Ocular Vestibular-Evoked Myogenic Potential Assists in the Differentiation of Multiple System Atrophy From Parkinson’s Disease

Article information

J Mov Disord. 2024;17(4):398-407
Publication date (electronic) : 2024 July 9
doi : https://doi.org/10.14802/jmd.24120
1Neurotology and Neuro-ophthalmology Laboratory, Korea University Medical Center, Seoul, Korea
2Department of Neurology, Korea University Medical Center, Seoul, Korea
3Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
4Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
5Dizziness Center, Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam, Korea
Corresponding author: Sun-Uk Lee, MD, PhD Department of Neurology, Korea University Medical Center, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea / Tel: +82-2-2199-3808 / Fax: +82-2-925-2472 / E-mail: sulee716@gmail.com
Received 2024 May 19; Revised 2024 June 21; Accepted 2024 July 8.

Abstract

Objective

Vestibular-evoked myogenic potentials (VEMPs) can help in assessing otolithic neural pathway in the brainstem, which may also contribute to the cardiovascular autonomic function. Parkinson’s disease (PD) is associated with altered VEMP responses; however, the associations between VEMP abnormalities and multiple system atrophy (MSA) remain unknown. Therefore, we compared the extent of otolith dysfunction using ocular (oVEMP) and cervical VEMPs between patients with MSA and PD.

Methods

We analyzed the clinical features, VEMP, and head-up tilt table test (HUT) findings using the Finometer in 24 patients with MSA and 52 with de novo PD who had undergone neurotologic evaluation at a referral-based university hospital in South Korea from January 2021 to March 2023.

Results

MSA was associated with bilateral oVEMP abnormalities (odds ratio [95% confidence interval] = 9.19 [1.77–47.76], p = 0.008). The n1–p1 amplitude was negatively correlated with the Unified Multiple System Atrophy Rating Scale I-II score in patients with MSA (r = -0.571, p = 0.033), whereas it did not correlate with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale-III score in patients with PD (r = -0.051, p = 0.687). The n1 latency was negatively correlated with maximum changes in systolic blood pressure within 15 s during HUT in patients with PD (r = -0.335, p = 0.040) but not in those with MSA (r = 0.277, p = 0.299).

Conclusion

Bilaterally abnormal oVEMP responses may indicate the extent of brainstem dysfunction in MSA. oVEMP reflects the integrity of otolith-autonomic interplay, reliably assists in differentiating between MSA and PD, and helps infer clinical decline.

GRAPHICAL ABSTRACT

INTRODUCTION

Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar and pyramidal signs. Along with Parkinson’s disease (PD) and dementia with Lewy bodies showing alpha-synucleinopathy in neurons, MSA is thought to be caused by the accumulation of aggregated alpha-synuclein in oligodendrocytes [1]. The diagnosis is often challenging, especially in the early stages, owing to the overlap in the clinical phenotype with other alpha-synucleinopathies. Therefore, MSA can often be misdiagnosed as PD, especially in the early stages.

In such cases, catching the slight differences in their clinical feature can aid in the differential diagnosis. In addition to parkinsonism, patients with MSA usually exhibit dysarthria, dysphagia, recurrent falls, and profound autonomic failure without the psychiatric side effects of antiparkinsonian drugs [2]. Furthermore, ancillary diagnostic modalities such as brain magnetic resonance imaging, [18F]-fluorodeoxyglucose positron emission tomography, and [123I]-metaiodobenzylguanidine cardiac scintigraphy can be helpful [3,4]. However, imaging findings often overlap without a generally accepted cutoff point for differentiation between the two pathologies; this further contributes to only 25% of patients being correctly diagnosed at initial presentation [5], and 20%–38% of patients are diagnosed otherwise on autopsy [6].

In addition to these diagnostics, vestibular-evoked myogenic potentials (VEMPs) provide valuable information regarding the involvement of the central vestibular system and the extent of brainstem dysfunction in neurodegenerative disorders [7,8]. The vestibular system is highly interconnected with the autonomic nervous system. Accordingly, VEMPs may be relevant in the development of orthostatic hypotension (OH) [9,10], a core feature both in MSA and PD patients.

It is largely agreed upon that VEMP responses can be altered in PD [11]. Defining this can be important since VEMP abnormalities can be related to compromised balance, risk of falling, or severe rapid eye movement sleep behavior disorders [12]. However, the prevalence and pattern of VEMP abnormalities in MSA remain largely unknown.

The pattern of VEMP responses has been reported as anecdotal evidence; however, some discrepancies remain. Some researchers have reported that cervical VEMP (cVEMP) is mostly preserved in MSA [13]. Conversely, another study has reported that ocular VEMP (oVEMP) is usually delayed and decreased [14]. In this study, we systematically compared the prevalence and clinical implications of cVEMP and oVEMP abnormalities between MSA and PD patients; we also assessed their diagnostic yield for differentiating MSA from PD and their relevance in the development of OH.

MATERIALS & METHODS

Patients

We retrospectively reviewed the medical records of 30 patients with MSA and 59 patients with de novo PD who underwent neurotologic evaluation between January 2021 and March 2023 at the Korea University Medical Center. We defined “de novo” as an individual newly diagnosed, not yet taking prescribed PD-specific medication at and prior to presentation. MSA and PD were diagnosed according to the Movement Disorder Society criteria [15,16]. All patients with PD met at least one supportive criterion for diagnosis, with no absolute exclusion criteria present. In addition, none of the patients developed red flag signs suggesting atypical parkinsonian syndrome initially or during follow-up (median follow-up period = 2 years, interquartile range [IQR] = 20–26 months).

We excluded patients with a history of central or vestibular disorders, including vestibular neuritis (n = 5), posterior circulation stroke (n = 4), Meniere’s disease (n = 2), and vestibular migraine (n = 2), which may have affected the VEMP results. Electrophysiologic studies (oVEMP, cVEMP, and head-up tilt [HUT]) were conducted before the administration of PD-specific medication in all patients.

Finally, 24 patients with MSA (18 with clinically established MSA and six with clinically probable MSA; 16 with MSA-cerebellar type and eight with MSA-parkinsonian type) and 52 patients with de novo PD were included in the analyses.

This study followed the tenets of the Declaration of Helsinki and was performed according to the guidelines of the Institutional Review Board of Korea University Anam Hospital (2023 AN0442). The written informed consent was obtained from all participants.

oVEMP and cVEMP

oVEMPs and cVEMPs were recorded by one examiner using a Nicolet Viking Select unit (Nicolet-Biomedical, Madison, WI, USA) as described previously [9].

oVEMPs were elicited by tapping the hairline at the AFz using an electric reflex hammer (VIASYS Healthcare, Conshohocken, PA, USA). Bilateral responses were recorded simultaneously after applying the tapping stimuli. Up to 60 tapping stimuli were applied at a 2 Hz frequency and approximately 0.45 g of force. The responses were averaged for each test, and the average latency of the initial negative peak (n1) and n1–p1 amplitude were determined. oVEMP responses were obtained at least twice, and the mean was calculated. The interaural difference (IAD, %) of the oVEMP amplitudes was calculated as [100 × (ARight − ALeft)/(Aright + Aleft)], where A is the n1–p1 amplitude.

cVEMPs were recorded with the patient lying supine on a bed, with the head raised by approximately 30° and rotated to one side to contract the sternocleidomastoid muscle (SCM). A short burst of alternating tone (110 dB nHL, 123.5 dB SPL, 500 Hz, rise time = 2 ms, plateau = 3 ms, and fall time = 2 ms) was applied at a 2.1 Hz frequency monoaurally via headphones. The signal was sampled (48 kHz), amplified, and bandpass-filtered at 30–1,500 Hz. No rectification or smoothing was performed while the cVEMP responses were recorded. cVEMP responses for up to 80 stimuli were averaged for each test. Responses were obtained at least twice for each ear, and the mean values were calculated.

Absolute cVEMP amplitudes were normalized and divided by the mean tonic activation of the SCM during recording. To compare the normalized p13–n23 amplitudes of cVEMP between the right and left sides, the IAD (%) was calculated. The peak latency of p13 was also calculated. To determine the reference ranges, oVEMP and cVEMP responses of 16 healthy participants (nine men, mean age ± standard deviation [SD] = 65 ± 9 years) with no prior history of auditory or vestibular disorders (reference range for oVEMP: n1 latency < 8.32 ms, IAD < 23.9%; reference range for cVEMP: p13 latency < 19.4 ms, normalized p13–n23 amplitude > 1.1 μV, IAD for cVEMP < 31.0%) were used [17].

For statistical analysis, the average values of both sides (right + left/2) were calculated for n1 and p13 peak latencies and n1–p1 and p13–n23 amplitudes. For IAD, the absolute values were used for statistical analyses. Patients with no VEMP responses on either side were excluded from the correlation analyses between amplitudes/latencies and Finometer parameters.

HUT test using the Finometer

The HUT test was performed as described previously [9]. Any medications that may affect the results of the autonomic function tests were discontinued for at least 48 hours before the test in all patients. To monitor the continuous changes in blood pressure (BP) during tilting, beat-to-beat BP was measured via a Finometer (Finapres Medical System BV, Amsterdam, The Netherlands). Predefined 5-s time averaging was applied via Beatscope software (Finapres Medical System BV) [18]. We measured the maximum changes in systolic BP (SBP) and diastolic BP (DBP) at 15 s (∆SBP15s, ∆DBP15s), 3 min (∆SBP3min, ∆DBP3min), and 10 min (∆SBP10min, ∆DBP10min) after the initiation of the tilt.

OH was categorized into initial, classic, and delayed types according to the decrease in BP [19,20]. Neurogenic OH was diagnosed when there was a blunted increase in heart rate (HR) relative to a ∆HR3min/∆SBP3min ratio < 0.5 or HR3min < 17 bpm [21]. Classic OH was defined as a sustained BP drop of at least 20 mmHg or 10 mmHg in SBP or DBP, respectively, within 3 min after tilting the table. Delayed OH was defined as a sustained drop in BP that occurred >3 min after tilting the table. For patients with supine hypertension, a drop in BP of at least 30 mmHg was required because the magnitude of orthostatic BP decrease is dependent on the baseline BP. Initial OH was defined as a transient decrease of >40 mmHg in SBP or 20 mmHg in DBP within 15 s upon standing.

Assessment of ataxia and parkinsonism

The severity of ataxia in patients with MSA was evaluated using the semiquantitative ataxia scale (Scale for the Assessment and Rating of Ataxia [SARA]) and the Unified Multiple System Atrophy Rating Scale (UMSARS) I and II. The severity of motor disability in patients with PD and MSA was assessed using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale III (MDS-UPDRS motor part) and Hohen and Yahr (H&Y) stages.

Statistical analysis

Nominal/independent variables were compared using the χ2 test or Fisher’s exact test. Continuous/independent variables were compared using the Student’s t-test (parametric variables such as n1, p13, and p23 latencies, baseline SBP, baseline DBP, HR, body weight, ∆SBP15s, 3min, 10min, and ∆DBP15s, 3min, 10min), the Mann–Whitney U test (nonparametric variables such as n1–p1 and p13–n23 amplitudes, Composite Autonomic Scoring Scale [CASS], and Composite Autonomic Symptom Score 31 [COMPASS 31]), and Spearman’s correlation. For regression analysis, age, sex, and variables with a p value < 0.2 in univariate analysis were included in the multivariate analysis. In addition, other variables of interest (oVEMP and cVEMP abnormalities and neurogenic OH) were included in the analysis. A p < 0.05 was considered significant in multivariable analysis.

Statistical analyses were performed using the R software package (version 3.4.0; http://www.r-project.org), and the significance level was set at two-tailed p < 0.05.

RESULTS

Clinical characteristics

The clinical profiles of the patients are summarized in Table 1. A total of 24 patients with MSA (mean age ± SD = 65 ± 10 years, 15 men) and 52 with PD (69 ± 12 years, 27 men) were included in the analyses. The MDS-UPDRS-III (median [IQR] = 38 [27–53] vs. 27 [22–33], p = 0.079), CASS (4 [3–5] vs. 4 [2–6], p = 0.796), and COMPASS-31 (22 [12–29] vs. 19 [9–31], p = 0.973) scores did not differ between the two groups. However, patients with MSA had higher H&Y stages than those with PD (2.5 [2.5–3] vs. 2.0 [2.0–2.5], p = 0.002). Hypertension (p = 0.011) and diabetes mellitus (p = 0.026) were more commonly observed in patients with PD than in those with MSA.

Clinical characteristics of patients with MSA and PD

oVEMPs

oVEMP values were abnormal in 37 patients (37/76, 49%), unilaterally in 19 (13 during left ear stimulation), and bilaterally in 18. Among the 55 ears (37 patients) whose results were abnormal, n1 responses were absent in 38 ears, delayed in 10 ears, and decreased in 9 ears (including two ears with both decreased and delayed responses). The frequency of oVEMP abnormalities did not differ between patients with MSA versus PD (p = 0.127) (Table 2). The n1 latency (7.0 ± 1.6 ms vs. 7.0 ± 1.3 ms, p > 0.999) and n1–p1 amplitude (7.7 ± 6.3 μV vs. 8.2 ± 6.4 μV, p = 0.733) did not differ between patients with PD and those with MSA. IAD also did not differ between the two groups (7.2% [2.4%–38.9%] vs. 10.0% [3.5%–15.5%], p = 0.717).

The results of VEMPs in patients with MSA and PD

cVEMPs

cVEMP values were abnormal in 24 patients (24/69, 35%, excluding seven patients with poor SCM contraction [four with MSA and three with PD]), bilaterally in 14 patients and unilaterally in the other 10 patients (four during right ear stimulation). Among the 38 ears (24 patients) whose results were abnormal, normalized p13–n23 responses were decreased in 24 ears, absent in 14 ears, and delayed in nine ears (nine ears showing both decreased and delayed responses). The frequency of cVEMP abnormalities did not differ between patients with MSA and those with PD (p = 0.510) (Table 2). Further, there were no differences in p13 (15.1 ± 3.8 ms vs. 15.9 ± 2.3 ms, p = 0.321), normalized p13–n23 amplitude (1.7 ± 1.5 μV vs. 2.1 ± 1.2 μV, p = 0.219), or IAD (7.1% [2.1%–39.4%] vs. 10.0% [3.5%–15.5%], p = 0.142) between patients with MSA and those with PD (Table 2).

HUT with the Finometer

Neurogenic OH, including classic OH (n = 36), initial OH (n = 1), and delayed OH (n = 2), was observed in 39 patients (39/76, 51%). The frequency of OH was similar between the two groups (p = 0.185) (Table 3). The Finometer parameters were also not different between the two groups, except for a higher baseline DBP in patients with MSA than in those with PD (74 ± 15 mmHg vs. 66 ± 11 mmHg, p = 0.015).

Results of head-up tilt table test using the Finometer in patients with MSA and PD

Correlation of VEMP findings with Finometer parameters and clinical findings

The statistics for the correlations between the oVEMP and cVEMP values and the Finometer parameters are listed in Supplementary Tables 1 and 2 (in the online-only Data Supplement).

The n1 latency was negatively correlated with ∆SBP15s in patients with PD (r = -0.335, p = 0.040) but not in those with MSA (r = 0.277, p = 0.299) (Figure 1 and Supplementary Table 1 in the online-only Data Supplement). The n1–p1 amplitude, normalized p13–n23 amplitude, and IAD were not associated with the Finometer parameters in patients with PD.

Figure 1.

Correlation of oVEMP parameters with Finometer parameters. A: The n1 latency shows a negative correlation with ∆SBP15s in patients with Parkinson’s disease (Spearman’s coefficient = -0.335, p = 0.040). B: On the contrary, it shows no correlation in patients with multiple system atrophy (r = 0.277, p = 0.299). oVEMP, ocular vestibular-evoked myogenic potential; ΔSBP15s, the maximum changes in systolic blood pressure at 15 s during head-up tilt table test.

p13 latency was positively correlated with ∆SBP15s in patients with MSA (r = 0.604, p = 0.029) but not in those with PD (r = 0.068, p = 0.670). The normalized p13–n23 amplitude was positively correlated with ∆HR15s (r = 0.589, p = 0.013), ∆HR3min (r = 0.636, p = 0.006), and ∆HR10min (r = 0.685, p = 0.002) in patients with MSA. Similarly, the normalized p13–n23 amplitude was positively correlated with ∆SBP15s (r = 0.310, p = 0.034), ∆DBP15s (r = 0.288, p = 0.049), and ∆DBP3min (r = 0.293, p = 0.045) in patients with PD. The IAD of cVEMP was positively correlated with ∆SBP15s (r = 0.389, p = 0.008), ∆DBP15s (r = 0.348, p = 0.018), ∆DBP3min (r = 0.313, p = 0.034), and ∆DBP10min (r = 0.318, p = 0.031) in patients with PD (Supplementary Table 2 in the online-only Data Supplement).

The n1–p1 amplitude was negatively correlated with the UMSARS I-II score in patients with MSA (r = -0.571, p = 0.033), whereas it did not correlate with the MDS-UPDRS-III score in patients with PD (r = -0.051, p = 0.687) (Figure 2). The SARA score was not correlated with n1 latency (r = -0.364, p = 0.272) or n1‒p1 amplitude (r = -0.343, p = 0.211) in patients with MSA. The n1 latency was not correlated with UMSARS I-II score in patients with MSA (r = -0.800, p = 0.104) or MDS-UPDRS-III score in patients with PD (r = 0.131, p = 0.476). The normalized p13–n23 amplitudes were not correlated with UMSARS I-II scores in patients with MSA (r = -0.422, p = 0.298) or with MDS-UPDRS-III scores in patients with PD (r = -0.158, p = 0.317). p13 latency was not associated with UMSARS I-II scores in patients with MSA (r = 0.500, p = 0.667) or MDS-UPDRS-III scores in patients with PD (r = -0.107, p = 0.527).

Figure 2.

Correlation of clinical disease scales and oVEMP parameters. A: n1–p1 amplitude was negatively correlated with UMSARS I-II in patients with MSA (r = -0.571, p = 0.033). B: Whereas it did not correlate with MDS-UPDRS-III scores in patients with PD (r = -0.051, p = 0.687). oVEMP, ocular vestibular-evoked myogenic potential; UMSARS I-II, Unified Multiple System Atrophy Rating Scale I-II; MDS-UPDRSIII, Movement Society Disorder-Unified Parkinson’s Disease Rating Scale-III score; MSA, multiple system atrophy; PD, Parkinson’s disease.

Prediction of MSA compared with PD

Multivariable logistic regression indicated that MSA was associated with bilateral oVEMP abnormalities (odds ratio [95% confidence interval] = 9.19 [1.77–47.76], p = 0.008) (Table 4 and Figure 3).

Logistic regression analysis of clinical and neurotologic findings for prediction of MSA compared to PD

Figure 3.

Forest plot of the results of logistic regression analysis. Multivariable logistic regression showed that MSA was associated with bilateral oVEMP abnormality (odds ratio [95% confidence interval] = 9.19 [1.77–47.76], p = 0.008]. *p value < 0.05. MSA, multiple system atrophy; cVEMP, cervical vestibular-evoked myogenic potential; oVEMP, ocular vestibular-evoked myogenic potential; OH, orthostatic hypotension.

Subgroup analysis with respect to MSA subtypes

Multivariable logistic regression revealed that MSA-cerebellar type was associated with bilateral oVEMP abnormalities (11.12 [1.76–70.04], p = 0.010) and younger age (0.90 [0.83–0.99], p = 0.025) (Table 5).

Subgroup analysis with respect to MSA subtypes for predicting MSA compared to PD

MSA-parkinsonian type was not associated with any variables (Table 5).

DISCUSSION

Our findings suggest that 1) bilateral oVEMP abnormalities are a predictor of MSA; 2) n1–p1 amplitudes were negatively correlated with UMSARS I-II scores in patients with MSA but not with MDS-UPDRS-III scores in patients with PD; and 3) ∆SBP15s was negatively correlated with n1 latency in patients with PD but not in patients with MSA.

Alterations in the otolith-ocular reflex in PD and MSA patients

In addition to VEMP, otolith function can be evaluated via subjective visual vertical (SVV), ocular tilt reaction (OTR), and head heave tests. The SVV and OTR reflect static otolith functions, and the values usually return to normal within weeks to months following a vestibular lesion owing to central compensation [22]. In contrast, VEMP is a measure of the short-latency phasic otolith-ocular reflex, and abnormal values persist even after central compensation [23]. Thus, discrete lesions involving the medial longitudinal fasciculus (for instance, multiple sclerosis, stroke, and tumors) result in alterations in oVEMPs [24].

VEMPs reportedly indicate the degree of brainstem dysfunction in PD [25]. cVEMP values may not differ between patients with PD and healthy participants [26]. However, subsequent studies have reported that approximately 44%–53% of patients exhibit altered cVEMP responses [11]. Furthermore, oVEMP responses exhibit distinct changes compared with relatively preserved cVEMP responses in PD, suggesting the preferential involvement of the upper brainstem by alpha-synuclein pathology [14,27]. The decrease in the cVEMP amplitude can even be reversed by levodopa administration [27].

We also observed cVEMP and oVEMP abnormalities in 31% and 42% of patients with PD, respectively. Nevertheless, our observations show that the abnormal oVEMP response is more profound in patients with MSA. Thus, abnormal oVEMP responses can be an independent predictor of MSA, especially when altered bilaterally. We speculate that these findings represent severely dampened brainstem function in MSA. Our findings agree with previous findings that demonstrated delayed and diminished oVEMP responses in patients with MSA [14]. Furthermore, we demonstrated that the n1–p1 amplitude, a representative indicator of brainstem dysfunction, decreases with neurological deterioration in MSA. These findings suggest that oVEMP has the potential to detect the therapeutic response or clinical decline observed in MSA. The assessment of this otolith function can be clinically significant, as it can be linked to postural instability and falls in patients with MSA [28].

Other neurotologic findings that aid in the differentiation between MSA and PD

In addition to VEMP abnormalities, several neurotologic abnormalities have been reported in patients with MSA [29]. Since the brainstem and cerebellum are profoundly affected, patients with MSA can exhibit downbeat, pendular, gaze-evoked, and central positional nystagmus; opsoclonus; perverted and reversed head-impulse tests; hypermetric saccades; and impaired cancellation of the vestibulo-ocular reflex (VOR) [30].

In contrast, patients with PD rarely exhibit neurotologic abnormalities. A few earlier anecdotes reported mild impairment of the VOR confined to low frequency and detected only on caloric and rotatory chair tests [31,32]. Nevertheless, vestibular dysfunction is negligible and has limited clinical significance. Our observations add to the evidence that oVEMP can aid in differentiating MSA from PD, which has previously drawn little attention.

Mechanism of orthostatic BP regulation, the pathogenesis of OH, and the relevance of VEMP

OH is prevalent both in patients with MSA (60%–84%) and PD (14%–31%) [2,33,34]. However, the early development of neurogenic OH indicates MSA rather than PD; symptomatic OH occurring within one year of disease onset strongly supports the diagnosis of MSA. Contrarily, OH develops approximately 10 years after disease onset in PD [35]. Furthermore, patients with PD generally have milder BP drops than those with MSA [36]. Collectively, although some differences are present in a large scale, cardiovascular autonomic findings in MSA and PD patients overlap and cannot be used to reliably distinguish between these disorders [37].

Orthostatic BP regulation depends on the cardiovascular autonomic reflex, normal blood volume, and defenses against excessive venous pooling [20]; its dysregulation results in cerebral hypoperfusion and, consequently, orthostatic intolerance. OH may ensue depending on the severity of the disruption of the afferent, central, or efferent components of autonomic BP control. Along with the baroreflex, the vestibulo-autonomic reflex contributes to the afferent autonomic BP control during postural changes [38]. Notably, the n1–p1 amplitude was positively associated with ∆SBP15s but not ∆SBP3min or ∆SBP10min in patients with PD. This may be attributed to the rapid adaptation of otolith-autonomic reflexes to orthostasis instead of the slow baroreflex. In this context, the otolithic influence on BP is prominent early during orthostasis [39].

Associations between oVEMP and Finometer parameters in PD and MSA

Some correlations were identified between the VEMP and the Finometer parameters in our patients. For oVEMPs, n1 latency was negatively correlated with ∆SBP15s in patients with PD but not in those with MSA. For cVEMPs, the normalized p13–n23 amplitude was positively correlated with ∆HR15s, ∆HR3min, ∆HR10min, and ∆SBP10min in patients with MSA. The normalized p13–n23 amplitude was positively correlated with ∆SBP15s in patients with PD. These correlations align with the notion that otoliths stabilize BP changes during orthostasis [10]. Therefore, otolithic dysfunction can be associated with the development of OH and postural orthostatic tachycardia syndrome [40]. Likewise, a substantial decrease in BP can be observed in patients with SVV, cVEMP, and oVEMP abnormalities [9].

However, these results should be interpreted with caution. In particular, as cVEMPs are highly dependent on SCM contraction [41], patients with MSA and PD may have difficulty generating cVEMP responses. Furthermore, cVEMP responses to sound stimuli deteriorate with age in healthy participants [41]. Thus, the correlation between cVEMP and the Finometer parameters should be interpreted while other factors are considered. Moreover, n1 latency was positively correlated with ∆SBP15s in patients with PD but not in those with MSA. As cVEMP responses to bone-conducted stimuli mostly remain unaffected by the aforementioned factors, they can hold statistical significance. Notably, this trend was not as robust as that observed in patients with OH without MSA or PD in our previous study [9]. These findings suggest that despite the frequent occurrence of otolithic dysfunction, it has a limited effect on cardiovascular autonomic control in MSA patients. In contrast, although rarely observed, utricular dysfunction can be associated with the development of OH in PD. We infer that this discrepancy might reflect the difference in the sites of neurodegeneration between MSA and PD patients.

As the utricle is involved in the graviceptive pathway, utricular dysfunction can impair the afferent limb of the neural pathway (otolith-autonomic coupling) responsible for orthostatic tolerance [9,10]. In MSA, autonomic failure results from central autonomic system involvement [42], which includes degeneration of the nucleus solitarius and ambiguus, the dorsal motor nucleus of the vagus, and neurons located in the caudal and rostral ventrolateral medulla [43]. Thus, the integrity of the afferent limb (otolith-ocular reflex or baroreflex) may have a limited effect on the profound degeneration of the central autonomic system. Conversely, degeneration occurs predominantly at the level of postganglionic (i.e., peripheral) sympathetic efferent neurons in PD [44]. Thus, neural substrates in the brainstem are relatively preserved, and the efferent limb of the neural pathway is partially functioning. Accordingly, the integrity of the afferent limb (otolith-autonomic coupling) can influence the regulation of orthostatic BP, although in a slightly more blunted manner than in patients with OH without PD.

Caveats and limitations of our study and suggestions for future studies

Our study had several limitations. First, the influence of cVEMP may have been underestimated. The interpretation of cVEMP must consider patients’ efforts to contract the SCM. Owing to weakness and aging, cVEMPs were not recordable in seven patients (four with MSA and three with PD), which limited the complete assessment of the saccule and sacculocolic reflex. Second, the small sample size limited a thorough analysis of associations between the variables. Differentiating MSA-parkinsonian type poses a challenge in the clinical setting [45,46]. Although the clinical diagnoses of PD and MSA strictly adhere to current diagnostic criteria, a follow-up period of 2 years may be insufficient. The MSA parkinsonian type can initially mimic PD, delaying the diagnosis by an average of 4 years [47]. Thus, the diagnostic utility of oVEMP should be determined on a larger scale and over a longer period in these patient populations. Third, the impact of diabetes mellitus was not explicitly assessed in our data, which should be addressed in future studies to offer a more nuanced understanding of the outcomes.

In conclusion, bilaterally abnormal oVEMP responses may indicate extensive brainstem involvement in MSA. oVEMP reflects the integrity of otolith-autonomic interplay, reliably assists in differentiating between MSA and PD, and helps infer clinical decline.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24120.

Supplementary Table 1.

Correlation of oVEMP with Finometer parameters

jmd-24120-Supplementary-Table-1.pdf
Supplementary Table 2.

Correlation of cVEMP with Finometer parameters

jmd-24120-Supplementary-Table-2.pdf

Notes

Conflicts of Interest

Drs. K.T. Kim, K. Baik, S.U. Lee, E. Park, C.N. Lee, T. Woo, Y. Kim, S. Kwag, and H. Park report no disclosures.

JS Kim serves as an Associate Editor of Frontiers in Neuro-otology and on the editorial boards of Frontiers in Neuro-ophthalmology, Journal of Neuroophthalmology, Journal of Vestibular Research, and Clinical and Translational Neuroscience.

Funding Statement

This study was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the MSIT (2022 R1A4A1018869).

Author Contributions

Conceptualization: Sun-Uk Lee. Data curation: Kyoungwon Baik, Sun-Uk Lee, Euyhyun Park, Chan-Nyoung Lee, Yukang Kim, Seoui Kwag, Hyunsoh Park. Formal analysis: Keun-Tae Kim, Sun-Uk Lee, Tonghoon Woo, Yukang Kim. Funding acquisition: Sun-Uk Lee. Investigation: Kyoungwon Baik, Sun-Uk Lee, Euyhyun Park. Methodology: Kyoungwon Baik, Sun-Uk Lee, Chan- Nyoung Lee. Project administration: Sun-Uk Lee. Resources: Sun-Uk Lee. Supervision: Kyoungwon Baik, Sun-Uk Lee, Chan-Nyoung Lee. Validation: Sun-Uk Lee, Tonghoon Woo, Ji-Soo Kim. Visualization: Sun-Uk Lee, Yukang Kim, Seoui Kwag, Hyunsoh Park. Writing—original draft: Keun-Tae Kim, Sun-Uk Lee. Writing—review & editing: Keun-Tae Kim, Sun-Uk Lee, Ji-Soo Kim.

Acknowledgements

None

References

1. Gai WP, Power JH, Blumbergs PC, Blessing WW. Multiple-system atrophy: a new alpha-synuclein disease? Lancet 1998;352:547–548.
2. Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000;68:434–440.
3. Pellecchia MT, Stankovic I, Fanciulli A, Krismer F, Meissner WG, Palma JA, et al. Can autonomic testing and imaging contribute to the early diagnosis of multiple system atrophy? A systematic review and recommendations by the movement disorder society multiple system atrophy study group. Mov Disord Clin Pract 2020;7:750–762.
4. Shin HW, Hong SW, Youn YC. Clinical aspects of the differential diagnosis of Parkinson’s disease and parkinsonism. J Clin Neurol 2022;18:259–270.
5. Litvan I, Goetz CG, Jankovic J, Wenning GK, Booth V, Bartko JJ, et al. What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study. Arch Neurol 1997;54:937–944.
6. Miki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, et al. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain 2019;142:2813–2827.
7. Su CH, Young YH. Differentiating cerebellar and brainstem lesions with ocular vestibular-evoked myogenic potential test. Eur Arch Otorhinolaryngol 2011;268:923–930.
8. Rosengren SM, Welgampola MS, Colebatch JG. Vestibular evoked myogenic potentials: past, present and future. Clin Neurophysiol 2010;121:636–651.
9. Kim JG, Lee JH, Lee SU, Choi JY, Kim BJ, Kim JS. Utricular dysfunction in patients with orthostatic hypotension. Clin Auton Res 2022;32:431–444.
10. Bogle JM, Benarroch E, Sandroni P. Vestibular-autonomic interactions: beyond orthostatic dizziness. Curr Opin Neurol 2022;35:126–134.
11. Pollak L, Prohorov T, Kushnir M, Rabey M. Vestibulocervical reflexes in idiopathic Parkinson disease. Neurophysiol Clin 2009;39:235–240.
12. de Natale ER, Ginatempo F, Paulus KS, Pes GM, Manca A, Tolu E, et al. Abnormalities of vestibular-evoked myogenic potentials in idiopathic Parkinson’s disease are associated with clinical evidence of brainstem involvement. Neurol Sci 2015;36:995–1001.
13. Takegoshi H, Murofushi T. Vestibular evoked myogenic potentials in patients with spinocerebellar degeneration. Acta Otolaryngol 2000;120:821–824.
14. Klunk D, Woost TB, Fricke C, Classen J, Weise D. Differentiating neurodegenerative parkinsonian syndromes using vestibular evoked myogenic potentials and balance assessment. Clin Neurophysiol 2021;132:2808–2819.
15. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30:1591–1601.
16. Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Mov Disord 2022;37:1131–1148.
17. Hong JP, Baik K, Park E, Lee SU, Lee CN, Kim BJ, et al. The vestibulospinal dysfunction has little impact on falls in patients with mild Parkinson’s disease. Parkinsonism Relat Disord 2024;122:106081.
18. van der Velde N, van den Meiracker AH, Stricker BH, van der Cammen TJ. Measuring orthostatic hypotension with the Finometer device: is a blood pressure drop of one heartbeat clinically relevant? Blood Press Monit 2007;12:167–171.
19. Seok HY, Kim YH, Kim H, Kim BJ. Patterns of orthostatic blood pressure changes in patients with orthostatic hypotension. J Clin Neurol 2018;14:283–290.
20. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci 2011;161:46–48.
21. Norcliffe-Kaufmann L, Kaufmann H, Palma JA, Shibao CA, Biaggioni I, Peltier AC, et al. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 2018;83:522–531.
22. Smith PF, Curthoys IS. Mechanisms of recovery following unilateral labyrinthectomy: a review. Brain Res Brain Res Rev 1989;14:155–180.
23. Papathanasiou ES, Straumann D. Why and when to refer patients for vestibular evoked myogenic potentials: a critical review. Clin Neurophysiol 2019;130:1539–1556.
24. Rosengren SM, Colebatch JG. Ocular vestibular evoked myogenic potentials are abnormal in internuclear ophthalmoplegia. Clin Neurophysiol 2011;122:1264–1267.
25. Heide G, Luft B, Franke J, Schmidt P, Witte OW, Axer H. Brainstem representation of vestibular evoked myogenic potentials. Clin Neurophysiol 2010;121:1102–1108.
26. Cicekli E, Titiz AP, Titiz A, Oztekin N, Mujdeci B. Vestibular evoked myogenic potential responses in Parkinson’s disease. Ideggyogy Sz 2019;72:419–425.
27. Pötter-Nerger M, Govender S, Deuschl G, Volkmann J, Colebatch JG. Selective changes of ocular vestibular myogenic potentials in Parkinson’s disease. Mov Disord 2015;30:584–589.
28. Hawkins KE, Chiarovano E, Paul SS, MacDougall HG, Curthoys IS. Static and dynamic otolith reflex function in people with Parkinson’s disease. Eur Arch Otorhinolaryngol 2021;278:2057–2065.
29. Smith PF. Vestibular functions and Parkinson’s disease. Front Neurol 2018;9:1085.
30. Kim JG, Kim SH, Lee SU, Lee CN, Kim BJ, Kim JS, et al. Head-impulse tests aid in differentiation of multiple system atrophy from Parkinson’s disease. J Neurol 2022;269:2972–2979.
31. Reichert WH, Doolittle J, McDowell FH. Vestibular dysfunction in Parkinson disease. Neurology 1982;32:1133–1138.
32. Lv W, Guan Q, Hu X, Chen J, Jiang H, Zhang L, et al. Vestibulo-ocular reflex abnormality in Parkinson’s disease detected by video head impulse test. Neurosci Lett 2017;657:211–214.
33. Velseboer DC, de Haan RJ, Wieling W, Goldstein DS, de Bie RM. Prevalence of orthostatic hypotension in Parkinson’s disease: a systematic review and meta-analysis. Parkinsonism Relat Disord 2011;17:724–729.
34. Jung YJ, Kim A, Okamoto LE, Hong WH. Effects of atomoxetine for the treatment of neurogenic orthostatic hypotension in patients with alphasynucleinopathies: a systematic review of randomized controlled trials and a focus-group discussion. J Clin Neurol 2023;19:165–173.
35. Wenning GK, Scherfler C, Granata R, Bösch S, Verny M, Chaudhuri KR, et al. Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study. J Neurol Neurosurg Psychiatry 1999;67:620–623.
36. Sandroni P, Ahlskog JE, Fealey RD, Low PA. Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res 1991;1:147–155.
37. Fanciulli A, Strano S, Ndayisaba JP, Goebel G, Gioffrè L, Rizzo M, et al. Detecting nocturnal hypertension in Parkinson’s disease and multiple system atrophy: proposal of a decision-support algorithm. J Neurol 2014;261:1291–1299.
38. Yates BJ, Bolton PS, Macefield VG. Vestibulo-sympathetic responses. Compr Physiol 2014;4:851–887.
39. Kaufmann H, Biaggioni I, Voustianiouk A, Diedrich A, Costa F, Clarke R, et al. Vestibular control of sympathetic activity. An otolith-sympathetic reflex in humans. Exp Brain Res 2002;143:463–469.
40. Kim KT, Lee SU, Kim JB, Choi JY, Kim BJ, Kim JS. Augmented ocular vestibular-evoked myogenic potentials in postural orthostatic tachycardia syndrome. Clin Auton Res 2023;33:479–489.
41. Rosengren SM, Govender S, Colebatch JG. Ocular and cervical vestibular evoked myogenic potentials produced by air- and bone-conducted stimuli: comparative properties and effects of age. Clin Neurophysiol 2011;122:2282–2289.
42. Mathias CJ, Bannister RB, Cortelli P, Heslop K, Polak JM, Raimbach S, et al. Clinical, autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta hydroxylase. Q J Med 1990;75:617–633.
43. Holstein GR, Friedrich VL Jr, Kang T, Kukielka E, Martinelli GP. Direct projections from the caudal vestibular nuclei to the ventrolateral medulla in the rat. Neuroscience 2011;175:104–117.
44. Taki J, Yoshita M, Yamada M, Tonami N. Significance of 123I-MIBG scintigraphy as a pathophysiological indicator in the assessment of Parkinson’s disease and related disorders: it can be a specific marker for Lewy body disease. Ann Nucl Med 2004;18:453–461.
45. Watanabe H, Shima S, Mizutani Y, Ueda A, Ito M. Multiple system atrophy: advances in diagnosis and therapy. J Mov Disord 2023;16:13–21.
46. Lee WW, Kim HJ, Lee HJ, Kim HB, Park KS, Sohn CH, et al. Semiautomated algorithm for the diagnosis of multiple system atrophy with predominant parkinsonism. J Mov Disord 2022;15:232–240.
47. Foubert-Samier A, Pavy-Le Traon A, Guillet F, Le-Goff M, Helmer C, Tison F, et al. Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study. Neurobiol Dis 2020;139:104813.

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Figure 1.

Correlation of oVEMP parameters with Finometer parameters. A: The n1 latency shows a negative correlation with ∆SBP15s in patients with Parkinson’s disease (Spearman’s coefficient = -0.335, p = 0.040). B: On the contrary, it shows no correlation in patients with multiple system atrophy (r = 0.277, p = 0.299). oVEMP, ocular vestibular-evoked myogenic potential; ΔSBP15s, the maximum changes in systolic blood pressure at 15 s during head-up tilt table test.

Figure 2.

Correlation of clinical disease scales and oVEMP parameters. A: n1–p1 amplitude was negatively correlated with UMSARS I-II in patients with MSA (r = -0.571, p = 0.033). B: Whereas it did not correlate with MDS-UPDRS-III scores in patients with PD (r = -0.051, p = 0.687). oVEMP, ocular vestibular-evoked myogenic potential; UMSARS I-II, Unified Multiple System Atrophy Rating Scale I-II; MDS-UPDRSIII, Movement Society Disorder-Unified Parkinson’s Disease Rating Scale-III score; MSA, multiple system atrophy; PD, Parkinson’s disease.

Figure 3.

Forest plot of the results of logistic regression analysis. Multivariable logistic regression showed that MSA was associated with bilateral oVEMP abnormality (odds ratio [95% confidence interval] = 9.19 [1.77–47.76], p = 0.008]. *p value < 0.05. MSA, multiple system atrophy; cVEMP, cervical vestibular-evoked myogenic potential; oVEMP, ocular vestibular-evoked myogenic potential; OH, orthostatic hypotension.

Table 1.

Clinical characteristics of patients with MSA and PD

Characteristics MSA (n = 24) PD (n = 52) p value
Age (yr) 65 ± 10 69 ± 12 0.194
Female sex 9 (38) 25 (48) 0.389
Disease duration (yr) 1.0 [0.5–2.0] 1.0 [0.5–3.0] 0.996
Body weight (kg) 62 ± 12 63 ± 10 0.902
MDS-UPDRS-III 38 (27–53) 27 (22–33) 0.079
H&Y stage 2.5 (2.5–3.0) 2.0 (2.0–2.5) 0.002
UMSARS I-II 36 (25–53) - -
SARA 14 (9–21) - -
CASS 4 (3–5) 4 (2–6) 0.796
COMPASS-31 22 (12–29) 19 (9–31) 0.973
RBD 11 (46) 16 (31) 0.224
Comorbidities
 Benign prostate hyperplasia 3/16 (19) 4/27 (15) >0.999
 Diabetes mellitus 0/24 (0) 10/52 (19) 0.026*
 Hypertension 5/24 (21) 27/52 (52) 0.011*
 Dyslipidemia 4/24 (17) 18/52 (35) 0.173
 Congestive heart failure 0/24 (0) 1/52 (2) >0.999
 Chronic kidney disease 1/24 (4) 7/52 (14) 0.423
 Anemia 6/24 (25) 9/52 (17) 0.434

Data are presented as mean ± standard deviation, median [interquartile range], or n (%).

*

indicates statistically significant values.

MSA, multiple system atrophy; PD, Parkinson’s disease; MDS-UPDRSIII, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale motor part; H&Y, Hoehn and Yahr; UMSARS, Unified Multiple System Atrophy Rating Scale; SARA, Scale for the Assessment and Rating of Ataxia; CASS, The Composite Autonomic Severity Scores; COMPASS-31, The Korean version of Composite Autonomic Symptom Score 31; RBD, REM sleep behavior disorder.

Table 2.

The results of VEMPs in patients with MSA and PD

MSA (n = 24) PD (n = 52) p value
oVEMP 0.127
 Normal 9 (38) 30 (58)
 Unilaterally abnormal 6 (25) 13 (25)
 Bilaterally abnormal 9 (38) 9 (17)
n1 latency (ms) 7.0 ± 1.6 7.0 ± 1.3 >0.999
n1–p1 amplitude (μV) 7.7 ± 6.3 8.2 ± 6.4 0.733
IAD (%) 7.2 [2.4–38.9] 10.0 [3.5–15.5] 0.717
cVEMP* 0.510
 Normal 11 (55) 34 (69)
 Unilaterally abnormal 4 (20) 6 (12)
 Bilaterally abnormal 5 (25) 9 (18)
p13 latency (ms) 15.1 ± 3.8 15.9 ± 2.3 0.321
Normalized p13–n23 amplitude (μV) 1.7 ± 1.5 2.1 ± 1.2 0.219
IAD (%) 7.1 [2.1–39.4] 10.0 [3.5–15.5] 0.142

Data are presented as mean ± standard deviation, median [interquartile range], or n (%).

*

after excluding seven patients whose cVEMP data cannot be assessed due to poor sternocleidomastoid contraction.

MSA, multiple system atrophy; PD, Parkinson’s disease; VEMP, vestibularevoked myogenic potential; oVEMP, ocular VEMP; cVEMP, cervical VEMP; IAD, interaural difference ratio of the amplitudes.

Table 3.

Results of head-up tilt table test using the Finometer in patients with MSA and PD

MSA (n = 24) PD (n = 52) p value
Neurogenic OH 15/24 (63) 24/52 (46) 0.185
 Initial 1 0
 Classic 14 22
 Delayed 0 2
Baseline SBP (mmHg) 139 ± 22 138 ± 26 0.824
Baseline DBP (mmHg) 74 ± 15 66 ± 11 0.015*
Baseline heart rate (beat/min) 69 ± 8 65 ± 9 0.081
ΔSBP15s (mmHg) -8 [-19– -1] -7 [-15–1] 0.750
ΔSBP3min (mmHg) -21 [-30– -5] -11 [-31– -1] 0.118
ΔSBP10min (mmHg) -26 [-37– -7] -13 [-37– -3] 0.194
ΔDBP15s (mmHg) 1 [-1–3] 1 [-4–5] 0.382
ΔDBP3min (mmHg) -2 [-9–1] -2 [-6–2] 0.601
ΔDBP10min (mmHg) -2 [-10–1] -2 [-8–2] 0.387
ΔHR15s (beat/min) 4 [2–6] 4 [1–6] 0.900
ΔHR3min (beat/min) 10 [7–18] 8 [4–14] 0.635
ΔHR10min (beat/min) 13 [8–19] 10 [7–18] 0.520

Data are presented as mean ± standard deviation, median [interquartile range], n (%), or numbers only.

*

indicates statistically significant values.

MSA, multiple system atrophy; PD, Parkinson’s disease; OH, orthostatic hypotension; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.

Table 4.

Logistic regression analysis of clinical and neurotologic findings for prediction of MSA compared to PD

Variables Univariate analysis
Multivariable analysis
OR (95% CI) p value OR (95% CI) p value
Age 0.97 (0.93–1.02) 0.193 0.94 (0.87–1.00) 0.065
Female sex 0.65 (0.24–1.74) 0.648 0.91 (0.25–3.40) 0.894
Diabetes mellitus 0.999*
Hypertension 0.24 (0.08–0.75) 0.014 0.34 (0.08–1.41) 0.340
oVEMP abnormality 0.138 0.029
 Unilateral 1.54 (0.45–5.22) 0.489 1.85 (0.38–8.98) 0.443
 Bilateral 3.33 (1.02–10.92) 0.047* 9.19 (1.77–47.76) 0.008
cVEMP abnormality 0.515 0.513
 Unilateral 2.06 (0.49–8.67) 0.324 2.39 (0.42–13.52) 0.325
 Bilateral 1.72 (0.47–6.22) 0.410 1.90 (0.41–8.67) 0.410
Neurogenic OH 1.47 (0.54–4.00) 0.448 0.92 (0.21–4.13) 0.913
*

there are insufficient data to estimate a difference (null incidence);

p value for type 3 analysis for assessment of the significance of the complete categorical variable;

indicates statistically significant values.

MSA, multiple system atrophy; PD, Parkinson’s disease; OR, odds ratio; CI, confidence interval; oVEMP, ocular vestibular-evoked myogenic potential; cVEMP, cervical vestibular-evoked myogenic potential; OH, orthostatic hypotension.

Table 5.

Subgroup analysis with respect to MSA subtypes for predicting MSA compared to PD

Variables Univariate analysis
Multivariable analysis
OR (95% CI) p value OR (95% CI) p value
MSA-cerebellar type (n = 16)
 Age 0.94 (0.89–0.99) 0.027 0.90 (0.83–0.99) 0.025
 Female sex 0.84 (0.27–2.59) 0.762 1.37 (0.29–6.40) 0.691
 Diabetes mellitus 0.999*
 Hypertension 0.21 (0.05–0.84) 0.027
 oVEMP abnormality 0.034 0.021
  Unilateral 0.33 (0.04–2.96) 0.322 0.53 (0.04–6.64) 0.618
  Bilateral 3.81 (1.08–13.41) 0.037 11.12 (1.76–70.04) 0.010
 cVEMP abnormality 0.520 0.480
  Unilateral 2.13 (0.44–10.37) 0.351 2.80 (0.37–21.16) 0.318
  Bilateral 1.89 (0.46–7.72) 0.376 2.21 (0.39–12.61) 0.371
 Neurogenic OH 1.24 (0.39–3.97) 0.722 1.11 (0.19–6.37) 0.909
MSA-parkinsonian type (n = 8)
 Age 1.03 (0.96–1.10) 0.393 1.00 (0.90–1.11) 0.993
 Female sex 0.36 (0.07–1.95) 0.236 0.15 (0.01–3.54) 0.151
 Diabetes mellitus 0.999*
 Hypertension 0.31 (0.06–1.67) 0.173 0.60 (0.07–5.07) 0.638
 oVEMP abnormality 0.128 0.201
  Unilateral 5.77 (0.99–33.68) 0.052 10.12 (0.81–127.24) 0.073
  Bilateral 1.67 (0.14–20.58) 0.690 3.31 (0.13–84.71) 0.470
 cVEMP abnormality 0.874 0.845
  Unilateral 1.89 (0.17–21.33) 0.607 1.55 (0.07–32.84) 0.779
  Bilateral 1.26 (0.12–13.60) 0.849 2.33 (0.10–53.24) 0.596
 Neurogenic OH 2.06 (0.46–9.25) 0.346 1.12 (0.07–17.96) 0.935
*

there are insufficient data to estimate a difference (null incidence);

p value for type 3 analysis for assessment of the significance of the complete categorical variable;

indicates statistically significant values.

MSA, multiple system atrophy; PD, Parkinson’s disease; OR, odds ratio; CI, confidence interval; cVEMP, cervical vestibular-evoked myogenic potential; oVEMP, ocular vestibular-evoked myogenic potential; OH, orthostatic hypotension.