Impact of intermittent hypoxia on peripheral nervous systems in obstructive sleep apnea syndrome

Mustafa Emir Tavsanli; Gulcin Benbir Senel; Aysegul Gunduz; Derya Karadeniz; Nurten Uzun Adatepe

doi:10.4103/2636-865X.283926

RESEARCH PAPER

Year : 2020 | Volume : 37 | Issue : 1 | Page : 18-23

Impact of intermittent hypoxia on peripheral nervous systems in obstructive sleep apnea syndrome

Mustafa Emir Tavsanli¹, Gulcin Benbir Senel², Aysegul Gunduz², Derya Karadeniz², Nurten Uzun Adatepe²
¹ Department of Neurology, Okmeydani Training and Research Hospital, Istanbul, Turkey
² Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

Date of Submission	23-Jun-2019
Date of Decision	17-Oct-2019
Date of Acceptance	22-Oct-2019
Date of Web Publication	8-May-2020

Correspondence Address:
Gulcin Benbir Senel
Department of Neurology, Faculty of Medicine, Istanbul University-Cerrahpasa, Fatih, 34098, Istanbul
Turkey

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2636-865X.283926

Abstract

Objectives: Intermittent hypoxia resulting in endothelial dysfunction in microvascular circulation constitutes one of the mechanisms underlying complications of obstructive sleep apnea syndrome (OSAS), such as hypertension and atherosclerosis. The role of intermittent hypoxia on peripheral nerves, however, is still debated. Here, we designed a study in patients with OSAS to investigate different levels of the central and peripheral nervous systems, in order to delineate what kind of pathologic substrate was present, if any, and at which level of the neuromuscular pathway. Methods: A total of 20 patients with OSAS and 18 sex- and age-matched healthy controls were enrolled in our study. All participants underwent nerve conduction studies (NCSs) to analyze peripheral nerves, evoked potentials for somatosensory, visual evoked potential (VEP) and brainstem auditory pathways, blink reflex studies to analyze brainstem and subcortical structures, and transcranial magnetic stimulation to analyze the motor cortex and corticospinal pathway. Results: A comparison of NCSs between the two groups showed that the motor amplitudes of the ulnar nerve (P = 0.015) and sensory amplitudes of the sural nerve (P = 0.026) were significantly smaller in the OSAS group than those in the control group. The mean P100 amplitudes of VEP responses were 7.11 ± 2.73 μV in the OSAS group and 9.75 ± 3.52 μV in the control group (P = 0.022). In correlation analysis, the amplitude of P100 responses was positively correlated with the lowest oxygen saturation (P = 0.026). Conclusion: Our results confirmed the presence of generalized axonal involvement in the peripheral nervous system in OSAS, probably secondary to chronic intermittent hypoxemia.

Keywords: Blink reflex, evoked potentials, nerve conduction studies, obstructive sleep apnea syndrome, transcranial magnetic stimulation

How to cite this article:
Tavsanli ME, Senel GB, Gunduz A, Karadeniz D, Adatepe NU. Impact of intermittent hypoxia on peripheral nervous systems in obstructive sleep apnea syndrome. Neurol Sci Neurophysiol 2020;37:18-23

How to cite this URL:
Tavsanli ME, Senel GB, Gunduz A, Karadeniz D, Adatepe NU. Impact of intermittent hypoxia on peripheral nervous systems in obstructive sleep apnea syndrome. Neurol Sci Neurophysiol [serial online] 2020 [cited 2023 Jun 10];37:18-23. Available from: http://www.nsnjournal.org/text.asp?2020/37/1/18/283926

Introduction

Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by repetitive episodes of complete or partial upper airway obstructions during sleep, resulting in fragmented sleep and intermittent hypoxia.^[1] Vasoconstriction and increased oxidative stress as a result of intermittent hypoxia lead to endothelial dysfunction in the microvascular circulation and constitute one of the mechanisms of OSAS-related complications such as hypertension and atherosclerosis.^[2] The role of intermittent hypoxia on peripheral nerves, however, is still debated. The most common peripheral neuropathy investigated associated with OSAS has been optic neuropathy; although there are opposing hypotheses, risk for nonarteritic anterior ischemic optic neuropathy (NAION) was reported to be higher in patients with OSAS.^[3] The detection of increased retinal arteriolar changes in patients with OSAS and NAIO has emphasized the role of intermittent hypoxia in these patients.

The impact of chronic intermittent hypoxemia in patients with OSAS on peripheral nerves has been neglected in the literature. Two studies investigated peripheral nerves in the lower limbs in patients with OSAS,^[4],[5] where the mean amplitude of sensory nerve action potential (SNAP) of sural nerves was reported to be smaller. There is one other study by Mihalj et al.,^[6] who claimed that both compound muscle action potentials (CMAPs) and SNAP amplitudes were significantly reduced in peripheral nerves of both upper and lower limbs in patients with OSAS.

Evaluation of motor-evoked potentials (MEPs) in patients with OSAS in two studies using transcranial magnetic stimulation (TMS) revealed reduced corticospinal excitability and increased intracortical inhibition.^[7],[8] Repeated bouts of nocturnal hypoxemia have been also suggested to lead to cellular and molecular modifications in peripheral muscles.^[9] It may, therefore, be suggested that OSAS has repercussions throughout the neuromuscular pathway, from the motor cortex to the peripheral nerves and muscles.

On this basis, we designed a study in patients with OSAS to investigate different levels of central and peripheral nervous systems, in order to delineate what kind of pathologic substrate is present, if any, and at which level of the neuromuscular pathway. For this reason, we performed nerve conduction studies (NCSs) to analyze peripheral nerves, evoked potentials for somatosensory, visual, and brainstem auditory pathways, blink reflex (BR) studies to analyze brainstem and subcortical structures, and TMS to analyze the motor cortex and corticospinal pathway.

Methods

We included 20 patients with OSAS, who were consecutively diagnosed as having OSAS using full-night video-polysomnography (v-PSG) recordings in the Sleep and Disorders Unit at Cerrahpasa University, Faculty of Medicine, Department of Neurology. Full-night v-PSG recordings performed on an Embla A-10 (Flaga, Reykjavik, Iceland) system were recorded and scored by two European sleep experts (GBS and DK) on the basis of standardized criteria defined by the American Academy of Sleep Medicine (AASM) in the Manual for the Scoring of Sleep and Associated Events.^[10] Diagnoses of sleep disorders were made according to the latest version of the International Classification of Sleep Disorders defined of the AASM.^[1] For the healthy control group, 18 sex- and age-matched participants who were evaluated as not having OSAS were included. All participants gave written informed consent, and our study was approved by the local ethics committee (No.: 2009-02-10/4355).

All participants were questioned in detail for sleep disorders and systemic and neurologic diseases, and a detailed neurologic examination was performed. Participants with coexisting neurologic or systemic diseases, such as diabetes, kidney, liver, or hematologic diseases that might interfere with electrophysiologic studies, or those under drug or substance use or alcoholism that might cause or trigger excitability changes in neurophysiologic studies, toxic status, deficiency of Vitamin B12 or folic acid, dysfunction of the thyroid gland, peripheral vascular disease, immune-mediated or rheumatic diseases, paraneoplastic conditions, compressive mononeuropathies, plexus lesions, and peripheral nerve damage were not included. Among the other exclusion criteria were being aged below 18 years and over 70 years, positive history of seizures, presence of metal implants or heart pacemaker, and being unwilling to participate in the study.

Electrophysiologic studies including NCSs, evoked potentials, BR studies, and TMS were performed between 13:00 PM and 17:00 PM with standard techniques using a Nihon Kohden, Neuropack MEB-9200. The attention level of the participants was simultaneously assessed during electrophysiologic investigations using the digit-span test. Motor and sensory NCSs were performed after percutaneous supramaximal stimulation of the ulnar, posterior tibial, and sural nerves. Evoked potentials were obtained from the right-sided median and posterior tibial nerves for somatosensory evoked potentials (SEPs). The monocular pattern reversal technique with interchanging white and black boxes with a frequency of 1 Hz was used for visual evoked potentials (VEPs). Brainstem auditory evoked potentials (BAEPs) were performed using a monaural “click” sound, lasting 100 ms in duration at a frequency of 10 Hz and with an intensity of 60 dB above the hearing threshold. Analysis of BR responses was performed by stimulating the supraorbital nerve at the supraorbital notch and recording the orbicularis oculi muscle. TMS studies were performed by stimulating the dominant motor cortex (left hemisphere) and cervical spinal cord while recording right-sided first dorsal interosseous muscle activity. The central conduction time (CCT) was either calculated as the interval between scalp MEP latency and cervical MEP latency (CCT-S) or according to F-wave responses (CCT-F calculated as MEP response – [shortest F-wave latency + motor response latency recorded by distal stimulation – 1] and divided by 2).

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) 10.0.1 software (Chicago, IL, USA). Data are reported as mean ± standard deviation (95% confidence interval) or in percentages. Comparisons between patients with OSAS and the control group were made using the Chi-square test for nominal variables, and the Mann–Whitney U test for ordinal and non-parametric variables. Correlation analysis was performed using Pearson's correlation test. The threshold level for statistical significance was established at a P ≤ 0.05.

Results

There were 12 women and 8 men in the OSAS group, and 10 women and 8 men constituted the control group (P = 0.999). The mean age of the patients with OSAS was calculated as 52.6 ± 8.0 (range, 37–67) years, and the mean age of healthy controls was 48.6 ± 8.2 (range, 38–65) years (P = 0.126). The level of education was also similar between the OSAS and control groups (8.9 ± 4.7 vs. 9.5 ± 3.9 years, respectively, P = 0.799). The mean disease duration in patients with OSAS was 10.1 ± 12.1 years. Patients with OSAS had a mean respiratory disturbance index of 48.1 ± 22.8 (range, 20–98)/h, associated with the lowest oxygen saturation of 77.3% ± 10.9% (range, 55%–92%).

A comparison of NCSs between the two groups showed that motor amplitudes of the ulnar nerve (P = 0.015) and sensory amplitudes of the sural nerve (P = 0.026) were significantly smaller in the OSAS group than those in controls. Motor amplitudes of the posterior tibial nerve were also smaller in the OSAS group, but this difference did not reach a statistically significant level (P = 0.067). Other parameters of motor and sensory NCSs in the upper and lower extremities in the two groups are given in [Table 1]. No significant correlation was found with smaller amplitudes or relevant nerves and demographic or polysomnographic data, including oxygen desaturation.

Table 1: Motor and sensory nerve conduction studies in the upper and lower extremities in patients with obstructive sleep apnea syndrome and healthy controls

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SEP studies showed that the mean P37 latencies of the posterior tibial nerve were 40.81 ± 3.8 ms in the OSAS group and 38.14 ± 2.82 ms in the control group (P = 0.050). Other parameters obtained in SEP studies were found similar between the two groups [Table 2]. In VEP studies, P100 amplitudes were 7.11 ± 2.73 μV in the OSAS group and 9.75 ± 3.52 μV in the control group (P = 0.022). Other VEP parameters were similar between the two groups and are given in [Table 2]. All BAEP responses resulted as similar between the groups [Table 2]. In the correlation analysis, the amplitudes of P100 responses were positively correlated with the lowest oxygen saturation (P = 0.026), whereas other parameters of evoked potentials failed to show a significant correlation.

Table 2: Evoked potential studies in obstructive sleep apnea syndrome and control groups

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In BR responses, latency, duration, and amplitudes of R1, R2, R2c, and recovery of the R2 response showed no significant difference between the patients with OSAS and healthy controls [Table 3] and [Figure 1]. Regarding TMS recordings, the mean latency and amplitude of the cortical and cervical MEP responses and ratio of amplitudes of MEPs and CMAPs failed to show a significant difference between the two groups [Table 4]. The central silent period, active and resting motor thresholds, as well as CCT-S and CCT-F were similar in patients with OSAS and controls [Table 4].

Table 3: Blink reflex responses in patients with obstructive sleep apnea syndrome and healthy controls

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Figure 1: Comparison of blink reflex recovery in the OSAS and control groups. Each bar represents the percentage of recovery in amplitudes of R2 responses in paired stimulation, which are given in 100 ms, 300 ms, and 500 ms ISIs

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Table 4: Responses obtained upon transcranial magnetic stimulation

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During electrophysiologic studies, the digit-span test was applied to all participants. Scores for counting forward were 5.26 ± 1.36 points in patients with OSAS and 5.47 ± 1.77 points in healthy controls (P = 0.851). Scores for counting backward were 4.73 ± 1.14 points vs. 4.35 ± 1.22 points in the OSAS and control groups, respectively (P = 0.219). The total scores were calculated as 10 ± 2.21 points in the OSAS group and 9.82 ± 2.45 points in controls (P = 0.684).

Discussion

As one of the major findings of our study, we found that both CMAP and SNAP amplitudes in both upper and lower extremities were clearly reduced in patients with OSAS. In VEP examinations, decreasing VEP amplitudes showed axonal loss, and the prolongation in VEP latencies demonstrated demyelination. These results confirmed the presence of generalized axonal involvement in OSAS, which was reported in only one study in the literature.^[6] The exact pathophysiologic mechanism of peripheral nerve damage in OSAS remains unexplained. OSAS was shown to be independently associated with diabetic peripheral neuropathy, and the severity of peripheral neuropathy showed a significant correlation with the severity of OSAS and nocturnal hypoxemia.^[11] Furthermore, increased levels of oxidative stress markers such as nitrotyrosine and lipid peroxide were reported in OSA in correlation with severity of hypoxemia. Intermittent hypoxemia leads to vasoconstriction and increased oxidative stress resulting in endothelial dysfunction and microvascular impairment.^[12] Alterations in peripheral nerves under chronic hypoxia were found similar to those observed in ischemic conditions secondary to damage in the vasa nervorum, and mainly, axonal type of damage was noted.^[13] Accordingly, chronic intermittent hypoxemia was proposed as the potential mechanism underlying axonal neuropathy in patients with OSAS. Nevertheless, the correlation analysis in our study failed to show a significant correlation between the lowest oxygen saturation level and decreased CMAP and SNAP amplitudes.

The second major finding of our study was the significantly lower amplitudes of P100 waves in VEP studies in patients with OSAS compared with those in controls. Furthermore, the lowest oxygen saturation levels showed a positive correlation with the amplitudes of P100 response. A significant latency delay coupled with a significant amplitude reduction of P100 wave of VEP was previously demonstrated in patients with OSAS and was interpreted to be related with optic nerve dysfunction provoked by recurrent nocturnal hypoxia in OSAS.^[14] Other different types of ocular pathologies have also been related to OSAS, including NAION, retinal vein occlusion, or corneal changes.^[15] In somatosensorial evoked-potential studies, we demonstrated that the mean P37 latency of the posterior tibial nerve was prolonged in patients with OSAS relative to healthy controls, though SEP responses were still within normal ranges.

We observed no significant changes in BAEP responses in our patients with OSAS. On the other hand, prolongation of wave I, III, and V latencies in OSAS have been reported in the literature.^[16] It was suggested that prolongation of BAEP wave I latency indicated impairment in the cochlear nerve, and increased latencies of wave III and wave V represented damage to the superior olivary nucleus and inferior colliculus. The authors have concluded that because patients with OSAS have a high prevalence of silent brain lesions related to chronic intermittent hypoxia, these changes in BAEP responses might be a sign of these silent brain lesions. Nevertheless, this hypothesis was not supported in subsequent studies, neither in our BAEP studies.

To the authors' knowledge, there is no other study in the literature investigating BR changes related to OSAS. In our study, we also studied BR responses; however, latency, duration, and amplitudes of R1, R2, R2c, and recovery of R2 responses showed no significant difference between patients with OSAS and healthy controls.

Finally, we performed TMS in all patients with OSAS and healthy controls. The evaluation of MEP responses showed that the mean latency and amplitude of cortical and cervical MEP responses and ratio of amplitudes of MEPs and CMAPs were all within normal ranges in patients with OSAS. In addition, the central silent period, active and resting motor thresholds, as well as CCT-S and CCT-F were found within normal limits. In two studies in the literature, it was reported that TMS responses revealed reduced corticospinal excitability and increased intracortical inhibition in patients with OSAS.^[7],[8] The authors reported that these changes in cortical excitability were more pronounced in patients with severe OSAS and were related to sleep fragmentation and hypoxia. Our results did not support these findings, which should be confirmed in larger studies.

Among the limitations of our study, our study sample was unfortunately too small to make certain conclusions. Exclusion of any other disease that may interpret our results made us study a very small but homogenous group. As another limitation, disease duration, an important factor in peripheral nerve damage, was not known, as well as in most present studies. However, this is not really possible due to the nature of sleep-disordered breathing in which patients would have a disease for a prolonged period of time before seeking medical assistance. Finally, we plan to re-evaluate our findings following the appropriate treatment of OSAS as a prospective study with a larger number of participants.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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