Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 2001 Oct 1;536(Pt 1):237–249. doi: 10.1111/j.1469-7793.2001.t01-1-00237.x

Pathogenesis of laryngeal narrowing in patients with multiple system atrophy

Shiroh Isono *, Keisuke Shiba †, Mika Yamaguchi ‡, Atsuko Tanaka *, Takamichi Hattori ‡, Akiyoshi Konno †, Takashi Nishino *
PMCID: PMC2278858  PMID: 11579172

Abstract

  1. We do not fully understand the pathogenesis of nocturnal laryngeal stridor in patients with multiple system atrophy (MSA). Recent studies suggest that inspiratory thyroarytenoid (TA) muscle activation has a role in the development of the stridor.

  2. The breathing pattern and firing timing of TA muscle activation were determined in ten MSA patients, anaesthetized with propofol and breathing through the laryngeal mask airway, while the behaviour of the laryngeal aperture was being observed endoscopically.

  3. Two distinct breathing patterns, i.e. no inspiratory flow limitation (no-IFL) and IFL, were identified during the measurements. During IFL, significant laryngeal narrowing was observed leading to an increase in laryngeal resistance and end-tidal carbon dioxide concentration. Development of IFL was significantly associated with the presence of phasic inspiratory activation of TA muscle. Application of continuous positive airway pressure suppressed the TA muscle activation.

  4. The results indicate that contraction of laryngeal adductors during inspiration narrows the larynx leading to development of inspiratory flow limitation accompanied by stridor in patients with MSA under general anaesthesia.

Patients with multiple system atrophy (MSA) including Shy-Drager syndrome (SDS) olivopontocerebellar atrophy (OPCA) and striatonigral degeneration (SND), are frequently known to develop nocturnal laryngeal stridor during the disease process (McNicholas et al. 1983; Isozaki et al. 1996; Sadaoka et al. 1996). A strong association between the stridor and nocturnal sudden death is speculated, and tracheostomy or nasal continuous positive airway pressure (nasal CPAP) are recommended as treatments (Williams et al. 1979; Kavey et al. 1989; Munschauer et al. 1990). Paralysis of the posterior cricoarytenoid muscle (PCA), a vocal cord abductor, due to degeneration of the nucleus ambiguus had been generally believed to cause passive laryngeal narrowing producing the inspiratory stridor (Lapresle et al. 1979; Guindi et al. 1981; Hayashi et al. 1997). Recently, injection of botulinum toxin into the thyroarytenoid muscle (TA) (a laryngeal adductor muscle) was demonstrated to abolish the stridor in MSA patients (Marion et al. 1992). Furthermore, Isozaki et al. (1994) measured TA muscle activity during diazepam-induced sleep in two MSA patients, and found augmented activation of the TA muscle during inspiration although they did not evaluate the relationship between the firing pattern of the vocal cord adductor and the pattern of breathing in detail. Based on this evidence, we hypothesized that patients with MSA develop inspiratory stridor in association with active glottal narrowing due to contraction of the vocal cord adductor muscles during inspiration. We tested the hypothesis under general anaesthesia during which we had an opportunity to place electromyogram (EMG) wires into the intra-laryngeal muscles without causing patient discomfort. Another purpose of this study was to evaluate the effects of continuous positive airway pressure (CPAP) on glottal narrowing and TA muscle activity. Accordingly, we assessed the discharge pattern of the TA muscle and the concomitant breathing pattern while observing the behaviour of the laryngeal aperture in ten anaesthetized MSA patients. The validity of testing the hypothesis under general anaesthesia was confirmed by measuring TA muscle activity during natural sleep at night immediately after recovery from anaesthesia in four patients.

METHODS

Patients

Ten MSA patients who have been followed by the Department of Neurology of Chiba University Hospital and whose family witnessed the presence of stridor during sleep were invited to participate in this study. Table 1 lists the anthropometric and clinical characteristics of each patient. They were middle-aged and non-obese persons. Diagnosis of MSA and categorization of the diseases were performed based on clinical symptoms according to the consensus statement by the American Autonomic Society and the American Academy of Neurology (Neurology, 1996). Sub-types of the MSA were determined by the predominance of the clinical symptoms for each patient.

Table 1.

Anthropometric and clinical characteristics of each patient

Patient Age (sex) (years) Height (m) Weight (kg) Sub-type Age at MSA onset (years) Age at stridor onset (years) Predominant symptom Accompanied major symptoms
1 50 (m) 1.62 52 SDS 47 49 OH UD, ataxia
2 62 (m) 1.56 56.6 OPCA 58 60 ataxia UD
3 57 (m) 1.70 72 OPCA 48 57 ataxia UD
4 62 (f) 1.48 41 SDS 59 60 UD, OH ataxia
5 57 ((f) 1.47 48 SND 53 53 PA ataxia
6 66 (m) 1.59 56.6 SND 62 63 PA UD, ataxia
7 64 (m) 1.63 63 OPCA 55 62 ataxia impotence, OH
8 59 (f) 1.44 49.8 OPCA 53 53 ataxia UD
9 64 (m) 1.64 64 SND 61 64 PA UA, ataxia
10 68 (m) 1.57 55.2 OPCA 66 66 ataxia UD, OH
Open in a new tab

m, male; f, female; MSA, multiple system atrophy; SDS, Shy-Drager syndrome; OPCA, olivopontocerebellar atrophy; SND, substantia nigra degeneration; OH, orthostatic hypotension; UD, urinary disturbance; PA, Parkinsonism.

The aim of the study and the potential risks were fully explained to each patient and informed written consent was obtained from each. The study protocol was approved by the hospital ethics committee and was performed in accordance with the Declaration of Helsinki.

Preparation of the subject

All patients were premedicated with 0.5 mg atropine given intramuscularly 30 min before anaesthesia. Anaesthesia was induced with a bolus injection of 1.5 mg kg−1 propofol and maintained with a continuous infusion of propofol at a rate of 5–10 mg kg−1 h−1. After induction of anaesthesia, intravenous administration of succinylcholine (1 mg kg−1) facilitated the insertion of a thin polyethylene catheter with a side hole (6 French diameter catheter, ATOM, Tokyo, Japan) through the vocal cords into the trachea. Placement of a laryngeal mask airway (LMA) provided an opportunity to endoscopically observe laryngeal behaviour and to directly measure the laryngeal resistance in the absence of the pharyngeal narrowing which usually occurs in unconscious subjects (Fig. 1). Lateral pressure of the trachea (Ptr) was measured by connecting the catheter to a pressure transducer (23NB 005G; Icsensors, Silicon Valley, CA, USA). The distal end of the LMA was connected to an elbow connector and then to a semiclosed anaesthetic breathing circuit through which 100 % oxygen was delivered at a rate of 6 l min−1. A fibre optic endoscope (FB-10X; Pentax, Tokyo, Japan) was passed through a self-sealing diaphragm of the elbow connector down to the end of the LMA to visualize the laryngeal aperture. Laryngeal images were recorded with a video recording system (ETV9X; Nisco, Saitama, Japan). Ventilatory airflow was measured using a Fleisch no. 2 pneumotachograph (4719, Hans Rudolph Inc., Kansas, Missouri) and a differential pressure transducer (TP-603T; Nihon Koden, Tokyo, Japan). Mask airway pressure (Pm) was measured continuously using a pressure transducer (23NB 005G; ICsensors). End-tidal carbon dioxide tension (PET,CO2) was measured continuously using a sidestream capnometer (CAPNOX CX-1; Nippon Colin, Aichi, Japan). The respiratory variables were recorded on an eight-channel thermal array recorder (WS 682G; Nihon Koden, Tokyo, Japan) and stored simultaneously in a computer. The laryngeal resistance at peak inspiratory effort was calculated by dividing the pressure difference between Pm and Ptr by the airflow. In addition to arterial oxygen saturation (Sa,O2) measurement, electrocardiogram and blood pressure were continuously monitored during the experiment.

Figure 1. Experimental settings under general anaesthesia, and a laryngeal mask airway.

Figure 1

Open in a new tab

Pm, mask pressure; Ptr, tracheal pressure; PET,CO2, partial pressure of end-tidal CO2; EMG-TA, electromyogram of the thyroarytenoid muscle; VCR, video recording system. a, cuff; b, grille for the larynx; c, airway tube; d, inflating tube.

EMG recordings

EMG of the TA muscle, a vocal cord adductor, was measured by a pair of intramuscular hooked wire electrodes as previously described by Kuna et al. (1990). A 25-gauge needle with a pair of fine platinum wires was inserted through the cricothyroid membrane and the needle was immediately removed leaving the platinum wires placed in the TA muscle. Correct placement of the intramuscular electrodes was confirmed by endoscopic observation of the tip of the needle during the insertion, and was further confirmed during the experiment by the presence of a burst of activity during laryngospasm induced by laryngeal stimulation with distilled water.

A pair of wire electrodes was endoscopically placed in the PCA muscle the vocal cord abductor, in four patients in accordance with a technique introduced by Kuna et al. (1990). Intramuscular wire electrodes were placed in the middle pharyngeal constrictor (MPC) and the external oblique muscle in four patients. All EMG signals were amplified and filtered below 50 and above 3000 Hz (AG601, Nihon Koden, Tokyo, Japan), and were recorded on the eight-channel recorder.

Influence of a laryngeal stimulation on breathing pattern and TA muscle activity

Our preliminary experiments under general anaesthesia without measuring TA muscle activity in MSA patients indicated that injection of distilled water (0.5 ml) on the vocal cords distinctively altered breathing pattern immediately after airway protective-reflexive responses. The condition of inspiratory flow limitation (IFL), which is defined as cessation of progressive increase in the airflow despite progressive reduction of Ptr, was produced by injection of distilled water on the vocal cords and was maintained, while no-IFL, defined as the proportional increase in airflow to the Ptr change, was observed before the laryngeal stimulation during anaesthesia. We, therefore, compared patterns of EMG activity of the laryngeal muscles and laryngeal mechanics between no-IFL and IFL breaths. We analysed five stable no-IFL breaths before the laryngeal stimulation, and five stable IFL breaths between 5 and 10 min after the laryngeal stimulation for each patient. While the presence of IFL does not indicate development of stridor sound, development of the stridor was recognized as high-pitched audible sounds accompanied by vibration of the vocal cords during inspiration (Kakitsuba et al. 1997). The stridor sound was recorded with a video recording system together with the laryngeal images.

Influence of CPAP on breathing pattern and TA muscle activity

The effects of 10 cmH2O of CPAP on laryngeal resistance and TA muscle activity were assessed in six patients under anaesthesia. The breathing circuit was changed from the anaesthetic circuit to a CPAP system (BiPAP, Respironics, Murrysville, PA, USA), which allowed abrupt changes in airway pressure between 2 and 10 cmH2O. Oxygen at a flow rate of 10 l min−1 was added to the air delivered by the CPAP apparatus to maintain hyperoxaemia during the examination.

Sleep study

In order to compare the discharge patterns of the TA muscle between general anaesthesia and natural sleep, nocturnal recordings of TA muscle activity were performed in four patients after recovery from the anaesthesia (Table 3). In addition to the TA EMG measurement, the patients were monitored by electroencephalogram (EEG, C3/A1 or C4/A2), electro-oculogram (EOG) and submental EMG. Respiration was evaluated by measurement of nasal pressure in three of them, and by thoraco-abdominal wall movements in one patient. We evaluated the timing of the TA muscle activation during development of nocturnal stridor. The effect of nasal CPAP on the firing pattern of TA muscle was assessed in one patient during sleep.

Table 3.

Discharge pattern of various muscles

Patient TA, no-IFL TA, IFL PCA, no-IFL PCA, IFL MPC EOM TA, sleep
1 oc-I-P I-P n/a n/a n/a n/a NREM
2 no I-P n/a n/a n/a n/a n/a
3 n/a I-P n/a n/a n/a n/a n/a
4 n/a I-P n/a n/a n/a n/a n/a
5 no I-P n/a n/a n/a n/a n/a
6 n/a I-P n/a n/a n/a n/a n/a
7 no I-P I-P I-P oc-I-P oc-E-P NREM/REM
8 no I-P no oc-I-P oc-I-P oc-E-P NREM
9 oc-I-P I-P no no no oc-E-P NREM
10 no E-P, I-P I-P I-P no n/a n/a
Open in a new tab

TA, thyroarytenoid muscle; IFL, inspiratory flow limitation; PCA, posterior cricothyroid muscle; MPC, middle pharyngeal constrictor muscle; EOM, external oblique muscle; oc-I-P, occasionally inspiratory phasic pattern; I-P, inspiratory phasic pattern; E-P, expiratory phasic pattern; n/a, not available; no, no phasic activity; NREM, non-rapid eye movement sleep; REM, rapid eye movement sleep.

Statistical analysis

The data are presented as means ±s.d.P < 0.05 was considered to be statistically significant. Statistical analysis was performed by Student's paired t test to compare respiratory variables between IFL and no-IFL breaths, and those with and without nasal CPAP when the variables were normally distributed. Wilcoxon signed rank test was used when the normality test failed to show normal distribution of the data. Fisher's exact test evaluated the association between presence of the phasic inspiratory activity of the TA muscle and breathing patterns.

RESULTS

Nine patients showed no-IFL during spontaneous breathing immediately after induction of anaesthesia while one patient (patient 3) continued to present IFL with audible laryngeal stridor throughout the experiment. IFL breaths were produced by injection of distilled water (0.5 ml) onto the vocal cords in nine patients as demonstrated in Fig. 2. The laryngeal stimulation immediately caused apnoea with laryngeal closure accompanied by a burst of TA muscle activity. Five minutes after laryngeal stimulation, respiration was stabilized, and IFL developed. This was indicated by no increase in inspiratory airflow despite a progressive increase in inspiratory efforts which was detected by a Ptr swing. Notably, inspiratory-phasic (I-P) activity of the TA muscle was observed during IFL with no electrical activity of the PCA muscle present before or after the laryngeal stimulation. The steady-state condition of IFL was achieved after the laryngeal stimulation and continued thereafter except in patient 10 in whom IFL disappeared within 5 min after the laryngeal stimulation. Figure 3 demonstrates another example of the steady-state measurements (patient 7). I-P activity of the PCA muscle during IFL breaths was less than that during no-IFL breaths while I-P activity of the TA muscle was only observed during IFL breaths. A decrease in maximal flow rate with an increase in tracheal pressure fluctuation indicated increase in the laryngeal resistance. Development of IFL was accompanied by an increase in PET,CO2.

Figure 2. Typical example of changes in breathing pattern in response to laryngeal stimulation (patient 8).

Figure 2

Open in a new tab

Typical example of changes in breathing pattern in response to laryngeal stimulation (patient 8). Distilled water (0.5 ml) was injected on the vocal cords as indicated by arrow. Note immediate occurrence of apnoea with laryngeal closure accompanied by a burst of TA muscle. During steady-state breathing, 5 min after the stimulation, inspiratory flow limitation (IFL) was developed. Typical stridor sound was detected and significant laryngeal narrowing was endoscopically observed during IFL. Note phasic inspiratory activation of the TA muscle and phasic expiratory activation of the abdominal muscle. Pm, mask pressure; Ptr, tracheal pressure; PCA, posterior cricoarytenoid muscle; TA, thyroarytenoid muscle and ABD, external oblique muscle.

Figure 3. Electromyogram (EMG) activity of thyroarytenoid (TA) and posterior cricoarytenoid (PCA) muscle during no-inspiratory flow limitation (no-IFL) and IFL.

Figure 3

Open in a new tab

A no-IFL pattern of breathing was observed during the steady-state condition before laryngeal stimulation, and IFL pattern was established 5 min after laryngeal stimulation (patient 7). Note appearance of inspiratory phasic activity of TA muscle activity and reduced PCA activity during IFL. PET,CO2, partial pressure of end-tidal CO2; Pm, mask pressure; Ptr, tracheal pressure.

Respiratory variables and laryngeal behaviour

Table 2 summarizes respiratory variables during no-IFL breaths and IFL breaths. Respiratory frequency was significantly higher during IFL breaths than during no-IFL breaths due to significant shortening of expiratory phase. This increase in the respiratory frequency was accompanied by a significant reduction of tidal volume during IFL, maintaining minute ventilatory volume compared with the no-IFL breaths. Despite these similar levels of minute ventilation, PET,CO2 significantly increased during IFL compared with the no-IFL condition. All the IFL breaths analysed were accompanied by the stridor sound while stridor was not detected in the no-IFL condition.

Table 2.

Respiratory variables in no-IFL and IFL breaths

no-IFL IFL
Respiratory rate (min−1) 13.7 ± 4.1 18.7 ± 5.3 **
Ti (s) 1.42 ± 0.45 1.27 ± 0.46
Ti/Ttot 0.31 ± 0.07 0.37 ± 0.06 **
Tidal volume (l) 0.40 ± 0.11 0.30 ± 0.09 **
Minute volume (l min−1) 5.4 ± 2.2 5.4 ± 1.6
PET,CO2 (mmHg) 51.0 ± 6.7 57.6 ± 4.4 *
Laryngeal resistance (cmH2O l−1 s) 8.5 ± 1.5 138 ± 98 **
Presence of stridor 0/7 10/10 **
Open in a new tab

IFL, inspiratory flow limitation; Ti, inspiratory duration; Ti/Ttot, duty ratio; PET,CO2, partial pressure of end-tidal CO2.

*

P < 0.05

**

P < 0.01 versus no-IFL.

Figure 4 illustrates typical pressure-flow relationships during no-IFL and IFL breaths observed in four patients. Flow limitation only occurred during inspiration, and notably, pressure-flow curves during expiratory phase in IFL breaths did not differ from those in no-IFL breaths. The discrepancy in the pressure-flow curves between no-IFL breaths and IFL breaths occurred only during the mid-inspiratory phase causing a significant increase in laryngeal resistance at peak inspiratory effort during IFL. Measurement of vocal cord angle at peak expiratory effort indicated that the vocal cord angle during expiration in IFL breaths did not differ from that in no-IFL breaths whereas the angle at peak inspiratory effort was significantly smaller in IFL breaths than in no-IFL breaths (Fig. 5). We found a significant correlation between the vocal cord angle and the laryngeal resistance in IFL breaths (Fig. 5). The vocal cords were endoscopically observed to vibrate finely during IFL producing the stridor sound while maintaining the narrowed position.

Figure 4. Pressure-flow relationships.

Figure 4

Open in a new tab

Pressure-flow relationships during inspiratory flow limitation (IFL) breaths (thin lines) and no-IFL breaths (thick lines) in 4 patients. The no-IFL breath curves were horizontally shifted by −2 cmH2O to avoid overlapping of the curves. Note that discrepancy of the curves between IFL and no-IFL occurred only during mid-inspiration. Pm, mask pressure; Ptr, tracheal pressure.

Figure 5. Vocal cord angle and laryngeal resistance.

Figure 5

Open in a new tab

A, vocal cord angle in no-IFL (inspiratory flow limitation) and IFL breaths for each respiratory phase. NS, not significant. B, relationship between vocal cord angle at peak inspiratory effort (PIE) and laryngeal resistance measured at peak inspiratory effort (PIE) during IFL.

Relationship between discharge patterns of TA muscles and concomitant breathing patterns

The TA muscle activities were recorded during no-IFL breaths in seven patients while TA muscle activities were successfully recorded in ten patients during IFL breaths, produced by injection of distilled water onto the vocal cords, under general anaesthesia (Table 3). As illustrated in Figs 2 and 3, inspiratory-phasic activity of the TA muscles was never observed during no-IFL breaths in five out of the seven patients while inspiratory-phasic activity of TA muscles was occasionally observed in two patients. In contrast, TA muscles were activated during inspiration in ten patients during IFL breaths (Figs 2 and 3). Fisher's exact test indicates that inspiratory TA activation was more frequently observed during IFL breaths than no-IFL breaths (P = 0.003) while the presence of inspiratory-phasic activity of TA muscles was not always associated with IFL.

Firing patterns of posterior cricoarytenoid muscle (PCA) and other expiratory muscles

We recorded PCA muscle activity in four patients under general anaesthesia (Table 3). Two patients showed a constant level of phasic inspiratory activity during both no-IFL and IFL breaths while the activity decreased in patient 7 (Fig. 3) and was augmented in patient 10 (Fig. 6) during IFL breaths. Phasic inspiratory activity was occasionally observed only during IFL in patient 8. Patient 9 showed no electrical activity throughout the experiment even after wakening from anaesthesia.

Figure 6. Response to laryngeal stimulation in patient 10.

Figure 6

Open in a new tab

Response to laryngeal stimulation in patient 10 who did not develop a stable inspiratory flow limitation (IFL) pattern is presented. Note that phasic thyroarytenoid (TA) activities were recruited both during inspiration and expiration, and that phasic inspiratory activity of posterior cricoarytenoid (PCA) was augmented during the temporal IFL breaths.

Electrical activity of the middle pharyngeal constrictor (MPC) was recorded in four patients. No respiratory-related activity was present in 2 patients (9 and 10) but a burst of the MPC was observed during swallowing. Surprisingly, phasic inspiratory MPC activity was transiently recorded in patients 7 and 8 during IFL (Fig. 7). Transient phasic expiratory activity of the external oblique muscle was recorded during IFL in three patients (Table 3).

Figure 7. Electromyogram (EMG) activity of the middle pharyngeal constrictor (MPC) during no inspiratory flow limitation and IFL breaths.

Figure 7

Open in a new tab

Phasic inspiratory bursts were transiently observed in the MPC muscle. Note increase in PET,CO2 (partial pressure of end-tidal CO2) and laryngeal resistance during IFL.

Influence of continuous positive airway pressure (CPAP) on breathing pattern and TA muscle activity

Figure 8 demonstrates two examples of effects of CPAP on respiratory variables and TA muscle activity. In patient 7 (Fig. 8A), phasic inspiratory activity of the TA muscle gradually decreased and disappeared within 90 s after sudden application of CPAP, and resumed 30 s after sudden withdrawal of CPAP. Although the CPAP application increased airflow immediately to some extent, further improvement of airflow and reduction of airway resistance appeared to be associated with a reduction of TA muscle activity. No IFL was identified when phasic TA muscle activity disappeared during CPAP. Reduction of PET,CO2 was also noted during CPAP in this case. By contrast, patient 9 responded to CPAP somewhat differently (Fig. 8B). Application of CPAP immediately eliminated the phasic inspiratory activity of the TA muscle as well as the instantaneous reduction of laryngeal resistance. Withdrawal of CPAP, in turn, recruited the TA muscle activity without delay. As illustrated by Fig. 9, application of CPAP increased the angle of the vocal cords both during expiration and inspiration, eliminating progressive laryngeal narrowing during inspiration. Two patients (6 and 7) exhibited the former response and the remaining three patients (4, 8 and 9) exhibited the latter pattern of response to CPAP. CPAP did not apparently change the discharge pattern of the TA muscle in one patient (5). An IFL pattern was not observed during CPAP in half of the patients. Table 4 presents changes of respiratory variables with and without CPAP. CPAP significantly reduced the respiratory frequency without changing inspiratory duration, and significantly increased the tidal volume resulting in no significant change in the minute ventilatory volume. The laryngeal resistance on inspiration was decreased by CPAP in all six patients although the difference was not statistically significant.

Figure 8.

Figure 8

Open in a new tab

The effects of CPAP on breathing pattern and thyroarytenoid (TA) muscle activities

A, in response to application of CPAP, gradual reduction of TA muscle activity in association with reduction of laryngeal resistance and PET,CO2 (partial pressure of end-tidal CO2) was observed in patient 7. B, by contrast, showed instantaneous suppression of the TA muscle activity induced by CPAP application in patient 9. Scale bar in B applies to both A and B.

Figure 9. Laryngeal images during expiration and at peak inspiratory effort with and without CPAP.

Figure 9

Open in a new tab

Table 4.

Respiratory variables with and without CPAP

no CPAP CPAP
Respiratory rate (min−1) 19.6 ± 5.4 16.2 ± 5.1**
Ti (s) 1.30 ± 0.38 1.30 ± 0.20
Ti/Ttot 0.41 ± 0.08 0.34 ± 0.08
Tidal volume (l) 0.27 ± 0.11 0.33 ± 0.08*
Minute volume (l min−1) 5.0 ± 1.5 5.2 ± 1.7
PET,CO2 (mmHg) 58.6 ± 8.2 51.9 ± 6.4
Laryngeal resistance (cmH2O l−1 s) 176 ± 217 37 ± 63
Open in a new tab

CPAP, continuous positive airway pressure; Ti, inspiratory duration; Ti/Ttot, duty ratio; PET,CO2, partial pressure of end-tidal CO2.

*

P < 0.05

**

P < 0.01 versus no CPAP.

n = 6.

TA muscle activation during sleep

Electrical activity of the TA muscle during sleep was successfully recorded in four patients (1, 7, 8 and 9) although the sleep was greatly fragmented probably due to instrumentation. Phasic inspiratory activation of TA muscle was recorded in association with development of audible stridor during non rapid-eye movement (NREM) and rapid-eye movement (REM) sleep as demonstrated in Fig. 10. Arousal induced by auditory stimulation resulted in disappearance of the inspiratory TA muscle activation indicating the significance of consciousness level.

Figure 10. Muscle activity during sleep.

Figure 10

Open in a new tab

Electromyogram (EMG) activities of thyroarytenoid (TA) muscle during NREM (A) and REM (B) sleep. Note that TA was active during inspiration, and the phasic inspiratory activity disappeared after arousal induced by auditory stimulation. EEG, electroencephalogram; EOG, electro-oculogram; EMGSM, submental electromyogram.

We examined the effects of nasal CPAP on TA muscle activity in patient 9 during sleep. As clearly illustrated in Fig. 11, 6 cmH2O of nasal CPAP eliminated the phasic inspiratory activity of TA muscle resulting in establishment of no-IFL while IFL with the stridor was accompanied by prominent TA muscle activity under 2 cmH2O of nasal CPAP.

Figure 11. Effects of nasal CPAP on breathing pattern and thyroarytenoid (TA) muscle activity during sleep.

Figure 11

Open in a new tab

Note the disappearance of phasic inspiratory activity of TA and inspiratory stridor evidenced by oscillation of the flow signal after increase in the nasal CPAP level. Pm, mask pressure; Sa,O2, arterial oxygen saturation; EEG, electroencephalogram; EOG, electro-oculogram; EMGSM, submental electromyogram. Numbers 2 and 6 above traces indicate Pm values of 2 and 6 cmH2O; numbers 93 and 95 indicate Sa,O2 values of 93 and 95 %.

DISCUSSION

In anaesthetized patients with MSA, we found that airflow limitation only occurred during inspiration in association with significant laryngeal narrowing leading to an increase in laryngeal resistance and PET,CO2 immediately after laryngeal stimulation by instillation of distilled water onto the vocal cords. The presence of phasic inspiratory TA activity was significantly associated with the development of IFL accompanied by stridor. Application of CPAP improved the breathing pattern in association with suppression of TA muscle activity. Our results strongly support a hypothesis that contraction of laryngeal adductors during inspiration causes active laryngeal narrowing leading to development of laryngeal stridor in patients with MSA.

Limitation of the study

Since the study was performed under general anaesthesia with laryngeal stimulation and a laryngeal mask airway, we must accept the criticism that our observations may not reflect the disordered breathing that occurs normally during sleep in these patients. Steady-state breathing patterns following the laryngeal stimulation in MSA patients, however, are apparently different from those of normal subjects under propofol anaesthesia (Tagaito et al. 1998). As demonstrated in Fig. 12, our previously performed experiments (Tagaito et al. 1998) on the laryngeal stimulation in normal subjects (17 females, 40 ± 11 years, 1.6 ± 0.04 m, 52 ± 6 kg) under propofol anaesthesia with similar experimental settings, but without electrode wires in the laryngeal muscle indicate that mean recovery time to steady-state breathing (defined as 80 % of tidal volume before stimulation) was less than 2 min (90 ± 33 s). No IFL was observed during the steady-state recovery periods. This is in significant contrast to the observation that the MSA patients continuously had IFL breaths with development of stridor after stimulation in this study, though the age and sex are not matched between the normal subjects and the patients in this study. Accordingly, we believe that the laryngeal function evaluation under general anaesthesia is beneficial for exploring mechanisms of breathing abnormalities of MSA patients, allowing the use of invasive techniques and recognizing that there must be some quantitative difference between breathing under general anaesthesia and during natural sleep. Our finding that the identical pattern of TA muscle discharge observed during sleep may further support the validity of our observations under general anaesthesia.

Figure 12. An example of responses to laryngeal stimulation in a normal subject.

Figure 12

Open in a new tab

Note that stable breathing pattern without inspiratory flow limitation was established within 2 min after the stimulation.

Correct placement of EMG wires was confirmed by anatomical knowledge of the larynx and endoscopic observations. Although the presence of a burst of activity during laryngospasm in all patients further supports the validity of the EMG of the TA muscle, functional assessment of PCA current was inappropriate since the absence of electrical activity was possibly caused by the nature of the disease. Although patient 9 showed no electrical activity throughout the experiment, this could be either paralysis of PCA or unsuccessful placement of the EMG wires.

Influences of laryngeal narrowing on breathing patterns

Reduction of tidal volume during IFL was compensated for by an increase in respiratory frequency. Regardless of maintenance of the minute ventilatory volume during IFL compared with the amount of no-IFL, PET,CO2 during IFL was significantly higher than that during no-IFL. While the increase in PET,CO2 during IFL may be simply due to the reduction of alveolar ventilation, an alternative explanation is that the increased work of breathing during IFL, as evidenced by significantly higher laryngeal resistance, possibly increased metabolism, resulting in retention of CO2 during IFL. Although the nature of nocturnal breathing abnormalities in MSA patients has not been described in detail, our results indicate that development of hypoxaemia may be secondary, due to an increase in PET,CO2 resulting from increased work of breathing. Therefore, only mild hypoxaemia without periodicity may be a feature of stridor in MSA patients during early stages of the disease process.

Mechanisms of laryngeal narrowing

The size of the laryngeal aperture is determined by a balance of forces between the laryngeal abductor and adductor muscles. Either reduction of the abductor muscle activity or increased activity of the adductor muscles could narrow the laryngeal aperture. Previous histological studies of PCA muscle and recurrent laryngeal nerve in MSA suggest that paralysis of PCA muscle caused by degeneration of the nucleus ambiguus, which contains the motoneurons innervating the PCA, results in laryngeal narrowing although involvement of the nucleus ambiguus in MSA is still controversial (Lapresle et al. 1979; Bannister et al. 1981; Hayashi et al. 1997). The velocity of the air at the passively narrowed vocal cords increases during inspiration, converting potential energy to kinetic energy. Due to the increased kinetic energy, lateral wall pressure at the vocal cords decreases, and therefore narrows the vocal cords further. Increased resistance upstream to the larynx during sleep or anaesthesia (increased pharyngeal resistance) may further decrease the lateral wall pressure at the vocal cords. In this way, the larynx can be narrowed passively due to the paralysis of PCA muscle. This passive mechanism is somewhat questionable in MSA patients because Isozaki et al. (1994) recorded phasic inspiratory activity of PCA muscle during sleep in MSA patients, and we recorded apparent PCA activity during inspiration in three out of four MSA patients during IFL, although the presence of electrical activity of the PCA muscle does not necessarily mean normal functioning of the muscle.

By contrast, positive association between the presence of TA inspiratory activity and the development of IFL strongly suggests a significant role of the active laryngeal narrowing mechanism. The occurrence of significant laryngeal narrowing only during inspiration indicated that the adductor muscle force was greater than the abductor muscle force during IFL, while we found that both muscles were electrically activated during inspiration in this study. During this active laryngeal narrowing, increased kinetic energy at the narrowed vocal cord area should further facilitate laryngeal narrowing during inspiration, indicating that the passive laryngeal mechanism also contributes to development of stridor in these patients.

Why is the TA muscle activated during inspiration?

The TA muscle is usually activated during expiration in quiet respiratory cycles, possibly regulating the laryngeal resistance during expiration (Bartlett, 1986). Although the behaviour of the TA muscle of MSA patients examined in this study appears to be completely abnormal in terms of the timing of the discharge, the upper airway muscles often switch to different respiratory phases in a variety of conditions. Kuna & Smickley (1997) reported that the pharyngeal constrictor, usually classified as an expiratory muscle, was activated during inspiration immediately after arousal from obstructive sleep apnoea. In turn, the PCA muscle, known as an inspiratory muscle of the larynx, was reported to fire during forced expiration (Kuna & Vanoye, 1994). Considering that we found the phase shift in the middle pharyngeal constrictor as well as in the TA muscle, a common specific influence to the expiratory motoneurons of the upper airway within the nucleus ambiguus possibly shifts the firing timing in these muscles. Based on the previous reports describing inspiratory activation of the TA muscle (St John et al. 1989; Insalaco et al. 1991), we speculate the following mechanisms to explain the seemingly abnormal pattern of TA muscle activation.

St John and his colleagues (1989) reported that purely phasic-inspiratory activity of the TA muscle branch of the recurrent laryngeal nerve was observed during gasping in two of five decerebrated and vagotomized cats. Gasping is a specific breathing pattern usually induced by dysfunction of the brain stem. We have no clear evidence to discard the possibility that stridor in MSA patients is a state related to gasping, presumably in association with degeneration of the brain stem region. However, this mechanism is unlikely because the pattern of gasping is characterized by a sudden beginning of inspiration with a lower gasping frequency. We found no abrupt change in the tracheal pressure during stridor but an increase in respiratory frequency during stridor (St John & Knuth, 1981). Preservation of the expiratory discharge of the abdominal muscle during stridor does not support this idea.

The most likely explanation for the inspiratory discharge of the TA muscle in MSA patients can be made based on the report of Insalaco et al. (1991) who demonstrated that application of external inspiratory resistive load reflexively induced and increased inspiratory activity of the TA muscle in normal awake subjects. Similarly, PCA muscle activity was reported to increase in response to airway occlusion and negative pressure (van Lunteren et al. 1984; Sant'Ambrogio et al. 1985). Considering that laryngeal narrowing is an internal resistor, the phasic-inspiratory activity of the TA muscle during IFL in MSA patients is possibly caused by a reflex response to the negative airway pressure. Co-activation of PCA and TA muscles in response to negative airway pressure during inspiration possibly serves to increase laryngeal stiffness and maintain the patency of the larynx in normal subjects. In MSA patients, however, the response of PCA muscle to the negative pressure may be depressed due to (partial) paralysis of PCA muscle. Accordingly, a net balance between the adductor and abductor muscles favours laryngeal narrowing. The introduction of sleep may contribute to the development of negative airway pressure because the upper airway resistance increases during sleep. This speculation is supported by our observation that the inspiratory TA muscle activity was suppressed by application of CPAP.

Several recent studies indicate involvement of the suppression of benzodiazepine receptors within the brain stem in the pathogenesis of MSA (Kanazawa et al. 1985; Tosca et al. 1992; Gilman et al. 1995). Ramirez et al. (1997) demonstrated that activities of post-inspiratory neurons within the pre-Botzinger complex switched to the inspiratory phase with application of antagonists of inhibitory neurotransmitters in an in vitro slice preparation of mice. Taking this evidence into consideration, the inspiratory discharge of the TA muscle in MSA patients may be explained by the dysfunction of the inhibitory neurotransmitters in the brain stem.

Clinical implications

In accordance with the findings of Gillespie et al. (1995) who demonstrated that 10 cmH2O of nasal CPAP reversed the breathing abnormality in MSA patients during sleep, we were able to improve the breathing abnormality leading to a reduction of laryngeal resistance and PET,CO2. In addition, application of CPAP significantly decreased the inspiratory activity of the TA muscle. Since our results strongly suggest a contribution from the TA muscle contraction during inspiration, to the development of the laryngeal stridor through a negative airway reflex, application of nasal CPAP may be a fundamental treatment for stridor. Accordingly, nasal CPAP serves to attenuate inspiratory discharge of the adductor muscles, and to splint the laryngeal wall mechanically. However, well-designed clinical trials and further fundamental investigations of nasal CPAP in the MSA patients should be performed before routine use of nasal CPAP for the treatment of stridor. Nasal CPAP may become ineffective with progression of the disease.

In conclusion, our results indicate that inspiratory contraction of the TA muscle is associated with severe laryngeal narrowing, leading to development of inspiratory flow limitation with stridor in patients with MSA, immediately after laryngeal stimulation by instillation of distilled water on the vocal cords under general anaesthesia. Application of CPAP diminished the TA inspiratory discharge and improved the breathing abnormality.

Acknowledgments

The authors thank to Dr J. E. Remmers (University of Calgary), Dr S. Kuna (University of Pennsylvania), and F. Hayashi (Chiba University) for their constructive comments to this study and their critical review on this manuscript. The authors also thank to Dr Y. Tagaito (Chiba University) for his agreement to using data previously collected from normal subjects.

References

  1. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngeal abductor paralysis in multiple system atrophy. A report on three necropsied cases, with observations on the laryngeal muscles and the nuclei ambigui. Brain. 1981;104:351–368. doi: 10.1093/brain/104.2.351. [DOI] [PubMed] [Google Scholar]
  2. Bartlett D., Jr . Upper airway motor systems. In: Cherniack NS, Widdicombe JG, editors. Handbook of Physiology, section 3, The Respiratory System, Control of Breathing. Vol. 2. Bethesda, MD: American Physiological Society; 1986. pp. 223–246. part I. [Google Scholar]
  3. Gillespie MB, Flint PW, Smith PL, Eisele DW, Schwartz AR. Diagnosis and treatment of obstructive sleep apnea of the larynx. Archives of Otolaryngology Head and Neck Surgery. 1995;121:335–339. doi: 10.1001/archotol.1995.01890030063010. [DOI] [PubMed] [Google Scholar]
  4. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, Laurent RT. Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography. Annals of Neurology. 1995;38:176–185. doi: 10.1002/ana.410380209. [DOI] [PubMed] [Google Scholar]
  5. Guindi GM, Michaels L, Bannister R, Gibson W. Pathology of the intrinsic muscles of the larynx. Clinical Otolaryngology. 1981;6:101–109. doi: 10.1111/j.1365-2273.1981.tb01794.x. [DOI] [PubMed] [Google Scholar]
  6. Hayashi M, Isozaki E, Oda M, Tanabe H, Kimura J. Loss of large myelinated nerve fibres of the recurrent laryngeal nerve in patients with multiple system atrophy and vocal cord palsy. Journal of Neurology, Neurosurgery and Psychiatry. 1997;62:234–238. doi: 10.1136/jnnp.62.3.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Insalaco G, Kuna ST, Costanza BM, Catania G, Cibella F, Bellia V. Thyroaryntenoid muscle activity during loaded and nonloaded breathing in adult humans. Journal of Applied Physiology. 1991;70:2410–2416. doi: 10.1152/jappl.1991.70.6.2410. [DOI] [PubMed] [Google Scholar]
  8. Isozaki E, Naito A, Horiguchi S, Kawamura R, Hayashida T, Tanabe H. Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy. Journal of Neurology, Neurosurgery and Psychiatry. 1996;60:399–402. doi: 10.1136/jnnp.60.4.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Isozaki E, Osanai R, Horiguchi S, Hayashida T, Hirose K, Tanabe H. Laryngeal electromyography with separated surface electrodes in patients with multiple system atrophy presenting vocal cord paralysis. Journal of Neurology. 1994;241:551–556. doi: 10.1007/BF00873518. [DOI] [PubMed] [Google Scholar]
  10. Kakitsuba N, Sadaoka T, Kanai R, Fujiwara Y, Takahashi H. Peculiar snoring in patients with multiple system atrophy: its sound source, acoustic characteristics, and diagnostic significance. Annals of Otology. Rhinology and Laryngology. 1997;106:380–384. doi: 10.1177/000348949710600504. [DOI] [PubMed] [Google Scholar]
  11. Kanazawa I, Kwak S, Sasaki H, Mizusawa H, Muramoto O, Yoshizawa K, Nukina N, Kitamura K, Kurisaki H, Sugita K. Studies on neurotransmitter markers and neuronal cell density in the cerebellar system in olivopontocerebellar atrophy and cortical cerebellar atrophy. Journal of the Neurological Science. 1985;71:193–208. doi: 10.1016/0022-510x(85)90059-0. [DOI] [PubMed] [Google Scholar]
  12. Kavey NB, Whyte J, Blitzer A, Gidro-Frank S. Sleep-related laryngeal obstruction presenting as snoring or sleep apnea. Laryngoscope. 1989;99:851–854. doi: 10.1288/00005537-198908000-00014. [DOI] [PubMed] [Google Scholar]
  13. Kuna ST, Smickley JS. Superior pharyngeal constrictor activation in obstructive sleep apnea. American Journal of Respiratory and Critical Care Medicine. 1997;156:874–880. doi: 10.1164/ajrccm.156.3.9702053. [DOI] [PubMed] [Google Scholar]
  14. Kuna ST, Smickley JS, Insalaco G. Posterior cricoarytenoid muscle activity during wakefulness and sleep in normal adults. Journal of Applied Physiology. 1990;68:1746–1754. doi: 10.1152/jappl.1990.68.4.1746. [DOI] [PubMed] [Google Scholar]
  15. Kuna ST, Vanoye CR. Laryngeal response during forced vital capacity manoeuvres in normal adult humans. American Journal of Respiratory and Critical Care Medicine. 1994;15:729–734. doi: 10.1164/ajrccm.150.3.8087344. [DOI] [PubMed] [Google Scholar]
  16. Lapresle J, Annabi A. Olivopontocerebellar atrophy with velopharyngolaryngeal paralysis: a contribution to somatotopy of the nucleus ambiguus. Journal of Neuropathology and Experimental Neurology. 1979;38:401–406. doi: 10.1097/00005072-197907000-00005. [DOI] [PubMed] [Google Scholar]
  17. McNicholas WT, Rutherford R, Grossman R, Moldofsky H, Zamel N, Phillipson EA. Abnormal respiratory pattern generation during sleep in patients with autonomic dysfunction. American Review of Respiratory Disease. 1983;128:429–433. doi: 10.1164/arrd.1983.128.3.429. [DOI] [PubMed] [Google Scholar]
  18. Marion MH, Klap P, Perrin A, Cohen M. Stridor and focal laryngeal dystonia. Lancet. 1992;339:457–458. doi: 10.1016/0140-6736(92)91060-l. [DOI] [PubMed] [Google Scholar]
  19. Munschauer FE, Loh L, Bannister R, Newsom-Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology. 1990;40:677–679. doi: 10.1212/wnl.40.4.677. [DOI] [PubMed] [Google Scholar]
  20. Ramirez JM, Telgkamp P, Elsen FP, Quellmalz UJA, Richter DW. Respiratory rhythm generation in mammals: synaptic and membrane properties. Respiration Physiology. 1997;110:71–85. doi: 10.1016/s0034-5687(97)00074-1. [DOI] [PubMed] [Google Scholar]
  21. Sadaoka T, Kakitsuba N, Fujiwara Y, Kanai R, Takahashi H. Sleep-related breathing disorders in patients with multiple system atrophy and vocal fold palsy. Sleep. 1996;19:479–484. doi: 10.1093/sleep/19.6.479. [DOI] [PubMed] [Google Scholar]
  22. St John WM, Knuth KV. A characterization of the respiratory pattern of gasping. Journal of Applied Physiology. 1981;50:984–993. doi: 10.1152/jappl.1981.50.5.984. [DOI] [PubMed] [Google Scholar]
  23. St John WM, Zhou D, Fregosi RF. Expiratory neural activities in gasping. Journal of Applied Physiology. 1989;66:223–231. doi: 10.1152/jappl.1989.66.1.223. [DOI] [PubMed] [Google Scholar]
  24. Sant'Ambrogio FB, Mathew OP, Clark WD, Sant'Ambrogio G. Laryngeal influences on breathing pattern and posterior cricoarytenoid muscle activity. Journal of Applied Physiology. 1985;58:1298–1304. doi: 10.1152/jappl.1985.58.4.1298. [DOI] [PubMed] [Google Scholar]
  25. Tagaito Y, Isono S, Nishino T. Upper airway reflexes during a combination of propofol and fentanyl anesthesia. Anesthesiology. 1998;88:1459–1466. doi: 10.1097/00000542-199806000-00007. [DOI] [PubMed] [Google Scholar]
  26. Tosca P, Canevari L, Di Paolo E, Ferrari R, Verze S, Zerbe F, Dagani F. Glutamate and GABA levels in CSF from patients affected by demetia and olivo-ponto-cerebellar atrophy. Acta Neurologica Scandinavica. 1992;85:430–435. doi: 10.1111/j.1600-0404.1992.tb06042.x. [DOI] [PubMed] [Google Scholar]
  27. Van Lunteren E, Van De Graaff WB, Parker DM, Mitra J, Haxhiu MA, Strohl KP, Cherniack NS. Nasal and laryngeal reflex responses to negative upper airway pressure. Journal of Applied Physiology. 1984;56:746–752. doi: 10.1152/jappl.1984.56.3.746. [DOI] [PubMed] [Google Scholar]
  28. Williams A, Hanson D, Calne DB. Vocal cord paralysis in the Shy-Drager syndrome. Journal of Neurology, Neurosurgery and Psychiatry. 1979;42:151–153. doi: 10.1136/jnnp.42.2.151. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES