Daytime Hypoxemia, Sleep-Disordered Breathing, and Laryngopharyngeal Findings in Multiple System Atrophy

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ORIGINAL CONTRIBUTION Daytime Hypoxemia, Sleep-Disordered Breathing, and Laryngopharyngeal Findings in Multiple System Atrophy

Takayoshi Shimohata, MD, PhD; Hideo Shinoda, MD, PhD; Hideaki Nakayama, MD, PhD; Tetsutaro Ozawa, MD, PhD; Kenshi Terajima, MD, PhD; Hirohisa Yoshizawa, MD, PhD; Yoko Matsuzawa, MD; Osamu Onodera, MD, PhD; Satoshi Naruse, MD, PhD; Keiko Tanaka, MD, PhD; Sugata Takahashi, MD, PhD; Fumitake Gejyo, MD, PhD; Masatoyo Nishizawa, MD, PhD

Background: The mechanism underlying nocturnal sud- of the 21 patients exhibited vocal cord abductor paraly- den death in patients with MSA remains unclear. It may sis, and laryngoscopy under anesthesia showed that 9 be explained by upper airway obstruction, such as vocal (45%) of 20 patients exhibited vocal cord abductor pa- cord abductor paralysis; an impairment of the respira- ralysis. Laryngoscopy under anesthesia also revealed that tory center, such as Cheyne-Stokes respiration; or an im- 11 (55%) of 20 patients showed upper airway obstruc- paired hypoxemic ventilatory response. tion in places other than the vocal cords, including obstruction at the base of the tongue or soft palate. In ad- Objective: To investigate the mechanism of sleep- dition, it demonstrated novel laryngopharyngeal findings, disordered breathing in multiple system atrophy (MSA) such as floppy epiglottis and airway obstruction at the arytenoid. Design: We recruited 21 patients with probable MSA who were admitted sequentially to our hospital, and per- Conclusions: We observed daytime hypoxemia with an formed daytime blood gas analysis, pulmonary function increased alveolar-arterial oxygen gradient, Cheyne- tests, polysomnography, and fiberoptic laryngoscopy during wakefulness and with the patient under anesthesia. Stokes respiration, and novel abnormal laryngopharyngeal movements in patients with MSA. We also found that Results: A decrease in arterial oxygen pressure and an laryngoscopy under anesthesia might be useful for evalu- increase in alveolar-arterial oxygen gradient signifi- ating upper airway obstruction. The significance of these cantly correlated with disease duration (P=.045 and .046, findings to the mechanism of sudden death in those with respectively). Polysomnography demonstrated Cheyne- MSA needs to be examined. Stokes respiration in 3 (15%) of 20 patients. Fiberoptic laryngoscopy during wakefulness showed that 3 (14%) Arch Neurol. 2007;64:856-861

OST PATIENTS WITH tients with MSA have abnormal laryngo- multiple system atro- pharyngeal movements other than VCAP phy (MSA) die within that contribute to upper airway obstruc- 6 to 9 years after symp- tion? What is the prevalence of CSR? Do toms begin to ap- patients with MSA have daytime respira- Author Affiliations: pear.1 Although the cause of death in MSA tory impairments that aggravate noctur- Department of Neurology, M is commonly related to the development nal hypoxemia? To elucidate these ques- Clinical Neuroscience Branch of bulbar palsy, predisposing a patient to tions, we recruited patients with probable (Drs Shimohata, Ozawa, aspiration pneumonia, sudden death dur- MSA5 and performed daytime blood gas Terajima, Matsuzawa, Naruse, 2 Tanaka, and Nishizawa), and ing sleep is also common. The mecha- analysis, pulmonary function tests, poly- Department of Molecular nism underlying nocturnal sudden death somnography, and laryngoscopy. Neuroscience, Resource Branch remains unclear; however, it may be ex- for Brain Disease Research, plained by upper airway obstruction, such METHODS Center for Bioresource-Based as vocal cord abductor paralysis (VCAP),3 Research (Dr Onodera), Brain or by abnormal respiration, resulting from Research Institute, Niigata an impairment of the respiratory center, We recruited patients admitted sequentially to University, and Department of such as Cheyne-Stokes respiration (CSR).2 the Department of Neurology, Niigata Univer- Otolaryngology (Drs Shinoda An impaired hypoxemic ventilatory re- sity, who were diagnosed as having MSA be- and Takahashi) and Division of 4 tween May 1, 2001, and April 30, 2004. All the Respiratory Medicine sponse may also be involved, because it patients fulfilled the diagnostic criteria of prob- (Drs Nakayama, Yoshizawa, and can aggravate hypoxemia during sleep. able MSA according to the consensus state- Gejyo), Niigata University Despite our better understanding of ment.5 A hyperintense putaminal rim and a “hot Graduate School of Medical and sleep-disordered breathing in MSA, sev- cross bun” sign on magnetic resonance imaging6 Dental Sciences, Niigata, Japan. eral unanswered questions remain. Do pa- were used to support the diagnosis. Patients

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 were excluded from the study if they showed evidence of being patients showed autonomic failure or urinary dysfunc- positive for spinocerebellar ataxia types 1, 2, 3, and 6; denta- tion; 14 of the 21 patients had orthostatic hypotension torubral pallidoluysian atrophy; or fragile X tremor/ataxia syn- (defined as a fall in blood pressure of Ն30 mm Hg sys- 7,8 drome by a molecular genetic test. The selection of hospital- tolic or Ն15 mm Hg diastolic) and 16 had urinary ized patients with MSA in this study is likely to be biased toward incontinence. No patients were receiving hypnotic or patients with a more severe condition. A patient with a history of recent respiratory infections (patient 21) was excluded from antidepressant agents, but the 3 patients with MSA-P blood gas analysis, pulmonary function tests, and polysom- were receiving dopaminergic agents during the study. nography. The severity of ataxia was evaluated using the In- Six patients (29%) experienced daytime sleepiness. All ternational Cooperative Ataxia Rating Scale.9 patients produced inspiratory noises during sleep: snor- Arterial oxygen pressure (PaO2) and arterial carbon diox- ing in 21 (100%) and laryngeal stridor in 5 (24%) ide pressure (PaCO2) were analyzed using an automatic acid- (Table 1). Their mean±SD body mass index (calcu- base analyzer. Severe hypoventilation was defined as PaCO2 lated as weight in kilograms divided by height in meters greater than 50 mm Hg. The alveolar-arterial oxygen gradient squared) was 22.9±4.2 (range, 17.9-34.7), and obesity ([A-a]DO2) was calculated as follows: [A-a]DO2=(150−PaCO2)/ (body mass index, Ͼ25) was observed in 2 patients (pa- (0.8−PaO2). Conventional spirometry was performed, and vi- tients 3 and 13). tal capacity and forced expiratory volume in 1 second were determined. These values were expressed as percentages of predicted values. DAYTIME PULMONARY FUNCTION Polysomnographic findings were classified according to the recommendations of the American Academy of Sleep Medi- Blood gas analysis revealed PaO2 and PaCO2 mean±SD val- cine Task Force in 1999. Sleep apnea syndrome was defined ues of 70.8±6.5 and 43.8±3.4 mm Hg, respectively. Day- as an apnea-hypopnea index (AHI) of greater than 10 per hour. Ͻ Severe nocturnal oxygen desaturation was defined as having time hypoxemia (PaO2, 80 mm Hg) was observed in 14 greater than 10% of sleep time with an oxygen saturation level (70%) of 20 patients. Severe hypoventilation was ob- of less than 90%. The CSR was defined as a crescendo- served in 1 patient (5%) (Table 1). The mean±SD Յ decrescendo pattern of hyperpnea, alternating with central ap- [A-a]DO2 increased (24.9±7.0 mm Hg; normal, 10 nea and hyperpnea, and was determined to be present when mm Hg), and 11 (55%) of 20 patients showed an 10 the central AHI was 10 or more per hour. [A-a]DO2 of greater than 20 mm Hg. Eighteen (90%) Fiberoptic laryngoscopy was performed under video moni- and 20 (100%) of 20 patients had a normal percentage toring during wakefulness in all the patients. It was also per- vital capacity and a normal percentage forced expira- formed with the patient under anesthesia induced by an intra- tory volume in 1 second, respectively. Chest x-ray film venous injection of 5 to 10 mg of diazepam (patients 1-3) or findings were normal in the patients with daytime hy- 100 to 200 mg of propofol (patients 4-21). We could not perform laryngoscopy under anesthesia for 1 patient (patient 1), poxemia. because he did not fall asleep after receiving 10 mg of diazepam. Vocal cord abductor paralysis was defined as the restric- POLYSOMNOGRAPHIC FINDINGS tion of vocal cord movement in abduction. The severity of VCAP was expressed as partial or complete, corresponding to fixa- tion at the midline in abduction. The apnea index and AHI were a mean±SD of 4.1±4.5 and The relationships between disease duration and variables 20.1±19.9 per hour, respectively. Of 20 patients, 13 (65%) related to sleep-disordered breathing were analyzed by the Spear- fulfilled the criteria of sleep apnea syndrome; 3 (15%) had man rank correlation test. The effects of continuous positive CSR (Table 1). Five patients, including 3 with CSR, pre- airway pressure on polysomnographic findings were analyzed sented with central sleep apnea, although the percentage by the paired t test when the variables were normally distrib- of obstructive sleep apnea was higher than that of central uted. The Wilcoxon signed rank test was used when the nor- sleep apnea in these patients. Future studies are necessary mality test failed to show a normal distribution of the data. Sta- to investigate the involvement of central neurogenic res- Ͻ tistical significance was defined as P .05. piratory disturbances. The sleep architectures were characterized by a decreased percentage of slow-wave sleep RESULTS (mean±SD with stage 3 plus 4, 13.3%±13.8%; normal value, 20%-35%) and a decreased percentage of rapid eye movement sleep (mean±SD with rapid eye movement, PATIENT CHARACTERISTICS 8.2%±7.6%; normal value, 20%-25%). Sleep efficiency also decreased (mean±SD, 47.7%±19.5%; normal value, Ͼ85%). We recruited 21 consecutive patients (9 men and 12 wom- The mean±SD oxygen saturation was 94.3%±17.2%, with en) with probable MSA. The mean±SD age of the patients the lowest value at 88.0%. Of 20 patients, 4 (20%) ful- was 59.8±8.3 years (range, 44-72 years); the mean±SD age filled the criteria of severe nocturnal oxygen desaturation. at onset of MSA was 56.3±9.2 years (range, 41-72 years); We investigated the relationships between disease du- and the mean±SD duration of disease was 3.8±1.8 years ration and variables related to the clinical features, day- (range, 1-7 years). Their mean±SD International Coop- time blood gas analysis findings, and polysomno- erative Ataxia Rating Scale score was 45.7±15.2 (range, 26- graphic findings (Table 2). The International Cooperative 73). Of these 21 patients, 18 (86%) had MSA of the cer- Ataxia Rating Scale score significantly correlated with dis- ebellar subtype (MSA-C) and the remaining 3 (14%) had ease duration. A significant inverse correlation was ob- MSA of the parkinsonian subtype (MSA-P). Twelve pa- served between PaO2 and disease duration, and a signifi- tients were able to walk without help, 2 were able to walk cant correlation was observed between [A-a]DO2 and with the help of a walker, and 7 could not walk. All the disease duration. Polysomnographic variables, includ-

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PSG Findings

ICARS Nocturnal PaCO2 Ͼ50 Cheyne-Stokes Patient No. Score Stridor mm Hg CT90 Ͼ10% Respiration 150− − − − 257− − ϩ − 356− ϩϩ − 460− − − − 551ϩ −− − 658− − − ϩ 727− − − ϩ 851ϩ −− − 961− − − − 10 62 − − − − 11 55 − − − ϩ 12 31 − − − − 13 47 − − ϩ − 14 73 ϩ −− − 15 31 ϩ − ϩ − 16 15 ϩ −− − 17 26 − − − − 18 34 − − − − 19 47 − − − − 20 26 − − − − 21 42 − NE NE NE

Abbreviations: CT90, sleep time with an oxygen saturation level of less than 90%; ICARS, International Cooperative Ataxia Rating Scale; MSA, multiple system

atrophy; NE, not examined; PaCO2, arterial carbon dioxide pressure; PSG, polysomnography; ϩ, present; −, absent.

FIBEROPTIC LARYNGOSCOPY Table 2. Correlation Coefficients Between Disease Duration and Variables Fiberoptic laryngoscopy during wakefulness was performed on all 21 patients (Table 3). We found VCAP Correlation Coefficient Variable (r Value) P Value in 3 patients (14%). Although upper airway obstruction at levels other than the vocal cords was not observed, bi- ICARS score 0.49 .02* BMI 0.36 .06 lateral rhythmical tremulous movements of the arytenoid were observed in 6 patients (29%). PaO2 −0.40 .045*

PaCO2 0.30 .10 Laryngoscopy while patients were under anesthesia [A-a]DO2 0.41 .046* showed that 9 (45%) of 20 patients exhibited VCAP % VC −0.33 .07 (Figure, A-D). Interestingly, all the patients presenting FEV1.0% 0.14 .27 with the rhythmical tremulous movements of the aryte- AI 0.02 .46 noid during wakefulness exhibited VCAP under anes- AHI 0.07 .37 thesia. Mean SpO2 −0.29 .11 Arousal index −0.16 .25 Laryngoscopy under anesthesia also revealed that 11 Sleep efficiency 0.01 .48 (55%) of 20 patients showed upper airway obstruction % Stage 1 plus 2 0.15 .27 at levels other than the vocal cords. The obstruction % Stage 3 plus 4 0.18 .47 was observed at the base of the tongue (in 4 patients) % REM stage −0.34 .08 and at the soft palate (in 4 patients). Five patients showed floppy epiglottis, a condition in which the epi- Abbreviations: [A-a]DO2, alveolar-arterial oxygen gradient; AHI, 11 apnea-hypopnea index; AI, apnea index; BMI, body mass index; (calculated glottis is sucked into the glottis during inspiration. as the weight in kilograms divided by height in meters squared); Three patients showed airway obstruction at the aryte- FEV1.0%, percentage of predicted forced expiratory volume in 1 second; noid, characterized by prolonged, sustained muscle ICARS, International Cooperative Ataxia Rating Scale; PaO2, arterial oxygen contractions during inspiration, resulting in glottic ste- pressure; PaCO2, arterial carbon dioxide pressure; REM, rapid eye movement; SpO2, oxygen saturation; VC, predicted vital capacity. nosis (Figure, E and F). Although we have performed *PϽ.05. laryngoscopy on patients with sleep apnea syndrome or laryngopharyngeal disorders using intravenous diazepam and propofol (in Ͼ80 and 70 patients, respec- ing apnea index, AHI, and mean oxygen saturation, tively), we have never encountered patients presenting showed no correlation with disease duration. Further- with VCAP, floppy epiglottis, or airway obstruction at more, there was no significant correlation between in- the arytenoid, suggesting that these drugs do not cause creased [A-a]DO2 and abnormalities in apnea index such conditions. Although we do not have experience (r=−0.02, P=.92) or AHI (r=0.27, P=.27). in fiberoptic laryngoscopy in patients under anesthesia

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Wakefulness Under Anesthesia

Arytenoid Stenosis of Stenosis of Tremulous the Base of the Soft Floppy Obstruction Patient No. VCAP Movements VCAP the Tongue Palate Epiglottis at Arytenoid 1− − NENENENENE 2−−−− − ϩϩ 3 ϩ (UP) ϩϩ(BP) − ϩ −− 4−−−− − − − 5 ϩ (BP) − ϩ (BP) − − − ϩ 6−−−− ϩ −− 7− − − ϩϩ −− 8− ϩϩ(BP) ϩ −−− 9− −ϩ (BP) − − − − 10−−−− − ϩ − 11−−−− − ϩ − 12 − ϩϩ(BP) − − − − 13−−−− − − − 14 − ϩϩ(BP) − − − − 15 − ϩϩ(BC) − − − − 16 ϩ (UP) ϩϩ(BP) − − − − 17 − − − ϩ − ϩ − 18 − − − ϩϩϩ− 19−−−− − − − 20−−−− − − − 21 − − ϩ (BP) − − − ϩ

Abbreviations: BC, bilateral complete abduction restriction of vocal cords; BP, bilateral partial abduction restriction of vocal cords; MSA, multiple system atrophy; NE, not examined; UP, unilateral partial abduction restriction of vocal cords; VCAP, vocal cord abductor paralysis; ϩ, present; −, absent.

with other neuromuscular disorders, we have suffi- DAYTIME HYPOXEMIA IN MSA cient experience in fiberoptic laryngoscopic examina- tion on otorhinolaryngological patients under anesthe- To our knowledge, this is the first study evaluating day- sia (Ͼ150 patients). We found that the abnormal time pulmonary function in MSA. We observed daytime movements of the arytenoid and epiglottis described hypoxemia with an increased [A-a]DO2 in the advanced in this study have been observed only in patients with stage of MSA, which suggests that daytime hypoxemia MSA. can exacerbate nocturnal hypoxemia caused by upper air- Concerning the relationship between the increase in way obstruction. [A-a]DO2 and abnormal findings on fiberoptic laryngos- The mechanism underlying hypoxemia with an in- copy, there was no significant correlation between the creased [A-a]DO2 remains to be elucidated. The [A- increase in [A-a]DO2 and laryngoscopic abnormalities, a]DO2 reflects the efficiency of oxygen exchange be- such as VCAP (PϾ.99). In addition, there was no sig- tween pulmonary alveoli and pulmonary capillaries and nificant difference in apnea index or AHI between pa- reflects increases in the presence of a ventilation/ tients with and those without VCAP under anesthesia perfusion mismatch, a shunt, or a diffusion impair- (P=.71 and .33, respectively). ment. Shunts or diffusion impairments are unlikely to be considered the cause of an [A-a]DO2 increase be- COMMENT cause these conditions are associated with organic changes in the alveolovascular system. Although it is conceiv- In this study, most of the patients (18 [86%]) had MSA-C. able that a ventilation/perfusion mismatch, such as a pul- A recent national epidemiological study12 in Japan showed monary microembolism, is the cause, additional studies that 82.5% of patients with MSA (n=3341) have MSA-C, should be performed to elucidate the mechanism. suggesting that MSA-C is more frequent among Japa- nese patients than among Western patients with MSA. RESPIRATORY DYSFUNCTION DURING Therefore, the generalization of our observations should SLEEP IN MSA be evaluated carefully. Although the number of patients with nocturnal stri- We found that patients with MSA had decreased sleep dor seems large (ie, 5 [24%]), this finding is compatible efficiency and abnormal sleep architectures, including de- with a recent report13 showing that nocturnal stridor is creased percentages of slow-wave sleep and rapid eye a common and early clinical symptom in Japanese pa- movement sleep, as demonstrated in a recent study.14 tients with MSA. Cheyne-Stokes respiration was observed in some pa-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 potentially abnormal conditions in the laryngopharynx in A B patients with MSA. The data obtained by fiberoptic laryngoscopy under anesthesia may need careful interpretation. Although we do not have sufficient experience in treat- ing patients with other neuromuscular disorders, we have never observed these abnormal findings in any patients other than those with MSA. Using this method, we observed laryngopharyngeal movements that, to our knowledge, have not previously been reported in patients with MSA. Floppy epiglottis was observed in 5 (25%) of 20 patients. Although congenital C D floppy epiglottis, which is caused by an abnormality in laryngeal cartilage, is a common cause of laryngeal stridor in infants, adult-onset floppy epiglottis is a rare condition. It has been observed in patients following a head injury16 or stroke syndrome,17 and the resulting central nervous system damage has been thought to be the cause of the loss of laryngeal motor tone with coordination impairments. In MSA, an abnormality in laryngeal motor tone caused by the degeneration of the nucleus ambiguus may influence the development of floppy epiglottis, although the relationship between the abnor- E F mality in laryngeal motor tone and the degeneration of the nucleus ambiguus still remains controversial.18 A recent study19 demonstrated that continuous positive airway pressure does not improve the airway patency of congenital floppy epiglottis; on the contrary, continuous positive airway pressure may exacerbate upper airway obstruction by further promoting the downward displacement of the epiglottis into the laryngeal inlet. It may be safer to avoid continuous positive airway pressure and to recommend partial epiglottidectomy in pa- Inspiration Expiration tients with floppy epiglottis. Figure. Fiberoptic laryngoscopic findings of vocal cord abductor paralysis Airway obstruction at the arytenoid during inspira- and airway obstruction at the arytenoid: in patient 14, laryngoscopy during tion was also observed in 3 (15%) of 20 patients. Regard- wakefulness revealed normal movements of the vocal cords, showing inspiratory abduction (A) and expiratory adduction (B); also in patient 14, ing the mechanism of the obstruction, 1 possibility is ary- laryngoscopy under anesthesia revealed bilateral partial abduction restriction tenoidal muscle dystonia because the movement was and a paradoxical movement of the vocal cords, showing inspiratory characterized by prolonged, sustained, muscle contrac- adduction (C) and expiratory abduction (D); in patient 21, airway obstruction tions, although we did not perform needle electromyog- at the arytenoid is characterized by prolonged sustained contractions of arytenoid muscles during inspiration, resulting in glottic stenosis (E); also in raphy of arytenoidal muscles. Another possibility is floppy patient 21, expiration is shown (F). Arrows indicate the arytenoid; arytenoid, which is a condition in which the arytenoid arrowheads, the vocal cords. is prolapsed over the larynx. We also observed bilateral rhythmical arytenoid tremu- tients (3 [15%] of 20 patients). This was not the focus of lous movement during wakefulness in 6 patients (29%). much attention in previous studies, although there is 1 All of these patients presented with VCAP under anes- report15 in which a patient presenting with CSR is de- thesia, suggesting that this movement is a prodromal find- scribed. Further studies should be performed to deter- ing or a mild form of VCAP. This movement may be clini- mine whether CSR is associated with nocturnal sudden cally pathognomonic for MSA because, to our knowledge, death in MSA, which occurred in 1 of our patients with it has not been reported in other diseases. CSR despite the fact that he underwent tracheotomy. In conclusion, we observed daytime hypoxemia, with an increased [A-a]DO2 and CSR during sleep, and novel ABNORMAL LARYNGOPHARYNGEAL abnormal laryngopharyngeal movements, including floppy FINDINGS IN MSA epiglottis and airway obstruction at the arytenoid, in patients with MSA. Further study is required to confirm We showed that laryngoscopy under anesthesia might be whether these findings are involved in the mechanism useful for evaluating upper airway obstruction. We have of nocturnal sudden death in patients with MSA. never encountered patients with sleep apnea syndrome or other laryngopharyngeal disorders who presented with Accepted for Publication: October 20, 2006. VCAP, floppy epiglottis, or airway obstruction at the ary- Correspondence: Masatoyo Nishizawa, MD, PhD, tenoid, suggesting that these conditions are not caused sim- Department of Neurology, Brain Research Institute, ply by the muscle relaxation effects of diazepam and pro- Niigata University, 1-757 Asahi-machi-dori Niigata, Ni- pofol. Instead, it is possible that these drugs may intensify igata 951-8585, Japan ([email protected]).

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Author Contributions: Study concept and design: Shimo- 5. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of mul- hata, Onodera, and Nishizawa. Acquisition of data: Shi- tiple system atrophy. J Neurol Sci. 1999;163:94-98. 6. Konagaya M, Konagaya Y, Iida M. Clinical and magnetic resonance imaging study mohata, Shinoda, Nakayama, Yoshizawa, Matsuzawa, Na- of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg ruse, Takahashi, and Gejyo. Analysis and interpretation Psychiatry. 1994;57:1528-1531. of data: Shimohata, Ozawa, Terajima, Tanaka, and Nish- 7. Koide R, Kobayashi S, Shimohata T, et al. A neurological disease caused by an izawa. Drafting of the manuscript: Shimohata, Ozawa, and expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new poly- Nishizawa. Critical revision of the manuscript for impor- glutamine disease? Hum Mol Genet. 1999;8(11):2047-2053. tant intellectual content: Shimohata, Shinoda, Na- 8. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum kayama, Terajima, Yoshizawa, Matsuzawa, Onodera, Na- Genet. 2003;72:869-878. ruse, Tanaka, Takahashi, Gejyo, and Nishizawa. Obtained 9. Trouillas P, Takayanagi T, Hallett M, et al; Ataxia Neuropharmacology Commit- funding: Nishizawa. Administrative, technical, and mate- tee of the World Federation of Neurology. International Cooperative Ataxia Rat- rial support: Nakayama and Nishizawa. Study supervi- ing Scale for pharmacological assessment of the cerebellar syndrome. J Neurol sion: Ozawa, Yoshizawa, Onodera, Tanaka, Gejyo, and Sci. 1997;145:205-211. Nishizawa. 10. Krachman SL, D’Alonzo GE, Berger TJ, Eisen HJ. Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration dur- Financial Disclosure: None reported. ing sleep in congestive heart failure. Chest. 1999;116:1550-1557. Funding/Support: This study was supported by a Grant- 11. Maurer JT, Stuck BA, Hein G, Hormann K. Videoendoscopic assessment of un- in-Aid for the Research Committee for Ataxic Diseases common sites of upper airway obstruction during sleep. Sleep Breath. 2000; of the Research on Measures for Intractable Diseases from 4:131-136. the Ministry of Health, Welfare, and Labour, Japan. 12. Tsuji S. MSA update [in Japanese]. Rinsho Shinkeigaku. 2005;45:821-823. 13. Yamaguchi M, Arai K, Asahina M, Hattori T. Laryngeal stridor in multiple system atrophy. Eur Neurol. 2003;49:154-159. REFERENCES 14. Vetrugno R, Provini F, Cortelli P, et al. Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med. 2004;5:21-30. 1. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system 15. Chokroverty S, Sharp JT, Barron KD. Periodic respiration in erect posture in Shy- atrophy: an analysis of 230 Japanese patients. Brain. 2002;125(pt 5):1070-1083. Drager syndrome. J Neurol Neurosurg Psychiatry. 1978;41:980-986. 2. Munschauer FE, Loh L, Bannister R, Newsom-Davis J. Abnormal respiration and 16. Wiggs WJ Jr, DiNardo LJ. Acquired laryngomalacia: resolution after neurologic sudden death during sleep in multiple system atrophy with autonomic failure. recovery. Otolaryngol Head Neck Surg. 1995;112:773-776. Neurology. 1990;40:677-679. 17. Archer SM. Acquired flaccid larynx: a case report supporting the neurologic theory 3. Isozaki E, Naito A, Horiguchi S, Kawamura R, Hayashida T, Tanabe H. Early di- of laryngomalacia. Arch Otolaryngol Head Neck Surg. 1992;118:654-657. agnosis and stage classification of vocal cord abductor paralysis in patients with 18. Benarroch EE, Schmeichel AM, Sandroni P, Low PA, Parisi JE. Involvement of multiple system atrophy. J Neurol Neurosurg Psychiatry. 1996;60:399-402. vagal autonomic nuclei in multiple system atrophy and Lewy body disease. 4. Tsuda T, Onodera H, Okabe S, Kikuchi Y, Itoyama Y. Impaired chemosensitivity Neurology. 2006;66:378-383. to hypoxia is a marker of multiple system atrophy. Ann Neurol. 2002;52:367- 19. De Beer D, Chambers N. Double trouble: prolapsing epiglottis and unexpected 371. dual pathology in an infant. Paediatr Anaesth. 2003;13:448-452.

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