Quantitative Sensory Testing in the Oropharynx

CHEST

Original Research SLEEP MEDICINE

Quantitative Sensory Testing in the Oropharynx A Means of Showing Nervous Lesions in Patients With Obstructive Sleep Apnea and Snoring Louise Hagander, MD, PhD; Richard Harlid, MD; and Eva Svanborg, MD, PhD

Background: It is not fully understood why habitual snoring frequently progresses to obstructive sleep apnea syndrome (OSAS). Vibrations per se may cause peripheral nerve lesions. Therefore, snoring vibrations could cause nervous lesions, leading to impaired reflex activation of dilating muscles at inspiration. In this study, the methodology for quantitative sensory testing in the oropharynx was developed, and the presence of sensory nerve lesions in patients with OSAS and snoring was evaluated. Methods: Vibration detection thresholds (VDTs) and/or cold detection thresholds (CDTs) were tested at the tonsillar pillars, tongue, lip, and finger in 23 nonsnoring individuals, 13 habitual snorers (apnea-hypopnea index [AHI] < 10), and 31 patients with OSAS (AHI > 20). Results: At tonsillar pillars, there were significant gender differences in both VDT and CDT, with women having lower thresholds. VDT showed no significant differences between any of the three groups when men only were tested. Two nonsnoring control subjects could not detect vibrations at all. When both genders were tested, there was significant difference only between nonsnorers and patients with OSAS (p ⴝ 0.003). CDT showed significant differences between nonsnorers and snorers (p ⴝ 0.001) and also between nonsnorers and patients with OSAS (p < 0.001), but not between snorers and patients with OSAS. CDT was easier to test than VDT with low variability in nonsnorers. Conclusions: CDT gave more discriminative results than VDT. Signs of sensory nervous lesions were present in the oropharynx of most patients with OSAS and some snorers, supporting the hypothesis of a progressive oropharyngeal nervous lesion. CDT testing could be a useful clinical method to evaluate the degree of oropharyngeal nervous lesions in patients who snore and in those with OSAS. (CHEST 2009; 136:481– 489) Abbreviations: AHI ⫽ apnea-hypopnea index; CDT ⫽ cold detection threshold; CI ⫽ confidence interval; OSA ⫽ obstructive sleep apnea; OSAS ⫽ obstructive sleep apnea syndrome; QST ⫽ quantitative sensory testing; VDT ⫽ vibration detection threshold

obstructive sleep apnea (OSA), the upper D uring airway dilating muscle activity is insufficient to overcome the negative inspiratory pressure. Sensory nervous lesions, causing impaired reflexes, could give Manuscript received November 20, 2008; revision accepted April 20, 2009. Affiliations: From the Department of Clinical Neurophysiology (Dr. Hagander), Karolinska Hospital, Stockholm, Sweden; Fysiologlab in Stockholm (Dr. Harlid), Stockholm, Sweden; and the Department of Clinical Neurophysiology (Dr. Svanborg), University Hospital, Linko¨ping, Sweden. Funding/Support: This study was supported by grants from the Swedish Society of Medicine, the Swedish Heart and Lung Fund, the Swedish Sleep Research Society, and the research funds of Karolinska Institute. www.chestjournal.org

rise to such upper airway collapse. Some previous studies have demonstrated signs of sensory impairment in patients with OSA syndrome (OSAS). Reduced sensibility regarding thermal stimuli,1 vibration,2 and two-point discrimination has been reported,3 as well as impaired mucosal sensory function at multiple upper airway sites.4 © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Eva Svanborg, MD, PhD, Department of Clinical Neurophysiology, University Hospital, 58223 Linko¨ping, Sweden; e-mail: [email protected] DOI: 10.1378/chest.08-2747 CHEST / 136 / 2 / AUGUST, 2009

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Table 1—Subject Characteristics Gender, No. Groups

Subjects, No.

Female

Male

Age, yr

Body Mass Index

AHI

Years Snoring

Control subjects Snorers OSAS patients

23 13 31

15 3 4

8 10 27

39 (15–64) 51 (27–81) 52 (23–72)

23 (18–32) 28 (24–34) 30 (23–47)

4 (2–9) 7 (2–10) 37 (20–69)

0 8 (0–20) 14 (1–20)

Values are given as the mean (maximum-minimum), unless otherwise indicated. For “Years Snoring,” 20 years is the maximum estimated time if the patient reported that snoring had been present since youth.

OSAS/rhoncopathia is in many cases a progressive disorder.5 The reason for this development is not fully understood. In many cases, there is a correlation between the impairment of obstructive respiration and weight increase, but not always. In one study,6 there was no certain correlation between increases in apnea-hypopnea index (AHI) and body weight, and in another study,7 marked worsening of obstructive breathing was found in some patients despite weight loss. Some other factor could, therefore, also be responsible for disease progression. A majority of patients have reported8 that they have been habitual snorers for years before apneas become apparent. Snoring implies vibrations of the tissues that produce the sound. It is well known from occupational medicine that long-term use of handheld vibrating tools may induce local peripheral nerve lesions in the hands.9 We, therefore, hypothesize that snoring-induced vibration may cause local peripheral nerve lesions in the oropharynx, contributing to OSA development. Quantitative sensory testing (QST), evaluating vibration detection thresholds (VDTs) as well as thermal thresholds, is increasingly used in clinical routine and research for the assessment of peripheral neuropathies. The VDT evaluates the function of large myelinated sensory neurons, and thermal thresholds evaluate the function of thin myelinated and unmyelinated fibers. Under standardized conditions, QST in the extremities is reliable and reproducible.10 –12 Impaired vibration and thermal thresholds may be an early sign of subclinical or mild peripheral neuropathy.13 Impaired vibration and thermal thresholds may, therefore, be early signs of subclinical OSAS (ie, snoring without significant apneas). Our aims for this study were to develop methods for QST of thermal and vibration sensitivity in the oropharynx, and to use this to compare oropharyngeal sensitivity in patients with OSAS, habitual snorers, and nonsnoring subjects.

characteristics are summarized in Table 1. The exclusion criteria were as follows: previous treatment for OSAS or snoring; neurologic illness or medical condition that might cause peripheral neuropathy; smoking; previous upper airway surgery; and recent upper respiratory tract infection. All patients were referred because of habitual snoring and suspicion of OSAS. The patients and the nonsnoring control subjects underwent whole-night sleep respiratory recordings including respiratory movements, airflow, snoring, body position, and pulse oximetry (Embletta; ResMed; Trollhättan, Sweden) the night before sensory testing. The QST investigator (L.H.) was unaware of the results of these recordings. OSA diagnosis was defined as an AHI ⱖ 20 events per hour. Habitual snorers were included if their AHI was ⬍ 10 and if they snored during ⬎ 50% of their estimated sleeping time. Control subjects were included if sleep respiratory recordings showed ⬍ 20% snoring time and an AHI ⬍ 5 events per hour, and if cohabiting persons denied habitual snoring. All patients estimated the number of years that they had snored habitually before testing (Table 1). VDTs were examined on both anterior tonsillar pillars, on the lower lip, and over the index finger pulp of the nondominant hand. A tool (Vibrameter Type IV; Somedic Inc; Sollentuna, Sweden) producing 100-Hz vibrations was used, with a custommade intraoral probe, consisting of a 10-cm long vibrating pin with a stimulating surface area of 6 mm2 in diameter (Fig 1). When testing the lower lip or the pharyngeal mucosa, a constant application pressure was visually ensured by the investigator. VDT was determined by the method of limits.10 The stimulus intensity was increased from zero to the point where vibration was first detected. Five stimuli were given at each site, and the mean was calculated as the threshold. If vibrations were not perceived, a value of 70 ␮m was used for the statistical analysis.

Materials and Methods Thirty-one patients with OSAS, 13 habitual snorers, and 23 nonsnoring control subjects were included in the study. Subject

Figure 1. The tool used for VDT testing with a custom-made intraoral probe.

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Original Research

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Oropharyngeal Testing

Figure 2. The intraoral probe for CDT testing.

Thermal thresholds were measured by using a thermal sensory analyzer (Medoc 2000 TSA; Medoc Inc; Ramat Yishai, Israel) with a custom-made intraoral probe (Fig 2) having a circular stimulating surface diameter of 9 mm2. A constant application pressure was visually ensured by the investigator. Cold detection thresholds (CDTs) and warm detection thresholds were tested separately on both anterior tonsillar pillars, on the tip of the tongue, and on the lower lip. Thermal thresholds were determined by the method of levels.10 The starting (adaptation) temperature was 32°C when testing the lower lip, 34°C at the tip of the tongue, and 36°C at the tonsillar pillars. The rate of temperature change was 1°C/s in all thermal tests. The first search step was 3°C and the final search step was 0.1°C. Random dummy stimuli were used. Thermal thresholds were expressed as the calculated difference between detection temperature and adaptation temperature. If no sensation of cold was perceived, a temperature of 15°C was used for the statistical analysis. Statistical Analysis The Mann-Whitney U test was used for the statistical comparison analysis among the three subject groups. Average values of the thresholds from both tonsillar pillars were used for each subject. Statistical significance was set at p ⬍ 0.05. Regression analysis was performed to compare the matched data. Ethical consent to conduct the study was given by the ethics committees at Karolinska Institute, Stockholm, and the Linko¨ping University Hospital. All patients and control subjects gave informed consent.

Results Extraoropharyngeal Testing The mean vibration threshold at the lip was 3.5 ␮m (range, 0.4 to 9.6 ␮m; 95% confidence interval [CI], 2.3 to 4.7 ␮m), and at the index finger it was 1.3 ␮m (range, 0.5 to 7.4 ␮m; 95% CI, 0.6 to 2.0 ␮m). CDTs were expressed as the difference between the threshold and the adaptation temperature. The mean CDT at the tip of the tongue was 1.2°C (range, 0.4 to 3.0°C; 95% CI, 1.0 to 1.6°C), and at the lower lip it was 0.6°C (range, 0.1 to 1.2°C; 95% CI, 0.5 to 0.8°C). There were no significant group differences at any of these sites. www.chestjournal.org

Warmth detection testing was not performed in any patient, since seven consecutive healthy subjects did not experience the sensation of warmth at the tonsillar pillars, despite testing at the maximal temperature level (50°C). One healthy subject and two patients with OSAS could not go through with any of the tests in the upper airway because of strong gag reflexes. VDT was not possible in one additional patient with OSAS due to a large tongue. Due to technical reasons, CDT could not be performed in 4 subjects, nor could VDT be performed in 10 subjects (ie, 16 nonsnorers underwent both tests and another 3 patients underwent either CDT or VDT only). Eleven snorers underwent both tests, and another two snorers underwent CDT only. Twenty-two patients with OSAS underwent both tests; another five patients underwent CDT only, and one patient underwent VDT only. There were gender differences in VDT and CDT at the tonsillar pillars. Such differences were not found in the other tested sites. Both oropharyngeal VDT and CDT were significantly higher in nonsnoring men compared with nonsnoring women (p ⫽ 0.006 and p ⫽ 0.02, respectively) [Fig 3]. All women except one were premenopausal. There were no significant age differences (mean age for women, 42 years; mean age for men, 36 years). The results of VDT testing at the tonsillar pillars for both men and women in all groups are given in Figure 4, A. VDT differed significantly between nonsnoring subjects and patients with OSAS (p ⫽ 0.003), but not between nonsnoring subjects and snorers or between snorers and patients with OSAS. However, there was a larger percentage of women in the control group than in the other two groups. When the results for men only were compared, there were no significant differences in VDT among any of the groups (Fig 4, B). The variability in the control group especially was large; two nonsnoring men did not experience any sense of vibration at all, despite maximal output of the equipment. Neither did one snorer and two patients with OSAS. Altogether 5 of 19 nonsnorers (26%), 7 of 11 snorers (64%) and 20 of 23 patients with OSAS (87%) had VDT values exceeding the upper 75th percentile (⬎ 15.8 ␮m) for nonsnoring subjects. CDT showed a low variability among the nonsnoring control subjects. None of the patients had a threshold for cold sensation below 31.8°C. CDT differed significantly between nonsnoring control subjects and patients with OSAS (p ⬍ 0.001), and also between nonsnoring subjects and habitual snorers (p ⫽ 0.001) [Fig 5, A]. There was no significant difference between snorers and patients with OSAS. Six patients with OSAS and one CHEST / 136 / 2 / AUGUST, 2009

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A Oropharyngeal VDT in non-snoring women and men p=0.006 80 70 60

VDT

50 40 30 20 10 Median 25%-75% Non-Outlier Min-Max

0 1

2

Women

Men

B Oropharyngeal CDT in non-snoring women and men p=0.02 4,0 3,5

Cold thresholds

3,0 2,5 2,0 1,5 1,0 0,5 0,0 1

Women

2

Median 25%-75% Min-Max

Men

Figure 3. A: gender difference in VDTs at tonsillar pillars. B: gender difference in CDTs at tonsillar pillars.

snorer did not perceive cold at the lowest tested temperature (15°C). When men only were examined, almost the same results were obtained (Fig 5, B). The significance for difference between control subjects and snorers was p ⫽ 0.005, and be-

tween control subjects and OSAS patients it was p ⫽ 0.001. There was no significant difference between snorers and patients with OSAS (Fig 5, B). Five of 9 snorers and 19 of 28 patients with OSAS had values exceeding maximum threshold

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A

Oropharyngeal VDT 80 70 60 50

VDT

40 30 20 10 0 -10 1

OSAS

B

2

Snorers

3

Median 25%-75% Min-Max

Controls

Oropharyngeal VDT in men only 80

Vibration thresholds, micrometer

70

60

50

40

30

20

10

0 1

OSAS

2

Snorers

3

Median 25%-75% Min-Max

Controls

Figure 4. A: VDTs at tonsillar pillars; comparison between patients with OSAS, habitual snorers, and nonsnoring control subjects. B: VDTs at tonsillar pillars in men only; comparison among patients with OSAS, habitual snorers, and nonsnoring control subjects.

values for nonsnoring control subjects. Six patients with OSAS and one snorer did not perceive the sensation of cold at the lowest tested temperature (15°C). There was no significant correlation between the degree of sensory impairment in terms of CDT or www.chestjournal.org

VDT vs the measures of apnea severity. Neither were there any correlations between CDT and VDT and the number of snoring-years, as reported by the patients, or VDT and CDT vs age in nonsnoring subjects. CHEST / 136 / 2 / AUGUST, 2009

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A

Oropharyngeal Cold Detection Thresholds 16

14

12

CDT Centigrades

10

8

6

4

2

0 1

OSAS

B

2

Snorers

3

Median 25%-75% Min-Max

Controls

Oropharyngeal CDT in men only 16

14

CDT, centigrades

12

10

8

6

4

2

0 1

OSAS

2

Snorers

3

Median 25%-75% Min-Max

Controls

Figure 5. A: CDTs at tonsillar pillars; comparison among patients with OSAS, habitual snorers, and healthy nonsnoring subjects. B: CDTs at tonsillar pillars in men only; comparison among patients with OSAS, habitual snorers, and healthy nonsnoring subjects.

Discussion A new finding in this study was the gender difference in oropharyngeal sensitivity, with significantly higher thresholds for sensations of both vibration

and cold in nonsnoring men. Gender differences were not found in any other tested site, which is in agreement with the findings of previous studies.14,15 One reason for our finding could be that healthy

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men are more likely to snore occasionally than healthy women. Also, greater intrathoracic negative inspiratory pressures usually develop in men than in women during sleep, which may harm their receptor structures. On the other hand, lower oropharyngeal sensitivity in men might be one explanation for why they are more prone to snoring than women. There was significantly reduced oropharyngeal sensitivity for both vibration and cold in patients with OSAS compared with the nonsnoring subjects, but not concerning vibration when men only were tested. In snorers, such a difference was present for cold but not vibration. The snorers showed less pathology in all tests, however, with greater variability. One reason for test results deviating from those of the control subjects in the snorers group could be that some of them actually experienced sleep apnea. In mild cases, the night-to-night variability can be considerable, and we only have data from one night of sleep respiratory recording. There were no statistically significant differences between snorers and patients with OSAS in VDT or CDT, but there was a trend, as seen in Figures 4 and 5. In most patients with OSAS, there was a good concordance between VDT and CDT. However, in habitual snorers, most subjects had discordant results. CDT was more commonly affected in those who underwent one pathologic test, both concerning patients with OSAS and snorers. Thus, CDT gave more discriminative results. Our findings regarding the sensory function in the oropharynx confirm the results of previous studies. Kimoff et al2 measured vibratory sensation and two-point discrimination at the tonsillar pillars and found significantly increased thresholds in patients with OSAS and snorers vs nonsnoring control subjects. Guilleminault et al3 reported reduced sensitivity to two-point discrimination in the upper airways in patients with OSAS and snorers compared with nonsnoring individuals, but there were no significant differences between patients with upper airway resistance syndrome (who may or may not snore) and nonsnoring control subjects.3,16 Nguyen et al4 reported reduced sensitivity to the touch of air pulses at different sites in airways. The “air-jet” technique has the advantage over the techniques we employed in that it may be applied to a much wider area in the upper and lower airways; but, it cannot discriminate between different sensory modalities, since it will stimulate pressure, cold, and touch receptors. Larsson et al1 tested oropharyngeal thresholds for warmth and cold in patients with OSAS and nonsnoring control subjects, and found significant differences. Most tested subjects experienced the sensation of warmth at the anterior tonsillar pillar. In the www.chestjournal.org

present study, no nonsnoring subject experienced warmth at this site despite testing at 50°C. The reasons for this discrepancy could be different probe size, type of equipment, or testing algorithm. Larsson et al1 employed custom made equipment with a smaller probe. Testing was performed according to the Marstock method,17 with alternating cold and warm stimuli. In the present study, the method of levels10 was employed, in which testing of cold and warmth was done separately. The Marstock method has been criticized, since cooling will influence the ensuing warm perception and vice versa.18 CDT and especially VDT were much higher at the tonsillar pillars than at any other site. Variability was much greater for VDT than for CDT in the nonsnoring group. Two control subjects did not experience vibration at this site at all. Some control subjects and patients had difficulties in defining the sensation as vibration; more like touch, pressure, or pain. In clinical routine, VDT is usually performed with application of the probe against skin closely overlying bone. If application is made against soft tissue, the thresholds will be higher and the sensation will have a different quality.19 Therefore, VDT is a less suitable test method in the soft palate. VDTs in the extremities are increased with age,20 while this is not as pronounced concerning CDT.14,21,22 Fowler et al23 found no effect of age on CDT in the face. In the present study, there were no age-related changes concerning either CDT or VDT in the nonsnoring control subjects. However, it cannot be ruled out that this was due to the small number of investigated subjects in different age groups. The findings in the present study support the previously formed hypothesis24 that the inability of the dilating upper airway muscles to maintain airway patency during sleep is due to peripheral nerve lesions, causing partial paresis and/or impaired dilating reflexes at inspiration, worsening over time. Snoring vibrations, repeated every night for several years, might cause progressive, local nervous lesions in the oropharynx as part of the pathogenesis of OSAS. In the present study, there were no signs of impaired sensitivity in any other location than the tonsillar pillars in the patient groups. The habitual snorers showed less pronounced pathology in both VDT and CDT than the patients with OSAS. However, there was no significant correlation between the degrees of sensory impairment vs the measures of apnea severity. An exposure-effect relationship for vibrationinduced neuropathy has been shown in humans.25 In animals, it has been shown26 that both unmyelinated and myelinated fibers in the hind leg are damaged after vibration exposure. Another possible reason for impaired oropharyngeal sensitivity could be excesCHEST / 136 / 2 / AUGUST, 2009

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sive pharyngeal pressure swings and violent muscle contractions against the occluded airway, causing inflammation and edema. Inflammatory cell infiltration has been found in the mucosa as well as the musculature of the upper airways in patients with OSAS.27–30 However, it has been demonstrated by Puig et al31 that vibration per se, simulating snoring, of the bronchial epithelial cells triggers inflammation, which is seen as a release of interleukin-8. There are also data indicating a local motor neuropathy in the oropharynx. Muscle biopsy studies27,28,32 of pharyngeal muscles have shown signs of denervation in patients with OSAS. Friberg et al33 found indications of progressive nervous lesions in histologic studies of palatopharyngeus muscles from heavy snorers and patients with OSAS. In occupational medicine, the avoidance of further vibration exposure is a critical part of treatment due to the dose-response relationship of vibration exposure and local neuropathy.34 In the study by Lundborg et al,26 the neuronal changes were reversible after 4 weeks without vibration exposure. We speculate that the early treatment of snoring in predisposed individuals could prevent OSAS. The elevated sensory thresholds in some snorers probably indicate an early sensory nervous lesion, and these patients may, therefore, be especially at risk for the development of OSAS. If this is the case, oropharyngeal CDT testing might, in the future, become a clinical routine test to find those snorers in whom active treatment is warranted.

Acknowledgments Author contributions: Dr. Hagander performed all the quantitative sensory tests and participated in the writing of the article. Dr. Harlid recruited most of the patients and participated in the writing of the article. Dr. Svanborg was the scientific mentor of Dr. Hagander, performed the statistical analysis, and participated in the writing of the article. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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26 Lundborg G, Dahlin LB, Hansson HA, et al. Vibration exposure and peripheral nerve fiber damage. J Hand Surg Am 1990; 15:346 –351 27 Boyd JH, Petrof BJ, Hamid Q, et al. Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:541–546 28 Lindman R, Stal PS. Abnormal palatopharyngeal muscle morphology in sleep-disordered breathing. J Neurol Sci 2002; 195:11–23 29 Carpagnano GE, Kharitonov SA, Resta O, et al. 8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest 2003; 124:1386 –1392 30 Paulsen FP, Steven P, Tsokos M, et al. Upper airway

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