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This slide was used in the plenary session of the 13th International Parkinson Disease Symposium in Takamatsu (iPDST) on 21, Feb, 2014.
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Multiple system atrophy
Takayoshi Shimohata, FAAN,FAHADepartment of Neurology, Brain Research Institute, Niigata University
The Prognosis,Sleep disturbanceand Sudden death
MSA is an adult-onset
neurodegenerative disorder
characterized by diverse clinical
symptoms
Introduction
Cerebellar ataxia
ParkinsonismAutonomic
dysfunction
Introduction
MSA is an adult-onset
neurodegenerative disorder
characterized by diverse clinical
symptoms
Introduction
Consensus diagnostic criteria for MSA
Gilman’s criteria
Possible MSA
Probable MSA
Definite MSA
This criteria define three diagnostic categories of increasing certainty.
1.Prognostic factors in MSA
2.Sleep disturbances related to MSA
3.Mechanisms of sudden death due to MSA
Overview
1.Prognostic factors in MSA
Duration(Y) Number Reference
Wenning GK et al. 203 Mov Dis 12, 133, 1997
Ben-Schlomo Y et al. 6.2 433 Neurology 48, 384, 1997
Wenning GK et al. 7.3 35 JNNP 58, 160, 1995
Test D et al. 7.5 59 J Neurol 243, 401, 1996
Hayashi et al. 7.3 29Neurol Therapeutics 13, 223, 1996
Watanabe et al. 230 Brain , 2002
The median survival time of MSA patients
5.5
9
Several retrospective studies revealed that survival time is about 5 to 9 years after disease onset.
49 definite (pathologically-proven) MSA patients(C:P=31:18)
Median time from disease onset
Wheelchair-dependent 3.5 yearsBecoming bedridden 5.0 yearsDeath 7.0 years
Autonomic dysfunction 2.5years
Tada M. et.al. Arch Neurol. 64:256-60. 2007
Survival time & Prognostic factor
The early development of autonomic dysfunction affects disease progression.
Hypothesis
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 MSAGroup B: others
The time from onset to being in a wheelchair-dependent
14121086420
1.0
0.8
0.6
0.4
0.2
0
pro
bab
ility
(years)
p<0.001
Autonomic dysfunction A <2.5 years(28 patients)B >2.5 years(21 patients)
Tada M. et.al. Arch Neurol. 64:256-60. 2007
14121086420
(years)
p<0.001
pro
ba
bili
ty1.0
0.8
0.6
0.4
0.2
0
Group A became bedridden earlier than group B
Autonomic dysfunction A <2.5 years(28 patients)B >2.5 years(21 patients)
Tada M. et.al. Arch Neurol. 64:256-60. 2007
201612840
(years)
p=0.03
pro
ba
bili
ty1.0
0.8
0.6
0.4
0.2
0
O‘Sullivan, et al. reported similar findings (Brain 131; 1362-72 2008)
Autonomic dysfunction A <2.5 years(28 patients)B >2.5 years(21 patients)
Group A died earlier than group B
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
141 patients
9.8 years
a prospective multicenter study to investigate the natural history of MSA.
Wenning et al. Lancet Neurol. 2013
・MSA-P predicted shorter survival.・Incomplete bladder emptying predicted shorter survival.
MSA-P
MSA-C
Comparison of MSA-C and MSA-P patients
Wenning et al. Lancet Neurol. 2013
10 patients
Another interesting finding
10 out of 141 patients survived for more than 15 years after disease onset.
These patients can be termed
“benign subgroup”.
Clinical features of 4 MSA patients with disease duration > 15 years
Late appearance of autonomic dysfunction may be a favorable prognostic factor in MSA.
A mean latency of 11 years to the development of
autonomic dysfunction
L-DOPA induced
dyskinesia
All patients were
MSA-P
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
Sleep deprivation
REM sleep behavior disorder
(RBD)
Restless legs
syndrome (RLS)
Sleep-disordered breathing
(SDB)
Excessive daytime
sleepiness (EDS)
① Sleep deprivation
A decrease in slow-wave sleep & REM sleep
Average ±SD
arousal index 18.4±14.8↑
% N1+2 78.5±17.2% N3 (slow wave sleep) 13.3±13.8% ↓% REM 8.2±7.6↓
We reported PSG findings from 21 patients (probable).
Shimohata et al. Arch Neurol 64:856-861, 2007
② REM sleep behavior disorder (RBD)
REM without atonia (RWA)
Nomura T, et al. Psychiatry Clin Neurosci 2011;65:264-271.
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.
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
Primary
• Iron deficiency
• Rheumatoid arthritis
• Renal failure
• Pregnancy
• Drug-induced
• Neurological disorders
• Parkinson disease, neuropathy, myelopathy
Secondary
The causes of RLS
The frequency of RLS in MSA
PD (N=62) 3.2%
MSA(N=57) 12.5%
France
SLEEMSA study
In Europe, a multicenter study for sleep disturbance in MSA, the SLEEMSA study, has been carried out.
Frequencies of RLS
Control(N=86) 7%
PD(N=86) 14%
MSA(N=86) 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%
SLEEMSA study
In MSA, RLS was more frequent in MSA-P than in MSA-C.
RLS frequency
PD(N=158) 11.4%
The frequencies of RLS in Japanese patients
Shimohata T et al. BMC Neurol 12; 130, 2012
RLS frequency
MSA(N=24) 12.5%
MSA-P(N= 3) 0%
MSA-C(N=21) 14.3%
Shimohata et al. Parkinsonism Relat Disord 19:571-2, 2013
RLS is frequently observed in MSA patients
regardless of ethnic differences.
④ Sleep-disordered breathing (SDB)
PSG
Drug-induced
sleep endoscopy
Evaluation of daytime sleepiness
To evaluate SDB in MSA, we performed several studies
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 index (AHI)
The average number of apneas and hypopneas per hour.
The AHI was abnormally high, especially
the number of hypopneas per hour.
Average ±SD
AI (/h) 4.1±4.5 (0-12.8)AHI (/h) 20.1±19.9 (0-85.5)↑SpO2 (%) 94.3±4.1 (88.0-99.8)
Our data
Using PSG, we investigated SDB in 21 MSA patients.
Shimohata et al. Arch Neurol 64:856-861, 2007
0
20
40
60
80
100
120
0 2 4 6 8 10
AHI
years
Changes in AHI over time
Matsuyama, et al. in submission
Upper airway obstruction
Fiber-optic transnasal laryngoscopy during wakefulness as well as under propofol sedation
Shimohata et al. Arch Neurol 64:856-861, 2007
Soft palate
Esophagus
Vocal cord
Trachea
TransnasalEndoscopy
Inspiratory abduction
Expiratory adduction
Movement of the vocal cords in a patient with MSA
Laryngoscopy performed during wakefulness revealed normal movements of the vocal cords
bilateral abduction restriction, paradoxical movements
Inspiratory adduction/expiratory abduction
Vocal cord abductor paralysis (VCAP)
prolonged sustained contractions of
the arytenoid muscles during inspiration
Arytenoid obstruction
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 (FE)
Downward displacement of the epiglottis covering
the laryngeal inlet during inspiration was observed.
Floppy epiglottis
Summary
MSA patients develop upper-airway obstructions
Vocal cords
Base of the tongue
Epiglottis
Arytenoid
Soft palate
Various types of
sleep disturbance
Sleep deprivation
RBD
RLS
SDB
Excessive daytime
sleepiness (EDS)
Excessive daytime sleepiness
SLEEMSA study Arch Neurol 2011
Patients86 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 studyBMC Neurol 2012
Patients86 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
EDS
RBD
RLS
SDB
Frequent urination
Urinary incontinence
Nycturia
Difficulty in turning
in bed
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
We prospectively followed up 45 patients
with probable MSA for 5 years.
The frequency and possible causes of sudden death
Intervention
① severe desaturation (CT90 >10%)
② severe vocal cord abductor paralysis
③ recurrent aspiration pneumonia
→ NPPV
Shimohata T et al. J Neurol. 255:1483-5, 2008
→ Tracheostomy
NPPV; Non-invasive Positive-airway Pressure Ventilation
NPPVNoninvasive Positive-airway
Pressure Ventilation
Tracheostomy
These treatments can prevent sudden death by counteracting upper airway obstruction.
Hypothesis
Shimohata T et al. J Neurol. 255:1483-5, 2008
45 cases
Survive32 cases
Dead10 cases
Anoxic brain3 cases
Sudden death of unknown etiology
7
Choking after vomiting
1
Lung cancer1
pneumonia1
Therapeutic interventions were performed in 25.
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.
(Tracheostomy 2, NPPV 1)
Tracheostomy and NPPV do not
always prevent sudden death in patients with MSA
Results
(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.
Choking during sleep
Central respiratory disturbance
Upper airway obstruction associated with NPPV
Cardiac autonomic dysfunction
The mechanisms of sudden death is
not due to a single cause but could be
due to multiple causes:
① Choking during sleep
Sputum Foods
Disease-related upper airway
obstruction
Choking could be caused by・・・
Vocal cords
Base of the tongue
Epiglottis
Arytenoid
Soft palate
Disease-related upper airway obstruction
We do not have evidence that it causes sudden death during sleep.
Choking caused by food regurgitation during sleep
Taniguchi et al. work in progressEsophageal dilatation with niveau formation
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
Shimohata T et al. Eur Neurol. 56:258-60 2006
progressive nocturnal hypoxemia
One of our patients exhibited progressive nocturnal hypoxemia. SpO2 decreased from 95% to 65%.
② Central respiratory disturbance
Hypopnea
Shimohata T et al. Eur Neurol. 56:258-60 2006
progressive nocturnal hypoxemia
② Central respiratory disturbance
Hypopnea
Tachypnea (50-60 /min)
Shimohata T et al. Eur Neurol. 56:258-60 2006
progressive nocturnal hypoxemia
Hypopnea
Cheyne-Stokes respiration
② Central respiratory disturbance
Shimohata T et al. Eur Neurol. 56:258-60 2006
progressive nocturnal hypoxemia
Tachypnea (50-60 /min)
Cheyne-Stokes respiration after tracheostomy
This patient is MSA-C .His disease duration was 15 years after onset.
Similar Cheyne-Stokes respiration in patients who had undergone tracheostomy.
Intervals from tracheostomy to
respirator use
Causes of respirator use
MSA-CM
3 m Respiratory arrest
MSA-PF
6 mRespiratory insufficiency
MSA-CM
24 mRespiratory insufficiency
Tracheostomized patients who had to be artificially respirated
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
Pre-CPAP CPAP 4cmH2O CPAP 6cmH2OSpO2↑
The Effect of NPPV on VCAP
Shimohata et al. Neurology 76:1841-1842, 2011
CPAP 6 cmH2O improved upper airway obstruction and desaturation.
wakefulness after sedation after NPPV(CPAP 4 cmH2O)
SpO2↓
The Effect of NPPV on floppy epiglottis
Shimohata et al. Neurology 76:1841-1842, 2011
Downward displacement of the epiglottis by NPPV could cause upper-airway 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
• Early detection of food stagnation within the esophagus
Choking during sleep
• Commencement of respirator treatment
Central respiratory disturbance
• Discontinuation of NPPV in patients with floppy epiglottis
Upper airway obstruction associated with NPPV
Cardiac autonomic dysfunction
A dilemma that we face in the treatment of MSA patients
The duration of CPAP treatment
months
Range 1~53 months
13.0 m
Shimohata T et al. in submission
The honeymoon period for CPAP treatment was not long.
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
19
pat
ien
ts w
ho
d
isco
nti
nu
ed C
PAP
Tracheostomy (-)
9
Tracheostomy (+)
10
Respirator (-)
6
Respirator (+); TPPV
4
32%
21%
47%
Treatment after CPAP discontinuation
Shimohata T et al. in submission
NPPV only37.5±8.5 months
NPPV→tracheostomy29.4±6.1 months
NPPV→TPPV51.8±18.3 months
Pribability
M
Median survival times of these three groups
It seems that TPPV can prolong survival.
We consider that respirator treatment enables long-term survival.
Onset of autonomic
failure was not always early
Respirator use was frequently
observed
They included MSA-C
Shimohata T et al. work in progress
9 MSA patients who survived > 15 years
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.
Prognostic factors
Various types of
Sleep disturbance
Various causes of sudden death
Conclusion
Autonomic dysfunctionRespirator therapy
My collaborators
Department of Neurology, Brain Research Institute, Niigata UniversityTetsutaro Ozawa, Masatoyo Nishizawa
Department of Respiratory Medicine, Tokyo Medical UniversityHideaki Nakayama
Division of Otolaryngology, Niigata University Graduate School of Medical and Dental SciencesNaotaka Aizawa
Division of Cardiology, Niigata University Graduate School of Medical and Dental SciencesHiroshi Furushima
Division of Dysphagia Rehabilitation, Niigata University Graduate School of Medical and Dental Sciences
Hiroshige Taniguchi
Department of PathologyMari Tada, Hiroshi Shimizu, Hitoshi Takahashi