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Mean Contact Quotient Using Electroglottography in Patients With Multiple Sclerosis
Mean Contact Quotient Using Electroglottography in Patients With Multiple Sclerosis *Bassem Yamout, †Zaid Al-Zaghal, †Iyad El-Dahouk, ‡Sahar Farhat, §Abla Sibai, and †Abdul-Latif H. Hamdan, *yzxBeirut, Lebanon
Summary: Objective. To compare the mean and standard deviation (SD) of the contact quotient (CQ) of the sustained vowels ([a] and [e]) in multiple sclerosis (MS) patients versus controls. Study Design. Cross-sectional study. Materials and Methods. Thirty-nine subjects (24 patients and 15 controls) participated in this study. Laryngeal electroglottography was performed on all subjects while phonating the vowels [a] and [e] at a comfortable pitch and loudness. The fundamental frequency, mean CQ, SDs, and jitter were computed for both vocal tasks. Results. The mean age of the MS group was 36.25 + 10.61 years. All laryngeal examinations were normal and five patients with MS had dysphonia described as voice breaks and fatigue in connected speech. For both vowels [a] and [e], the mean closed quotients were comparable in groups, MS and control (43.90 vs 53 for [a] and 44.75 vs 43.63 for [e]) with no significant difference. When comparing five MS patients with dysphonia versus controls, for the vowel [a], the mean closed quotient was significantly lower in MS patients with dysphonia (P values of 0.043). Conclusion. The mean closed quotient for sustained vowels [a] and [e] are comparable in MS patients and healthy controls except in patients with dysphonia. Key Words: Contact quotient–Electroglottography–Multiple sclerosis. INTRODUCTION Multiple Sclerosis (MS) is an autoimmune inflammatory disorder that affects various parts of the central nervous system. The disease was first described in 1868 by Charcot1 as a chronic degenerative neurologic disorder that results in demyelination and loss of conductive properties of axons within the brain and spinal cord. Women are affected more than men and the prevalence rate ranges from 2 to 150 per 100 000 with varying geographic distribution.2,3 Several etiologic factors have been implicated and these include genetic, infectious, and environmental. As a result of the widespread involvement of the nervous system, MS has a wide range of neurologic manifestations with motor, sensory, and cognitive impairments. The most common symptoms attributed to MS are optic neuritis, nystagmus, tremors, gait instability, sexual and bladder incontinence, scanning speech, and last but not the least phonatory instabilities. The ‘‘scanning speech’’ or dysarthria of MS is predominantly mixed with both an ataxic and a spastic component to it.4,5 Phonatory disturbances on the other hand span a large array of symptoms ranging from impairments of loudness control, pitch control, voice breaks, harshness, hypernasality, and breathiness.6–9 Despite the fact that dysarthria and phonatory symptoms have been reported in more than 50% of MS patients, research on dysAccepted for publication October 31, 2012. No conflict of interest or financial support in relation to this manuscript. The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. From the *Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon; yDepartment of Otolaryngology–Head and Neck Surgery, American University of Beirut Medical Center, Beirut, Lebanon; zDepartment of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; and the xDepartment of Epidemiology and Population Health, American University of Beirut, Beirut, Lebanon. Address correspondence and reprint requests to Abdul-Latif H. Hamdan, Department of Otolaryngology–Head and Neck Surgery, American University of Beirut, PO Box 11-0236, Beirut, Lebanon. E-mail: [email protected] Journal of Voice, Vol. 27, No. 4, pp. 506-511 0892-1997/$36.00 Ó 2013 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2012.10.016
phonia in association with this disease remains scarce.4,5,10–12 Very few studies have discussed the phonatory symptoms in MS patients using objective measures.6–9,13,14 Many of these were based on the self-reported questionnaires and perceptual evaluation with less focus on acoustic analysis and particularly on electroglottography (EGG) as a descriptive tool.7,9 The contact quotient (CQ), an outcome measure of EGG, is an important indicator of vocal folds closure during phonation. It provides an indirect and noninvasive measure of the closure pattern by reflecting the amount of transverse impedance across the glottis. A decrease in the mean closed quotient would suggest a glottic insufficiency with an increase in the mean flow rate, whereas an increase in the mean closed quotient would suggest a hyperfunctional glottic behavior. Organic lesions of the vocal fold resulting in an increase in the closing phase are associated with an elevated closed quotient, whereas bowing of the vocal folds with glottic insufficiency is associated with a reduced closed quotient.15–17 Konstantopoulos et al6 was the only one to use EGG as an objective voice analysis tools to investigate the vocal fold closure in MS patients. In his investigation, the EGG parameters used were vocal jitter, mean fundamental frequency, and standard deviation (SD) of the average fundamental frequency. The results indicated that these vocal parameters differentiated the MS group from controls, but there was no mentioning of the mean CQ. The purpose of this study is to make a comparative analysis of the mean and SD of the CQ of the sustained vowels [a] and [e] in MS patients versus controls. The fundamental frequency, SD, and jitter will also be reported. MATERIALS AND METHODS A total of 39 subjects were asked to participate in this study after having read and signed the informed consent approved by
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the Institutional Review Board at the American University of Beirut. Confidentiality was maintained throughout the data collection process. All data were kept under lock and key and it was accessible only to the principal investigator and his research team. Subjects with recent history of upper respiratory tract infection, laryngeal manipulation, or previous laryngeal surgery were excluded from this study. All subjects with evidence of vocal fold lesion on laryngeal examination were also excluded. The subjects were divided into two groups, 24 with MS and 15 as controls matched according to age and gender. Because of the known gender effect on fundamental frequency and mean CQ, the female to male ratio was similar in both groups. The prevalence of smoking was also comparable in both groups in view of its confounding effect. Patients with MS were all in the relapse remitting stage and were referred from the private clinic of the neurology service. Demographic variables included age, gender, and history of smoking. Variables taken into consideration included duration of the disease in years, the expanded disability status scale (EDSS) reflecting the severity of the disease, the severity of fatigue, and depression. For the disability status, a score between 0 and 3 was considered mild, 3.5–6 as moderate, and above 6 as severe18; the presence and severity of fatigue were assessed by means of the Fatigue Severity Scale (FSS). This test consists of nine items concerning fatigue each rated on a seven-point scale. The average rating is computed for all nine items with higher scores indicating increasing fatigue. A cutoff point of 4 was taken in this study. This test was chosen in view of its accepted consistency, stability, and sensitivity to clinical stage.19–21 Depression was evaluated using the Hamilton Rating Scale for Depression, which consists of 21 items rated from 0 to 4 with a higher score indicating increasing severity of depression.22 All subjects underwent laryngeal examination and were asked about the prevalence of dysphonia. Dysphonia was defined as change in voice quality, pitch, loudness, or effort. All subjects underwent laryngeal EGG while seated in the upright position in a quiet room at the ‘‘Hamdan voice unit.’’ For this study, the EGG amplifier model 6103 by KayPENTAX (Pine Brook, NJ) and Real Time EEG Analyzer software package model 5138 (KayPENTAX) were used for data collection and analysis. All the participants’ neck and the surfaces of the electrodes were cleaned with alcohol before the testing. The participants were assisted in placing and holding the surface electrodes on either side of the thyroid cartilages. These were held in place using a neck strap and/or by asking the participant to hold them in position. Each participant phonated the vowels [a] and [e] at a comfortable pitch and loudness. The test was repeated several times until we obtained a good tracing of the graph. In many subjects, the system gain had to be put on the high position to ensure an adequate wave. Using the cursor, the middle 3 seconds of each sample measured was used for analysis disregarding the onset and offset time. The fundamental frequency, mean CQ, SDs, and jitter were computed for both vocal tasks. CQ was measured using an algorithm in the software that estimated glottal closure based on the temporal width 70% of the peak-to-peak amplitude below the positive peak. The authors have selected this measurement algorithm based
on its availability in the program used and given the frequency of its reported usage in the literature. Demographic characteristics of the participants were examined separately for cases and controls using frequency distributions for categorical variables (gender and smoking) and means with SDs for continuous ones (age, duration of MS, EDSS, FSS score, and Hamilton Depression Scale [HDS]). Two independent samples t tests were done to measure the differences between controls and all cases and then between controls and only cases having dysphonia, in terms of the selected variables (mean CQ, SD CQ, range, jitter, and fundamental frequency for both [a] and [e]). Two other independent samples t tests were performed for males and females separately to measure the differences between cases and controls in terms of fundamental frequencies of [a] and [e]. Linear regressions model was used to report R2 as a measure of association between the dependent variable mean CQ and the independent variables FSS score, HDS, EDSS score, and disease duration among cases. A P value <0.05 was considered as significant. Analyses were performed using Statistical Analysis Package for Social Sciences (Version 19.0; SPSS, Chicago, IL). RESULTS Demographic data The mean age of the MS group was 36.25 + 10.61 years. Fortyfive percent were males and close to one-third were smokers. The mean duration of the disease was 5.37 + 5.09 years, and the mean EDSS score was 1.45 + 1.79. The FSS score was 3.97 + 2.28. The HDS score was 8.58 + 9.63, Table 1. Laryngeal findings and phonatory symptoms All the laryngeal examinations were normal with no evidence of bowing, glottic insufficiency, or hypoadduction. No abnormal closure or pathology were observed in any of the diseased or control subjects. In the MS group, five patients had dysphonia, whereas in the control group, only one had change in voice
TABLE 1. Demographics Cases, N ¼ 24
Controls, N ¼ 15
Variables
Mean
SD
Mean
SD
Age (y) Duration of MS (y) EDSS score FSS score HDS score
36.25 5.37 1.45 3.97 8.58
10.61 5.09 1.79 2.28 9.63
30.60 N/A N/A N/A N/A
7.28 N/A N/A N/A N/A
n
(%)
n
(%)
11 9
45.8 37.5
7 5
46.7 33.3
Gender (% male) Smoking (% yes)
Abbreviations: EDSS, expanded disability status scale; FSS, fatigue severity scale; HDS, Hamilton Depression Scale.
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quality. In the MS group, the change in voice quality for connected speech was described as vocal breaks and increased effort. Mean closed quotient, SD, fundamental frequency, and jitter for vowels [a] and [e] in all MS patients and controls For the vowel [a], the mean closed quotient was comparable in both MS and control groups (43.90 and 45.53) with no significant difference between the two (P value 0.299). Similarly for all other parameters, namely SDs, jitter, and fundamental frequency, there were no significant differences between the two groups, even though it is worth noting that the jitter value was higher in the MS group (3.38 vs 1.82). For the vowel [e], the mean closed quotient was comparable in both MS and control groups (44.75 vs 43.63) with no significant difference between the two (P value 0.480). Similarly for all other parameters, namely SDs, jitter, and fundamental frequency, there were no significant differences between the two groups, Table 2. When stratified by gender, there was still no significant difference in the fundamental frequency between the MS group and the controls for both [a] and [e], Table 3. Mean CQ in patients with MS and phonatory symptoms versus controls For the vowel [a], the mean CQ was significantly lower in patients with MS and phonatory symptoms compared with controls with P values of 0.043. For the vowel [e], there was no significant difference between the two groups in any of the EGG parameters, Table 4. It is worth noting that the jitter SD for MS patients with dysphonia was high compared with controls. This is attributed to the fact that one of the five patients had an elevated jitter value. Excluding this subject from the analysis did not change the significance of the results. The P values for both vowels /a/ and /e/ in comparison with controls were 0.129 and 0.3191, respectively. Association between mean CQ and FSS score, HDS score, EDSS score, and disease duration in patients with MS There was a significant association between the mean CQ and the FSS score (P value of 0.002), albeit the r value was 0.36
indicating a rather moderate correlation. There was no significant association between the mean CQ and any of the remaining variables, namely duration of the disease, extent of disability, and depression score, Table 5. Correlation was also made between dysphonic patients and the aforementioned variables namely: FSS score, HDS score, EDSS score, and duration of the disease. The results indicated additional moderate correlation (R2 ¼ 0.43) that was not significant (P value of 0.231). DISCUSSION The larynx is a complex structure that depends heavily on neural control. As a result, disorders of the nervous system affect phonation with voice symptoms being among the earliest to develop. Dysphonia in association with many neurologic diseases such as stroke, Parkinson disease, and vocal fold paralysis has been extensively reported in the literature with less emphasis on MS.6–9 In MS patients, dysphonia has been described as voice breaks, increase in vocal fatigue, harshness, impaired control of loudness and pitch, breathiness, and at times hypernasality. The prevalence of dysphonia in MS patients varies between 25% and 70%.6–9,13,14 The variation in the prevalence rate has been attributed to differences in the selection of participants, study designs, and most of all to the variability in the outcome measures. Lower rates have been noted when self-reported symptoms have been analyzed, whereas higher rates have been found when objective voice analysis instruments have been used. Hartelius et al5 has described impairment of speech and voice in 44% of MS patients, whereas Feijo et al7 reported dysphonia in 70% of MS patients compared with control. The former has used a survey in his investigation, whereas the later has used wideband and narrowband spectrogram in his analysis. Feijo et al has found an association between dysphonia and MS with higher fundamental frequency in affected individuals. When stratified by gender, the fundamental frequency deviation was significantly higher in MS women and jitter was higher in MS men compared with controls. Dogan et al8 in his report on 27 female patients with MS, the frequency of varying degrees of dysphonia was 33.4% compared with 7.4% in controls based on the perceptual evaluation. His results were partially substantiated by the findings on acoustic analysis where the mean jitter, shimmer, and Soft Phonation Index in MS patients were
TABLE 2. Mean CQ, SD, Range, Jitter, and Fundamental Frequency for Vowels [a] and [e] in MS Patients and Controls [a] Cases Variables Mean CQ SD CQ Range Jitter Fundamental frequency Abbreviation: CQ, contact quotient.
[e] Controls
Cases
Controls
Mean ± SD
Mean ± SD
P Value
Mean ± SD
Mean ± SD
P Value
43.90 ± 5.14 4.69 ± 5.06 25.56 ± 23.75 3.38 ± 7.58 168.95 ± 54.33
45.53 ± 3.87 5.41 ± 4.38 26.63 ± 21.53 1.82 ± 2.35 175.48 ± 52.97
0.299 0.649 0.888 0.446 0.715
44.75 ± 4.75 4.18 ± 5.11 20.98 ± 19.17 2.90 ± 8.32 176.54 ± 61.04
43.63 ± 4.79 4.33 ± 5.03 20.63 ± 19.20 2.76 ± 8.35 178.34 ± 49.54
0.480 0.930 0.957 0.959 0.924
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TABLE 3. Difference Between MS Patients and Controls in Terms of Fundamental Frequencies for Vowels [a] and [e] Among Males and Females Males, N ¼ 18
Fundamental Frequency [a] [e]
Cases
Control
Mean ± SD
Mean ± SD
120.15 ± 28.97 123.58 ± 25.51
125.56 ± 10.62 133.94 ± 20.83
significantly increased, but there were no significant differences in terms of mean fundamental frequency and noise-to-harmonic ratio. The authors of this manuscript have previously reported on the vocal symptoms in MS patients and acoustic findings. The results of the investigation indicated a significant decrease in the fundamental frequency, habitual pitch, and maximum phonation time with a significant increase in shimmer in males. In the female group, there was a significant decrease in the maximum phonation time only. The results of this investigation are in partial agreement with the previous reports in terms of acoustic findings. Similar to the results of Dogan et al, the mean fundamental frequency was not statistically different between the MS group and controls even when stratified by gender as seen in Table 3. With respect to jitter, there was an increase in the MS group compared with control, even though the difference was not statistically significant. The phonatory and acoustic changes in MS patients can been attributed to alterations in periaqueductal gray matter with neuronal concentrations and projections into the nucleus retroambigualis. These alterations are related to abdominal, intercostal, pharyngeal, palatal, lingual, facial, and laryngeal motor neurons and thus have an effect on phonation. The slowing down of the electrical impulse through the demyelinated neurons in MS patients causes an alteration of the recovery synchrony, leading to the variability in muscle contraction and a larger variation in cycle-to-cycle frequency. In other words, there is an increase in short-term phonatory instability.23–25 This was evidenced in our study by the increase in jitter even though it was not statistically significant. Looking at the vocal folds contact time, the results of our study showed no significant difference in any of the EGG pa-
Females, N ¼ 21 Cases
Control
P Value
Mean ± SD
Mean ± SD
P Value
0.645 0.382
210.25 ± 30.44 221.36 ± 43.03
219.16 ± 29.03 217.20 ± 28.98
0.516 0.812
rameters between MS patients and controls, even though we would have expected a difference with a decrease in the mean CQ in diseased patients. The lack of significant difference between the mean CQ in the overall MS group versus controls in this study can be attributed to several factors: One is the fact that all our patients were in the relapse remitting stage and did not have actively progressive disease. Second is the low disability status score with a mean of 1.45 + 1.79 indicating minimal if any disability, and the low FSS score indicating no or minimal fatigability. Third is the lack of any abnormal findings on endoscopy such as bowing or hypoadduction and the relatively low percentage of patients who had dysphonia, namely 20% of the total group. On the other hand, when comparing the patients with MS and phonatory symptoms to controls, the mean closed quotient of vowel [a] was statistically lower in dysphonic MS patients compared with controls. The difference in closed quotient in MS patients with phonatory symptoms versus controls is based on several studies confirming the presence of incomplete closure of the vocal fold in MS patients with hypoadduction.8,9 As a result, several phonatory symptoms such as breathiness, vocal fatigue, harshness, and aphonia may arise. In a study by Dogan et al, videolaryngostroboscopic examination revealed a noncomplete glottic closure pattern among 23 of 27 MS patients (posterior chink, spindle-shaped noncomplete closure compared with eight who had ‘‘posterior chink’’ as the closure pattern in the control group.8 An association between this noncomplete closure of vocal folds and the perceived more asthenic voice quality has been drawn. As a conclusion, noncomplete closure was more frequent in MS patients compared with control group. This would lead us to expect a decrease in the
TABLE 4. Mean CQ, SD, Range, Jitter, and Fundamental Frequency for Vowels [a] and [e] in MS Patients With Dysphonia Versus Controls [a]
Variables Mean CQ SD CQ Range Jitter Fundamental frequency Abbreviation: CQ, contact quotient.
[e]
Cases, N ¼ 5
Controls, N ¼ 14
Mean ± SD
Mean ± SD
39.98 ± 6.99 5.85 ± 5.85 38.78 ± 32.46 3.80 ± 6.88 174.67 ± 45.02
45.54 ± 4.02 5.34 ± 4.53 26.71 ± 22.34 1.86 ± 2.44 178.03 ± 54.00
Cases, N ¼ 5
Controls, N ¼ 14
P Value
Mean ± SD
Mean ± SD
P Value
0.043 0.844 0.369 0.567 0.903
42.65 ± 2.99 6.99 ± 8.76 32.19 ± 28.28 4.37 ± 8.62 172.45 ± 39.15
44.01 ± 4.74 4.40 ± 5.22 20.95 ± 19.87 2.91 ± 8.64 180.56 ± 50.64
0.506 0.437 0.344 0.750 0.751
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TABLE 5. Association Between Mean CQ and FSS Score, HDS Score, EDSS Score, and Disease Duration Mean CQ [a] Variables FSS score HDS score EDSS score Disease duration (y)
Mean CQ [e]
R2
P Value
R2
P Value
0.360 0.125 0.067 0.003
0.002 0.091 0.270 0.812
0.035 0.091 0.115 0.017
0.380 0.153 0.144 0.538
Abbreviations: EDSS, expanded disability status scale; FSS, fatigue severity scale; HDS, Hamilton Depression Scale. Bold means statistically significant.
closing time and subsequently a difference in the mean CQ in MS patients versus controls. Another possible cause for a change in the mean closed quotient is the effect of MS on respiration and subsequently on phonation. Carriers of neurologic diseases such as MS have a spectrum of pathophysiological mechanisms in view of the scattered central nervous system lesions. As a result, all phases of phonation, breathing, oscillation, and resonance can be affected. At the respiratory level, it is well known that patients with MS suffer from respiratory fatigue and have compromised respiratory muscle strength.26 These findings directly impact the first phase of voice production resulting in a labored speech with disorders of loudness. Among the common causes of altered glottal quotient in pathologic conditions are the changes in subglottal pressure as well as mechano-acoustic effects as reported by Gaskill and Erickson.27 Compromised respiratory strength in MS patients may be associated with poor respiratory support and reduced loudness, as a result of which the closed quotient may be affected. This would be in accordance with studies documenting the variation on closed quotient in relation to vocal registers with a smaller CQ being documented at a low register.28,29 An important finding in this study is the weak correlation between the FSS score and the mean closed quotient. This means that the higher the FSS score, the lower the mean closed quotient. This can be explained by the fact that with an increase in overall fatigability and vocal fatigue, there is less closure time during phonation, a fact that can be attributed to either bowing or incomplete closure of the vocal folds. These findings have been reported by previous authors indicating that with vocal fatigue and following prolonged phonatory tasks, there is incomplete closure of the vocal folds with bowing, spindle shaped opening, or presence of glottic chink.30 This study carries several limitations: One main limitation is the relatively small number of MS patients with phonatory symptoms. A larger study is needed to confirm the findings of this investigation. A second limitation is the history of smoking, a confounding factor that was present in almost one-third of the subjects. Last but not the least is the fact that the study is limited to the central section of the sustained vowels [a] and [e] and not to the connected speech. This is an important point because most vocal symptoms described in patients with MS are related to running speech rather than sustained vowels.
CONCLUSION The results of this investigation indicate that the closure pattern and closing time for sustained vowels [a] and [e] are comparable in MS patients and healthy controls. However, in patients with MS and dysphonia, the mean CQ is reduced compared with controls. This reduction hypothetically implicates to the glottic origin of phonatory symptoms in affected individuals. REFERENCES 1. Charcot J. Lectures on the Diseases of the Nervous System. London, UK: The New Sydenham Society; 1877, 1:157–222. 2. Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 2001;22:117–139. 3. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9:520–532. 4. Darley FL, Brown JR, Goldstein NP. Dysarthria in multiple sclerosis. J Speech Hear Res. 1972;15:229–245. 5. Hartelius L, Runmarker B, Andersen O. Prevalence and characteristics of dysarthria in a multiple-sclerosis incidence cohort: relation to neurological data. Folia Phoniatr. 2000;52:160–177. 6. Konstantopoulos K, Vikelis M, Seikel JA, et al. The existence of phonatory instability in multiple sclerosis: an acoustic and electroglottographic study. Neurol Sci. 2010;31:259–268. 7. Feijo AV, Parente MA, Behlau M, et al. Acoustic analysis of voice in multiple sclerosis patients. J Voice. 2004;18:341–347. 8. Dogan M, Midi I, Yazici MA, et al. Objective and subjective evaluation of voice quality in multiple sclerosis. J Voice. 2007;21:735–741. 9. Yamout B, Fuleihan N, Hajj T, et al. Vocal symptoms and acoustic changes in relation to the expanded disability status scale, duration and stage of disease in patients with multiple sclerosis. Eur Arch Otorhinolaryngol. 2009; 266:1759–1765. 10. Beukelman DR, Kraft G, Freal J. Expressive communication disorders in persons with multiple sclerosis: a survey. Arch Phys Med Rehabil. 1985; 66:675–677. 11. Hartelius L, Runmarker B, Andersen O. Prevalence and characteristics of dysarthria in multiple sclerosis incidence cohort: relation to neurological data. Folia Phoniatr. 2000;52:160–177. 12. Hartelius L, Svensson P. Speech and swallowing symptoms associated with Parkinson’s disease and multiple sclerosis: a survey. Folia Phoniatr (Basel). 1994;46:9–17. 13. El-Salem K, Al-Shimmery E, Horany K, et al. Multiple sclerosis in Jordan: a clinical and epidemiological study. J Neurol. 2006;253: 1210–1216. 14. Ramig LA, Scherer RC, Titze IR, et al. Acoustic analysis of voices of patients with neurologic disease: rationale and preliminary data. Ann Otol Rhinol Laryngol. 1988;97:164–172. 15. Baken RJ. Electroglottography. J Voice. 1992;6:98–110. 16. Ma EP, Love AL. Electroglottographic evaluation of age and gender effects during sustained phonation and connected speech. J Voice. 2010;24: 146–152. 17. Kitzing P. Clinical applications of electroglottography. J Voice. 1990;4: 238–249. 18. Hughes S, Spelman T, Trojano M, et al. The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry. J Neurol Neurosurg Psychiatry. Epub ahead of print 28 December, 2011. DOI: 10.1136/jnnp-2011-301051. 19. Krupp LB, La Rocca NG, Muir-Nash J, et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121–1124. 20. Freal JG, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1984;5:135–137. 21. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45:435–437. 22. Hamilton M. Development of a rating scale for primary depressive illnesses. Br J Soc Clin Psychol. 1967;6:278–296.
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23. Holstege G, Ehling T. Two motor systems involved in the production of speech. In: Davis PJ, Fletcher NH, eds. Vocal Fold PhysiologyControlling Complexity and Chaos. San Diego, CA: Singular; 1996: 153–169. 24. Zhang SP, Davis PJ, Bandler R. Brain stem integration of vocalization: role of the nucleus retroambigualis. J Neurophysiol. 1995;74:2500–2512. 25. Ludlow C, Bassich C, Connor N, et al. Phonatory characteristics of vocal fold tremor. J Phon. 1986;14:509–515. 26. Smeltzer SC, Skurnick JH, Troiano R, et al. Respiratory function in multiple sclerosis. Utility of clinical assessment of respiratory muscle function. Chest. 1992;101:479–484.
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27. Gaskill CS, Erickson ML. The effect of a voiced lip trill on estimated glottal closed quotient. J Voice. 2008;22:634–643. 28. Kitzing P. Photo-and electroglottographical recording of the laryngeal vibratory pattern during different registers. Folia Phoniatr (Basel). 1982; 34:234–241. 29. Roubeau B, Chevrie-Muller C, Arabia-Guidet C. Electroglottographic study of the changes of voice registers. Folia Phoniatr (Basel). 1987;39: 280–289. 30. Chang A, Karnell MP. Perceived phonatory effort and phonation threshold pressure across a prolonged voice loading task: a study of vocal fatigue. J Voice. 2004;18:454–466.
Summary: Objective. To compare the mean and standard deviation (SD) of the contact quotient (CQ) of the sustained vowels ([a] and [e]) in multiple sclerosis (MS) patients versus controls. Study Design. Cross-sectional study. Materials and Methods. Thirty-nine subjects (24 patients and 15 controls) participated in this study. Laryngeal electroglottography was performed on all subjects while phonating the vowels [a] and [e] at a comfortable pitch and loudness. The fundamental frequency, mean CQ, SDs, and jitter were computed for both vocal tasks. Results. The mean age of the MS group was 36.25 + 10.61 years. All laryngeal examinations were normal and five patients with MS had dysphonia described as voice breaks and fatigue in connected speech. For both vowels [a] and [e], the mean closed quotients were comparable in groups, MS and control (43.90 vs 53 for [a] and 44.75 vs 43.63 for [e]) with no significant difference. When comparing five MS patients with dysphonia versus controls, for the vowel [a], the mean closed quotient was significantly lower in MS patients with dysphonia (P values of 0.043). Conclusion. The mean closed quotient for sustained vowels [a] and [e] are comparable in MS patients and healthy controls except in patients with dysphonia. Key Words: Contact quotient–Electroglottography–Multiple sclerosis. INTRODUCTION Multiple Sclerosis (MS) is an autoimmune inflammatory disorder that affects various parts of the central nervous system. The disease was first described in 1868 by Charcot1 as a chronic degenerative neurologic disorder that results in demyelination and loss of conductive properties of axons within the brain and spinal cord. Women are affected more than men and the prevalence rate ranges from 2 to 150 per 100 000 with varying geographic distribution.2,3 Several etiologic factors have been implicated and these include genetic, infectious, and environmental. As a result of the widespread involvement of the nervous system, MS has a wide range of neurologic manifestations with motor, sensory, and cognitive impairments. The most common symptoms attributed to MS are optic neuritis, nystagmus, tremors, gait instability, sexual and bladder incontinence, scanning speech, and last but not the least phonatory instabilities. The ‘‘scanning speech’’ or dysarthria of MS is predominantly mixed with both an ataxic and a spastic component to it.4,5 Phonatory disturbances on the other hand span a large array of symptoms ranging from impairments of loudness control, pitch control, voice breaks, harshness, hypernasality, and breathiness.6–9 Despite the fact that dysarthria and phonatory symptoms have been reported in more than 50% of MS patients, research on dysAccepted for publication October 31, 2012. No conflict of interest or financial support in relation to this manuscript. The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. From the *Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon; yDepartment of Otolaryngology–Head and Neck Surgery, American University of Beirut Medical Center, Beirut, Lebanon; zDepartment of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; and the xDepartment of Epidemiology and Population Health, American University of Beirut, Beirut, Lebanon. Address correspondence and reprint requests to Abdul-Latif H. Hamdan, Department of Otolaryngology–Head and Neck Surgery, American University of Beirut, PO Box 11-0236, Beirut, Lebanon. E-mail: [email protected] Journal of Voice, Vol. 27, No. 4, pp. 506-511 0892-1997/$36.00 Ó 2013 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2012.10.016
phonia in association with this disease remains scarce.4,5,10–12 Very few studies have discussed the phonatory symptoms in MS patients using objective measures.6–9,13,14 Many of these were based on the self-reported questionnaires and perceptual evaluation with less focus on acoustic analysis and particularly on electroglottography (EGG) as a descriptive tool.7,9 The contact quotient (CQ), an outcome measure of EGG, is an important indicator of vocal folds closure during phonation. It provides an indirect and noninvasive measure of the closure pattern by reflecting the amount of transverse impedance across the glottis. A decrease in the mean closed quotient would suggest a glottic insufficiency with an increase in the mean flow rate, whereas an increase in the mean closed quotient would suggest a hyperfunctional glottic behavior. Organic lesions of the vocal fold resulting in an increase in the closing phase are associated with an elevated closed quotient, whereas bowing of the vocal folds with glottic insufficiency is associated with a reduced closed quotient.15–17 Konstantopoulos et al6 was the only one to use EGG as an objective voice analysis tools to investigate the vocal fold closure in MS patients. In his investigation, the EGG parameters used were vocal jitter, mean fundamental frequency, and standard deviation (SD) of the average fundamental frequency. The results indicated that these vocal parameters differentiated the MS group from controls, but there was no mentioning of the mean CQ. The purpose of this study is to make a comparative analysis of the mean and SD of the CQ of the sustained vowels [a] and [e] in MS patients versus controls. The fundamental frequency, SD, and jitter will also be reported. MATERIALS AND METHODS A total of 39 subjects were asked to participate in this study after having read and signed the informed consent approved by
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the Institutional Review Board at the American University of Beirut. Confidentiality was maintained throughout the data collection process. All data were kept under lock and key and it was accessible only to the principal investigator and his research team. Subjects with recent history of upper respiratory tract infection, laryngeal manipulation, or previous laryngeal surgery were excluded from this study. All subjects with evidence of vocal fold lesion on laryngeal examination were also excluded. The subjects were divided into two groups, 24 with MS and 15 as controls matched according to age and gender. Because of the known gender effect on fundamental frequency and mean CQ, the female to male ratio was similar in both groups. The prevalence of smoking was also comparable in both groups in view of its confounding effect. Patients with MS were all in the relapse remitting stage and were referred from the private clinic of the neurology service. Demographic variables included age, gender, and history of smoking. Variables taken into consideration included duration of the disease in years, the expanded disability status scale (EDSS) reflecting the severity of the disease, the severity of fatigue, and depression. For the disability status, a score between 0 and 3 was considered mild, 3.5–6 as moderate, and above 6 as severe18; the presence and severity of fatigue were assessed by means of the Fatigue Severity Scale (FSS). This test consists of nine items concerning fatigue each rated on a seven-point scale. The average rating is computed for all nine items with higher scores indicating increasing fatigue. A cutoff point of 4 was taken in this study. This test was chosen in view of its accepted consistency, stability, and sensitivity to clinical stage.19–21 Depression was evaluated using the Hamilton Rating Scale for Depression, which consists of 21 items rated from 0 to 4 with a higher score indicating increasing severity of depression.22 All subjects underwent laryngeal examination and were asked about the prevalence of dysphonia. Dysphonia was defined as change in voice quality, pitch, loudness, or effort. All subjects underwent laryngeal EGG while seated in the upright position in a quiet room at the ‘‘Hamdan voice unit.’’ For this study, the EGG amplifier model 6103 by KayPENTAX (Pine Brook, NJ) and Real Time EEG Analyzer software package model 5138 (KayPENTAX) were used for data collection and analysis. All the participants’ neck and the surfaces of the electrodes were cleaned with alcohol before the testing. The participants were assisted in placing and holding the surface electrodes on either side of the thyroid cartilages. These were held in place using a neck strap and/or by asking the participant to hold them in position. Each participant phonated the vowels [a] and [e] at a comfortable pitch and loudness. The test was repeated several times until we obtained a good tracing of the graph. In many subjects, the system gain had to be put on the high position to ensure an adequate wave. Using the cursor, the middle 3 seconds of each sample measured was used for analysis disregarding the onset and offset time. The fundamental frequency, mean CQ, SDs, and jitter were computed for both vocal tasks. CQ was measured using an algorithm in the software that estimated glottal closure based on the temporal width 70% of the peak-to-peak amplitude below the positive peak. The authors have selected this measurement algorithm based
on its availability in the program used and given the frequency of its reported usage in the literature. Demographic characteristics of the participants were examined separately for cases and controls using frequency distributions for categorical variables (gender and smoking) and means with SDs for continuous ones (age, duration of MS, EDSS, FSS score, and Hamilton Depression Scale [HDS]). Two independent samples t tests were done to measure the differences between controls and all cases and then between controls and only cases having dysphonia, in terms of the selected variables (mean CQ, SD CQ, range, jitter, and fundamental frequency for both [a] and [e]). Two other independent samples t tests were performed for males and females separately to measure the differences between cases and controls in terms of fundamental frequencies of [a] and [e]. Linear regressions model was used to report R2 as a measure of association between the dependent variable mean CQ and the independent variables FSS score, HDS, EDSS score, and disease duration among cases. A P value <0.05 was considered as significant. Analyses were performed using Statistical Analysis Package for Social Sciences (Version 19.0; SPSS, Chicago, IL). RESULTS Demographic data The mean age of the MS group was 36.25 + 10.61 years. Fortyfive percent were males and close to one-third were smokers. The mean duration of the disease was 5.37 + 5.09 years, and the mean EDSS score was 1.45 + 1.79. The FSS score was 3.97 + 2.28. The HDS score was 8.58 + 9.63, Table 1. Laryngeal findings and phonatory symptoms All the laryngeal examinations were normal with no evidence of bowing, glottic insufficiency, or hypoadduction. No abnormal closure or pathology were observed in any of the diseased or control subjects. In the MS group, five patients had dysphonia, whereas in the control group, only one had change in voice
TABLE 1. Demographics Cases, N ¼ 24
Controls, N ¼ 15
Variables
Mean
SD
Mean
SD
Age (y) Duration of MS (y) EDSS score FSS score HDS score
36.25 5.37 1.45 3.97 8.58
10.61 5.09 1.79 2.28 9.63
30.60 N/A N/A N/A N/A
7.28 N/A N/A N/A N/A
n
(%)
n
(%)
11 9
45.8 37.5
7 5
46.7 33.3
Gender (% male) Smoking (% yes)
Abbreviations: EDSS, expanded disability status scale; FSS, fatigue severity scale; HDS, Hamilton Depression Scale.
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quality. In the MS group, the change in voice quality for connected speech was described as vocal breaks and increased effort. Mean closed quotient, SD, fundamental frequency, and jitter for vowels [a] and [e] in all MS patients and controls For the vowel [a], the mean closed quotient was comparable in both MS and control groups (43.90 and 45.53) with no significant difference between the two (P value 0.299). Similarly for all other parameters, namely SDs, jitter, and fundamental frequency, there were no significant differences between the two groups, even though it is worth noting that the jitter value was higher in the MS group (3.38 vs 1.82). For the vowel [e], the mean closed quotient was comparable in both MS and control groups (44.75 vs 43.63) with no significant difference between the two (P value 0.480). Similarly for all other parameters, namely SDs, jitter, and fundamental frequency, there were no significant differences between the two groups, Table 2. When stratified by gender, there was still no significant difference in the fundamental frequency between the MS group and the controls for both [a] and [e], Table 3. Mean CQ in patients with MS and phonatory symptoms versus controls For the vowel [a], the mean CQ was significantly lower in patients with MS and phonatory symptoms compared with controls with P values of 0.043. For the vowel [e], there was no significant difference between the two groups in any of the EGG parameters, Table 4. It is worth noting that the jitter SD for MS patients with dysphonia was high compared with controls. This is attributed to the fact that one of the five patients had an elevated jitter value. Excluding this subject from the analysis did not change the significance of the results. The P values for both vowels /a/ and /e/ in comparison with controls were 0.129 and 0.3191, respectively. Association between mean CQ and FSS score, HDS score, EDSS score, and disease duration in patients with MS There was a significant association between the mean CQ and the FSS score (P value of 0.002), albeit the r value was 0.36
indicating a rather moderate correlation. There was no significant association between the mean CQ and any of the remaining variables, namely duration of the disease, extent of disability, and depression score, Table 5. Correlation was also made between dysphonic patients and the aforementioned variables namely: FSS score, HDS score, EDSS score, and duration of the disease. The results indicated additional moderate correlation (R2 ¼ 0.43) that was not significant (P value of 0.231). DISCUSSION The larynx is a complex structure that depends heavily on neural control. As a result, disorders of the nervous system affect phonation with voice symptoms being among the earliest to develop. Dysphonia in association with many neurologic diseases such as stroke, Parkinson disease, and vocal fold paralysis has been extensively reported in the literature with less emphasis on MS.6–9 In MS patients, dysphonia has been described as voice breaks, increase in vocal fatigue, harshness, impaired control of loudness and pitch, breathiness, and at times hypernasality. The prevalence of dysphonia in MS patients varies between 25% and 70%.6–9,13,14 The variation in the prevalence rate has been attributed to differences in the selection of participants, study designs, and most of all to the variability in the outcome measures. Lower rates have been noted when self-reported symptoms have been analyzed, whereas higher rates have been found when objective voice analysis instruments have been used. Hartelius et al5 has described impairment of speech and voice in 44% of MS patients, whereas Feijo et al7 reported dysphonia in 70% of MS patients compared with control. The former has used a survey in his investigation, whereas the later has used wideband and narrowband spectrogram in his analysis. Feijo et al has found an association between dysphonia and MS with higher fundamental frequency in affected individuals. When stratified by gender, the fundamental frequency deviation was significantly higher in MS women and jitter was higher in MS men compared with controls. Dogan et al8 in his report on 27 female patients with MS, the frequency of varying degrees of dysphonia was 33.4% compared with 7.4% in controls based on the perceptual evaluation. His results were partially substantiated by the findings on acoustic analysis where the mean jitter, shimmer, and Soft Phonation Index in MS patients were
TABLE 2. Mean CQ, SD, Range, Jitter, and Fundamental Frequency for Vowels [a] and [e] in MS Patients and Controls [a] Cases Variables Mean CQ SD CQ Range Jitter Fundamental frequency Abbreviation: CQ, contact quotient.
[e] Controls
Cases
Controls
Mean ± SD
Mean ± SD
P Value
Mean ± SD
Mean ± SD
P Value
43.90 ± 5.14 4.69 ± 5.06 25.56 ± 23.75 3.38 ± 7.58 168.95 ± 54.33
45.53 ± 3.87 5.41 ± 4.38 26.63 ± 21.53 1.82 ± 2.35 175.48 ± 52.97
0.299 0.649 0.888 0.446 0.715
44.75 ± 4.75 4.18 ± 5.11 20.98 ± 19.17 2.90 ± 8.32 176.54 ± 61.04
43.63 ± 4.79 4.33 ± 5.03 20.63 ± 19.20 2.76 ± 8.35 178.34 ± 49.54
0.480 0.930 0.957 0.959 0.924
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TABLE 3. Difference Between MS Patients and Controls in Terms of Fundamental Frequencies for Vowels [a] and [e] Among Males and Females Males, N ¼ 18
Fundamental Frequency [a] [e]
Cases
Control
Mean ± SD
Mean ± SD
120.15 ± 28.97 123.58 ± 25.51
125.56 ± 10.62 133.94 ± 20.83
significantly increased, but there were no significant differences in terms of mean fundamental frequency and noise-to-harmonic ratio. The authors of this manuscript have previously reported on the vocal symptoms in MS patients and acoustic findings. The results of the investigation indicated a significant decrease in the fundamental frequency, habitual pitch, and maximum phonation time with a significant increase in shimmer in males. In the female group, there was a significant decrease in the maximum phonation time only. The results of this investigation are in partial agreement with the previous reports in terms of acoustic findings. Similar to the results of Dogan et al, the mean fundamental frequency was not statistically different between the MS group and controls even when stratified by gender as seen in Table 3. With respect to jitter, there was an increase in the MS group compared with control, even though the difference was not statistically significant. The phonatory and acoustic changes in MS patients can been attributed to alterations in periaqueductal gray matter with neuronal concentrations and projections into the nucleus retroambigualis. These alterations are related to abdominal, intercostal, pharyngeal, palatal, lingual, facial, and laryngeal motor neurons and thus have an effect on phonation. The slowing down of the electrical impulse through the demyelinated neurons in MS patients causes an alteration of the recovery synchrony, leading to the variability in muscle contraction and a larger variation in cycle-to-cycle frequency. In other words, there is an increase in short-term phonatory instability.23–25 This was evidenced in our study by the increase in jitter even though it was not statistically significant. Looking at the vocal folds contact time, the results of our study showed no significant difference in any of the EGG pa-
Females, N ¼ 21 Cases
Control
P Value
Mean ± SD
Mean ± SD
P Value
0.645 0.382
210.25 ± 30.44 221.36 ± 43.03
219.16 ± 29.03 217.20 ± 28.98
0.516 0.812
rameters between MS patients and controls, even though we would have expected a difference with a decrease in the mean CQ in diseased patients. The lack of significant difference between the mean CQ in the overall MS group versus controls in this study can be attributed to several factors: One is the fact that all our patients were in the relapse remitting stage and did not have actively progressive disease. Second is the low disability status score with a mean of 1.45 + 1.79 indicating minimal if any disability, and the low FSS score indicating no or minimal fatigability. Third is the lack of any abnormal findings on endoscopy such as bowing or hypoadduction and the relatively low percentage of patients who had dysphonia, namely 20% of the total group. On the other hand, when comparing the patients with MS and phonatory symptoms to controls, the mean closed quotient of vowel [a] was statistically lower in dysphonic MS patients compared with controls. The difference in closed quotient in MS patients with phonatory symptoms versus controls is based on several studies confirming the presence of incomplete closure of the vocal fold in MS patients with hypoadduction.8,9 As a result, several phonatory symptoms such as breathiness, vocal fatigue, harshness, and aphonia may arise. In a study by Dogan et al, videolaryngostroboscopic examination revealed a noncomplete glottic closure pattern among 23 of 27 MS patients (posterior chink, spindle-shaped noncomplete closure compared with eight who had ‘‘posterior chink’’ as the closure pattern in the control group.8 An association between this noncomplete closure of vocal folds and the perceived more asthenic voice quality has been drawn. As a conclusion, noncomplete closure was more frequent in MS patients compared with control group. This would lead us to expect a decrease in the
TABLE 4. Mean CQ, SD, Range, Jitter, and Fundamental Frequency for Vowels [a] and [e] in MS Patients With Dysphonia Versus Controls [a]
Variables Mean CQ SD CQ Range Jitter Fundamental frequency Abbreviation: CQ, contact quotient.
[e]
Cases, N ¼ 5
Controls, N ¼ 14
Mean ± SD
Mean ± SD
39.98 ± 6.99 5.85 ± 5.85 38.78 ± 32.46 3.80 ± 6.88 174.67 ± 45.02
45.54 ± 4.02 5.34 ± 4.53 26.71 ± 22.34 1.86 ± 2.44 178.03 ± 54.00
Cases, N ¼ 5
Controls, N ¼ 14
P Value
Mean ± SD
Mean ± SD
P Value
0.043 0.844 0.369 0.567 0.903
42.65 ± 2.99 6.99 ± 8.76 32.19 ± 28.28 4.37 ± 8.62 172.45 ± 39.15
44.01 ± 4.74 4.40 ± 5.22 20.95 ± 19.87 2.91 ± 8.64 180.56 ± 50.64
0.506 0.437 0.344 0.750 0.751
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TABLE 5. Association Between Mean CQ and FSS Score, HDS Score, EDSS Score, and Disease Duration Mean CQ [a] Variables FSS score HDS score EDSS score Disease duration (y)
Mean CQ [e]
R2
P Value
R2
P Value
0.360 0.125 0.067 0.003
0.002 0.091 0.270 0.812
0.035 0.091 0.115 0.017
0.380 0.153 0.144 0.538
Abbreviations: EDSS, expanded disability status scale; FSS, fatigue severity scale; HDS, Hamilton Depression Scale. Bold means statistically significant.
closing time and subsequently a difference in the mean CQ in MS patients versus controls. Another possible cause for a change in the mean closed quotient is the effect of MS on respiration and subsequently on phonation. Carriers of neurologic diseases such as MS have a spectrum of pathophysiological mechanisms in view of the scattered central nervous system lesions. As a result, all phases of phonation, breathing, oscillation, and resonance can be affected. At the respiratory level, it is well known that patients with MS suffer from respiratory fatigue and have compromised respiratory muscle strength.26 These findings directly impact the first phase of voice production resulting in a labored speech with disorders of loudness. Among the common causes of altered glottal quotient in pathologic conditions are the changes in subglottal pressure as well as mechano-acoustic effects as reported by Gaskill and Erickson.27 Compromised respiratory strength in MS patients may be associated with poor respiratory support and reduced loudness, as a result of which the closed quotient may be affected. This would be in accordance with studies documenting the variation on closed quotient in relation to vocal registers with a smaller CQ being documented at a low register.28,29 An important finding in this study is the weak correlation between the FSS score and the mean closed quotient. This means that the higher the FSS score, the lower the mean closed quotient. This can be explained by the fact that with an increase in overall fatigability and vocal fatigue, there is less closure time during phonation, a fact that can be attributed to either bowing or incomplete closure of the vocal folds. These findings have been reported by previous authors indicating that with vocal fatigue and following prolonged phonatory tasks, there is incomplete closure of the vocal folds with bowing, spindle shaped opening, or presence of glottic chink.30 This study carries several limitations: One main limitation is the relatively small number of MS patients with phonatory symptoms. A larger study is needed to confirm the findings of this investigation. A second limitation is the history of smoking, a confounding factor that was present in almost one-third of the subjects. Last but not the least is the fact that the study is limited to the central section of the sustained vowels [a] and [e] and not to the connected speech. This is an important point because most vocal symptoms described in patients with MS are related to running speech rather than sustained vowels.
CONCLUSION The results of this investigation indicate that the closure pattern and closing time for sustained vowels [a] and [e] are comparable in MS patients and healthy controls. However, in patients with MS and dysphonia, the mean CQ is reduced compared with controls. This reduction hypothetically implicates to the glottic origin of phonatory symptoms in affected individuals. REFERENCES 1. Charcot J. Lectures on the Diseases of the Nervous System. London, UK: The New Sydenham Society; 1877, 1:157–222. 2. Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 2001;22:117–139. 3. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9:520–532. 4. Darley FL, Brown JR, Goldstein NP. Dysarthria in multiple sclerosis. J Speech Hear Res. 1972;15:229–245. 5. Hartelius L, Runmarker B, Andersen O. Prevalence and characteristics of dysarthria in a multiple-sclerosis incidence cohort: relation to neurological data. Folia Phoniatr. 2000;52:160–177. 6. Konstantopoulos K, Vikelis M, Seikel JA, et al. The existence of phonatory instability in multiple sclerosis: an acoustic and electroglottographic study. Neurol Sci. 2010;31:259–268. 7. Feijo AV, Parente MA, Behlau M, et al. Acoustic analysis of voice in multiple sclerosis patients. J Voice. 2004;18:341–347. 8. Dogan M, Midi I, Yazici MA, et al. Objective and subjective evaluation of voice quality in multiple sclerosis. J Voice. 2007;21:735–741. 9. Yamout B, Fuleihan N, Hajj T, et al. Vocal symptoms and acoustic changes in relation to the expanded disability status scale, duration and stage of disease in patients with multiple sclerosis. Eur Arch Otorhinolaryngol. 2009; 266:1759–1765. 10. Beukelman DR, Kraft G, Freal J. Expressive communication disorders in persons with multiple sclerosis: a survey. Arch Phys Med Rehabil. 1985; 66:675–677. 11. Hartelius L, Runmarker B, Andersen O. Prevalence and characteristics of dysarthria in multiple sclerosis incidence cohort: relation to neurological data. Folia Phoniatr. 2000;52:160–177. 12. Hartelius L, Svensson P. Speech and swallowing symptoms associated with Parkinson’s disease and multiple sclerosis: a survey. Folia Phoniatr (Basel). 1994;46:9–17. 13. El-Salem K, Al-Shimmery E, Horany K, et al. Multiple sclerosis in Jordan: a clinical and epidemiological study. J Neurol. 2006;253: 1210–1216. 14. Ramig LA, Scherer RC, Titze IR, et al. Acoustic analysis of voices of patients with neurologic disease: rationale and preliminary data. Ann Otol Rhinol Laryngol. 1988;97:164–172. 15. Baken RJ. Electroglottography. J Voice. 1992;6:98–110. 16. Ma EP, Love AL. Electroglottographic evaluation of age and gender effects during sustained phonation and connected speech. J Voice. 2010;24: 146–152. 17. Kitzing P. Clinical applications of electroglottography. J Voice. 1990;4: 238–249. 18. Hughes S, Spelman T, Trojano M, et al. The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry. J Neurol Neurosurg Psychiatry. Epub ahead of print 28 December, 2011. DOI: 10.1136/jnnp-2011-301051. 19. Krupp LB, La Rocca NG, Muir-Nash J, et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121–1124. 20. Freal JG, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1984;5:135–137. 21. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45:435–437. 22. Hamilton M. Development of a rating scale for primary depressive illnesses. Br J Soc Clin Psychol. 1967;6:278–296.
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27. Gaskill CS, Erickson ML. The effect of a voiced lip trill on estimated glottal closed quotient. J Voice. 2008;22:634–643. 28. Kitzing P. Photo-and electroglottographical recording of the laryngeal vibratory pattern during different registers. Folia Phoniatr (Basel). 1982; 34:234–241. 29. Roubeau B, Chevrie-Muller C, Arabia-Guidet C. Electroglottographic study of the changes of voice registers. Folia Phoniatr (Basel). 1987;39: 280–289. 30. Chang A, Karnell MP. Perceived phonatory effort and phonation threshold pressure across a prolonged voice loading task: a study of vocal fatigue. J Voice. 2004;18:454–466.