in cVEMP responses and decreased P1-N1 peak-to-peak amplitudes. We could not get a response in approximately one-third of cVEMP records. Di Stadio et al. [22] included 819 patients with MS in their systematic review and they found that vertigo was present in 37% of patients and abnormalities were present in 71% of cVEMP records. A notable finding was that MRI was normal in 35.4% of patients with cVEMP abnormalities. They concluded that this was due to peripheral vestibular system impairment, in which the diagnostic power of MRI was low. Our findings were similar to the findings of Di Stadio et al. [22]. Harirchian et al. found abnormalities in 70% of patients of MS, showing that these were associated with the duration of the disease [23]. Eleftheriadou et al. found that the abnormality rate was 50%, and when they added the P34-N44 waves, the abnormality rate increased up to 71% [24]. Skorić et al. [11] found brainstem findings in 25% of patients with MS during clinical examinations. However, they showed that, in MRI examinations, pathologic brainstem involvement was present in 40% of patients and that electrophysiologic examinations with VEMP showed abnormal results in 63% of patients. This result shows that electrophysiologic examinations can be used to show subclinical impairment in the brainstem compared with clinical examination and MRI. In addition, Güven et al. reported that a cVEMP response was absent in 25% of the patients [25].

Study Limitation:

The most important limitation of the study was the low number of patients without central vestibular system involvement in MRI.

In conclusion, we found subclinical involvement in electrophysiologic tests (vHIT and cVEMP) in patients with MS without MRI lesions and without subjective vestibular system symptoms. We believe that vHIT and cVEMP can be used for subclinical evaluation in patients with MS without central vestibular system involvement in MRI.

REFERENCES

1. Milo R, Miller A. Revised diagnostic criteria of multiple sclerosis.Autoimmun Rev. 2014 Apr-May;13(4-5):518-24.

2. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173.

3. Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Curr Opin Neurol 2018 Dec;31(6):752-759.

4. Eraksoy M, Akman-Demir G. Myelin Diseases of the Central Nervous System. Öge AE, Baykan B eds. Neurology second edition. Nobel Tıp Yayınları. 2015; 603-30

5. Marrie RA, Cutter GR, Tyry T. Substantial burden of dizziness in multiple sclerosis. Mult Scler Relat Disord. 2013 Jan;2(1):21-8.

6. Pula, J.H., Newman-Toker, D.E., Kattah, J.C. Multiple sclerosis as a cause of the acute vestibular syndrome. J. Neurol. 2013; 260 (6): 1649-54.

7. Mostafa, B.E., Kahky, A.O., Kader, H.M., Rizk, M. Central vestibular dysfunction in an otorhinolaryngological vestibular unit: incidence and diagnostic strategy. Int. Arch. Otorhinolaryngol. 2014; 18 (3): 235-8.

8. Li, Y., Peng, B. Pathogenesis, diagnosis, and treatment of cervical vertigo. Pain Physician. 2015 Jul-Aug;18(4):E583-95.

9. Venneti, S., Lopresti, B.J., Wiley, C.A. Molecular imaging of microglia/macrophages in the brain. Glia. 2013; 61 (1): 10-23.

10. 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.

11. Skorić MK, Adamec I, Mađarić VN, Habek M. Evaluation of brainstem involvement in multiple sclerosis. Can J Neurol Sci. 2014 May;41(3):346-9.

12. Magliulo, G, Iannella, G, Manno, A, Libonati, L, Onesti, E, Vestri, A, Fegatelli, DA, Angeletti, D, Pace, A, Gulotta, G, Gagliardi, S, Inghilleri, M, 2018. Chronic inflammatory demyelinating polyneuropathy: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials. Eur. Arch. Otorhinolaryngol 275 (6), 1507–1512. https://doi.org/10.1007/s00405-018-4981-9. Jun.

13. Kim, H.J., Lee, S.H., Park, J.H., Choi, J.Y., Kim, J.S., 2014. Isolated vestibular nuclear infarction: report of two cases and review of the literature. J. Neurol. 261, 121–129.

14. Canbal M, Cebeci1 S, Çamur Duyan G, Kurtaran H, Arslan I. A Study of Reliability and Validity for the Turkish Version of Dizziness Handicap Inventory. TJFM&PC, 2016;10(1):19-24.

15. Wang, L., Lai, H.M., Thompson, A.J., Miller, D.H. Survey of the distribution of lesion size in multiple sclerosis: implication for the measurement of total lesion load. J. Neurol. Neurosurg. Psychiatry. 1997; 63: 452–455.

16. Blödow, A., Heinze, M., Bloching, M.B., von Brevern, M., Radtke, A., Lempert, T. Caloric stimulation and video-head impulse testing in Ménière's disease and vestibular migraine. Acta Otolaryngol. 2014; 134: 1239-44.

17. Kang, W.S., Lee, S.H., Yang, C.J., Ahn, J.H., Chung, J.W., Park, H.J. Vestibular Function Tests for Vestibular Migraine: clinical Implication of Video Head Impulse and Caloric Tests. Front Neurol. 2016; 7: 166.

18. Magliulo, G., Iannella, G., Gagliardi, S., Iozzo, N., Plateroti, R., Plateroti, P., Re, M., Vingolo, E.M. Usher's syndrome: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials and the video head impulse test. Otol. Neurotol. 2015; 36: 1421-27.

19. Luis, L., Costa, J., Muñoz, E., de Carvalho, M., Carmona, S., Schneider, E., Gordon, C.R., Valls-Solé, J. Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia. J. Vestib. Res. 2016; 26: 327-34.

20. Cardenas-Robledo, S., Saber Tehrani, A., Blume, G., Kattah, J.C. Visual, Ocular Motor, and Cochleo-Vestibular Loss in Patients With Heteroplasmic, Maternally- Inherited Diabetes Mellitus and Deafness (MIDD), 3243 Transfer RNA Mutation. J. Neuroophthalmol. 2016; 36: 134-40.

21. Pavlović I, Ruška B, Pavičić T, Krbot Skorić M, Crnošija L, Adamec I, Habek M. Video head impulse test can detect brainstem dysfunction in multiple sclerosis. Mult Scler Relat Disord. 2017 May;14:68-71.

22. Di Stadio A, Dipietro L, Ralli M, Greco A, Ricci G, Bernitsas E. The role of vestibular evoked myogenic potentials in multiple sclerosis-related vertigo. A systematic review of the literature. Mult Scler Relat Disord. 2019 Feb;28:159-64.

23. Harirchian MH, Karimi N, Nafisi S, Akrami S, Ghanbarian D, Gharibzadeh S. Vestibular evoked myogenic potential for diagnoses of multiple sclerosis: is it beneficial? Med Glas (Zenica). 2013 Aug;10(2):321-6.

24. Eleftheriadou A, Deftereos SN, Zarikas V, Panagopoulos G, Sfetsos S, Karageorgiou CL, et al. The diagnostic value of earlier and later components of Vestibular Evoked Myogenic Potentials (VEMP) in multiple sclerosis. J Vestib Res. 2009;19(1-2):59-66.

25. Güven H, Bayır O, Aytaç E, Ozdek A, Comoğlu SS, Korkmaz H. Vestibular evoked myogenic potentials, clinical evaluation, and imaging findings in multiple sclerosis. Neurol Sci. 2014 Feb;35(2):221-6.

26. A. Bl¨odow, S. Pannasch and L. Walther, Detection of isolated covert saccades with the video head impulse test in peripheral vestibular disorders, Auris Nasus Larynx 40 (2013), 348–351.

27. Kavasoğlu G, Gökçay F, Yüceyar N, Çelebisoy N. Cervical vestibular-evoked myogenic potentials in patients with multiple sclerosis: sensitive in detecting brainstem involvement? Neurol Sci. 2018 Feb;39(2):365-371.

28.

Figure 2. Dizziness Handicap Inventory scores. The mean values of both groups were in the normal range and there was no difference between groups (p=0.086).

Figure 1. cVEMP test was performed in the sitting position.

Table 1. Patient characteristics

Table 2. Treatment of patients with multiple sclerosis (n=27).

Table 3. Horizontal-video head impulse test (h-vHIT) results of both groups. There was no difference between the groups in terms of h-vHIT results (p<0.05). (SD: Standard Deviation).

Table 4. Abnormal value ratios measured in participants in both groups when the h-vHIT cut-off value was taken as 0.8. h-vHIT abnormalities were present in about half of patients with multiple sclerosis.

Table 5.Cervical vestibular evoked myogenic potential (c-VEMP) results of both groups. (SD: Standard Deviation).