Association between vestibular dysfunction and findings of horizontal head-shaking and vibration-induced nystagmus

Abstract

BACKGROUND:

The association between vestibular function and findings of horizontal head-shaking nystagmus (HHSN) and vibration-induced nystagmus (VIN) tests is not well understood.

OBJECTIVE:

To investigate the association between function in the five distinct vestibular end organs and findings of these nystagmus tests.

METHODS:

We retrospectively reviewed the medical records of 50 patients with vestibular diseases who underwent HHSN testing, VIN testing, video head impulse testing (vHIT), cervical vestibular evoked myogenic potential testing to air-conducted sound (ACS cVEMP) and ocular VEMP testing to ACS (ACS oVEMP). We performed mixed-effects logistic regression analyses to see whether age, sex or the presence of nystagmus in HHSN or VIN have an association with the presence of peripheral vestibular dysfunction on the opposite side to the direction of nystagmus.

RESULTS:

The presence of HHSN had a significant association with abnormal vHIT in the lateral semicircular canal (LSCC) on the opposite side to the direction of nystagmus. The presence of VIN had a significant association with abnormal vHIT in all the SCCs and abnormal ACS oVEMP on the opposite side to the direction of nystagmus.

CONCLUSIONS:

HHSN had an association with LSCC dysfunction alone. VIN had an association with dysfunction in all the SCCs and the utricle.

Keywords

Nystagmus vestibular diseases vestibular function tests vestibule

1 Introduction

Horizontal head-shaking nystagmus (HHSN) is induced after repetitively shaking the head in the plane of the lateral semicircular canal (LSCC) and suggests an asymmetry of vestibular function. The ability of HHSN to detect and identify vestibular dysfunction remains controversial due to the variety of definitions of vestibular dysfunction used in previous reports [1 , 45]. HHSN was able to predict canal paresis (CP) equal to or more than 20% in ice water caloric testing with a sensitivity of 66% and a specificity of 77% [18]. It has been reported that 84% of unilateral vestibulopathy (UVP) patients with CP equal to or more than 20% showed HHSN toward the healthy side and 13% toward the affected side [18].

Vibration-induced nystagmus (VIN) or skull VIN is induced when vibration stimulation is applied to the skull, and its usefulness in the evaluation of vestibular disorders has also been reported ([15, 32] and a review in [6]). VIN is found in 60% of UVP patients with CP equal to or more than 20% and 90% of UVP patients with CP equal to or more than 50% in ice water caloric testing [32]. Nystagmus induced by bone-conducted vibration (BCV) is generally directed to the healthy side in UVP and is more frequently evoked by stimulation at the mastoids than the forehead [6].

Thus, in the clinical setting, HHSN and VIN are both considered to be indicators of asymmetry of vestibular function because of their association with dysfunction of the LSCC and/or the superior vestibular nerve system. However, the association between these nystagmus tests and function in the vertical SCCs (VSCCs) and otolith organs is not well understood at the moment, although more recently developed tests open the door to a better understanding. Cervical vestibular evoked myogenic potential (cVEMP) testing measures the integrity of the sacculo-collic pathway [5 , 28], and ocular VEMP (oVEMP) testing measures the integrity of the utriculo-ocular pathway [17, 27]. The development of the video head impulse test (vHIT) has made it possible to easily measure the vestibulo-ocular reflex (VOR) function of the VSCC as well as the LSCC [24]. Combined use of these tests enables us to evaluate the function of all five distinct end organs. The purpose of the present study is to investigate the association between vestibular dysfunction and findings of HHSN and VIN.

2 Methods

2.1 Study design

This study was approved by the ethics committee of Teikyo University and was conducted according to the tenets of the Declaration of Helsinki.

2.2 Subjects

We reviewed the medical records of 50 patients (21 males and 29 females; age range 20–88 years, mean age±standard deviation 54.2±16.6 years) who visited the Department of Otolaryngology, Teikyo University School of Medicine Mizonokuchi Hospital between November 2018 and September 2019. They did not show spontaneous nystagmus in the supine position using an infrared charge-coupled device (CCD) camera. All patients underwent both HHSN and VIN testing. They underwent vHIT testing and at least one of cVEMP testing to air-conducted sound (ACS-cVEMP) or oVEMP testing to air-conducted sound (ACS-oVEMP). The rationale for this sample size of 50 is described in section 2.8 (Statistical analysis). The vestibular diagnoses in the 50 patients are shown in Table 1. The diagnostic criteria used in this study were: vestibular neuritis [39], definite Meniere’s disease (MD) [23], vestibular migraine (VM) [22], inferior vestibular neuritis [4], VM/MD overlapping syndrome [30], sudden hearing loss [38], delayed endolymphatic hydrops [36], benign paroxysmal positional vertigo [44], Ramsay Hunt syndrome [40], idiopathic otolithic vertigo [29] and idiopathic bilateral vestibulopathy [9]. We used a caloric test for the diagnosis of vestibular neuritis and idiopathic bilateral vestibulopathy. Caloric testing was administered using ice water irrigation of the external auditory canal (2 ml at 4 deg C for 20 secs) followed by aspiration of water. This method has been shown to have a high sensitivity and specificity for detecting canal paresis (CP) [35]. We defined an abnormal caloric response by either of the following criteria: (1) CP percentage >20% for unilateral dysfunction [19]; (2) maximum slow phase eye velocity <10 deg/s bilaterally for bilateral dysfunction [11].

Table 1
Diagnosis of vestibular disease in the 50 patients

Diagnosis No.

Vestibular neuritis 11

Meniere’s disease (MD) 6

Vestibular migraine (VD) 5

Inferior vestibular neuritis 5

VM/MD overlapping syndrome 3

Sudden hearing loss with vertigo 2

Delayed endolymphatic hydrops 2

Benign paroxysmal positional vertigo 1

Ramsay Hunt syndrome 1

Idiopathic otolithic vertigo 1

Idiopathic bilateral vestibulopathy 1

Unilateral vestibulopathy with unknown cause 12

Diagnosis	No.
Vestibular neuritis	11
Meniere’s disease (MD)	6
Vestibular migraine (VD)	5
Inferior vestibular neuritis	5
VM/MD overlapping syndrome	3
Sudden hearing loss with vertigo	2
Delayed endolymphatic hydrops	2
Benign paroxysmal positional vertigo	1
Ramsay Hunt syndrome	1
Idiopathic otolithic vertigo	1
Idiopathic bilateral vestibulopathy	1
Unilateral vestibulopathy with unknown cause	12

2.3 HHSN testing

HHSN was monitored using an infrared CCD camera after 20 cycles of passive head rotation in the LSCC plane at a rate of 2 Hz with an amplitude of 30 degrees. During the head-shaking procedure the patient’s eyes were closed. After the cessation of head-shaking, the patient was instructed to open their eyes and stare straight ahead. A positive HHSN was defined as the presence of at least 3 beats of nystagmus.

2.4 VIN testing

A vibration stimulator was used to apply several seconds of vibration at approximately 100 Hz to each mastoid, the contact area was approximately 3 cm². During the stimulus, eye movements were monitored using an infrared CCD camera. A positive VIN was defined as the presence of nystagmus during the vibratory stimulus to at least one mastoid. If the direction of nystagmus to the stimulus on one side was different from that on the other side, the patient was excluded from this study.

2.5 ACS cVEMP testing

Electromyographic (EMG) signals were recorded from surface electrodes placed on the upper half of each sternocleidomastoid muscle (SCM), with a reference electrode on the upper sternum. Subjects in the supine position were asked to raise their heads to contract the SCM. The EMG signal was amplified and bandpass-filtered (20–2000 Hz) using the Neuropack system (Nihon Kohden, Tokyo, Japan). 500 Hz air-conducted short tone bursts (125 dBSPL, rise/fall time 1 ms, plateau time 2 ms) were used for stimulation at a rate of 5 Hz. Signals were analyzed during a time period of 100 ms (20 ms before and 80 ms after the stimulus). The amplitude and latency of the first positive–negative peaks (p13–n23) were measured from the average of 2 responses after confirming the reproducibility. Corrected amplitude (CA) for cVEMPs was calculated as the p13–n23 amplitude divided by the measure of SCM contraction. The asymmetry ratio (AR) for cVEMPs (cVEMP AR) was calculated as AR = 100×(CAu-CAa)/(CAu+CAa), where CAu represents the CA on the unaffected side and CAa represents the CA on the affected side. The upper limit of the normal cVEMP AR was set at 41.6 on the basis of the mean+2 SD in normal subjects. If there was no reproducible p13–n23, it was judged as an absent response. If the cVEMP AR was greater than the normal upper limit in the presence of a reproducible p13-n23, it was judged as a decreased response. The normal range of the p13 latency was set at 15.1±2.6 ms on the basis of the mean±2SD in normal subjects. Abnormal latency was defined as a p13 latency outside the normal range. An abnormal cVEMP response was defined as a response that was absent or decreased, or a response of abnormal latency. The present study measured SCM contraction and bilateral cVEMP abnormality was defined as bilateral absent cVEMPs.

2.6 ACS oVEMP testing

EMG signals were recorded from surface electrodes placed on the skin just below (active) and 2 cm below (reference) the center of each lower eyelid. Subjects in the supine position were asked to maintain an upward gaze. The signal was amplified and bandpass-filtered (20–2000 Hz) using the Neuropack system. 500 Hz air-conducted short tone bursts (125dBSPL, rise/fall time 1 ms, plateau time 2 ms) were used for stimulation at a rate of 5 Hz. Analysis time was set at 100 ms. The amplitude and latency of the first positive–negative peaks (nI–pI) was measured from the average of 2 responses on the side contralateral to stimulation after confirming the reproducibility. The AR for oVEMPs (oVEMP AR) was calculated as AR = 100×(Au - Aa)/(Aa+Au), where Au represents the nI–pI amplitude on the unaffected side and Aa represents the nI–pI amplitude on the affected side. The upper limit of the normal oVEMP AR was set at 44.3 on the basis of the mean + 2 SD in normal subjects. If there was no reproducible nI–pI, it was judged to be an absent response. If the oVEMP AR was greater than the normal upper limit in the presence of a reproducible nI–pI, it was judged as a decreased response. The normal range of the pI latency was set at 11.2±2.4 ms on the basis of the mean±2SD in normal subjects. Abnormal latency was defined as a pI latency outside the normal range. An abnormal oVEMP response was defined as an absent or decreased response, or a response with an abnormal latency. ACS oVEMPs can be bilaterally absent even in normal healthy subjects. Data from the patients with bilaterally absent oVEMP responses were excluded from the present study because it is difficult to determine the contribution of the inferior oblique muscle alone on EMG activity when only using surface electrodes, or to distinguish between dysfunction and a lack of muscle contraction.

2.7 vHIT

vHIT was performed using the ICS-Impulse system (Otometrics, Denmark). Subjects were instructed to sit 1.5 m in front of a visual target. A calibration was performed based on the manufacturer’s protocol. While the subject was asked to stare at the target, the examiner briefly and unpredictably rotated the subject’s head with a low amplitude. The head rotations were made in the lateral, the left anterior-right posterior (LARP) and the right anterior left posterior (RALP) SCC planes. Eye movements were evaluated using video-oculography while the head movements were recorded using inertial sensors. At least 8 valid head impulses were recorded in each direction. The vestibulo-ocular reflex (VOR) gains were automatically measured using software that computed the regression slope between head and eye velocity [46]. When a mean gain in vHIT of <0.7 for the VSCC plane or <0.8 for the LSCC plane was detected and catch-up saccades were observed, the relevant SCC function was regarded as abnormal [26].

2.8 Statistical analysis

To investigate the association between vestibular dysfunction and the findings of HSN and VIN, we estimated odds ratios using data composed of two records per patient. If nystagmus was observed toward the left and vestibular dysfunction was observed on the right side, we set the patient‘s first record as nystagmus for left “yes” and vestibular dysfunction for opposite direction “yes,” and second record as nystagmus for right “no” and vestibular dysfunction for opposite direction “no”. When a patient had no nystagmus, their nystagmus was set as “no” for both directions. When a patient had vestibular dysfunction for both directions, their vestibular dysfunction was set as “yes” for both directions. To account for correlation within patients, we performed mixed-effects logistic regression analyses with age, sex and nystagmus as fixed effects, assuming a compound symmetry structure for error term, to estimate odds ratios of fixed effects. To assess the association between vestibular dysfunction and findings of HSN and VIN by a logistic regression analysis, at least five events (here, vestibular dysfunction) per number of variables are required as a rule-of-thumb [2]. Because we put 3 fixed effects in the models, we planned to collect a total of 50 patients to obtain 15 vestibular dysfunctions. We set the significance level as 0.05. We did not impute missing data. We performed all statistical analyses using SAS software (version 9.4).

3 Results

3.1 Patient characteristics

Out of the 50 patients, HHSN and VIN were observed in 17 (34%) and 26 (52%), respectively (Table 2). Downbeat nystagmus was observed in 2 (4%) for HHSN testing and 2 (4%) for VIN testing, and we classified them as patients with no nystagmus observed in the left or right direction. There were no patients whose VIN direction during mastoid stimulation was different on one side from the other. Analysis of vestibular function in the 50 patients revealed abnormal vHIT findings in the LSCC, ASCC and PSCC planes in 6 patients (12%), 16 patients (32%) and 23 patients (46%), respectively (Table 3). Abnormal ACS cVEMP findings and ACS oVEMP findings were observed in 32 patients (64%) and 36 patients (72%), respectively (Table 3). Because ACS cVEMP testing was not performed in 5 patients (10%) and ACS oVEMP testing in 6 patients (12%), it was treated as missing data in the statistical analysis. Twenty-one patients (42%) with bilaterally absent oVEMP responses were excluded from the present study. Details of the number of patients based on findings in the vestibular function tests, HHSN and VIN are shown in Table 3.

Table 2
Characteristics of the 50 patients with vestibular disease

Characteristics Number of patients (%)

Age

> = 50 27 (54%)

< 50 23 (46%)

Sex

Female 29 (58%)

Male 21 (42%)

HHSN

No 33 (66%)

Yes 17 (34%)

Leftward 4 (8%)

Rightward 11 (22%)

Downbeat 2 (4%)

VIN

No 24 (48%)

Yes 26 (52%)

Leftward 10 (20%)

Rightward 14 (28%)

Downbeat 2 (4%)

Characteristics	Number of patients (%)
Age
> = 50	27 (54%)
< 50	23 (46%)
Sex
Female	29 (58%)
Male	21 (42%)
HHSN
No	33 (66%)
Yes	17 (34%)
Leftward	4 (8%)
Rightward	11 (22%)
Downbeat	2 (4%)
VIN
No	24 (48%)
Yes	26 (52%)
Leftward	10 (20%)
Rightward	14 (28%)
Downbeat	2 (4%)

Table 3

Summary of vestibular function tests, HHSN and VIN in the 50 patients

Vestibular function test			Total No.	HHSN (No.)				VIN (No.)
				No	Left	Right	Downbeat	No	Left	Right	Downbeat
vHIT-LSCC	Normal		44	30	3	9	2	23	8	11	2
		Left	3	1	0	2	0	1	0	2	0
	Abnormal	Right	2	1	1	0	0	0	2	0	0
		Bilateral	1	1	0	0	0	0	0	1	0
vHIT-ASCC	Normal		34	23	2	8	1	19	6	8	1
		Left	9	5	1	3	0	3	1	5	0
	Abnormal	Right	5	3	1	0	1	1	2	1	1
		Bilateral	2	2	0	0	0	1	1	0	0
vHIT-PSCC	Normal		27	19	1	6	1	13	4	9	1
		Left	6	6	0	0	0	4	0	2	0
	Abnormal	Right	6	4	1	1	0	4	2	0	0
		Bilateral	11	4	2	4	1	3	4	3	1
ACS cVEMP	Normal		13	10	2	1	0	5	3	5	0
		Left	5	2	0	3	0	8	1	0	1
	Abnormal	Right	10	7	1	1	1	3	1	1	0
		Bilateral	17	10	1	6	0	2	2	0	1
		No data	5	4	0	0	1	6	3	8	0
ACS oVEMP	Normal		8	5	0	3	0	7	1	0	0
		Left	8	4	1	3	0	4	2	2	0
	Abnormal	Right	7	7	0	0	0	6	1	0	0
		Bilateral	21	13	3	5	0	5	4	12	0
		No data	6	4	0	0	2	2	2	0	2

HHSN = horizontal head-shaking nystagmus, VIN = vibration induced nystagmus, vHIT = video head impulse test, LSCC = lateral semicircular canal, ASCC = anterior semicircular canal, PSCC = posterior semicircular canal, ACS = air-conducted sound, cVEMP = cervical vestibular evoked myogenic potential, oVEMP = ocular vestibular evoked myogenic potential.

3.2 Association between vestibular dysfunction and findings of HHSN

Firstly, we investigated whether HHSN, age or sex had an association with vestibular dysfunction in patients with vestibular disease (Table 4). The presence of HHSN had a significant positive association with abnormality on the opposite side to HHSN direction in vHIT testing in the LSCC plane (p = 0.0151). The odds ratio of an abnormal vHIT result on the opposite side to HHSN direction in LSCC for the presence of HHSN compared with the absence of HHSN was 6.845 (95% CI, 1.451–32.287). Age had a significant positive association with abnormality in ACS cVEMP testing (p = 0.0016). The odds ratio of abnormal ACS cVEMPs for 50 years of age or older compared with under 50 years of age was 5.215 (95% CI, 1.870–14.543).

Table 4
Mixed-effects binomial logistic regression analyses for investigating the association between HHSN and age, sex and vestibular dysfunction

Vestibular dysfunction Variables Odds ratio 95% CI p-value

vHIT-LSCC Age:> = 50,<50 0.913 0.122–6.829 0.930

Sex: Female, Male 1.293 0.176–9.522 0.801

HHSN: Yes, No 6.845 1.451–32.287 0.0151^*

vHIT-ASCC Age:> = 50,<50 1.733 0.541–5.555 0.355

Sex: Female, Male 1.571 0.538–4.588 0.409

HHSN: Yes, No 1.933 0.512–7.301 0.331

vHIT-PSCC Age:> = 50,<50 1.459 0.518–4.102 0.475

Sex: Female, Male 2.279 0.772–6.729 0.136

HHSN: Yes, No 1.436 0.650–3.175 0.371

ACS cVEMP Age:> = 50,<50 5.215 1.870–14.543 0.0016^**

Sex: Female, Male 1.016 0.374–2.760 0.975

HHSN: Yes, No 2.397 0.651–8.824 0.189

ACS oVEMP Age:> = 50,<50 0.390 0.120–1.265 0.117

Sex: Female, Male 1.161 0.498–2.709 0.729

HHSN: Yes, No 1.633 0.280–9.540 0.586

Vestibular dysfunction	Variables	Odds ratio	95% CI	p-value
vHIT-LSCC	Age:> = 50,<50	0.913	0.122–6.829	0.930
	Sex: Female, Male	1.293	0.176–9.522	0.801
	HHSN: Yes, No	6.845	1.451–32.287	0.0151^*
vHIT-ASCC	Age:> = 50,<50	1.733	0.541–5.555	0.355
	Sex: Female, Male	1.571	0.538–4.588	0.409
	HHSN: Yes, No	1.933	0.512–7.301	0.331
vHIT-PSCC	Age:> = 50,<50	1.459	0.518–4.102	0.475
	Sex: Female, Male	2.279	0.772–6.729	0.136
	HHSN: Yes, No	1.436	0.650–3.175	0.371
ACS cVEMP	Age:> = 50,<50	5.215	1.870–14.543	0.0016^**
	Sex: Female, Male	1.016	0.374–2.760	0.975
	HHSN: Yes, No	2.397	0.651–8.824	0.189
ACS oVEMP	Age:> = 50,<50	0.390	0.120–1.265	0.117
	Sex: Female, Male	1.161	0.498–2.709	0.729
	HHSN: Yes, No	1.633	0.280–9.540	0.586

For each parameter, the second category served as the reference for the binomial logistic regression. HHSN =horizontal head-shaking nystagmus, vHIT = video head impulse test, LSCC = lateral semicircular canal, ASCC =anterior semicircular canal, PSCC = posterior semicircular canal, ACS = air-conducted sound, cVEMP = cervical vestibular evoked myogenic potential, oVEMP = ocular vestibular evoked myogenic potential, CI = confidence interval, ^*significant difference (^*p<0.05, ^**p<0.01)

3.3 Association between vestibular dysfunction and findings of VIN

Next, we investigated whether VIN, age or sex had an association with vestibular dysfunction in patients with vestibular diseases (Table 5). The presence of VIN had a significant positive association with abnormalities on the opposite side to VIN direction in vHIT testing in all the SCCs [p = 0.0034 (LSCC), p = 0.0348 (ASCC), p = 0.0290 (PSCC)] and in ACS oVEMP testing (p = 0.0319). The odds ratio of an abnormal vHIT result on the opposite side to VIN direction for the presence of VIN compared with the absence of VIN was 9.302 (95% CI, 2.090–41.395) for LSCC, 3.199 (95% CI, 1.087–9.420) for ASCC and 2.026 (95% CI, 1.075–3.820) for PSCC. The odds ratio of abnormal ACS oVEMPs on the opposite side of VIN direction for the presence of VIN compared with the absence of VIN was 4.816 (95% CI, 1.145–20.251). Age had a significant positive association with abnormality in ACS cVEMP testing (p = 0.0010). The odds ratio of abnormal ACS cVEMPs for 50 years of age or older compared with under 50 years of age was 5.571 (95% CI, 2.008–15.456).

Table 5
Mixed-effects binomial logistic regression analyses for investigating the association between VIN and age, sex and vestibular dysfunction

Vestibular dysfunction Variables Odds ratio 95% CI p-value

vHIT-LSCC Age:> = 50,<50 0.814 0.120–5.139 0.827

Sex: Female, Male 0.979 0.166–5.757 0.981

VIN: Yes, No 9.302 2.090–41.395 0.0034^**

vHIT-ASCC Age:> = 50,<50 1.529 0.484–4.825 0.470

Sex: Female, Male 1.625 0.541–4.881 0.387

VIN: Yes, No 3.199 1.087–9.420 0.0348^*

vHIT-PSCC Age:> = 50,<50 1.364 0.470–3.954 0.568

Sex: Female, Male 2.337 0.784–6.963 0.128

VIN: Yes, No 2.026 1.075–3.820 0.0290^*

ACS cVEMP Age:> = 50,<50 5.571 2.008–15.456 0.0010^**

Sex: Female, Male 0.921 0.345–2.460 0.870

VIN: Yes, No 0.959 0.441–2.085 0.914

ACS oVEMP Age:> = 50,<50 0.357 0.104–1.230 0.103

Sex: Female, Male 1.271 0.519–3.112 0.600

VIN: Yes, No 4.816 1.145–20.251 0.0319^*

Vestibular dysfunction	Variables	Odds ratio	95% CI	p-value
vHIT-LSCC	Age:> = 50,<50	0.814	0.120–5.139	0.827
	Sex: Female, Male	0.979	0.166–5.757	0.981
	VIN: Yes, No	9.302	2.090–41.395	0.0034^**
vHIT-ASCC	Age:> = 50,<50	1.529	0.484–4.825	0.470
	Sex: Female, Male	1.625	0.541–4.881	0.387
	VIN: Yes, No	3.199	1.087–9.420	0.0348^*
vHIT-PSCC	Age:> = 50,<50	1.364	0.470–3.954	0.568
	Sex: Female, Male	2.337	0.784–6.963	0.128
	VIN: Yes, No	2.026	1.075–3.820	0.0290^*
ACS cVEMP	Age:> = 50,<50	5.571	2.008–15.456	0.0010^**
	Sex: Female, Male	0.921	0.345–2.460	0.870
	VIN: Yes, No	0.959	0.441–2.085	0.914
ACS oVEMP	Age:> = 50,<50	0.357	0.104–1.230	0.103
	Sex: Female, Male	1.271	0.519–3.112	0.600
	VIN: Yes, No	4.816	1.145–20.251	0.0319^*

For each parameter, the second category served as the reference for the binomial logistic regression. VIN = vibraion-induced nystagmus, vHIT = video head impulse test, LSCC = lateral semicircular canal, ASCC = anterior semicircular canal, PSCC = posterior semicircular canal, ACS = air-conducted sound, cVEMP = cervical vestibular evoked myogenic potential, oVEMP = ocular vestibular evoked myogenic potential, CI = confidence interval, ^*significant difference (^*p<0.05, ^**p<0.01)

In summary, the presence of HHSN had a significant positive association with abnormality on the opposite side to HHSN direction only in vHIT for the LSCC. On the other hand, the presence of VIN had a significant positive association with abnormalities on the opposite side of VIN direction in vHIT for all the SCCs and in ACS oVEMPs.

4 Discussion

In the present study, HHSN had a significant positive association with abnormal function in the LSCC. On the other hand, the presence of VIN had a significant positive association with abnormal function in not only the LSCC but also the VSCC and the utricle. Although both nystagmus tests have been used in clinical practice as indicators of asymmetry of vestibular function, the results of the present study suggest that VIN is associated with a wider range of asymmetry of vestibular function than HHSN.

The mechanism of the appearance of HHSN due to an asymmetry of vestibular function is considered as follows: the excitatory activity induced by head rotation to the intact ear is greater than that induced by head rotation to the affected ear. This asymmetry in activity is accumulated over the duration of the head-shaking procedure (velocity storage mech-anism). When this procedure is stopped, the accumulated activity gradually discharges through the vestibulo-ocular pathway, resulting in the appearance of nystagmus toward the intact ear [8, 14]. A vertical component of HHSN has been reported, and the effect of asymmetrically impaired vertical canals on HHSN cannot be denied [21]. However, since the HHSN test uses head stimulation in the LSCC plane, it is considered that the presence of HHSN is mainly associated with abnormal function in the LSCC.

VIN starts with stimulation onset and stops at stimulation offset and can easily be recognized during the stimulus. It does not persist after the cessation of the stimulus because the effect of the velocity storage mechanism is very low. A study using three-dimensional eye movement recordings revealed that VIN induced by 100 Hz mastoid stimulation had horizontal, torsional, and vertical components in 98%, 75%, and 47% respectively, in patients with a complete UVP [7]. Since the VIN test uses vibration applied to all the vestibular end organs, the result of the above-mentioned study suggests that the function of the LSCC is primarily associated with VIN, but other vestibular end organs are also associated. The results of this previous report support the results of the present study. Regarding the association between VIN and the function of the otolith organs, our study revealed that VIN was associated with abnormal ACS oVEMPs on the opposite side of VIN direction, whereas VIN was not associated with ACS cVEMPs. Electrophysiological experiments using cats reported that the sacculoocular reflex connectivity is relatively weaker in comparison with utriculoocular or sacculocollic pathways [16]. The results of the present study might be due to the greater contribution of the utricle than the saccule to the VOR.

The PSCC and the saccule are both innervated by the inferior vestibular nerve. In the present study, the presence of VIN had a significant positive association with abnormalities on the opposite side to VIN direction in vHIT testing for the PSCC but not in ACS cVEMP testing. A previous study analyzed the interaural amplitude difference in ACS cVEMPs with a positive rate of vHIT for the PSCC according to gain and catch-up saccades in patients with vestibular neuritis and revealed relatively lower inter-test agreement between two tests [33]. The difference of the results between the vHIT for the PSCC but the ACS cVEMPs in the present study may be due to the fact that the cVEMP test examines a reflex that involves skeletal muscles, while the vHIT examines a reflex that involves ocular muscles. Alternatively, the difference may occur in labyrinthine disorders. Patients with inner ear lesions may show dissociation between PSCC dysfunction and saccular dysfunction and difference of function among the SCCs [31].

In the present study, age (50 years of age or older) had a significant positive association with abnormal ACS cVEMPs. Previous studies on the effects of age on ACS cVEMPs in healthy subjects have shown that the response rate of ACS cVEMPs decreases with age, although how the response rate declines is still controversial [25 , 37]. One report showed that the response rate gradually declines starting at 50 years old [37]. In our study, abnormal findings in ACS cVEMPs might be influenced by the effects of aging to some extent.

The present study has several limitations. First, this is a retrospective study, with the potential for both selection bias and information bias. Some patients did not undergo cVEMPs and/or oVEMPs, and these were treated as missing data. Second, the confidence interval for odds ratios in variables that showed significant differences was relatively wide. In future, the large-scale studies are necessary to confirm our results. Third, data from the patients with bilaterally absent ACS oVEMP responses were excluded, because it is difficult to determine the contribution of the inferior oblique muscle on EMG activity using surface electrodes alone and to distinguish between dysfunction and a lack of muscle contraction. BCV oVEMPs show a lower rate of bilateral absent responses, and some reports have regarded bilaterally absent responses as having bilateral vestibulopathy [10, 12]. In order to avoid excluding data derived from subjects with bilaterally absent responses, the use of BCV oVEMPs rather than ACS oVEMPs is recommended. Fourth, since HSN and VIN can be detected in normal subjects, it is difficult to determine whether the nystagmus detected in the patients in the present study is pathological or not. Measurement of the slow phase velocity of nystagmus is recommended.

In conclusion, in this study, the presence of HHSN is associated with abnormal LSCC function only, while the presence of VIN is associated with abnormal function in all SCCs and the utricle. VIN is associated with a wider range of asymmetry of vestibular function than HHSN.

Conflict of Interest Statement

None of the authors have potential conflicts of interest to be disclosed.

Footnotes

Acknowledgments

We thank all of the members of the Department of Otolaryngology, Tokyo Teishin Hospital for helpful discussions. This work was funded by the Ministry of Education, Culture, Sports, Science and Technology (18K09369). This work was partially supported by AMED under Grant Number JP19dk0310092.

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