Sleep & sudden deasth in msa

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