Assessment of Vestibular and Oculomotor Function in Patients with Vestibular Migraine: A Preliminary Study

Background: The purpose of the study is to assess the vestibular and oculomotor function in patients with vestibular migraine(VM).And we also investigate the relationship between test resultsandeffectiveness of prophylactic medication. Methods: We recruited 41 patientswith VM. They were examinedwith vestibular-evoked myogenic potentials(VEMP), video head impulse test(vHIT) and videonystagmography(VNG), including spontaneous or positional nystagmus, gaze-evoked nystagmus, smooth pursuit and caloric irrigation testing.All VM patients were treated withprophylactic medications. Theintensity of vertigo were evaluated with dizziness handicap inventory(DHI) before and after treatment. After 6 months, we evaluate the effectiveness of prophylactic medication. We analyzed the relationship between test resultsandeffectiveness of prophylactic medication. Results:In vestibular function test,71% of VM patients showed abnormal result. 20% showed abnormal air-conducted cVEMP and 42% showed abnormal air-conducted oVEMP. 32% showed abnormal vHIT and 56% showed abnormal caloric irrigation test.The abnormal rate of oVEMP was signicantly higher than cVEMP (p<0.05). And the abnormal rate of caloric irrigation test was signicantly higher than vHIT(p<0.05). In oculomotor function test, 42% showed pathological result. The abnormal rate of oculomotor function test was signicantly lower than vestibular function test (p<0.05). After 6 months follow-up, rate of good effectiveness was signicantly higher in normal vestibular function test group compared with the abnormal vestibular function test group (p<0.05). Rate of good effectiveness was no statistically signicant difference between normal oculomotor function test group and abnormal oculomotor function test group (p>0.05). Conclusions: Abnormal vestibular and oculomotor function are commonly observed in VM patients. And VM

56% showed abnormal caloric irrigation test.The abnormal rate of oVEMP was signi cantly higher than cVEMP (p<0.05). And the abnormal rate of caloric irrigation test was signi cantly higher than vHIT(p<0.05). In oculomotor function test, 42% showed pathological result. The abnormal rate of oculomotor function test was signi cantly lower than vestibular function test (p<0.05). After 6 months follow-up, rate of good effectiveness was signi cantly higher in normal vestibular function test group compared with the abnormal vestibular function test group (p<0.05). Rate of good effectiveness was no statistically signi cant difference between normal oculomotor function test group and abnormal oculomotor function test group (p>0.05).
Conclusions: Abnormal vestibular and oculomotor function are commonly observed in VM patients. And VM patients with abnormal vestibular function have a weak effectiveness of prophylaxis medications. Background Vestibular migraine (VM) is a common cause of attacks of episodic vertigo [1].It can accounts for 7% of patients seen in dizziness clinics and 9% of patients seen in headache clinics [1]. Although the committee of the bárány society and a subcommitteeof the international headache society (IHS)have developed a clearercriteria for VM [2,3]. Diagnosis of vestibular migraine is challenging. Since the criteria for VMis based on clinical manifestations. And symptoms associated with vestibular migraine arevaried. It is di culty that clinical diagnosis competely ful ll thediagnostic criteria of VM. And the pathophysiology of VM is not uncertain. Some studies reported that it was likely of a central nervous system origin [4,5].Other studies considered that peripheral vestibular was probably involved [6].Therefore,clinical tests, such as vestibular function and oculomotor function test, would be helpfulon VM understanding.
During the last decade, vestibular function test has evolved such that the semicircularcanalsandtheotolithsystem [7]. Vestibular-evoked myogenic potentials(VEMP) is a useful Page 3/13 method forevaluating function from the otolithsystem [8]. And video head impulse test(vHIT) evaluates the semicircularcanal function in response tohigh-frequency headmovements and caloric irrigation test, and low-frequency head movements [9].Recording and measurement of oculomotoris performedwith videonystagmography(VNG) [7]. These testshave providedclinicians with useful diagnostic tools to identifydysfunctions of different vestibular pathways. However,there is not adequate assessment in VM patients.
In this study, we assess the vestibular and oculomotor function in patients with VM.And we also investigate the relationship between test result andeffectiveness of prophylactic medication.

Participants
We recruited 41 patients with VM from the period between 2017 and 2019 (26 females, 15 males; mean age 49.3 years; range 19-76 years). They were diagnosed to VM according to the criteria of thecommittee of the báránysociety and a subcommittee of the IHS [2,3].All patients were assessed using VEMP, vHIT and VNG(including spontaneous or positional nystagmus, gaze-evoked nystagmus, smooth pursuit, saccade test and caloric irrigation test). And all VM patients were treated withprophylactic medications. After 6 months, we evaluate the effectiveness of prophylactic medication.All VM patients were inquired the intensity of vertigo and completed the chinese version of the dizziness handicap inventory (DHI) questionnaire before and after treatment. And VM patients were then classi ed as good effectiveness (symptomatic improvement ≥ 50%),partial effectiveness (30%≤symptomatic improvement 50%) and poor effectiveness(symptomatic improvement 30%). VEMP VEMP recordings were performed with a evoked potential instrument (GN Otometrics EP200; version 6.2.1). 500 Hz air-conducted tone bursts were presented monaurally via a pair of calibrated insert earphones at an intensity of 100 dB nHL. We used the following stimulus pro le: 2 ms rise time, 2 ms plateau time and 2 ms fall time. The stimulation rate was 5/s, with the analysis time for each response of 60 ms, and 100 repetitions per trial were delivered.The EMG signals were ampli ed and bandpass-ltered between 1 and 1000 Hz.In cVEMP, after the patients were laid supine,an active electrode was placed on the upper third of the sternocleidomastoidmuscle. The forehead served asthe site for the ground electrode.The electrode impedance was kept under 5 kΩ. During recording, patients were asked to elevate theirheads. In oVEMP, an active electrode was placed on the face just inferior to each eye, around 1 cm below the center of the lower eyelid. The reference electrode was positioned on the cheek, about 1-2cm below the corresponding active electrode, and the ground electrode was placed on the forehead. The electrode impedance was kept under 5 kΩ. During recording, the subject was instructed to look upward at a small xed point approximately 30°at a distance of approximately 60 cm from the eyes. And the biphasic waveform were performed to con rm the reproducibility at least 3 times. Peak-to-peak amplitudeswere calculated from the mean value of the replicate waveforms for each condition. The
vHIT The vHIT was recordedusing the ICS Impulsesystem (Otometrics, Denmark). All horizontal and vertical canals wereevaluated. The subject was instructed to gaze at a target thatwas 1.2 m away. First, calibration is performed. In each trial,the examiner stood behind the patients and performed headimpulses by a small angle (10-20•) and an appropriatevelocity (150-200•/s). And 20 impulses were recorded for eachdirection. The lowest and highest valuesof the normal gain were 0.8 and 1.2 at horizontalvHIT and 0.63 and 1.15 at vertical vHIT. Besides, a corrective saccades peak velocity > 100•/swas considered pathologic [11][12][13].

Videonystagmography
Videonystagmography was performed using the Chart 200 VEG/ENG system (Otometrics, Denmark). Calibration with the patient seated was done as the rst step. Oculomotor test battery including spontaneous or positional nystagmus, gaze-evoked nystagmus, smooth pursuit, saccade test and caloric irrigation test.The bithermal air caloric irrigations were performed with the patient in the supine position.Each ear were irrigated witha air ow of 8 L/min at 50℃ and 24℃ for seconds. Unilateral weakness(UW) making was based on Jongkee's formula. Abnormal criteria is the UW values 25% [14].

Statistical Analysis
Chi-square or Fisher exact test was used to compare rate of abnormal vestibular and oculomotortests.Statistical comparisons ofsymptomatic improvement in different test groups were made using the Chi-square or Fisher exact. p < 0.05 was consideredstatistically signi cant. Statistical analysis were done by usingSPSS software (version19, SPSS Inc., Chicago, IL, USA).
Symptomatic improvement in VM patients at the follow-up After 6 months follow-up, 21(51%) VM patients reported a good effectiveness in their symptoms and 17(42%) reported a partial effectiveness in their symptoms while 3(7%) experienced poor effectiveness. Rate of good effectiveness was signi cantly higher in normal vestibular function test group compared with the abnormal vestibular function test group (p < 0.05, Table 2, Fig. 2). Rate of good effectiveness was no statistically signi cant difference between normal oculomotor function test group and abnormal oculomotor function test group(p > 0.05, Table 3, Fig. 3).

Discussion
VM is a distinct clinical entity that accounts for a high proportion of vestibular symptoms.Diagnosis of VM mainly dependson recurrent vestibular symptoms, ahistory of migraine, a temporal association between vestibular symptoms and migraine symptoms and exclusion of other reasons [2].And vestibular symptoms is based on the bárány society's classi cation of vestibular symptoms such as spontaneous vertigo, positional vertigo, visually-induced vertigo,head motion-induced vertigo and head motion-induced dizziness with nausea [15].In our studies, more than half of VM patientsare found spontaneous vertigo.10-20%VM patients have other forms of vertigo. We can nd thatthe most common vestibular symptom is spontaneous vertigo.Findings of most of studiesare similar our results [1,16,17]. Although most of VM patients have moderate to severevestibular symptoms.We still found some mild VM patients. This may be due todifferent measurements. In VM diagnostic criteria,vestibular symptoms are rated "moderate" whenthey interfere with but do not prohibit daily activities and "severe" if daily activities cannot becontinued [2].However, in our studies, vestibular symptoms is assess with DHI.In VM, duration of episodes have been reported at varying lengths, rangingfrom seconds to days and most often between minutes to hours [18].In our study, most VM patients were reported lasting minutes to hours. Thisis consistent with the previous literature [18].Besides,different migraine features may occur duringvestibular episodes, including unilaterality, pulsating quality, moderateto severe intensity,worsening with physical activity, photophobia, phonophobia and visual aura.In our study,the visual aura is infrequent in VM patients.Furman et al.reported thatVM is more common in patients without aura than in patients with aura [19].The view support our study result. We also found thatauditory symptoms is like tinnitus and hearing loss have been foundin 49% and 39% of VM patients. It is reported thatthe number of patients with auditory symptoms will be more than doubles as the progression of VM [20]. However, hearing loss does not progress to profoundlevels [21].
VM is classi ed entirely on the basisof clinical features as reported by the patient [21].However, VM patients can also nd abnormal results in vestibular and oculomotor function test.In our study,most of VM patients have abnormal vestibular function test.It includes otolithfunction(VEMP) and semicircular canalfunction(vHITand caloric irrigation test).In VEMP,we found that oVEMP has a higher abnormal rate. After testing 39VM patients with cVEMP and oVEMP, Zaleski et al.reported that oVEMP may be especially vulnerable in patients with VM [22]. This is consistent with our result.In semicircularcanalsystem,vHIT evaluated the semicircularcanal function in response tohigh-frequency head rotationand caloric irrigation test, and low-frequency head rotation [9]. According to our study result,the abnormal rateof caloric irrigation test was higher than vHIT.It suggests that low-frequencysemicircularcanal function is vulnerablein VM patients.And the results in our studyis also in accordance with the previous reports [23,24].Apart from vestibular function, oculomotorfunction is also a important sign in VM.In the symptomfree interval, nearly half of VM patientswere found abnormal oculomotor tests in our study. Such signsinclude spontaneous nystagmus, positional nystagmus, gaze-evoked nystagmus and smooth pursuit.In previous reports,oculomotorabnormalities were reported in 8 to 60% of VM patients [6,[25][26][27].
There is a wide incidence of oculomotorabnormalities.It may be relate to course of disease. Incidence rate of oculomotorabnormalities can increase over time [20].Besides,oculomotorabnormalities is especially common during attacks of VM [18]. In addition, we furtherfound thatpositional nystagmus and smooth pursuit are common in oculomotorabnormalities. It similar to previous studies [20,28]. These results related to mechanisms of VM. Apart from central mechanisms an inner ear involvement may explain abnormal ndings. Trigeminovascularre ex-mediated vasodilatation of cranial blood vessels andsubsequently plasma extravasation causing meningealin ammation are the key reasonand trigeminovascular system also innervates the inner ear [1,19].
Medications used for migraine prophylaxis can be used totreat VM [18].In our study,we found that half of VM patientsreported good effectivenes in their symptoms through prophylactic medications after 6 monthsfollow-up.However, there are still nearly half of VM patients that requiring medication continued or medication change(partial or poor effectiveness). How to identify the possible in uencing factors before preventative medications in VM. Therefore, according to vestibular and oculomotor test results, wedivided them into different subgroups.Compared with abnormal vestibular function group, we found that most of VM patients with normal vestibular function group were good effectiveness.It suggest that vestibular function abnormalities are closely related to the effectiveness of prophylaxis medication of VM.However,the effectiveness of prophylaxis medication was no signi cant difference between normal and abnormal oculomotor function test in VM patients. Kang et al.found that abnormal results of vHIT and caloric tests were closely related to the necessity for continued medication in VM patientsat 6-month follow-up [29]. Besides, Jung et al.also report that there was a good drug responsiveness in VM patients with normal VEMP [30]. These results were similar to ourstudy. It was proved that there is a weak effectiveness of prophylaxis medications in VM patients with abnormalvestibular function.But the speci c mechanism is not clear. Future basic studies are promising in the prophylaxis medicationmechanisms of VM.

Limitations
There are some limitations in this study. First, the number of VM patients and follow-up time were insu cient. The future studywith a large samples and longer follow-up time need to furthercon rm our results. Second, different prophylaxis medications or a combination of multiplemedications requires further evaluation. Last, future studies need to investigate the role of speci c parameters in vestibular and oculomotor function tests. Authors' contributions WF, JH, YB and NC designed the experiment, analyzed the data, and wrote the article. FH, DW, and YS collected data and prepared gures.YW guided the study. All authors have read and approved the nal document.

Funding
Not applicable.
Availability of data and materials The retrospective datasets are available by request from the corresponding author of this manuscript.
Ethics approval and consent to participate Comparison of abnormalities rate in VM patients with otolith tests(cVEMP and oVEMP) and canal tests(vHIT and caloric irrigation test).

Figure 2
Comparison of VM patients with good effectiveness in normal vestibular test and abnormal test.