Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3294-x

OTOLOGY

Vestibular evoked myogenic potential responses in obstructive sleep apnea syndrome ¨ mer Bayır • Melike B. Yu¨ceege Murad Mutlu • O ¨ zdek • Tug˘ba Karago¨z • Hikmet Fırat • Ali O I˙stemihan Akın • Hakan Korkmaz



Received: 25 February 2014 / Accepted: 17 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Obstructive sleep apnea syndrome (OSAS) provokes oxidative stress and ischemia, which affects the central nervous system. The degeneration of neurons in the brainstem due to periodic hypoxia can be evaluated by vestibular and audiologic tests. The objective of this study is to determine brainstem damage in severe OSAS patients with the help of vestibular evoked myogenic potential (VEMP) responses. Prospective, randomize, double-blind. Research—training hospital. We compared cervical vestibular evoked myogenic potential (cVEMP) responses between severe OSAS patients and a control group. 54 This article was presented at the 29th Politzer Society Meeting on November 2013. ¨ . Bayır  T. Karago¨z M. Mutlu (&)  O Department of Otorhinolaryngology and Head and Neck Surgery, Ministiry of Health, Dıs¸ kapı Yıldırım Beyazıt Research and Training Hospital, Yes¸ iltepe 4. Blok D: 61, Emek, 06510 Ankara, Turkey e-mail: [email protected] M. B. Yu¨ceege  H. Fırat Department of Pulmonary Diseases, Ministiry of Health, Dıs¸ kapı Yıldırım Beyazıt Research and Training Hospital, Ankara, Turkey ¨ zdek A. O Department of Otorhinolaryngology and Head and Neck Surgery, Faculty of Medicine, Karabu¨k University, Karabu¨k, Turkey ˙I. Akın Department of Otorhinolaryngology and Head and Neck Surgery, Faculty of Medicine, Kafkas University, Kars, Turkey H. Korkmaz Department of Otorhinolaryngology and Head and Neck Surgery, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey

patients were included and divided into the OSAS group, with severe OSAS (apnea-hypopnea index, AHI [70), and a control group with snoring without OSAS (AHI \5). Both groups underwent cVEMP. Bilateral recordings with simultaneous binaural logon stimulations were used during VEMP recordings. The existing p1n1 and n2p2 responses, p1, n1, n2, and p2 latencies and amplitudes, and p1n1 and n2p2 intervals were measured. Statistically significant differences were revealed between patients and controls for the response rate of the p1n1, n2p2 and p1n1, n2p2 amplitudes. There were no significant differences between the two groups with respect to the latencies of p1, n1, n2 and p2, or the p1n1 and n2p2 intervals. The VEMP response rate was lower in severe OSAS patients, and all amplitudes were shorter than in healthy subjects. VEMP recordings in severe OSAS subjects demonstrates abnormalities in brainstem pathways. It appears that brainstem damage in severe OSAS can be detected by cVEMP recordings. Keywords Obstructive sleep apnea  Vestibular evoked myogenic potentials  Brainstem  Ischemia

Introduction Obstructive sleep apnea syndrome (OSAS) is a common sleep disorder affecting 6–13 % of adults, characterized by recurrent upper airway collapse during sleep [1]. Several symptoms including excessive daytime sleepiness, snoring, fatigue, impaired concentration or memory, and cardiorespiratory dysfunctions are some results of OSAS [2]. Cycles of oxygen desaturation and re-oxygenation in OSAS cause activation of the inflammatory cascade, oxidative stress and endothelial cell dysfunction [2]. Harm to

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the vasa nervorum due to insufficient oxygenation and chronic intermittent hypoxia give rise to neural loss in the central nervous system and damage to peripheral nerves [3]. Previous data indicates that the hypoxia affects nervous system cells in the brainstem as well as in the forebrain [4]. To evaluate the brainstem damage, some data have relied on immunohistochemical techniques in an animal model of sleep apnea [2] or magnetic resonance spectroscopy to determine whether cerebral metabolites change [5] or audiologic tests like auditory brainstem responses (ABR) [6]. In 1992, the cervical vestibular-evoked myogenic potential (cVEMP) was identified by Colebatch and Halmagyi [7]. A loud stimulus results in cervical muscle contraction recorded by ‘‘cervical’’ VEMP via the vestibulocollic arc, including neuroreceptors in the saccular macula, the inferior vestibular nerve, the lateral vestibular nucleus, the medial vestibulospinal tract and the motor neurons of the spinal cord extending through the neck muscles [8]. Normal cVEMP responses are described by biphasic (positive–negative) waves. The first biphasic complex is usually called p1–n1, and the second is referred to as n2–p2. As a result of lesions in the vestibulocollic pathway, abnormal results such as prolonged latencies or even a complete absence of response have been found [8]. Like ABR, cVEMP has also been shown to be sensitive to lesions in the brainstem, especially in the lower brainstem, and multiple sclerosis (MS), vestibular neuritis, brainstem lesion (Wallenberg’s syndrome) and stroke can all change VEMP responses [8, 9]. Unlike other methods cVEMP is an inexpensive, noninvasive and comfortable technique to evaluate whether the brainstem is affected. In this context, we hypothesized that VEMP can be used to detect brainstem damage in severe OSAS patients via the effected reflex arc that passes through the brainstem. This study was designed to evaluate the presence of abnormal cVEMP in severe OSAS patients in comparison to a control group with snoring but without OSAS.

Methods Study design This prospective, randomize, double-blind clinical study was performed between September 2011 and July 2012. Double-blind study means that the researchers who study the AHI values did not know the results of VEMP and the ones who study VEMP did not know AHI values and also they did not know if the studied individuals were belong to control or OSAS group. All subjects were also evaluated by performing an otoscopic examination, pure tone audiometry, tympanometry

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and stapedial reflexes on the first visit to document the otologic pathologies. The hearing thresholds of all subjects were \25 dB HL at frequencies of 250, 500, 1,000, 2,000, 4,000 and 8,000 Hz in the two groups. Patients with a previous diagnosis of neurotological disease, diabetes mellitus, uncontrolled high blood pressure, vascular disease, hearing loss, metabolic alterations, head or acoustic trauma, age older than 60 years, history of cervical surgery and ophthalmologic disease and body mass index (BMI) over 40 were excluded from the study. The study protocol was approved by our Institutional Review Board (#11/21) and written informed consent was obtained from all subjects. Twenty-eight patients (56 ears) with a diagnosis of severe OSAS (apnea–hypopnea index, AHI [70) and 26 (52 ears) age- and sex-matched controls with a diagnosis of snoring without OSAS (AHI \5) were included in the study. The SaO2 (arterial oxygen saturation) value was below 90 %, especially in the OSAS with AHI[70. This is why AHI [70 was in the study group. Sleep study Diagnosis of OSAS was established with respect to the results of an overnight computerized polysomnogram system (64-channel Compumedics E seriesÒ, Melbourne, Victoria, Australia) at the sleep laboratory of our institution. The apnoea-hypopnoea index (AHI) (events per hour of sleep) was calculated according to the American Academy recommendations. VEMP recording This study’s recordings were performed in the same way as in our previous studies [7, 9]. Each subject was seated in a chair with his or her back against the back support of the chair. The subject had to flex their head approximately 30° forward and rotate it approximately 30° to each side to record potentials from the opposite side. The sternocleidomastoid muscles (SCM) was targeted to record the VEMPs. The activity of the surface EMG was recorded with an Epic-Plus evoked acoustic potentials system (Labat S.r.l. Mestre, Italy). The ground electrode was placed on the centre of the sternal manubrium, the recording electrode was placed on the middle of the ipsilateral clavicle and the reference electrode was placed on the middle third of the ipsilateral SCM. The electrodes were carefully placed bilaterally on symmetrical sites. The VEMP responses were obtained by binaural acoustic stimulation and recorded from the bilateral SCM. A logon type stimulus (500 Hz; 120 dB hearing level intensity; stimulation rate 4/s) was used as an acoustic stimulation using headphones (ER-3A, Etymotic Research Inc., Elk Grove

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82.7%

P1-N1 cervical response

80.0%

response-

70.0%

62.5%

60.0% 50.0% 37.5%

40.0% 30.0% 20.0%

17.3%

80.0%

response-

70.0% 60.0%

53.6% 46.4%

50.0% 40.0% 30.0% 20.0%

0.0%

control

response+

78.8%

21.2%

10.0%

10.0% 0.0%

90.0%

response+

N2-P2 cervical response

90.0%

OSAS

Fig. 1 Cervical response rate of p1n1 in severe OSA patient and control group

Village, IL, USA), which could produce [110 dB hearing level between 0.5 and 4 kHz among standard audiologic frequencies. The EMG signal was amplified and bandpassfiltered (10–1,500 Hz). Recordings were obtained averaging 200 stimuli and two traces from each test were obtained to assess reproducibility. Data analysis The VEMP responses were evaluated for the presence of positive (p1) and negative (n1) peaks in the first biphasic wave complex; latency (p1 and n1 latency) and peak-topeak amplitude (p1–n1 amplitude) were measured for each peak. The negative (n2) and positive (p2) peaks in the second biphasic wave complex were also evaluated for latency (n2 and p2 latency) and peak-to-peak amplitude (n2–p2 amplitude). The severe OSAS group (56 ears) and the control group (52 ears) were compared to the presence of VEMP waves; p1, n1, n2, and p2 latencies; and p1–n1 and n2–p2 amplitudes. Groups’ response rate was compared by Chi-square test. The Student’s t test was used to analyze the numerical results, adopting a 5 % level of significance (p \ 0.05).

Results There was no neurotologic disease or history of vertigo and hearing loss in the control group and hearing thresholds were normal (\25 dB) in all subjects. The mean age was 46.5 ± 9.7 (range 20–59) for both groups. There were no statistically significant differences in age or sex between

control

OSAS

Fig. 2 Cervical response rate of n2p2 in severe OSA patient and control group

the two groups. AHI value was in the range of 87.9 ± 14.4 in severe OSAS group while it was 2.7 ± 1.4 in the control group. We considered each ear’s VEMP responses separately. p1n1 and n2p2 biphasic wave responses were obtained at different rates for both OSAS and control groups. Thus in the tables, number of ears which waves obtained are different in each group. Amplitude, latency and interval evaluations were made through the ear which biphasic waves obtained. The response rate of the p1n1 wave was 62.5 % for the severe OSAS group (35 ears), and 82.7 % for the control group (43 ears) (Fig. 1). The difference was statistically significant for the p1n1 wave (v2: 4.52, p value = 0.034). The response rate of the n2p2 wave was 46.4 % for the severe OSAS group, and 78.8 % for the control group (Fig. 2). The difference was statistically significant for the n2p2 wave (v2: 10.694, p = 0.034). For the severe OSAS group, the mean latencies of p1, n1, n2 and p2 were 15.9 ± 7.2, 16.2 ± 6, 32.7 ± 6.6 and 34.8 ± 9.1 ms, respectively; and for the control group these values were 13.0 ± 0.9, 19.5 ± 1.1, 30.7 ± 1.9 and 38.8 ± 2.2 ms (Table 1). The differences were insignificant for p1, n1, n2 and p2 latencies (Table 1). However, for the severe OSAS group the mean amplitude of the p1n1 wave was 15.9 ± 7.2 lV and for the control group it was 20.5 ± 6.2 lV. There was a significant difference in p1n1 amplitude (Student’s t test, p = 0.003) between the two groups (Table 2). For the severe OSAS group the mean amplitude of the n2p2 wave was 16.2 ± 6.0 lV; and this value was 19.2 ± 5.2 lV in the control group. All amplitudes were significantly shorter than for the control subjects (Table 2).

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Eur Arch Otorhinolaryngol Table 1 Comparision of latencies in both groups Latency (ms) p1 n1 n2 p2

Group Control (n:43)

Mean ± SD 13 ± 0.9

OSAS (n:35)

15.9 ± 7.2

Control (n:43)

19.5 ± 1.1

OSAS (n:35)

16.2 ± 6

Control (n:41)

30.7 ± 1.9

OSAS (n:26)

32.7 ± 6.6

Control (n:41)

38.8 ± 2.2

OSAS (n:26)

34.8 ± 9.1

p value 0.74 0.82 0.14 0.30

Table 2 Comparision of p1n1 and n2p2 amplitudes in both groups Amplitude (lV) p1n1 n2p2

Group

Mean ± SD

p value 0.003

Control (n:45)

20.5 ± 6.2

OSAS (n:35)

15.9 ± 7.2

Control (n:41)

19.2 ± 5.2

OSAS (n:25)

16.2 ± 6

0.04

Bold values indicate statistical significance (p \ 0.05)

Table 3 Comparision of p1n1 and n2p2 intervals in both groups Interval p1n1 n2p2

Group

Mean ± SD

Control (n:43)

6.5 ± 1.3

OSAS (n:35)

6.5 ± 1.3

Control (n:41)

8.2 ± 1.6

OSAS (n:26)

8.08 ± 2.9

p value 0.86 0.84

The mean value of the p1n1 and n2p2 intervals were 6.5 ± 1.3 and 8.08 ± 2.9 in the severe OSAS group. In the control group, these values were 6.5 ± 1.3 and 8.2 ± 1.6. So there was no statistically significant difference between the groups (Table 3).

Discussion The vestibulocollic reflex arc passes from the saccule of the inner ear through the inferior vestibular nerve to the vestibular nuclei, the vestibulospinal tracts, and to the SCM muscles. It is indicated that retrolabyrinthine lesions, especially in the vestibulospinal tract, may prolong latencies in VEMP [10]. Abnormal VEMPs can be recorded by lesions from the medulla oblongata to the mesencephalon [11]. The afferent part of the reflex is conducted by the vestibular nuclei at the level of the lateral lower pons and the efferent part by the accessory nucleus at the level of the medulla oblongata [12]. VEMP abnormalities in patients with brainstem stroke were found as well [13]. Itoh et al. [14] found abnormalities including VEMP absence,

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delayed latencies and/or decreased amplitudes in medullary and pontine lesions of several etiologies. VEMP has been proven to be a reliable method in detecting brainstem involvement in MS, comparable with MRI, but superior to clinical examination or ABR [6]. Abnormal latencies like prolonged p1 and n1 peak are also observed in MS due to the slowing of conduction along the vestibulospinal pathways consequent to demyelination [15]. Yet another study implied prolonged VEMP latencies can be caused by tumor compression to the brainstem or vestibular spinal tract [16]. Neurogenic inflammation inducing central vestibular deficits is revealed by delayed cVEMPs [17]. Bayir et al. [7] indicated that due to the inflammatory process in Behc¸et’s Disease affecting the sacculocollic reflex, the VEMP response rate was significantly lower in this condition than in the control group. Chronic hypoxia that typically occurs in severe OSAS during sleep results in alterations in the normal physiology of several organ systems by provoking oxidative stress and ischemia, which also affects the nervous system by inducing neural loss, evidenced by the nucleus ambiguus in rats. Chronic intermittent hypoxia was suggested to contribute to a decrease in the baroreflex and control of cardiac activity so that hypoxia/ischemia affects neuronal populations in the brainstem as well as in the forebrain [4, 18]. In another study, the effects of sleep apnoea and hypoxia on the peripheral and central vestibular systems were evaluated with the help of videonystagmography, caloric vestibular responses recorded with videonystagmography and auditory brainstem response in OSAS patients [19]. The damage caused by hypoxia in brainstem centres is proven by an alteration in ABR tracks and a further worsening of the sleep apnea due to damage to the respiratory centres, creating a vicious circle that also has repercussions on the auditory system [3]. Therefore, we aimed to show brainstem damage secondary to hypoxia in severe OSAS by the VEMP response. In our study, we observed that the responses of both of the biphasic waves were significantly different in severe OSAS patients than in the control group. The amplitudes of p1n1 and n2p2 in severe OSAS patients were statistically lower as well. Analysing our data, we suggest the hypoxia in severe OSAS damages the sacculocollic reflex in the brainstem and reduces the VEMP response. However, we could not clarify the clinical importance of the data that in the severe OSA group there were no significant alterations in latencies but there were decreases in the amplitudes. As a result, this is the first paper in the literature to document VEMP alterations in severe OSA patients. According to our results to evaluate brainstem damage in severe OSA, VEMP can be used as a diagnostic test. However, this study has some limitations. First, we need larger population studies to classify the characteristics of

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cVEMP in OSAS. On the other hand, we also wanted to make both cVEMP and oVEMP analysis. However, in our device there is no program for oVEMP anaysis. In the future, we plan to re-evaluation of these patients after CPAP usage. Thus, we would like to identify the benefit of CPAP devices after treatment.

10.

Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this article.

11.

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Vestibular evoked myogenic potential responses in obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) provokes oxidative stress and ischemia, which affects the central nervous system. The degeneration of neurons ...
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