Published on February 21, 2014
The Prognosis ， Sleep disturbance and Sudden death Takayoshi Shimohata, FAAN ， FAHA Department of Neurology, Brain Research Institute, Niigata University
Introduction MSA is an adult-onset neurodegenerative disorder characterized by diverse clinical symptoms Autonomic dysfunction Parkinsonism
Consensus diagnostic criteria for MSA This criteria define three diagnostic categories of increasing certainty. Gilman’s criteria Possible MSA Probable MSA Definite MSA
Overview １． Prognostic factors in MSA ２． Sleep disturbances related to MSA ３． Mechanisms of sudden death due to MSA
１． Prognostic factors in MSA
The median survival time of MSA patients Duration （ Y ） Number Wenning GK et al. Ben-Schlomo Y et al. Wenning GK et al. Test D et al. Hayashi et al. Watanabe et al. 5.5 6.2 7.3 7.5 7.3 9 Reference 203 Mov Dis 12, 133, 1997 433 Neurology 48, 384, 1997 35 JNNP 58, 160, 1995 59 J Neurol 243, 401, 1996 29 230 Neurol Therapeutics 13, 223, 1996 Brain , 2002 Several retrospective studies revealed that survival time is about 5 to 9 years after disease onset.
Survival time & Prognostic factor 49 definite (pathologically-proven) MSA patients （ C ： P ＝ 31 ： 18 ） onset Median time from disease Wheelchair-dependent Becoming bedridden Death 3.5 years 5.0 years 7.0 years Autonomic dysfunction 2.5 years Tada M. et.al. Arch Neurol. 64:256-60. 2007
Hypothesis The early development of autonomic dysfunction affects disease progression. We divided the 46 patients into 2 groups in terms of the onset time of autonomic dysfunction. Group A: within 2.5 years from the onset of MSA Group B: others
The time from onset to being in a wheelchair-dependent Autonomic dysfunction patients ） patients ） 1.0 A <2.5 years （ 28 B >2.5 years （ 21 probability 0.8 0.6 0.4 0.2 p<0.001 0 (years) 0 2 4 6 8 10 12 14 Tada M. et.al. Arch Neurol. 64:256-60. 2007
Group A became bedridden earlier than group B Autonomic dysfunction patients ） patients ） 1.0 A <2.5 years （ 28 B >2.5 years （ 21 probability 0.8 0.6 0.4 0.2 p<0.001 0 years) ( 0 2 4 6 8 10 12 14 Tada M. et.al. Arch Neurol. 64:256-60. 2007
Group A died earlier than group B Autonomic dysfunction patients ） patients ） 1.0 A <2.5 years （ 28 B >2.5 years （ 21 probability 0.8 0.6 0.4 0.2 p=0.03 0 years) ( 0 4 8 12 16 20 O‘Sullivan, et al. reported similar findings (Brain 131; 1362-72 2008 ）
The early development of autonomic dysfunction is a prognostic factor for rapid disease progression and a shorter survival in MSA.
European MSA study group Wenning et al. Lancet Neurol. 2013 a prospective multicenter study to investigate the natural history of MSA. 141 patients 9.8 years
Comparison of MSA-C and MSA-P patients Wenning et al. Lancet Neurol. 2013 MSA-C ・ MSA-P predicted shorter survival. ・ Incomplete bladder emptying predicted shorter survival. MSA-P
Another interesting finding Wenning et al. Lancet Neurol. 2013 10 out of 141 patients survived for more than 15 years after disease onset. 10 patients
These patients can be termed “benign subgroup”.
Clinical features of 4 MSA patients with disease duration > 15 years L-DOPA induced dyskinesia All patients were MSA-P A mean latency of 11 years to the development of autonomic dysfunction Late appearance of autonomic dysfunction may be a favorable prognostic factor in MSA. Petrovic IN. et al. Mov Disord. 2012
Summary 1 ． Prognosis Survival time in MSA is 7-10 years Some patients survive for more than 15 years Autonomic dysfunction might be a prognostic factor
2 ． Sleep disturbances related to MSA
MSA patients develop various types of sleep disturbance
① Sleep deprivation We reported PSG findings from 21 patients (probable). arousal index % N1+2 % N3 (slow wave sleep) % REM Average ±SD 18.4±14.8↑ 78.5±17.2 13.3±13.8% ↓ 8.2±7.6↓ A decrease in slow-wave sleep & REM sleep Shimohata et al. Arch Neurol 64:856-861, 2007
② REM sleep behavior disorder (RBD) REM without atonia (RWA)
② REM sleep behavior disorder (RBD) A) 11 out of 16 patients with MSA (69%) had REM without atonia (RWA) on PSG. B) Most of the RBD symptoms occurred just prior to or at the onset of MSA and then disappeared within a short period. C) In MSA, RBD is one of the premotor symptoms, or earliest symptoms. Nomura T, et al. Psychiatry Clin Neurosci 2011;65:264-271.
③ Restless legs syndrome (RLS) IRLSSG diagnostic criteria for RLS （ 2003 ） １ Urge to move the extremities ２ Worse at rest ３ Motor relief ４ Worse at night
The causes of RLS
The frequency of RLS in MSA France PD （ N=62 ） 3.2% MSA （ N=57 ） 12.5%
SLEEMSA study In Europe, a multicenter study for sleep disturbance in MSA, the SLEEMSA study, has been carried out.
SLEEMSA study Control （ N=86 ） PD （ N=86 ） MSA （ N=86 ） Frequencies of RLS 7% 14% 28%
SLEEMSA study Frequencies of RLS Control （ N=86 ） 7% PD （ N=86 ） 14% MSA （ N=86 ） 28% MSA-P （ N=73 ） 32% MSA-C （ N=13 ） 8% In MSA, RLS was more frequent in MSA-P than in MSA-C.
The frequencies of RLS in Japanese patients RLS frequency PD （ N=158 ） 11.4% Shimohata et al. Parkinsonism Relat Disord 19:571-2, 2013 RLS frequency MSA （ N=24 ） MSA-P （ N= 3 ） MSA-C （ N=21 ） 12.5% 0% 14.3% Shimohata T et al. BMC Neurol 12; 130, 2012
RLS is frequently observed in MSA patients regardless of ethnic differences.
④ Sleep-disordered breathing (SDB) To evaluate SDB in MSA, we performed several studies PSG Druginduced sleep endoscopy Evaluation of daytime sleepiness
ポリソムノグラフィー PSG measures for evaluation of SDB Apnea index (AI) The average number of apneas per hour. Apnea hypopnea The average number of apneas and index (AHI) hypopneas per hour.
Our data Using PSG, we investigated SDB in 21 MSA patients. AI (/h) AHI (/h) SpO2 (%) Average ±SD 4.1±4.5 (0-12.8) 20.1±19.9 (0-85.5)↑ 94.3±4.1 (88.0-99.8) The AHI was abnormally high, especially the number of hypopneas per hour. Shimohata et al. Arch Neurol 64:856-861, 2007
Changes in AHI over time years Matsuyama, et al. in submission
Upper airway obstruction Fiber-optic transnasal laryngoscopy during wakefulness as well as under propofol sedation Transnasal Endoscopy Soft palate Esophagus Vocal cord Trachea Shimohata et al. Arch Neurol 64:856-861, 2007
Movement of the vocal cords in a patient with MSA Laryngoscopy performed during wakefulness revealed normal movements of the vocal cords Inspiratory abduction Expiratory adduction
Vocal cord abductor paralysis (VCAP) bilateral abduction restriction, paradoxical movements Inspiratory adduction/expiratory abduction
Arytenoid obstruction prolonged sustained contractions of the arytenoid muscles during inspiration
Floppy epiglottis (FE) Obstruction of the laryngeal inlet by the epiglottis leads to a condition known as FE. In FE, the epiglottis is aspirated into the laryngeal inlet during inspiration.
Floppy epiglottis Downward displacement of the epiglottis covering the laryngeal inlet during inspiration was observed.
Summary MSA patients develop upper-airway obstructions Soft palate Arytenoid Base of the tongue Epiglottis Vocal cords
Excessive daytime sleepiness (EDS)
Excessive daytime sleepiness SLEEMSA study Arch Neurol 2011 Patients 86 cases （ C 13, P 73 ） Epworth sleepiness score （ 0-24 ） 7.7±5.1 EDS （ ESS≧11 ） 28% Epworth sleepiness score (ESS) a subjective questionnaire-based measure of sleepiness with a maximum score of 24.
Excessive daytime sleepiness SLEEMSA study Arch Neurol 2011 Our study BMC Neurol 2012 Patients 86 cases （ C 13, P 73 ） 25 cases （ P 4, C 21 ） Epworth sleepiness score （ 0-24 ） 7.7±5.1 6.2±1.0 EDS （ ESS≧11 ） 28% 25% These data were almost the same as those of SLEEMSA study.
EDS might be caused by several factors Treatments aimed at the underlying causes are required.
Summary 2. Sleep disturbances SDB caused by upper airway obstruction Various types of sleep disturbance Excessive daytime sleepiness
3 ． Mechanisms of sudden death
The frequency and possible causes of sudden death We prospectively followed up 45 patients with probable MSA for 5 years. Intervention ① severe desaturation (CT90 >10%) → NPPV ② severe vocal cord abductor paralysis ③ recurrent aspiration pneumonia → Tracheostomy NPPV; Non-invasive Positive-airway Pressure Ventilation Shimohata T et al. J Neurol. 255:1483-5, 2008
Hypothesis NPPV Noninvasive Positive-airway Pressure Ventilation Tracheostomy These treatments can prevent sudden death by counteracting upper airway obstruction. Shimohata T et al. J Neurol. 255:1483-5, 2008
Results Of the 7 patients who succumbed to sudden death, 6 were found to have died during sleep. Among these patients, 2 had been treated with tracheostomy and 3 with NPPV during sleep. Therapeutic interventions were performed in 25. 45 cases Survive 32 cases Anoxic brain 3 cases Dead 10 cases （ Tracheostomy 2, NPPV 1 ） Tracheostomy and NPPV do not always prevent sudden death in patients with MSA Sudden death of pneumonia Choking Lung cancer 1 1 unknown etiology after vomiting 7 1 （ Tracheostomy 2, NPPV 3 ） Shimohata T et al. J Neurol. 255:1483-5, 2008
Causes of sudden death The Niigata MSA study, aimed at investigating the causes of sudden death in MSA, has been running since 2001.
The mechanisms of sudden death is not due to a single cause but could be due to multiple causes:
① Choking during sleep Choking could be caused by ・・・ Sputum Foods Diseaserelated upper airway obstruction
Disease-related upper airway obstruction We do not have evidence that it causes sudden death during sleep. Soft palate Arytenoid Base of the tongue Epiglottis Vocal cords
Choking caused by food regurgitation during sleep Esophageal dilatation with niveau formation Taniguchi et al. work in progress
A) Regurgitation of foods may be exacerbated by NPPV, because NPPV causes aerophagia and elevation of the lower esophageal sphincter pressure. B) Therefore, careful monitoring of the effects of NPPV on food regurgitation is required.
② Central respiratory disturbance progressive nocturnal hypoxemia One of our patients exhibited progressive nocturnal hypoxemia. SpO2 decreased from 95% to 65%. Shimohata T et al. Eur Neurol. 56:258-60 2006
② Central respiratory disturbance progressive nocturnal hypoxemia Hypopnea Shimohata T et al. Eur Neurol. 56:258-60 2006
② Central respiratory disturbance progressive nocturnal hypoxemia Hypopnea Tachypnea (50-60 /min) Shimohata T et al. Eur Neurol. 56:258-60 2006
② Central respiratory disturbance progressive nocturnal hypoxemia Hypopnea Tachypnea (50-60 /min) Cheyne-Stokes respiration Shimohata T et al. Eur Neurol. 56:258-60 2006
Cheyne-Stokes respiration after tracheostomy Similar Cheyne-Stokes respiration in patients who had undergone tracheostomy. This patient is MSA-C . His disease duration was 15 years after onset.
Tracheostomized patients who had to be artificially respirated Intervals from tracheostomy to respirator use MSA-C M Causes of respirator use 3m Respiratory arrest MSA-P Respiratory 6m F insufficiency MSA-C Respiratory 24 m M insufficiency Central respiratory disturbance could occur after tracheostomy.
③ Upper airway obstruction associated with NPPV We had patients who developed sudden death immediately after the initiation of NPPV treatment. → We examined the effect of NPPV on upper airway obstruction and oxygen saturation.
③ Upper airway obstruction associated with NPPV
The Effect of NPPV on VCAP Pre-CPAP CPAP 4cmH2O CPAP 6cmH2O SpO2↑ CPAP 6 cmH2O improved upper airway obstruction and desaturation. Shimohata et al. Neurology 76:1841-1842, 2011
The Effect of NPPV on floppy epiglottis wakefulness after sedation after NPPV (CPAP 4 cmH2O) SpO2↓ Shimohata et al. Neurology 76:1841-1842, 2011
Downward displacement of the epiglottis by NPPV could cause upperairway obstruction and thus result in death by choking. The presence of FE and the effect of CPAP on FE should be investigated.
④ Cardiac autonomic dysfunction A) One of our patients succumbed to sudden death from ventricular fibrillation during sleep. B) Using heart rate variability, which can predict sudden death in CHF, the cardiac autonomic state of MSA was characterized by severe decreases in both sympathetic and para-sympathetic tones. Furushima et al. Mov Disord 27:570-574, 2012
Summary 3. Sudden death has multiple causes
A dilemma that we face in the treatment of MSA patients
The duration of CPAP treatment Range 1 ～ 53 months 13.0 m months The honeymoon period for CPAP treatment was not long. Shimohata T et al. in submission
Causes of discontinuation of CPAP 1. Pulmonary infection, Sputum 2. Respiratory insufficiency 3. Difficulty in opening mouse 4. Dyspnea caused by CPAP or floppy epiglottis Shimohata T et al. in submission
Treatment after CPAP discontinuation 47% 32% 21% Shimohata T et al. in submission
Median survival times of these three groups Pribability NPPV only 37.5±8.5 months NPPV→tracheostomy 29.4±6.1 months NPPV→TPPV 51.8±18.3 months M It seems that TPPV can prolong survival.
9 MSA patients who survived > 15 years Onset of autonomic failure was not always early They included MSA-C Respirator use was frequently observed We consider that respirator treatment enables long-term survival. Shimohata T et al. work in progress
CT findings in one of our patients who survived for 15y He cannot communicate with us due to his severe dementia
A dilemma of therapeutic choice • We are trying to prevent sudden death of MSA patients using artificial respiration. • However, choosing respirator therapy may allow the patient to survive for long enough for dementia to set in. • If I were an MSA patient, it would be difficult to decide whether I should receive respirator therapy.
Conclusion Prognostic factors Autonomic dysfunction Respirator therapy Various types of Sleep disturbance Various causes of sudden death
My collaborators Department of Neurology, Brain Research Institute, Niigata University Tetsutaro Ozawa, Masatoyo Nishizawa Department of Respiratory Medicine, Tokyo Medical University Hideaki Nakayama Division of Otolaryngology, Niigata University Graduate School of Medical and Dental Sciences Naotaka Aizawa Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences Hiroshi Furushima Division of Dysphagia Rehabilitation, Niigata University Graduate School of Medical and Dental Sciences Hiroshige Taniguchi Department of Pathology Mari Tada, Hiroshi Shimizu, Hitoshi Takahashi
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