Brain, Vol. 123, No. 1, 125-140,
January 2000
© 2000 Oxford University Press
Pathophysiological mechanisms of oropharyngeal dysphagia in amyotrophic lateral sclerosis
1 Departments of Clinical Neurophysiology and 2 Neurology, Medical School Hospital, Ege University Bornova, Izmir, Turkey
Correspondence to:
Professor Cumhur Ertekin, Nilhan Apt. 1357 Sok. No. 1 D-10, Alsancak, Izmir, Turkey E-mail: erteker{at}unimedya.net.tr
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Abstract |
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We investigated the pathophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis. Forty-three patients with sporadic amyotrophic lateral sclerosis were examined by clinical and electrophysiological methods that objectively measured the oropharyngeal phase of voluntarily initiated swallowing, and these results were compared with those obtained from 50 age-matched control subjects. Laryngeal movements were detected by a piezoelectric sensor and EMG of submental muscles, and needle EMG of the cricopharyngeal muscle of the upper oesophageal sphincter of both the amyotrophic lateral sclerosis and control groups was recorded during swallowing. Amyotrophic lateral sclerosis patients with dysphagia displayed the following abnormal findings. (i) Submental muscle activity of the laryngeal elevators, which produce reflex upward deflection of the larynx during wet swallowing, was significantly prolonged whereas the laryngeal relocation time of the swallowing reflex remained within normal limits. (ii) The cricopharyngeal sphincter muscle EMG demonstrated severe abnormalities during voluntarily initiated swallows. The opening of the sphincter was delayed and/or the closure occurred prematurely, the total duration of opening was shortened and, at times, unexpected motor unit bursts appeared during this period. (iii) During voluntarily initiated swallows there was significant lack of co-ordination between the laryngeal elevator muscles and the cricopharyngeal sphincter muscle. These results point to two pathophysiological mechanisms that operate to cause dysphagia in amyotrophic lateral sclerosis patients. (i) The triggering of the swallowing reflex for the voluntarily initiated swallow is delayed and eventually abolished, whereas the spontaneous reflexive swallows are preserved until the preterminal stage of amyotrophic lateral sclerosis. (ii) The cricopharyngeal sphincter muscle of the upper oesophageal sphincter becomes hyper-reflexic and hypertonic. As a result, the laryngeal protective system and the bolus transport system of deglutition lose their co-ordination during voluntarily initiated swallowing. We conclude that these pathophysiological changes are related mainly to the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres.
sporadic ALS; oropharyngeal dysphagia; pathophysiology of dysphagia; voluntarily initiated swallow; spontaneous swallow
CP-EMG = EMG of the cricopharyngeal; SM-EMG = EMG of the submental muscle complex; UES = upper oesophageal sphincter
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Dysphagia is one of the most important clinical problems encountered in amyotrophic lateral sclerosis. It is not uncommon as an initial symptom in amyotrophic lateral sclerosis, but it appears typically several months after the onset of the disease. Most patients with amyotrophic lateral sclerosis ultimately show oropharyngeal involvement (Roller et al., 1974
; Carpenter et al., 1978; McGuirt and Blalock, 1980). When amyotrophic lateral sclerosis presents predominantly with dysphagia, further investigation may reveal bulbar and/or pseudobulbar palsy. The presence of dysphagia can be diagnosed by videofluoroscopic/manometric methods even before the bulbar symptoms or swallowing difficulty appear clinically (Leighton et al., 1994; Briani et al., 1998). The dysphagia and related aspiration pneumonia are usually the major handicaps to the quality of life, in addition to the risk of poor nutrition and dehydration, which occur particularly in older patients (Hillel and Miller, 1989; Strand et al., 1996).
Although dysphagia can be frequent or very severe and may be life-threatening in amyotrophic lateral sclerosis patients, the pathophysiological nature of dysphagia in amyotrophic lateral sclerosis has not been systematically studied and documented either clinically or by EMG, although a number of videofluoroscopic studies have been reported (Bosma and Brodie, 1969; Robbins, 1987; Leighton et al., 1994; MacDougall et al., 1995; Wright and Jordan, 1997; Briani et al., 1998). So far, neither clinical nor X-ray studies have been able to explain clearly the neurophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis.
In this study, we investigated the pathophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis by means of clinical and electrophysiological methods. The electrophysiological methods have been described by our group previously (Ertekin, 1996; Ertekin et al., 1995, 1996, 1997). The results of this study strongly indicate that the pathophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis patients are primarily associated with the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres that control the bulbar swallowing centre.
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Patients and methods |
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We investigated 43 amyotrophic lateral sclerosis patients (16 female, 27 male), with a mean age of 54.6 years and an age range of 36–72 years. Amyotrophic lateral sclerosis was diagnosed according to the El Escorial criteria (Brooks, 1994
). Bulbar involvement of the lower motor neuron type was absent in eight patients without dysphagia. Electrodiagnostic studies, including needle EMG, supported the clinical diagnosis in all patients. The clinical duration of amyotrophic lateral sclerosis since the patient became aware of the first symptoms related to the disease varied from 1 to 36 months, with a mean of 14 months. At the time of investigation, signs of lower motor neuron involvement in the limbs were prominent in 13 patients, while signs of upper motor neuron involvement in the limbs predominated in 15 patients. Bulbar and suprabulbar signs other than dysphagia were also apparent in all of the patients except eight non-dysphagic patients. Among the dysphagic group of 35 patients, 18 had predominant pseudobulbar involvement. Their clinical picture was prominent, with spastic laughing/crying, an increase in brainstem reflexes and lingual motor dysfunction without clinical atrophy. In eight dysphagic patients, the bulbar lower motor neuron involvement was apparent, with fasciculations and atrophy in the tongue, normal or decreased brainstem reflexes and no hyperemotionalism. In the remaining dysphagic patients, pseudobulbar and bulbar symptoms and signs were present in almost equal amounts.
All patients were specifically questioned and examined with respect to their suprabulbar and bulbar involvement, including dysphagia and aspiration (Logemann, 1983; Splaingard et al., 1988; Linden et al., 1993; Hughes and Wiles, 1996a). After a complete neurological examination had been carried out, needle EMG and nerve conduction tests were performed. Some patients were also investigated by cranial and/or cervical MRI and by CT scanning.
The degree of dysphagia was graded as follows. Grade 1: no clinical signs and symptoms of dysphagia. Grade 2: very mild dysphagia was suspected by clinical examination, but the patient never complained directly of dysphagia. Grade 3: the patient complained of dysphagia, and this was supported by other clinical signs; however, non-oral feeding was not necessary at the time of investigation. Grade 4: the patient had obvious clinical signs and symptoms of dysphagia, including aspiration, and dysphagia was severe enough to necessitate non-oral feeding.
Electrophysiological methods for the evaluation of oropharyngeal swallowing
The methods that we used for the evaluation of dysphagia have been described previously (Ertekin, 1996; Ertekin et al., 1995, 1996, 1997; Pehlivan et al., 1996). In brief, during the examination, the seated patient was instructed to hold his or her head in a neutral upright position. Swallows were initiated voluntarily with the bolus (liquid) positioned on the tongue and the tip of the tongue touching the upper incisors (Dantas et al., 1990). Swallow signals were recorded following the delivery of 1 or 3 ml of liquid (water) through a graduated syringe. The patients were also investigated while performing dry swallows. Mechanical upward and downward laryngeal movements during swallowing were detected by means of a piezoelectric sensor designed in our laboratory. This was a simple piezoelectric wafer with a 4x2.5 mm rubber bung fixed to its centre. The rubber bung was placed on the coniotomy region between the cricoid and thyroid cartilages at the midline, this region being located by palpation. The sensor was taped onto the neck and its output signal was filtered (bandpass 0.01–20 Hz) and fed into one of the channels of the EMG apparatus (Medelec Mystro, MS-20, Surrey, UK). The submental EMG (SM-EMG) was recorded by bipolar silver chloride EEG electrodes taped under the chin over the submental muscle complex (mylohyoid, geniohyoid and anterior digastric muscles). Signals were filtered (bandpass 100 Hz to 10 kHz), amplified, rectified and integrated.
Cricopharyngeal muscle activity of the upper oesophageal sphincter (UES) was recorded with a sterile needle electrode (Medelec disposable needle electrode DMC-37, diameter 0.46 mm, recording area 0.07 mm2) inserted through the skin at the level of the cricoid cartilage ~1.5 cm lateral to its palpable lateral border in the posteromedial direction. High-frequency tonic EMG activity and its cessation during swallowing served as the criterion for correct electrode penetration into the cricopharyngeal muscle. In this study, we refer to the cessation of tonic EMG activity of the cricopharyngeal muscle during swallowing as the `CP-EMG pause'. The cricopharyngeal sphincter EMG (CP-EMG) was recorded together with the laryngeal movement sensor signal, under the same recording conditions as for the SM-EMG.
The electrophysiological traces obtained from the piezoelectric laryngeal movement sensor and from the SM-EMG are illustrated in Fig. 1, in which the labels 0, 2, A and C indicate the points of measurement. The laryngeal sensor output shows two deflections during swallowing. The first deflection represents the upward movement of the larynx and the second deflection its downward movement (Fig. 1; upper traces of the superimposed and averaged recordings). The upward and downward deflections of the laryngeal sensor were sometimes diphasic or triphasic for technical reasons. Their shortest time with high amplitude at the beginning of deflexion from the baseline was important, and this was accepted as the point of onset. The midregion of the first deflection was stabilized on the oscilloscopic screen by using the delay-line technique, so that, throughout successive recordings, the deflections appeared at the same location of each sweep (~800 ms after the onset of the sweep). In this way, all electromechanical events were displayed synchronously. The onsets of the two deflections in the laryngeal sensor signal recordings are denoted as `0' and `2' (Fig. 1). The interval between the onsets of two deflections, indicated in Fig. 1 by `0
2', is thought to reflect the time necessary for the elevation, closure and upward relocation of the larynx (Ertekin, 1996; Ertekin et al., 1995), i.e. a physiological event that is one of the components of the swallowing reflex (Logemann, 1983; Donner et al., 1985; Jacob et al., 1989). Total analysis time was adjusted to between 2 and 5 s, and at least five successive sensor and SM-EMG traces were recorded. The individual traces were examined, superimposed and then averaged.
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When the first deflection was stabilized on the EMG screen, the onset of the second deflection showed variability for the same subject for boluses of the same volume. This variability of the laryngeal downward movement was measured at the peaks of the second deflections (asterisk in the uppermost trace of Fig. 1
). The interval between the earliest second deflection peak to the latest peak of the superimposed traces is called the `swallowing jitter', and is a measure of the variation in swallowing response from one swallow to another, for boluses of the same volume (Ertekin et al., 1995, 1996, 1997).
Since the submental muscle complex (mylohyoid, geniohyoid and anterior digastric muscles) fire concurrently to initiate a swallow and function as laryngeal elevators, pulling the larynx upwards (Miller, 1982; Logemann, 1983; Donner et al., 1985; Jacob et al., 1989; Gay et al., 1994; Perlman and Christenson, 1997), the rectified and integrated surface EMG activity of the submental muscles (SM-EMG) gives a considerable amount of information about the onset and duration of the pharyngeal phase of swallowing. The onset and end of the SM-EMG activity are labelled `A' and `C' in Figs 1, 3 and 4 (e.g. the lower traces of the superimposed and averaged recordings in Fig. 1). The duration and the peak amplitude of the integrated EMG activities were also measured from the averaged traces.
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We also measured another important parameter that is related to the triggering of the reflex swallow. This parameter is the interval between the onset of the SM-EMG and the first deflection of the laryngeal sensor signal reflecting the upward movement of the larynx, which is one of the first events of pharyngeal reflex swallowing (Miller, 1982
; Logemann, 1983; Donner et al., 1985; Dodds et al., 1990). This interval, which we term the `A–0 interval' (oblique arrow in the lower part of Fig. 1), can provide information about the temporal relationship between the instant of the voluntary activation of the submental muscle complex and the instant of reflex triggering of the swallowing response (Ertekin, 1996; Ertekin et al., 1998a).
The phenomena of piecemeal deglutition and the dysphagia limit have also been investigated using the same technique (Ertekin et al., 1996). Piecemeal deglutition refers to division of the bolus into two or three successive swallows (Logemann, 1983). To investigate this phenomenon, the same recording system was used, with the sweep duration set at 10 s and the delay line starting at 2 s. After a certain amount of water had been ingested, the effect of the bolus was followed for 8 s. The patients were given 1, 3, 5, 10, 15 and 20 ml of water and oscilloscopic traces were initiated at the examiner's order to swallow. The laryngeal sensor signals and the integrated activities of the SM-EMG and/or the CP-EMG were recorded from the beginning of these long sweeps. It was requested that the patient swallow all the liquid given in a single effort. Any swallowing-related recurrence of the EMG activity and the laryngeal sensor signal within 8 s after the onset of the sweep was accepted as piecemeal deglutition or as a sign of a dysphagia limit. However, as piecemeal deglutition is observed physiologically in normal subjects when swallowing >20 ml of water, duplication or multiplication at or below 20 ml of water is referred to as the `dysphagia limit' (Ertekin et al., 1996).
Normal values of electrophysiological parameters were obtained from 50 normal adult subjects (20 female, 30 male) with ages ranging between 30 and 75 years (mean 52.2 ± 14.4 years). The lower and upper limits of normal values for different swallowing parameters were compared with the results obtained from individual patients. The CP-EMG was performed in 21 normal subjects (11 female, 10 male) within the age range of 30–75 years (mean 46.2 ± 13.2).
This study was approved by the ethics committee of our university hospital, and informed consent was obtained from each subject.
Values of the mean ± standard error of the mean were calculated for all parameters measured and statistical analyses were performed to assess the differences in swallowing parameters using variance and correlation analysis as appropriate.
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Results |
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Clinical findings associated with dysphagia in amyotrophic lateral sclerosis patients
Clinical symptoms and signs of dysphagia were common in patients with amyotrophic lateral sclerosis (35 out of 43 patients). In the dysphagic group, dysphagia was the first symptom in 11 patients, whereas in other patients dysphagia developed after a mean period of 11 months (range 1–33 months). At the time of investigation, the mean duration of dysphagia was ~6 months in the dysphagic group. In the majority of patients the primary symptom was difficulty controlling liquid and solid boluses in the oral cavity because of the weakness of the tongue. Other clinical observations were probably related to the delay in the triggering of swallows (i.e. accumulation of saliva in the mouth and delay in elevating the larynx). Subglottal aspiration often occurred in amyotrophic lateral sclerosis patients with pseudobulbar and bulbar signs, as evaluated by the following clinical observations: coughing during or after swallowing, a wet voice after swallowing water and a choking sensation when attempting to drink a 10–20 ml volume of water. Although it was difficult for these patients to swallow solid food, they were at much greater risk of aspirating liquid material. Therefore, most of the patients preferred to take semisolid food. Twenty-one out of 35 patients with dysphagia were aware of their recent weight loss.
In most patients with bulbar/suprabulbar involvement (26 out of 35), the perioral muscles, tongue and submental-suprahyoid muscles were often weak. The mandibular and gag reflexes were also brisk in the majority of cases (25 out of 35 patients) and weakness of the laryngeal and respiratory muscles was determined clinically by the presence of dysphonia and/or weak coughing (28 out of 35 patients).
On the basis of clinical evaluations, the grading of dysphagia was severe (grade 4) in three patients in whom non-oral feeding was necessary. Dysphagia was clinically evident in 21 patients with amyotrophic lateral sclerosis, but these patients could manage by measures other than non-oral feeding (grade 3). In 11 amyotrophic lateral sclerosis patients, dysphagia was probable (grade 2) and in eight patients no difficulty related to swallowing was detected. In all amyotrophic lateral sclerosis patients, the degree of dysphagia was more easily and objectively determined by evaluating piecemeal deglutition and the dysphagia limit.
Piecemeal deglutition and the dysphagia limit
The dysphagia limit was >20 ml of water in all of the normal subjects investigated, whereas it was definitely pathological and 
20 ml in all amyotrophic lateral sclerosis patients with dysphagia. At this volume the bolus was divided into two or more parts in all patients with amyotrophic lateral sclerosis suffering from different degrees of dysphagia, as determined by objective electrophysiological methods (Ertekin et al., 1996, 1998a). The dysphagia limits of the eight amyotrophic lateral sclerosis patients without dysphagia were normal (i.e. >20 ml water). Figure 2 shows the normal and pathological dysphagia limits for two patients with amyotrophic lateral sclerosis. The clinical severity of dysphagia was significantly correlated with the dysphagia limit in amyotrophic lateral sclerosis patients (r = -0.86, P < 0.001). The dysphagia limit ranged between 1 and 3 ml water in severely dysphagic patients, whereas in patients with mild dysphagia it ranged between 10 and 15 ml.
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SM-EMG and reflex movements of the larynx during voluntarily initiated swallowing
In dysphagic amyotrophic lateral sclerosis patients, one of the prominent electrophysiological disorders was delay in the triggering of the swallowing reflex during the voluntarily initiated deglutition, as can be seen in Fig. 3
. The oblique arrows indicate the A–0 interval in wet swallowing in a normal subject and two amyotrophic lateral sclerosis patients with moderate (grade 3) and severe (grade 4) dysphagia. The A–0 interval was significantly prolonged in the amyotrophic lateral sclerosis patient with moderate dysphagia (middle panel in Fig. 3). This interval was ~274 ms in control subjects but had a much longer mean value (482 ms) in amyotrophic lateral sclerosis patients with dysphagia during wet swallowing (Table 1) (P < 0.01 for both wet and dry swallowing). On the other hand, the duration of the laryngeal relocation time (the interval between points 0 and 2 in Fig. 3, referred to here as the `0–2 interval') was not significantly different between normal subjects and amyotrophic lateral sclerosis patients with mild or moderate dysphagia. Although the 0–2 interval was slightly prolonged in some amyotrophic lateral sclerosis patients (nine out of 32 patients) when compared individually with the normal range, these individual differences were not statistically significant in either wet or dry swallowing. Collectively, these results indicate that, in amyotrophic lateral sclerosis patients with dysphagia, one of the prominent disorders is a delay or difficulty in triggering reflex swallowing during voluntarily initiated deglutition. However, once the swallowing reflex has been initiated, reflex swallowing can be carried to completion in these patients, just as in normal subjects.
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When amyotrophic lateral sclerosis patients were severely dysphagic (grade 4 or a dysphagia limit of ~1 ml), voluntarily triggered swallows could not be completed and all swallows remained at the reflex or so-called `spontaneous' stage, as can be seen in the bottom traces of Fig. 3
. In this situation, the A–0 interval or reflex triggering time was very short (<50 ms). In practice, the SM-EMG activity and the upward deflection of the larynx almost coincided. In some patients with severe dysphagia it was possible to see both a prolonged A–0 interval for the initiation of the swallowing reflex during a voluntary attempt and spontaneous swallowing with almost the same initiation time of SM-EMG and upward relocation of the larynx. Spontaneous swallows with the same characteristics have been observed and produced in normal subjects under some special conditions or during sleep (Fig. 4) (Ertekin et al., 1998b).
The total duration of SM-EMG (A–C interval) was prolonged in dysphagic patients, partly because of an increase in the A–0 interval (P < 0.001). Other electrophysiological parameters, such as the amplitude of submental muscle activity and the swallowing jitter, did not deviate from normal values (Table 1).
The A–0 interval and the 0–2 laryngeal relocation time during the swallowing of 3 ml water were compared in two dysphagic groups of patients with amyotrophic lateral sclerosis. The two groups comprised patients with either clinically predominant upper motor neuron (suprabulbar palsy; 18 cases) or lower motor neuron (bulbar palsy; eight cases) involvement. Figure 5 shows such a comparison with the mean values of A–0 and 0–2 intervals. The A–0 interval was significantly prolonged in patients with predominantly suprabulbar symptomatology (mean ± SEM, 559.6 ± 72.7 ms versus 298.0 ± 37.7 ms, P < 0.05). On the other hand, the 0–2 laryngeal relocation time did not differ significantly between the two groups (mean ± SEM, 676.7 ± 26.1 ms for the suprabulbar group and 713.5 ± 37.7 ms for the bulbar group, P > 0.05). Other parameters, such as the total duration of the SM-EMG, the amplitude of the SM-EMG and swallowing jitter, were not significantly different between the two groups.
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CP-EMG of the upper oesophageal sphincter during swallowing
The CP-EMG was investigated in 25 of 35 patients with amyotrophic lateral sclerosis, all of whom had dysphagia, and in four of eight patients without dysphagia. In amyotrophic lateral sclerosis patients with dysphagia, the most striking findings were found in the CP-EMG of the UES and in its relationship with laryngeal movements and the SM-EMG (Table 2
). Figure 6 shows the CP-EMG and the sensor signals of laryngeal movements during wet swallowing in two amyotrophic lateral sclerosis patients with dysphagia and a normal control subject. There were some distinguishing features of the CP-EMG results obtained from amyotrophic lateral sclerosis patients compared with those of normal subjects. First, the duration of the CP-EMG pause associated with the passage of the bolus into the oesophagus from the UES was considerably shortened (P < 0.001) (Fig. 6). Secondly, the CP-EMG pause produced by a swallow ended too early before the onset of the laryngeal downward movement (P < 0.05) (oblique arrow in Fig. 6B). In other words, the cricopharyngeal sphincter closed prematurely while the larynx was still in its elevated position. Thirdly, during the elevation of the larynx the cricopharyngeal muscle of the UES was not completely silent and some unexpected motor unit bursts appeared (Fig. 6C). This was in contrast to the complete silence of the cricopharyngeal muscle in normal subjects (Fig. 6A). Fourthly, there was a mild but statistically significant delay in the onset of the CP-EMG pause in relation to upward movement of the larynx. Individual results indicating the late opening and premature closing of the cricopharyngeal sphincter of the UES with respect to laryngeal movements are depicted graphically in Fig. 7.
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The last abnormality related to CP-EMG was encountered only in three patients with dysphagia who had other advanced bulbar and pseudobulbar clinical signs. In normal subjects, the SM-EMG normally begins earlier and ends later than the cricopharyngeal sphincter pause, whereas in these amyotrophic lateral sclerosis patients with dysphagia this activity ended almost in the middle of the CP-EMG pause (arrows in Fig. 8
). Similarly, a mild but statistically significant delay in the onset of the CP-EMG pause was observed in these patients when compared temporally with the negative peak of SM-EMG activity (Table 2).
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Shorter mean values were found for the CP-EMG pause in amyotrophic lateral sclerosis patients, probably as a result of the late opening and the premature closing of the UES. Unexpected extra motor unit bursts with an amplitude of >20 µV, occurring during the CP-EMG pause, must have been another factor that shortened the duration of the CP-EMG pause. Despite the pathological CP-EMG findings described above, individual motor unit potentials of the cricopharyngeal sphincter were similar to those of normal control subjects, and their values remained within the normal range for all amyotrophic lateral sclerosis patients at the different stages investigated. The incidences of all electrophysiological abnormalities are given separately in Table 3
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Electrophysiological abnormalities in relation to dysphagia
In normal control subjects, the CP-EMG pause significantly correlated with the 0–2 interval of the laryngeal sensor signal (r = 0.71, P < 0.001) (Fig. 9
). In other words, at the onset of the swallowing reflex the tonic activity of the cricopharyngeal sphincter was switched off and remained silent during transport of the bolus to the oesophagus. The EMG pause of the cricopharyngeal sphincter has a very close temporal correlation with the upward repositioning of the larynx. This important correlation of the time of the closure and upward repositioning of the larynx with the opening time of the CP-EMG was lost in patients with amyotrophic lateral sclerosis (r = -0.10, P > 0.05) (Fig. 9). In normal subjects, this correlation may indicate that, during a swallow, the upper relocation time of the larynx clearly coincides with the CP-EMG pause or vice versa, whereas the significance of this time relationship is not preserved in amyotrophic lateral sclerosis patients with dysphagia. Such lack of co-ordination between the laryngeal elevators and the cricopharyngeal muscle of the UES during swallowing is proposed as an obvious cause, among others, of dysphagia and the source of aspiration in amyotrophic lateral sclerosis patients. The severity of dysphagia and the level of the dysphagia limit also correlate well with the shortening of the CP-EMG pause (Fig. 10) (r = -0.56 and 0.54 respectively, P < 0.05), and this may also be closely linked with the same pathophysiological mechanism.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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In this study, we obtained the following electrophysiological findings in amyotrophic lateral sclerosis patients: (i) abnormalities in the reflex initiation of swallowing and in the elevation of the larynx during oropharyngeal swallowing; (ii) abnormalities in the dynamic features of the cricopharyngeal sphincter EMG during swallowing; and (iii) lack of co-ordination between the laryngeal elevator muscles (including the submental muscles) and cricopharyngeal sphincter muscles during oropharyngeal swallowing.
Abnormalities in the initiation of oropharyngeal swallowing and in the elevation of the larynx
The interval between the onset of SM-EMG (voluntary onset) and the first deflection of the laryngeal movement signal (reflex onset) (the A–0 interval), is prolonged during attempts to swallow in amyotrophic lateral sclerosis patients. This is probably caused by the delay in the triggering of the swallowing reflex, which has also been shown by cinefluoroscopic and videofluoroscopic studies (Bosma and Brodie, 1969; Logemann, 1983; Robbins, 1987; Briani et al., 1998). This delay in reflex activation may be the result of poor tongue and submental muscle control due to involvement of either lower or upper motor neurons or both. As a result of difficulties in the triggering of voluntary swallows, the bolus in the mouth will escape into the airway before the swallowing reflex takes over, resulting in subglottal aspiration (Logemann, 1983).
In order to keep the larynx in the upward-suspended position, the laryngeal elevators, including the submental muscles, need to overcome their weakness during swallowing. The weakness of the tongue muscles and the muscles of the mouth floor, including the submental muscles in amyotrophic lateral sclerosis, must be similar regardless of whether these muscles are mainly affected by upper motor neuron or lower motor neuron disorders. We propose that an upper motor neuron type of weakness of the muscles of the tongue and the mouth floor is more important in the development of swallowing disorders in voluntarily triggered deglutition. In this type of weakness, it is more difficult to move these muscles voluntarily while reflex movements can still occur easily. However, in patients with pure lower motor neuron disorders, both voluntary and reflexive movements are expected to be similarly weak. There is evidence for this conjecture, as summarized in the following paragraphs.
- (i) One of the important findings concerning dysphagia in amyotrophic lateral sclerosis is the difficulty in triggering a reflex swallow. This can be inferred from the significant prolongation of the A–0 interval, especially in patients with mild and moderate dysphagia (grade 2 or 3, or a dysphagia limit between 10 and 20 ml). Furthermore, dysphagic amyotrophic lateral sclerosis patients with predominant suprabulbar/corticobulbar involvement show significant prolongation of the A–0 interval in comparison with dysphagic patients with predominant bulbar lower motor neuron involvement. However, the laryngeal relocation time (0–2 interval) of the swallowing reflex does not differ between the two groups of patients (Fig. 5
). Thus, the voluntarily activated submental and tongue muscle fibres that control the first part of the SM-EMG would be weaker and less responsive to a volitional onset of swallowing because of a lesser degree corticobulbar excitatory drive. The remaining intact excitatory corticobulbar fibres would first try to compensate for the weakness in these striated muscles by sending more descending impulses, which would be dispersed throughout a longer time period than normal. Therefore, the voluntarily triggered swallowing reflex would be delayed and the A–0 interval observed in our records would be longer than normal. However, once the reflex was triggered, the laryngeal elevator muscles would have a reflex contraction and the laryngeal relocation time (0–2 interval) would frequently be within normal limits, as we have found in our patients. The delay in triggering the swallowing reflex from the voluntary initiation of dry and wet swallows can thus be attributed to the progressive degeneration of excitatory corticobulbar fibres. In the advanced stages of amyotrophic lateral sclerosis with severe dysphagia, it would be expected that the A–0 interval should get progressively shorter because of further degeneration of the corticobulbar fibres associated with swallowing. When all corticobulbar control was lost, all swallows would be spontaneous and controlled by the bulbar swallowing centre (Miller, 1982; Ertekin et al., 1998b). (ii) The observation that dysphagia is more often present in amyotrophic lateral sclerosis patients with prominent suprabulbar palsy has also been reported by other investigators (Buchholz, 1994
; Leighton et al., 1994; Hughes and Wiles, 1996b). (iii) The presence of lower motor neuron involvement in bulbar amyotrophic lateral sclerosis should not exclude the possibility of dysphagia. It is known that dysphagia is not rare in other disorders with pure lower motor neuron involvement associated with bulbar muscles, such as acute poliomyelitis, postpolio syndrome (Buchholz and Jones, 1991
; Silbergleit et al., 1991; Jones et al., 1992; Sonies and Dalakas, 1995) and X-linked bulbospinal muscle atrophy (Kennedy et al., 1968; Harding et al., 1982; Sobue et al., 1989). However, dysphagia appears to be mild and the incidence is lower in such anterior horn cell disorders. (iv) Using the same electrophysiological methods, we have shown that, in dysphagic patients with myasthenia gravis (Ertekin et al., 1998c
) and polymyositis (Ertekin et al., 1998a), triggering of reflex swallowing is not very severely disturbed or may even be normal, as judged by the normality of the A–0 interval. However, in these patients the relocation time of the larynx (0–2 interval) is often prolonged. Further evidence about the importance of suprabulbar motor fibres comes from our previous results obtained from patients with suprabulbar palsy with lacunar states. In these patients also, the A–0 interval was found to be as prolonged as in amyotrophic lateral sclerosis patients (Ertekin, 1996; Ertekin et al., 1998a). Therefore, we can reiterate that the major cause of dysphagia in amyotrophic lateral sclerosis, especially in relation to the triggering of the swallowing reflex, is due to the degeneration of the corticobulbar motor pathway.
Abnormalities in the dynamic features of the CP-EMG during swallowing
In amyotrophic lateral sclerosis patients with dysphagia, the most striking and common findings were obtained from the cricopharyngeal EMG: namely, the late opening and premature closure of the cricopharyngeal sphincter and unexpected bursts during the EMG pause. The duration of the CP-EMG pause was also shorter than in normal subjects, probably as a result of these abnormal changes. The cricopharyngeal sphincter, like other sphincter muscles, such as the external urethral sphincter muscle, has special functions and properties that are different from those of skeletal muscles. Although a striated muscle, it is innervated by the vagus nerve, and therefore it is not readily controlled by the voluntary motor system and is closed at rest (Miller, 1982; Goyal, 1984). During a swallow, the UES opens and the tonic activity of the cricopharyngeal muscle ceases simultaneously (Shipp et al., 1970; Asoh and Goyal, 1978; van Overbeek et al., 1985; Kahrilas et al., 1988; Cook et al., 1989; Elidan et al., 1990; Goyal et al., 1993; Ertekin et al., 1995). According to one view, the cessation of tonic activity of the cricopharyngeal sphincter muscle is believed to be due to central inhibition rather than to activity originating from the peripheral nervous system (Doty and Bosma, 1956; Miller, 1972, 1982; Jean and Car, 1979). However, no systematic study is available which shows this kind of inhibition in man. The contrary view is that the opening of the UES, together with the cessation of tonic activity in the cricopharyngeal muscle, is brought about by traction of the suprahyoid muscles which produce the anterior displacement of larynx (Asoh and Goyal, 1978; Goyal, 1984; Ekberg, 1986; Dodds et al., 1988; Cook et al., 1989; Jacob et al., 1989; Lang et al., 1991). Whatever the mechanism of opening of the upper oesophageal sphincter (i.e. central or peripheral), there is a time relationship between the activities of the suprahyoid-submental muscles of the laryngeal elevators and of the cricopharyngeal sphincter muscle during swallowing in normal subjects (Kahrilas et al., 1988; Lang et al., 1991; Ertekin et al., 1995, 1997). It is obvious that opening and closing mechanisms are remarkably disordered in amyotrophic lateral sclerosis patients with dysphagia, as detected by the CP-EMG and the laryngeal elevation parameters presented in this study. The shortening of the cricopharyngeal sphincter pause and late opening and premature closure with unexpected EMG bursts during the CP-EMG pause suggest that the cricopharyngeal sphincter muscle is hyper-reflexic/hypertonic, probably because of the central disinhibition of this muscle. On the other hand, the same abnormalities have been described by means of radiological and manometric studies in various non-neurological disorders which is known as `cricopharyngeal achalasia' (Goyal, 1984; Dantas et al., 1990). Cricopharyngeal achalasia is basically described as incomplete relaxation of the cricopharyngeal muscle. Paradoxical contraction or fibrosis that shortens the cricopharyngeal muscle may prevent full dilatation of the UES during swallowing (Goyal, 1984). By means of the same radiological methods, achalasia-like phenomena have also been reported in certain neurological disorders (Donner and Silbiger, 1966; Jones et al., 1985; Dodds et al., 1990). The nature and cause of cricopharyngeal sphincter abnormalities cannot be determined easily by radiological observations alone, as it is necessary to apply neurophysiological techniques to determine the neurological or non-neurological origin of these conditions. The abnormalities in the cricopharyngeal sphincter EMG presented in this study have not been described previously, especially from the electrophysiological point of view, in particular for neurogenic dysphagia in amyotrophic lateral sclerosis patients. These abnormalities are probably not only related to simple spasms of the sphincter muscle but are also caused by lack of co-ordination and/or disinhibition caused by a central disorder linked to upper motor neuron disease.
Lack of co-ordination between laryngeal elevator muscles and the cricopharyngeal sphincter
Kristmundsdottir and colleagues have shown that the cricopharyngeal muscle in amyotrophic lateral sclerosis is not significantly different from that in normal subjects with respect to most histometric and histopathological parameters (Kristmundsdottir et al., 1990). These authors thought that dysphagia was caused by interference from higher control centres leading to poorly co-ordinated relaxation of the pharyngo-oesophageal sphincter in amyotrophic lateral sclerosis. Therefore, it is possible that different kinds of involvement of the perioral, tongue and suprahyoid–submental muscle groups on the one hand and of the cricopharyngeal sphincter muscle of the UES on the other is one of the mechanisms of dysphagia in amyotrophic lateral sclerosis patients. The former group of bulbar muscles is involved in upper and/or lower motor dysfunction while the cricopharyngeal sphincter muscle is not affected by lower motor neuron involvement and is not paretic at all. But co-ordination between these two groups is disordered, probably because of upper motor neuron involvement, especially in the suprabulbar descending motor fibres. In this context, the first group of muscles is controlled densely by excitatory corticobulbar fibres and becomes weak in the course of amyotrophic lateral sclerosis, while the cricopharyngeal sphincter of the UES is not under strong voluntary control in normal conditions (Kahrilas et al., 1991) and becomes hyper-reflexic and hypertonic without any weakness during the course of amyotrophic lateral sclerosis. The hyper-reflexic cricopharyngeal muscle of the UES is very important for dysphagia. It is probable that the inhibitory effects on cricopharyngeal motor neurons and/or interneurons are not in effect due to the central pathologies of the pseudobulbar syndrome of amyotrophic lateral sclerosis. The hyper-reflexic nature of the cricopharyngeal sphincter of the UES is not surprising, as it is well known that the mandibular reflex is often brisk in amyotrophic lateral sclerosis, and it has been reported that other brainstem reflexes, such as palatal and gag reflexes, are often initiated more easily in amyotrophic lateral sclerosis (Buchholz, 1994; Leighton et al., 1994; Hughes and Wiles, 1996b). Hughes and Wiles have stated that the loss of corticobulbar pyramidal fibres may lead to brisker palatopharyngeal reflex responses because of a reduction in descending inhibition, and therefore probably produces the swallowing disorders in amyotrophic lateral sclerosis (Hughes and Wiles, 1996b).
In patients with amyotrophic lateral sclerosis, UES abnormalities akin to those found in electrophysiological recordings have been described by others using videofluoroscopic methods (Bosma and Brodie, 1969; Leighton et al., 1994; Briani et al., 1998). Indeed, for a long time cricopharyngeal myotomy has been used for relieving dysphagia in amyotrophic lateral sclerosis and in a number of other neurological disorders. The rationale behind this operation has been to alleviate upper oesophageal spasm and hypertonus, although the place of cricopharyngeal myotomy in the treatment of dysphagia in amyotrophic lateral sclerosis and in other disorders has long been debated and questioned (Lebo et al., 1976; Duranceau et al., 1987; Milford and Price, 1989; Elidan et al., 1990; MacDougall et al., 1995; Poirier et al., 1997; Briani et al., 1998).
The relationship between the laryngeal relocation time and the opening of the UES has been demonstrated clearly with different bolus volumes in normal subjects (Kahrilas et al., 1988; Cook et al., 1989; Jacob et al., 1989; Ertekin et al., 1997). The correlation of the laryngeal elevation and relocation time with the opening of the cricopharyngeal sphincter of the UES was found to disappear in the amyotrophic lateral sclerosis patients investigated in this study. This finding indicates that the biological adaptation and co-ordination between the submental muscles and the cricopharyngeal striated sphincter disappear during voluntarily triggered swallowing in amyotrophic lateral sclerosis. As a result of the shorter opening time and the premature closure of the cricopharyngeal sphincter that occur before the larynx descends from its upward position, the bolus will be retained in the pharyngeal spaces, and then, after the larynx has descended from its upper location, the bolus will escape into the airway and result in subglottal aspiration.
It is possible that the voluntarily triggered swallows are initiated by cortical descending inputs to the swallowing centres while the spontaneous and reflex swallows are initiated only by the bulbar swallowing centre (Jean and Car, 1979; Miller, 1982, 1993; Martin and Sessle, 1993). Therefore, in amyotrophic lateral sclerosis, voluntarily triggered swallows would become difficult as a result of progressive degeneration of the corticobulbar-pyramidal motor fibres. In the advanced stages of amyotrophic lateral sclerosis, voluntarily triggered swallows cannot be performed because of excessive loss of corticobulbar fibres. However, the purely reflex mechanism would still be in operation under the control of the bulbar swallowing centre. Therefore, the spontaneous and reflex swallows would be intact and the patients would be able to swallow their saliva, which was ~1 ml in volume (Logemann, 1996). Such spontaneous saliva swallowing was demonstrated by our electrophysiological method (Ertekin et al., 1998b).
It has been shown recently that the corticospinal and corticobulbar descending motor fibres are involved early and frequently in amyotrophic lateral sclerosis, as demonstrated by transcranial magnetic stimulation (Eisen et al., 1993; Prout and Eisen, 1994; Desiato and Caramia, 1997). As a result, striated spinal and bulbar muscles can become deficient both in their excitatory and in their inhibitory corticospinal/corticobulbar drives (Yokota et al., 1996; Desiato and Caramia, 1997; Enterzari-Taher et al., 1997; Ziemann et al., 1997). The motor neurons of the cricopharyngeal sphincter muscle must be released from this descending inhibitory control, and consequently they become hyper-reflexic, uncontrollable and unco-ordinated during swallowing in amyotrophic lateral sclerosis patients. This may lead to dysphagia, especially when accompanied by weakness in the striated muscles of the oropharynx and larynx. In other words, the central pacemaker or central swallowing programme at the bulbar centre becomes disturbed by the removal of inhibitory corticobulbar influences (Doty and Bosma, 1956; Doty et al., 1967; Miller, 1982; Zoungrana et al., 1997). Swallowing is finally restricted to the spontaneous-reflexive swallows; however, this kind of swallow can become risky for the patient because of lack of co-ordination in the cricopharyngeal sphincter during the advanced stages of the disease (Hillel and Miller, 1989; Strand et al., 1996).
In conclusion, two pathophysiological mechanisms operate in the dysphagia of amyotrophic lateral sclerosis patients: (i) the triggering of the swallowing reflex for the voluntarily initiated swallows is delayed, disordered and eventually absent while the spontaneous reflexive swallows are preserved until the preterminal stage of amyotrophic lateral sclerosis; and (ii) the cricopharyngeal sphincter muscle of the pharyngo-oesophageal segment becomes hyper-reflexic and hypertonic. As a result, the laryngeal protective system and the bolus transport system of deglutition lose their co-ordination during voluntarily initiated oropharyngeal swallowing. Thus, we propose that these pathophysiological changes in the dysphagia of amyotrophic lateral sclerosis patients are primarily associated with the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres.
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We wish to thank Professor Gürbüz Cielebi, Dr Bülent Turman and Dr Nilüfer Ertekin-Taner for their invaluable help in preparing this manuscript. This study was supported by a grant from the Turkish Scientific and Technological Research Council (TUBTAK) (Project SBAG-1739).
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Asoh R, Goyal RK. Manometry and electromyography of the upper esophageal sphincter in the opossum. Gastroenterology 1978; 74: 514–20.[Web of Science][Medline]
Bosma JR, Brodie DR. Disabilities of the pharynx in amyotrophic lateral sclerosis as demonstrated by cineradiography. Radiology 1969; 92: 97–103.[Web of Science][Medline]
Briani C, Marcon M, Ermani M, Constantini M, Bottin R, Iurilli V, et al. Radiological evidence of subclinical dysphagia in motor neuron disease. J Neurol 1998; 245: 211–6.[Web of Science][Medline]
Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Disease/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial `Clinical limits of amyotrophic lateral sclerosis' workshop contributors. J Neurol Sci 1994; 124 Suppl: 96–107.
Buchholz DW. Neurogenic dysphagia: what is the cause when the cause is the not obvious? [Review]. Dysphagia 1994; 9: 245–55.[Medline]
Buchholz D, Jones B. Dysphagia occurring after polio. Dysphagia 1991; 6: 165–9.[Medline]
Carpenter RJ 3rd, McDonald TJ, Howard FM Jr. The otolaryngologic presentation of amyotrophic lateral sclerosis. Otolaryngology 1978; 86: ORL479–84.[Medline]
Cook IJ, Dodds WJ, Dantas RO, Massey B, Kern MK, Lang IM, et al. Opening mechanisms of the human upper esophageal sphincter. Am J Physiol 1989; 257: G748–59.
Dantas RO, Kern MK, Massey BT, Dodds WJ, Kahrilas PJ, Brasseur JG, et al. Effect of swallowed bolus variables on oral and pharyngeal phases of swallowing. Am J Physiol 1990; 258: G675–81.
Desiato MT, Caramia MD. Towards a neurophysiological marker of amyotrophic lateral sclerosis as revealed by changes in cortical excitability. Electroencephalogr Clin Neurophysiol 1997; 105: 1–7.[Medline]
Dodds WJ, Man KM, Cook IJ, Kahrilas PJ, Stewart ET, Kern MK. Influence of bolus volume on swallow-induced hyoid movement in normal subjects. AJR Am J Roentgenol 1988; 150: 1307–9.
Dodds WJ, Stewart ET, Logemann JA. Physiology and radiology of the normal oral and pharyngeal phases of swallowing. AJR Am J Roentgenol 1990; 154: 953–63.
Donner MW, Silbiger ML. Cinefluorographic analysis of pharyngeal swallowing in neuromuscular disorders. [Review]. Am J Med Sci 1966; 251: 600–16.[Web of Science][Medline]
Donner MW, Bosma JF, Robertson DL. Anatomy and physiology of the pharynx. Gastrointest Radiol 1985; 10: 196–212.[Web of Science][Medline]
Doty RW, Bosma JF. An electromyographic analysis of reflex deglutition. J Neurophysiol 1956; 19: 44–60.
Doty RW, Richmond WH, Storey AT. Effect of medullary lesions on coordination of deglutition. Exp Neurol 1967; 17: 91–106.[Web of Science][Medline]
Duranceau A, Lafontaine ER, Taillefer R, Jamieson GG. Oropharyngeal dysphagia and operations on the upper esophageal sphincter. [Review]. Surg Annu 1987; 19: 317–62.[Medline]
Eisen A, Pant B, Stewart H. Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 1993; 20: 11–6.[Web of Science][Medline]
Ekberg O. The normal movements of the hyoid bone during swallow. Invest Radiol 1986; 21: 408–10.[Web of Science][Medline]
Elidan J, Shochina M, Gonen B, Gay I. Manometry and electromyography of the pharyngeal muscles in patients with dysphagia. Arch Otolaryngol Head Neck Surg 1990; 116: 910–3.
Enterzari-Taher M, Eisen A, Stewart H, Nakajima M. Abnormalities of cortical inhibitory neurons in amyotrophic lateral sclerosis. Muscle Nerve 1997; 20: 65–71.[Web of Science][Medline]
Ertekin C. Clinical diagnosis and electrodiagnosis of swallowing disorder. In: Swenson MR, editor. Disorders of speech and swallowing. American Association of Electrodiagnostic Medicine, 19th Annual Continuing Education Course, Minneapolis (MN): Johnson Printing Company; 1996. p. 23–33.
Ertekin C, Pehlivan M, Aydogdu I, Ertas M, Uludag B, Cielebi G, et al. An electrophysiological investigation of deglutition in man. Muscle Nerve 1995; 18: 1177–86.[Web of Science][Medline]
Ertekin C, Aydogdu I, Yüceyar N. Piecemeal deglutition and dysphagia limit in normal subjects and in patients with swallowing disorders. J Neurol Neurosurg Psychiatry 1996; 61: 491–6.
Ertekin C, Aydogdu I, Yüceyar N, Pehlivan M, Ertas M, Uludag B, et al. Effects of bolus volumes on the oropharyngeal swallowing: an electrophysiological study in man. Am J Gastroenterol, 1997; 92: 2049–53.[Web of Science][Medline]
Ertekin C, Aydogdu I, Yüceyar N, Tarlaci S, Kiylioglu N, Pehlivan M, et al. Electrodiagnostic methods for neurogenic dysphagia. Electroencephalogr Clin Neurophysiol 1998a; 109: 331–40.[Medline]
Ertekin C, Kiylioilu N, Tarlaci S, Aydogdu I, Yüceyar N. Electrophysiological identification of voluntary and reflex swallows. Electroencephalogr Clin Neurophysiol 1998b; 106 Suppl: 60.
Ertekin C, Yüceyar N, Aydogdu I. Clinical and electrophysiological evaluation of dysphagia in myasthenia gravis. J Neurol Neurosurg Psychiatr 1998c; 65: 848–56.
Gay T, Rendell JK, Spiro J. Oral and laryngeal muscle coordination during swallowing. Laryngoscope 1994; 104: 341–9 .[Web of Science][Medline]
Goyal RK. Disorders of the cricopharyngeus muscle. Otolaryngol Clin North Am 1984; 17: 115–30.[Web of Science][Medline]
Goyal RK, Martin SB, Shapiro J, Spechler SJ. The role of cricopharyngeus muscle in pharyngoesophageal disorders. [Review]. Dysphagia 1993; 8: 252–8.[Medline]
Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan-Hughes JA, Ponsford JR. X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 1982; 45: 1012–9.
Hillel AD, Miller R. Bulbar amyotrophic lateral sclerosis: patterns of progression and clinical management. Head Neck 1989; 11: 51–9.[Web of Science][Medline]
Hughes TA, Wiles CM. Clinical measurement of swallowing in health and in neurogenic dysphagia. QJM 1996a; 89: 109–16.[Abstract]
Hughes TA, Wiles CM. Palatal and pharyngeal reflexes in health and motor neuron disease. J Neurol Neurosurg Psychiatry 1996b; 61: 96–8.
Jacob P, Kahrilas PJ, Logemann JA, Shah V, Ha T. Upper esophageal sphincter opening and modulation during swallowing. Gastroenterology 1989; 97: 1469–78.[Web of Science][Medline]
Jean A, Car A. Inputs to the swallowing medullary neurons from the peripheral afferent fibers and the swallowing cortical area. Brain Res 1979; 178: 567–72.[Web of Science][Medline]
Jones B, Ravich WJ, Donner MW, Kramer SS, Hendrix TR. Pharyngoesophageal interrelationships: observations and working concepts. Gastrointest Radiol 1985; 10: 225–133.[Web of Science][Medline]
Jones B, Buchholz DW, Ravich WJ, Donner MW. Swallowing dysfunction in the postpolio syndrome: a cinefluorographic study. AJR Am J Roentgenol 1992; 158: 283–6.
Kahrilas PJ, Dodds WJ, Dent J, Logemann JA, Shaker R. Upper esophageal sphincter function during deglutition. Gastroenterology 1988; 95: 52–62.[Web of Science][Medline]
Kahrilas PJ, Logemann JA, Krugler C, Flanagan E. Volitional augmentation of upper esophageal sphincter opening during swallowing. Am J Physiol 1991; 260: G450–6.
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968; 18: 671–80.
Kristmundsdottir F, Mahon M, Froes MM, Cumming WJ. Histomorphometric and histopathological study of the human cricopharyngeus muscle: in health and in motor neuron disease. Neuropathol Appl Neurobiol 1990; 16: 461–75.[Web of Science][Medline]
Lang IM, Dantas RO, Cook IJ, Dodds WJ. Videoradiographic, manometric and electromyographic analysis of canine upper esophageal sphincter. Am J Physiol 1991; 260: G911–9.
Lebo CP, U KS, Norris FH Jr. Cricopharyngeal myotomy in amyotrophic lateral sclerosis Laryngoscope 1976; 86: 862–8.
Leighton SE, Burton MJ, Lund WS, Cochrane GM. Swallowing in motor neurone disease. J R Soc Med 1994; 87: 801–5.[Abstract]
Linden P, Kuhlemeer KV, Patterson C. The probability of correctly predicting subglottic penetration from clinical observations. Dysphagia 1993; 8: 170–9.[Medline]
Logemann JA. Evaluation and treatment of swallowing disorders. San Diego: College Hill Press; 1983.
Logemann JA. Screening, diagnosis, and management of neurogenic dysphagia. [Review]. Semin Neurol 1996; 16: 319–27.[Web of Science][Medline]
MacDougall G, Wilson JA, Pryde A, Grant R. Analysis of the pharyngoesophageal pressure profile in amyotrophic lateral sclerosis. Otolaryngol Head Neck Surg 1995; 112: 256–61.
Martin RE, Sessle BJ. The role of the cerebral cortex in swallowing. [Review]. Dysphagia 1993; 8: 195–202.[Medline]
McGuirt WF, Blalock D. The otolaryngologist's role in the diagnosis and treatment of amyotrophic lateral sclerosis. Laryngoscope 1980; 90: 1496–501.[Web of Science][Medline]
Milford CA, Price G. Dysphagia in motor neurone disease: the place of cricopharyngeal myotomy [abstract]. Clin Otolaryngol 1989; 14: 270.
Miller AJ. Significance of sensory inflow to the swallowing reflex. Brain Res 1972; 43: 147–59.[Web of Science][Medline]
Miller AJ. Deglutition. [Review]. Physiol Rev 1982; 62: 129–84.
Miller AJ. The search for the central swallowing pathway. The quest for clarity. [Review]. Dysphagia 1993; 8: 185–194.[Medline]
Pehlivan M, Yüceyar N, Ertekin C, Cielebi G, Ertas M, Kalayci T, et al. An electronic device measuring the frequency of spontaneous swallowing: digital phagometer. Dysphagia 1996; 11: 259–64.[Web of Science][Medline]
Perlman AL, Christenson J. Topography and functional anatomy of the swallowing structures In: Perlman AL, Schulze-Delrieu KS, editors. Deglutition and its disorders. San Diego: Singular Publication Group; 1997. p. 15–42.
Poirier NC, Bonavina L, Taillefer R, Nosadini A, Peracchia A, Duranceau A. Cricopharyngeal myotomy for oropharyngeal neurogenic dysphagia. J Thorac Cardiovasc Surg 1997; 113: 233–41.
Prout AJ, Eisen AA. The cortical silent period and amyotrophic lateral sclerosis. Muscle Nerve 1994; 17: 217–23.[Web of Science][Medline]
Robbins J. Swallowing in ALS and motor neuron disorders. Neurol Clin 1987; 5: 213–29.[Web of Science][Medline]
Roller NW, Garfunkel A, Nichols C, Ship II. Amyotrophic lateral sclerosis. Oral Surg Oral Med Oral Pathol 1974; 37: 46–52.[Web of Science][Medline]
Shipp T, Deatsch WW, Robertson K. Pharyngoesophageal muscle activity during swallowing in man. Laryngoscope 1970; 80: 1–16.[Web of Science][Medline]
Silbergleit AK, Waring WP, Sullivan MJ, Maynard FM. Evaluation, treatment and follow-up results of postpolio patients with dysphagia. Otolaryngol Head Neck Surg 1991; 104: 333–8.[Web of Science][Medline]
Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A. X-linked recessive bulbospinal neuronopathy: a clinicopathological study. Brain 1989; 112: 209–32.
Sonies BC, Dalakas MC. Progression of oral motor and swallowing symptoms in the post-polio syndrome. Ann NY Acad Sci 1995; 753: 87–95.[Web of Science][Medline]
Splaingard ML, Hutchins B, Sulton LD, Chaudhuri G. Aspiration in rehabilitation patients: videofluoroscopy vs bedside clinical assessment. Arch Phys Med Rehabil 1988; 69: 637–40.[Web of Science][Medline]
Strand EA, Miller RM, Yorkston KM, Hillel AD. Management of oral-pharyngeal dysphagia symptoms in amyotrophic lateral sclerosis. Dysphagia 1996; 11: 129–39.[Web of Science][Medline]
van Overbeek JJ, Wit HP, Paping RH, Segenhout HM. Simultaneous manometry and electromyography in the pharyngoesophageal segment. Laryngoscope 1985; 95: 582–4.[Web of Science][Medline]
Wright R, Jordan C. Videofluoroscopic evaluation of dysphagia in motor neurone disease with modified barium swallow. Palliat Med 1997; 11: 44–8.
Yokota T, Yoshino A, Inaba A, Saito Y. Double cortical stimulation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1996; 61: 596–600.
Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 1997; 49: 1292–8.
Zoungrana OR, Amri M, Car A, Roman C. Intracellular activity of motoneurons of the rostral nucleus ambiguus during swallowing in sheep. J Neurophysiol 1997; 77: 909–22.
Received June 3, 1999. Accepted July 16, 1999.
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